History of Neurology: Handbook of Clinical Neurology (Series Editors: Aminoff, Boller and Swaab)

HANDBOOK OF CLINICAL NEUROLOGY Series Editors

MICHAEL J. AMINOFF, FRANC¸OIS BOLLER, AND DICK F. SWAAB VOLUME 95

EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2010

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Handbook of Clinical Neurology 3rd series Available titles Vol. 79, The human hypothalamus: basic and clinical aspects, Part I, D.F. Swaab ISBN 9780444513571 Vol. 80, The human hypothalamus: basic and clinical aspects, Part II, D.F. Swaab ISBN 9780444514905 Vol. 81, Pain, F. Cervero and T.S. Jensen ISBN 9780444519016 Vol. 82, Motor neuron disorders and related diseases, A.A. Eisen and P.J. Shaw ISBN 9780444518941 Vol. 83, Parkinson’s disease and related disorders, Part I, W.C. Koller and E. Melamed ISBN 9780444519009 Vol. 84, Parkinson’s disease and related disorders, Part II, W.C. Koller and E. Melamed ISBN 9780444528933 Vol. 85, HIV/AIDS and the nervous system, P. Portegies and J.R. Berger ISBN 9780444520104 Vol. 86, Myopathies, F.L. Mastaglia and D. Hilton Jones ISBN 9780444518996 Vol. 87, Malformations of the nervous system, H.B. Sarnat and P. Curatolo ISBN 9780444518965 Vol. 88, Neuropsychology and behavioral neurology, G. Goldenberg and B.L. Miller ISBN 9780444518972 Vol. 89, Dementias, C. Duyckaerts and I. Litvan ISBN 9780444518989 Vol. 90, Disorders of consciousness, G.B. Young and E.F.M. Wijdicks ISBN 9780444518958 Vol. 91, Neuromuscular junction disorders, A.G. Engel ISBN 9780444520081 Vol. 92, Stroke Part I: Basic and epidemiological aspects, M. Fisher ISBN 9780444520036 Vol. 93, Stroke Part II: Clinical manifestations and pathogenesis, M. Fisher ISBN 9780444520043 Vol. 94, Stroke Part III: Investigations and management, M. Fisher ISBN 9780444520050 Forthcoming titles Vol. 96, Bacterial infections of the central nervous system, K. Roos and A. Tunkel ISBN 9780444520159 Vol. 97, Headache, G. Nappi and M.A. Moskowitz ISBN 9780444521392

Foreword

This is the first of over 90 volumes of the Handbook of Clinical Neurology that is entirely devoted to the history of neurology. We owe the editors – Stanley Finger, Franc¸ois Boller and Kenneth L. Tyler – our congratulations for bringing together a tremendous amount of rich historical material in a fascinating book. It is only by looking back that we can appreciate how far neurology, psychiatry and the basic neurosciences have advanced. Only by studying the history of neurology can we truly appreciate the extent of new developments and the rate at which they are occurring. The 55 chapters of this book are organized around different aspects of the history of the field. In the first part, ‘Beginnings’, it becomes apparent that when societies flourished, neurology, too, progressed, as happened in Mesopotamia, Ancient Egypt, and the Greco-Roman and Islamic worlds. From the chapter dealing with the birth of localization theory and other chapters in the second part, ‘Origins of modern neurology’, it becomes clear that the neurosciences did not develop along a straight line; rather, their path resembles a tree with many dead branches, just like the phylogenetic trees describing the origin of species. Only by looking back into history can the real breakthroughs and advances be discerned. The next part, ‘Further developments of the discipline’, shows the beginning of neurosurgery, child neurology, neuroendocrinology, molecular biology and other disciplines. The history of neurology can also be described for each disease or symptom separately, as is shown in ‘Dysfunctions of the nervous system’, which deals with, for example, muscular dystrophy, epilepsy, aphasia and alexia. In their own ways, individual countries and continents have also contributed to the history of neurology, as is described in ‘Regional landmarks’: from France to Russia, from China to Australia and New Zealand, and from Italy to Japan and the tropics. The last chapters deal with the ultimate aim of the neurosciences, ‘Treatments and recovery’, from redundancy and vicariation to neural transplantation. Turn back a few pages and you will see a standard disclaimer from the publisher that seems totally redundant: Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. . . To the fullest extent of the law, neither the Publisher nor the Editors assumes any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. Of course, nobody will be using this volume to look for the best therapies and the most recent diagnostic tools. It is, however, highly appropriate to pay homage to the giants from the past who made our present work possible. Behind every eponym that we use in our clinics on a daily basis, there is a fascinating personal story, as many examples illustrate in this book. In addition, it is interesting to see in various chapters how the small steps achieved by so many clinicians and scientists throughout the centuries have enabled a few to make the giant leaps forward. Not only are old concepts replaced by new ones, but old and forgotten concepts are regularly reinvented. However, history is more than an intellectual exercise. It helps to keep us humble and keep in perspective our own efforts, as well as the ‘breakthroughs’ that reach us daily via the media.

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FOREWORD

We are greatly indebted not only to the volume editors who brought together so many experts on vastly differing topics, but also to the authors who have put together outstanding chapters that will be of great interest to practicing neurologists, psychiatrists, basic neuroscientists, and medical historians. As always, we are also much indebted to the team at Elsevier – particularly Timothy Horne and Michael Parkinson – for their expert assistance in the development and production of this exceptional book. Michael J. Aminoff Dick F. Swaab

Preface

The Handbook of Clinical Neurology has never had a volume entirely devoted to the rich history of neurology. Hence, this volume was assembled to fill this needed void, with its many roots and ramifications. Our contributors begin with what could be gleaned about neurological disorders from ancient times to the 19th century, and then turn to the origins of more “modern” neurology, including ancillary developments within the discipline. Chapters sampling a number of disorders of the nervous system follow. The reader will then see how neurology evolved in some parts of Europe, the Americas, and in other places. The concluding chapters deal with recovery from brain damage, a subject that was as fascinating to the pioneers of neurology as it is to clinicians and researchers today. A tremendous amount of material is included in this volume. We are aware that some topics are missing. This is due in part to the scope of the discipline, the ever-growing number of neurological disorders, and the number of pages that can be included in one volume. Hopefully, such omissions will stimulate future chapters, articles, and perhaps even books, much as we hope that the chapters of this volume will stimulate deeper historical analyses. With these thoughts in mind, we dedicate this book to those intrepid scholars who, even with their many other commitments, have contributed to the history of clinical neurology and have done so much to make this survey possible. Stanley Finger Franc¸ois Boller Kenneth L. Tyler

List of contributors

J.A. Aarli Department of Neurology, Haukeland University Hospital, Bergen, Norway R.F. Allegri Services of Neurology & Neuropsychology (SIREN), Instituto Universitario CEMIC (Centro de Estudios Me´dicos e Investigaciones Clı´nicas); CONICET (Consejo Nacional de Investigaciones Cientı´ficas y Tecnolo´gicas); Department of Neurology, Hospital Abel Zubizarreta, Buenos Aires, Argentina

M.Z. Darkhabani Department of Neurology, The Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, NY, USA S.B. Dunnett School of Biosciences, Cardiff University, Cardiff, UK P. Eling Department of Psychology, Radboud University, Nijmegen, The Netherlands

C. Angelini Department of Neurosciences, University of Padova, Padova, Italy

F.M. Fales Dipartmento di Storia e Tutela dei Beni Culturali (DIBE), University of Udine, Udine, Italy

G. Aubert Chef de Clinique, Universite´ Catholique de Louvain, Cliniques Universitaires St-Luc, Centre de Me´decine du Sommeil, Brussels, Belgium

M. Feinsod Department of Neurosurgery, Faculty of Medicine, The Technion – Israel Institute of Technology, Haifa, Israel

M. Bentivoglio Department of Morphological and Biomedical Sciences, Faculty of Medicine, University of Verona, Verona, Italy G. Berlucchi Department of Neurological and Visual Sciences and National Neuroscience Institute, University of Verona, Verona, Italy

C.M. Filley Departments of Neurology and Psychiatry, Behavioral Neurology Section, University of Colorado Denver School of Medicine and the Denver Veterans Affairs Medical Center, Denver, CO, USA

F. Boller Bethesda, MD, USA; INSERM, Paris, France

E.J. Fine Department of Neurology, The Jacobs Neurological Institute at Kaleida Buffalo General Hospital; Department of Neurology, University at Buffalo, The State University at Buffalo, Buffalo, NY, USA

N.-S. Chu Department of Neurology, Chang Gung Memorial Hospital and Chang Gung University, Taipei, Taiwan

S. Finger Department of Psychology, Washington University, St. Louis, MO, USA

F. Clarac CNRS P3M (Plasticite´ et Physio-Pathologie de la Motricite´), Marseille, France

P.B. Foley Prince of Wales Medical Research Institute, Sydney, Australia

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LIST OF CONTRIBUTORS

F.R. Freemon Department of Neurology, Vanderbilt University, Nashville, TN, USA

M.P. Lorch Department of Neurolinguistics, Birkbeck College, University of London, London, UK

C.G. Goetz Department of Neurological Sciences and Pharmacology, Rush University Medical Center, Chicago, IL, USA

P. Mazzarello Department of Experimental Medicine, University of Pavia; Museum for the History of the University of Pavia, Pavia, Italy

C. Guilleminault Sleep Medicine Center, Stanford University School of Medicine, Stanford, CA, USA P. Hellal Applied Linguistics, Birkbeck College, University of London, London, UK V.W. Henderson Departments of Health Research & Policy (Epidemiology) and Department of Neurology & Neurological Sciences, Stanford University, Stanford, CA, USA

D. Millett Department of Neurology, Keck School of Medicine at USC, Los Angeles, CA, USA A. Ogunniyi Department of Medicine, University College Hospital, Ibadan, Nigeria R. Pelayo Sleep Medicine Center, Stanford University School of Medicine, Redwood City, CA, USA

N. Hodgson Stanford University Sleep Medicine Program, Stanford, CA, USA

H. Pols Unit for History and Philosophy of Science, University of Sydney, Sydney, Australia

A. Ione The Diatrope Institute, Berkeley, CA, USA

M.E. Raichle Department of Radiology and Neurology, Washington University School of Medicine, St. Louis, MO, USA

H. Isler In private practice, Zu¨rich, Switzerland A. Karenberg Department of the History of Medicine, Institute for the History of Medicine and Medical Ethics, University of Cologne, Cologne, Germany A. Keyser Department of Neurology, University Medical Center St. Radboud, Radboud University, Nijmegen, The Netherlands F. Kreier Department of Pediatrics, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands D.J. Lanska Department of Neurology, Veterans Affairs Medical Center, Tomah, WI, USA B. Lichterman Research Institute for the History of Medicine, Russian Academy of Medical Sciences, Moscow, Russia

F.C. Rose Academic Unit of Neurosciences; Formerly Charing Cross and Westminster School of Medicine, University of London, London, UK G.A. Russell Department of Humanities in Medicine, Texas A&M System Health Science Center, College Station, TX, USA K. Sammet Department of History and Ethics of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany W.O. Schalick, III Department of Medical History & Bioethics, Department of Orthopedics & Rehabilitation, Department of Pediatrics, Department of History of Science, University of Wisconsin, Madison, WI, USA

LIST OF CONTRIBUTORS C.U.M. Smith Vision Sciences, Aston University; Universities of Aston and Birmingham, Birmingham, UK T.L. Sourkes Departments of Psychiatry, Biochemistry and Pharmacology and Therapeutics, McGill University, Montreal, Canada F.W. Stahnisch Department of Community Health Sciences and Department of History, University of Calgary, Calgary, Canada D.A. Steinberg Fiddletown Institute, Fiddletown, CA, USA R. Stien Department of Neurology, Ullevaal University Hospital, Oslo, Norway J.L. Stone Departments of Neurological Surgery and Neurology, University of Illinois at Chicago, Chicago, IL, USA C.E. Storey Northern Clinical School, University of Sydney, Sydney; Department of Neurology, Royal North Shore Hospital, St Leonards, Australia D.F. Swaab Department of Neurobiology, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands A. Takahashi Department of Neurology, School of Medicine, Nagoya University, Gifu, Japan

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D.E. Tupper Neuropsychology Section, Hennepin County Medical Center; Department of Neurology, University of Minnesota Medical School, Minnesota, MN, USA K.L. Tyler Department of Neurology, University of Colorado Health Sciences Center and the Denver Veterans Affairs Medical Center, Denver, CO, USA J.W. Verano Department of Anthropology, Tulane University, New Orleans, LA, USA N.J. Wade Department of Visual Psychology, School of Psychology, University of Dundee, Dundee, UK H. Whitaker Department of Psychology, Northern Michigan University, Marquette, MI, USA A.N. Williams Virtual Academic Unit, Child Development Centre, Northampton General Hospital, Northampton, UK G.K. York, III Department of Neurology, University of California at Davis; Fiddletown Institute, Fiddletown, CA, USA G. Zanchin Headache Center, Department of Neuroscience and Pinali’s Library Ancient Section, University of Padua Medical School, Padua, Italy

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 1

Ancient trepanation JOHN W. VERANO 1 * AND STANLEY FINGER 2 Department of Anthropology, Tulane University, New Orleans, LA, USA 2 Department of Psychology, Washington University, St. Louis, MO, USA

1

INTRODUCTION Trepanation is the oldest surgical procedure known from antiquity, extending back more than 5000 years in Europe and to at least the 5th century BC in the New World (Arnott et al., 2003). Since the recognition of prehistoric trepanation in the mid-19th century, the practice and motivation for cranial surgery have been topics of considerable interest to neurologists and neurosurgeons, as well as to anthropologists, archeologists, and medical historians. According to one recent estimate, more than a thousand articles alone have been published on the subject (Rose, 2003). The evidence that trepanation was practiced in the Neolithic Period or New Stone Age (a time associated with polished stone tools, community life, farming, and the domestication of cattle; c. 4000–2000 BC in France) was slow to be appreciated (Schiller, 1992). Indeed, trepanned skulls had been found in Western Europe prior to the mid-19th century, but these specimens were misinterpreted with regard to their antiquity and/or it was not realized that human operators had made these openings on the living. Today we know that a surprisingly large number of ancient cultures actively practiced cranial surgery on the living, but the subject is still highly controversial. One reason for this is that so little is really known about why the surgery was performed so long ago. Was the purpose just to make a hole in the cranium, or was it more closely tied to the brain itself? That many patients survived such surgery is not contested, but were the chosen operated on for medical reasons, such as to treat skull fractures or closed head injuries – injuries that could have affected life or altered behavior? In addition to the long-held belief that “primitive” cultures lack the capacity for rational, scientific thinking, some of the debates about trepanation reflect

*

surgical statistics. Until the introduction of aseptic techniques in the second half of the 19th century, mortality from infection following craniotomies was very high, particularly when performed in the diseaseridden, city hospitals of the day (Aufderheide, 1985; Martin, 2003). Moreover, prior to the guiding theory of cortical localization of function in the 1860s and 1870s, surgeons had little idea where to open a skull, unless there were external breaks, discolorations, or other clear cranial signs (see Ch. 14). Hence, prominent surgeons concerned with upholding their reputations and not hastening death tended to avoid performing such procedures, even when dealing with seemingly hopeless cases (Wehrli, 1939; Ruisinger, 2003). Hence, the idea that Stone Age people would have been so bold as to attempt such a dangerous surgical procedure could indeed seem far-fetched from this surgical perspective. Yet two surgeons who operated on the brain, and stand among the most important brain scientists in the 19th century, figured prominently in recognizing trepanation and bringing it to the fore. One of these individuals was Paul Broca and the other was Victor Horsley, and although both tied trepanation to neurological problems, as we shall show, they promoted different theories.

EPHRAIM GEORGE SQUIER AND PAUL BROCA Paul Broca was born in 1824 in Sainte-Foy-la-Grande, a town east of Bordeaux (Schiller, 1992; Finger, 2000). He attended medical school in Paris, graduated in 1848, and remained there for the rest of his life. A man of diverse interests, Broca published over 500 papers in neurology, neuroanatomy, neurosurgery, comparative anatomy, human evolution, pathology, statistics, oncology, and medical therapeutics.

Correspondence to: Dr. John W. Verano, Department of Anthropology, Tulane University, 1021 Audubon St., New Orleans, LA 70118, USA. E-mail: [email protected], Tel: +1-504-862-3049, Fax: +1-504-865-5338.

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J.W. VERANO AND S. FINGER

To neurologists today, Broca is best known for his landmark paper of 1861 on the frontal cortex language area that now bears his name (the first cortical localization to be accepted [Broca, 1861]; see Ch. 10). He is also recognized for suggesting that the left hemisphere plays the leading role in speech – the concept of cerebral dominance – which he addressed 4 years later (Broca, 1865). Yet another of his contributions from the 1860s was the use of skull landmarks (craniography) to localize underlying regions of the cerebral cortex for neurosurgery, although he did not publish this report until 1876 (Broca, 1876a; Stone, 1991). Broca was also deeply involved with human prehistory and physical anthropology at this time. In 1859 he founded the first anthropological society, the Socie´te´ d’Anthropologie de Paris. In contrast to his papers on language, which can be counted on one hand, he published hundreds of papers on human origins, variation, and other facets of physical anthropology. There was no literature on ancient trepanned skulls when Broca began to write on aphasia and the brain. The situation changed dramatically after he was shown an “Inca” skull with distinct cross-hatched cuts around an opening (Fig. 1.1). The Peruvian skull came from an old cemetery in Yucay, near Cuzco. It had been given to Ephraim George Squier (Fig. 1.2), an American diplomat, writer, anthropologist, and archeologist, who had been sent to Peru in 1863 by President Abraham Lincoln to settle a dispute between the governments of Peru and the United States (Finger and Fernando, 2001; Fernando and Finger, 2003; Finger and Clower, 2003). Squier brought the unusual skull to the New York Academy of Medicine in 1865. The members that saw it agreed with him that only human hands could have made such an opening, and that the skull predated the

Fig. 1.2. Ephraim George Squier (1821–1888), American writer, diplomat, traveler, and archeologist.

European conquest of Peru (the skull is currently dated between 1400 and 1530 AD). But because not everyone accepted his contention that the operation had been performed on a living person, Squier now sought Broca’s opinion. Thus, the skull was sent to Paris, where Broca studied it and commented on it in 1867. Examination of the unusual skull left no doubt in Broca’s mind that “advanced surgery” was performed by “aborigines” long ago in the New World (Broca, 1867a, b). The opening was made with a cutting tool like a burin, and signs of inflammation suggested to Broca and a colleague that the individual probably died between a week and 15 days after the operation. But, he wondered, what was the conceptual framework for this operation? Because there were no unusual cracks in the skull, Broca rejected the idea that the surgery was performed to treat a depressed broken bone or a less severe fracture. Instead, he maintained that the operation was more likely to have been performed to relieve “an effusion of blood under the dura mater” – an internal problem causing “functional troubles,” to use more of his own words, “so that the surgical act was preceded by a diagnosis” (Broca, 1867a; trans. in Fernando and Finger, 2003, pp. 10–12).

THE DISCOVERY OF NEOLITHIC TREPANATION Fig. 1.1. The skull with a cross-hatch obtained by Ephraim George Squier on a trip to Peru in the 1860s. From Squier, 1877.

To Broca’s delight, hundreds of older perforated crania were soon to be discovered on French soil. In 1868, his friend Prunie`res recognized the first

ANCIENT TREPANATION trepanned French skull from the Neolithic Era, and Broca soon had many more crania and fragments (Clower and Finger, 2001). In addition, Prunie`res found small pieces of carefully sculpted human skull bones, some with holes in them, near or even within these skulls. Based on the fact that many had oval shapes, he called them rondelles. In 1874, Prunie`res gave two speeches to French scientists, in which he explained that trepanation was practiced in their country thousands of years ago (Prunie`res, 1874a, b). Today, most of these specimens are thought to be between 4000 and 5000 years old. Moreover, specimens several thousand years older than these have now been found in other parts of the world (Lillie, 1998; Arnott et al., 2003). In contrast, crania from South America, such as Squier’s cross-hatched Peruvian skull, are typically between 500 and 2500 years old. One skull, presented by Prunie`res in 1874, had three elliptical regions cut out of the bone (Fig. 1.3). Strangely, the middle circle seemed to be more smoothed or polished than the other two. He theorized that the holes were made after death and then worked with care to serve as ritualistic drinking cups (in Scandinavia the word skol can still be heard when drinkers lift their glasses). Prunie`res discovered a carefully crafted rondelle, one made from a different skull, in the very same skull. Over time, he gathered more of these rondelles and showed that they often had grooves and perforations fashioned so that they might be suspended from a string. Prunie`res postulated that they most likely served as amulets or good luck charms.

5

Although Broca agreed with Prunie`res about the rondelles, he interpreted the skull openings quite differently. After listening to what Prunie`res had to say, he opined that at least some of the openings were made while subjects were living (Broca, 1874a, b). The smooth surfaces were not intentionally polished for the eager lips of drinkers; they were the result of a lengthy period of healing and new bone growth. In contrast, the openings with coarse, unhealed surfaces were made after death to produce amulets, or were due to death occurring during or right after a surgery on the living. Broca became so enthused with these early discoveries that he personally joined in the search for more crania and tried to accumulate as many specimens as he could from all available sources. Not only were many more trepanned skulls now excavated in France, they started to be uncovered throughout Western Europe and in other places as well. It was then realized that some excellent examples of Stone Age trepanned skulls had been in collections for years, although they had been misinterpreted prior to this time. Indeed, a few were simply not thought to be very old, or the openings had been attributed to weapons of war, diseases, or gnawing animals. During the 1870s, Broca published a book, many detailed journal articles, and dozens of shorter commentaries on the newly discovered French skulls and the bone amulets found with them (Clower and Finger, 2001). In response to the enthusiasm generated by Broca’s various papers, a number of museums and universities sent expeditions to highland Peru and Bolivia to search for additional examples of trepanation in the New World (Tello, 1913; Hrdlicˇka, 1914; MacCurdy, 1923). Hundreds of skulls were found in the late-19th and early-20th centuries, revealing that trepanation had been a fairly common practice, with origins that substantially predated the powerful Inca Empire (Yacovleff and Muelle, 1932; Tello and Mejı´a Xesspe, 1979). In fact, Peru and Bolivia would produce more ancient trepanned skulls than the rest of the world combined, today estimated at more than 1000 specimens (Stewart, 1958; Verano, 2003).

DIAGNOSING TREPANATION

Fig. 1.3. A trepanned Neolithic skull found in a dolmen in France by Prunie`res. Broca (1876b) published this illustration and concluded that this skull was trepanned both before and after death.

Of course, not all holes in the head are trepanations, and this must be kept in mind when evaluating any ancient skull with an opening or defect. A freshly drilled or scraped hole may show tool marks indicating how it was made. An older opening with rounded margins will not be as simple to diagnose. Many pathological conditions (e.g., congenital and developmental defects, neoplasms, infection, trauma) can also produce cranial openings, and post-burial taphonomic

6 J.W. VERANO AND S. FINGER processes can further cause defects in skulls that could 1987; Mueller and Finch III, 1994). These reports sugbe misdiagnosed as trepanations (Donnabha´in, 2003; gest that the need to treat head wounds, and possibly Ortner, 2003). headache and other neurological complaints, has led Goldsmith, Stewart, and others have, in fact, many cultures, both ancient and modern, at least to described a variety of cranial defects that have been experiment with scraping openings in the skull, in mistaken for healed trepanations (Goldsmith, 1945; accord with deep-seated spiritual and medical beliefs. Steinbock, 1976; Stewart, 1976), and Kaufman et al (1997) provide an excellent survey of trepanation lookA TEMPORAL AND GEOGRAPHIC alikes. These studies serve as a cautionary warning SURVEY OF ANCIENT TREPANATION about loosely interpreting holes in ancient skulls. For Scattered finds of skulls with possible healed trepanaexample, the author of a recent re-examination of tions have been reported from many parts of the Old some presumed trepanned skulls from prehistoric World (for a recent survey, see Arnott et al., 2003), Denmark concluded that most probably they were not but there are relatively few areas (France being one) trepanned (Bennike, 2003). Hence, as Broca repeatedly with a large number of skulls that show convincing stated, a careful diagnosis is absolutely essential to evidence of surgery. In Western Europe, the skulls minimize the risk of a mistake. come primarily from Neolithic sites. Approximately The best case for trepanation in ancient times can 200 specimens were identified in a classic work by be made if significant numbers of skulls are found that Piggott (1940), and since his time many additional disshow clear evidence of surgical intervention (cutting, coveries have been made (Roberts and McKinley, scraping, or drilling of the vault). Especially if these 2003; Silva, 2003). skulls show varying periods of post-operative survival, Two trepanation techniques predominate in Western then it can be concluded with high confidence that the Europe: scraping and cutting out of pieces of bone by procedure was done on living patients. Bone reaction grooving. In the latter case, pieces of skull vault have was, in fact, critical to Broca’s argument in the case been found archeologically – sometimes still associated of the Squier skull. He knew that the cross-hatched patwith the skull – or more commonly, as perforated amutern could only have been made by human hands, but lets. Some of these charms appear to have been had this skull not shown evidence of a vital response, removed from skulls post-mortem, and sometimes they this Peruvian specimen might have been classified as include a portion of a healed trepanation, as was the a less interesting post-mortem artifact. case with the skull described by Prunie`res (also see If ancient trepanation can be thought of as a skill Piggott, 1940, p. 122). But while there is good evidence acquired through regular practice, and one passed on of post-mortem cutting to make amulets, many from generation to generation, the expectation might Neolithic trepanned skulls also show clear evidence of be that trepanned skulls should be concentrated in parbone reaction, convincing evidence that operations ticular geographic areas and time periods. To date, the were performed on living patients. While Piggott did strongest evidence for regional traditions remains in not provide statistics in his survey of Neolithic skulls, Neolithic Europe and Andean South America (Tello, he noted that survival rates were “extremely high.” 1913; Piggott, 1940; Brothwell, 2003; Verano, 2003). Trepanations might have been performed in Europe These “centers” are distant both geographically and even before Neolithic times, but here the evidence is temporally, each has produced large numbers of treless secure. There are several reports of possible healed panned skulls, and both are characterized by distinct trepanations from Mesolithic contexts, although these clusters of discoveries – factors strongly suggesting are isolated skulls with healed defects of uncertain that local trepanation traditions evolved in certain origin (Alt et al., 1997; Lillie, 1998). One problem with areas and continued for significant periods of time. these cases is that in many instances no alternative In other regions and at other times, trepanation might diagnoses for the defects are considered, and judging have been a rare practice, perhaps marking an occafrom published photographs, there might be more sional experiment in a new type of medicine (Richards, likely and less exciting explanations for the openings. 1995; Martin, 2003). In the Americas, two centers of ancient trepanation Still, accounts of trepanations being performed in have been identified: the region of South America recent times by traditional societies in many parts of occupied by modern day Peru and Bolivia, and the the world, including North and East Africa, the South less intensively studied Valley of Oaxaca in Central Pacific, Polynesia, and South America, serve to remind Mexico. Isolated skulls with possible healed trepanaus that trepanation is a surprisingly widespread and tions have been reported from some areas of North enduring practice (Bandelier, 1904; Hilton-Simpson, America, but most of these have been questioned 1922; Margetts, 1967; Furnas et al., 1985; Bastien,

ANCIENT TREPANATION (Stewart, 1958), and only one case – a skull from California – has tool marks, demonstrating that it was intentionally scraped (Richards, 1995). The evidence for Central Mexico and South America, however, is unequivocal. In the Oaxaca Valley, a trepanation tradition developed during the Classic Period (250–900 AD). First identified in simple graves in residential areas surrounding the monumental site of Monte Alba´n (Romero, 1970; Wilkinson, 1975; Wilkinson and Winter, 1975), additional examples have since been found at other valley sites (Stone and Urcid, 2003). The total sample of trepanned skulls from the Oaxaca Valley is relatively small, numbering about two dozen, but they are interesting nonetheless, and for several reasons. First, although most skulls from Monte Alba´n were trepanned by scraping or grooving methods, seven have been found that were trepanned by a drilling technique not known prior to the development of the crown trepan by the ancient Greeks (Wilkinson, 1975). Metal tools were unknown at Monte Alba´n, but a tradition of drilled lapidary work and dental incrustations had developed centuries before, and it is believed that these trepanations were accomplished with hollow drills of cane or bone, using sand as an abrasive. The end result was a circular drilled hole with an average diameter of about 11 mm (Stone and Urcid, 2003). Although smaller in diameter than holes made with a typical crown trephine, these openings still closely resemble them. Interestingly, skulls from Monte Alba´n trepanned with this technique tend to show multiple holes, up to five in a single individual. But while innovative, the local technique might not have been very successful. Only one of the seven skulls shows any evidence of bone reaction around its drilled holes, and none exhibit long-term healing (Wilkinson, 1975; Stone and Urcid, 2003). The second reason that Oaxaca trepanned skulls are unusual has to do with the archeological contexts in which they were found. While a few isolated trepanned skulls were found in excavations at Monte Alba´n in the 1930s and 1940s (Romero, 1970), in 1972 a grouping of five skeletons – all of them trepanned – was found buried in an area with domestic architecture. A year later, a second group of four trepanned individuals was discovered. Few goods were associated with any of these simple graves, indicating that these individuals were of relatively low status. The burial of groups of trepanned individuals initially suggested that the procedure might have been done for ritual purposes (no clear association with skull fractures was found) or as a possible experiment in surgical technique (Wilkinson, 1975; Wilkinson and Winter, 1975). Nevertheless, this scenario is complicated by later discoveries of trepanned skulls in elite

7 tombs at Monte Alba´n, as well as in isolated tombs at other valley sites, indicating that trepanation was not limited to a specific social group or site (Stone and Urcid, 2003). Future excavations in the Oaxaca Valley may shed further light on this unusual practice, which disappears from the archeological record following the collapse and abandonment of Monte Alba´n, c. 800 AD. In contrast, trepanation was practiced continuously in the Andean region from roughly the time of classical Greece (c. 400 BC) until the Spanish conquest in the 16th century (Verano, 2003). Isolated reports of trepanations being performed by traditional healers have continued to appear well into the 20th century, suggesting an even longer tradition in some isolated areas of the Andean highlands (Bandelier, 1904; Bastien, 1987). The earliest known trepanned skulls from South America were discovered in ancient cemeteries on the Paracas Peninsula of southern coastal Peru, and they date from approximately 400 BC to 200 AD (Tello and Mejı´a Xesspe, 1979). More than 70 trepanned skulls are known from these sites (Allison and Pezzia, 1976; Verano, 2003). Scraping was the method used to make relatively large openings in the skull (Fig. 1.4). Bifacial, flaked obsidian knives, which have been recovered from these sites, were used to make these openings. Copper and bronze tools were unknown at this time, so early South American trepanations were performed with chipped stone tools similar to those used in New Stone Age Europe. Following this early period of trepanation, the practice seemed to fall out of favor on the south coast of South America for reasons unknown (Verano, 2003).

Fig. 1.4. A trepanned skull from the Paracas Peninsula on the south coast of Peru dating to c. 400 BC.

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Skulls trepanned after 200 AD have appeared at numerous archeological sites over a broad area of the Peruvian and Bolivian highlands. The precise dating of most of these skulls is uncertain, as the majority were collected from disturbed tombs in the late-19th and early-20th centuries, when insufficient attention was given to identifying cultural context (Tello, 1913; Hrdlicˇka, 1914). In recent years, a small but growing number of more carefully excavated specimens has come to light, and they have allowed researchers to assign approximate dates to the collections lacking good contextual data. Many ancient trepanation techniques were used in South America: scraping, linear cutting, circular grooving, and boring and cutting (Lastres and Cabieses, 1960; Lisowski, 1967). The linear cutting technique (seen in Squier’s skull) is characteristic of the central highlands of Peru, although trepanations by the scraping and boring and cutting techniques are also found here, as well as in the southern highlands and high jungles of northern Peru. Some central highland trepanations show a combination of more than one technique, suggesting that some experimentation might have been occurring. Circular grooving appeared later, and might have evolved in the southern highlands during the height of the Inca Empire. Copper and bronze knives and chisels have been recovered from late central and southern highland sites, and these may have been the tools used to trepan skulls, although this can be difficult to prove. Nevertheless, in an experiment conducted in 1944, a Peruvian surgeon demonstrated that these ancient tools were quite capable of cutting through crania. He performed a successful craniotomy on a living patient to drain a subdural hematoma using archeological specimens from Peru’s National Museum of Anthropology and Archaeology (Ano´nimo, 1945). As is the case of trepanned skulls from Neolithic Europe, a significant percentage of Peruvian trepanned skulls show evidence of healing, indicating good survival following the procedure. Success rates improved from the earliest south coast trepanations to the later central highlands and southern highlands surgeries, reaching an impressive long-term rate of 78% by Inca times (Verano, 2003). Some of the most evocative cases of multiple trepanations with long-term healing are from Inca Peru, where an impressive seven healed openings have been found on one skull (Brothwell, 1959).

WHY DID THEY TREPAN? Depressed skull fractures are commonly observed in skeletal collections from Ancient Peru. Most breaks were probably produced by blows from clubs or stones

Fig. 1.5. A trepanation placed at the margin of a skull fracture, probably produced by a sling stone. Cinco Cerros, central highlands of Peru.

from slings, weapons widely used in the Andes prior to the Conquest, although some could have resulted from falls or other accidents. Beginning with the earliest studies of Peruvian trepanned skulls by Tello and Hrdlicˇka, the frequent co-occurrence of skull fractures and trepanations has been noted (Fig. 1.5). In a study of the largest sample of central highland Peruvian trepanned skulls to date, 26.2% of 457 trepanations were directly associated with visible skull fractures (Verano, 2003). The collection included a number of examples where trepanning was initiated at the site of a depressed fracture but never completed, perhaps because the patient died during the procedure. Incomplete operations suggest that evidence of many fractures and penetrating wounds could have been removed by the trepanation procedure itself, and that the incidence of trepanation to treat acute head trauma might have been quite high. Although a clear relationship between skull fracture and trepanation has been found in some sites in Ancient Peru, the larger picture remains quite complex. For example, there are a number of skulls with multiple trepanations of consistent size and shape associated with the late prehistoric period in the Cuzco region (Fig. 1.6). In these cases, it is hard to imagine that each trepanation is in response to a distinct crack or penetrating skull wound. Hence, alternative explanations, such as an attempt to treat recurring headaches or some other neurological symptom, also have to be entertained. Modern ethnographic examples are known of patients receiving multiple trepanations to treat recurring headaches, for example among the Kisii of Kenya (Furnas et al., 1985). These Inca skulls may represent a similar attempt to treat a problem of unknown cause, and perhaps one not relieved by previous interventions, although this cannot be stated with certainty.

ANCIENT TREPANATION

Fig. 1.6. An Inca skull with five healed trepanations (four are visible in this photograph) of similar size and shape. From the site of Patallacta, near Cuzco, Peru.

In Neolithic Europe, the motivation for trepanning is obscure, because relatively few trepanations are associated with recognizable skull fractures. It was this absence of hard evidence for why Neolithic practitioners operated that led Paul Broca and Victor Horsley to speculate on the motive. Paul Broca devoted a great deal of time to try to determine why trepanation was so common in his native France and in Neolithic Europe in general (Clower and Finger, 2001; Finger and Clower, 2003). He flatly rejected the hypothesis that the procedure was performed for depressed skull fractures. If this were the case, Broca thought, a greater percentage of Neolithic skulls would have been found with fracture lines close to the openings. He also noted that healed openings were not found on the skull bones in the facial region, which he presumed would be a common site for injuries and concussions, whether from weapons of war or head accidents. Interestingly, Broca also discarded the notion that the operation was routinely performed to treat closed head injuries in Neolithic times. The ratio of male to female trepanned skulls did suggest that combat, the usual cause of closed head injuries, was not involved to a significant degree. Thus, Broca turned his attention to diseases, and how they might have been perceived by the “primitive mind.” He had by now learned that these operations were still being performed in Africa, the South Pacific, and other parts of the world, to exorcise demons

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thought to cause convulsions and other frightening disorders. He did not consider it a large jump to hypothesize that earlier humans also believed in evil spirits and probably reasoned in similar ways. Broca now concluded that skull openings might have been made by Neolithic healers to give intrusive and confined demons affecting the brain a noticeable exit from the head. In particular, cranial surgery could have been the method of choice for seizures, since the afflicted would have been hard to hold down, as if possessed by demons of superhuman strength. With a large hole, and perhaps some accompanying rituals and incantations, the thought was that these demons could be coaxed, lured, or forced out. From this anthropological starting point, and stimulated by one exceptional specimen, Broca theorized that trepanations were usually, if not always, performed on children during the Stone Age. His hard evidence was the markedly deviated suture on the side of the hole in the very first skull presented by Prunie`res. It could only mean that the surgery had to have taken place very early in life in this case, and he was ready to generalize. Broca combined this evidence with the fact that children between the ages of 9 months and 5 years are commonly affected by “benign” seizures, like those occasionally observed during teething and fevers. In doing so, he developed the idea that these “simple” convulsions provided the motivation for ancient trepanation. He now explained that the convulsions were probably not true epilepsy, because epilepsy is not very common before the age of 10. But more importantly, he reasoned that the trepanation procedure would not have persisted unless it was deemed a success, and opening the skull would not have lessened the fits if the children were truly epileptic. In contrast, children with simple convulsions recover. Thus, the operation would have provided the illusion of success, even if it were not causal. Broca further argued that the surgery would have been more easily performed on infants, because the thin young skull is easier to penetrate and its wounds would heal more rapidly. To drive home his point, he even conducted some experiments to show just how quickly an immature skull could be trepanned with flint or glass (Broca, 1876c). He found he could scrape a hole in the skull from a deceased two-year-old child in just 4 minutes, whereas it took 50 minutes to open the thicker skull of an adult. He was even forced to rest his hands because of fatigue and pain that accompanied opening an adult skull. Broca also trepanned living dogs. He showed that it was relatively easy to avoid damaging the dura mater – the penetration of which surely would have caused more fatal infections and dramatically lowered survival rates. His canine subjects, with dura intact, survived the operation with no detectable problems.

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J.W. VERANO AND S. FINGER Finally, but not to be overlooked, Broca also to build a truly modern medicine (Sparrow and Finger, brought forth historical support for his infant convul2001). Together, the two men conducted important sion theory. He made reference to Jean Taxil’s Traité mapping studies on the motor cortex of monkeys, with
de l’Epilepsie, his treatise from 1602. Taxil discussed Horsley skillfully performing the surgeries (Horsley, how epilepsy was then ascribed to demon possession, 1885; Horsley and Scha¨fer, 1888). and he wrote that scraping a hole in the cranium down After graduation, Horsley served as Surgeon to the to the dura was a good treatment for it. Taxil not only National Hospital for the Paralysed and Epileptic, Queens presented the surgical approach as common, but also Square, in addition to accepting several other research, referred to the use of human cranial bones as a nonteaching, and administrative posts. He believed in Lister’s surgical approach for epilepsy. In his day, the bones were new principles of asepsis, and he became adept at perapplied as plasters, given as potions, and, of even more forming difficult new surgical techniques based on what interest to Broca and the anthropologists, worn or carried he had learned from his research on animals. as protective amulets (Taxil, 1602). In 1886, he began to operate at the National HospiBroca took what Taxil wrote as good support for tal on his first patients with severe epilepsy. Among the belief in the curative powers of cranial bones in the outstanding brain scientists and practitioners who cases with convulsions. He was careful to point out, aided with the diagnoses, were at his side during the however, that Taxil and others had mislabeled childsurgery, or helped in other ways were John Hughlings hood convulsions as epilepsy. By Broca’s day, it was Jackson, David Ferrier, and Charles Beevor. understood that epilepsy was a distinct form of convulUnlike previous surgeries for epilepsy, Horsley’s sive disorder. Thus, as noted, Broca reasoned that operations were based on John Hughlings Jackson’s Neolithic trepanation was performed for childhood (Jackson, 1870, 1873) revelation that epilepsy can origiconvulsions, but probably not for true epilepsy. nate at the cortical level, and on what had been learned Broca’s contemporaries described him as a highly about cortical localization of function during the preinformed, brilliant thinker, and he combined anthropolovious two decades. Also contributing to the new, more gical, medical, and historical information to come forth optimistic environment were better anesthetics, which with his explanation for why Stone Age people engaged minimized the chances of infection. in trepanation. But his theory was still controversial, and Horsley’s first and third cases had skull breaks that others did not hesitate to propose alternative hypotheses. helped him localize the source of the convulsions. His Some of the opposing ideas had more to do with tribal second case, however, was considerably more notable, rituals and rites of passage than with the brain and medibecause the patient had suffered a severe seizure disorcine (Mun˜iz and McGee, 1897). Other theories were based der caused by a tuberculoma that could only be locaon medicine, and the cranial fracture notion that Broca lized on the basis of signs and symptoms. Jackson, the doubted was not about to be discarded by everyone. dean of British neurology, suspected a tumor and The idea that trepanation might have originated as advised surgery. Because he had worked on movements an attempt to treat fractured skulls had been chamof different body parts elicited by cortical stimulation in pioned by Squier, who had seen pre-Columbian skulls monkeys, Horsley knew just where to open the skull and from Peru that were penetrated by sharp-pointed weapprobe. Like his other two cases, this man survived the ons. In his book from 1877, Squier mentioned a second surgical removal of a small part of his motor cortex, supporter of the fracture idea, Josiah Nott, a leading and he was thereafter cured of his epilepsy. American researcher and cataloguer of skulls. Horsley received accolades when he presented these It was Victor Horsley, however, who adopted the cases at a meeting of the British Medical Association in fracture idea and raised it to a new level with Broca’s 1886 and had his results published that year (Horsley, own Neolithic finds (Finger and Clower, 2001, 2003). 1886). Never before had people successfully diagnosed Unlike Broca, whose involvement with trepanned skulls and removed diseased pieces of cerebral cortex as a came from anthropology, Horsley was drawn to these means to combat epilepsy. One admirer even commented crania because of what he had learned as a laboratory that these successful surgeries were “a sure guarantee scientist who did physiological experiments on monthat this splendid and successful surgery would be perpekeys and other animals, and because he had just boldly tuated” (Horsley, 1886, p. 675). The idea of discovering a operated on the human brain in London. successful new procedure for epilepsy, and then promotHorsley was born in Kensington, London in 1857, ing it and using it for related problems, registered with the and he studied medicine at University College (Paget, pioneer neurosurgeon. In effect, it led him to his fracture1919; Lyons, 1966). There he fell under the influence based theory of ancient cranial trepanation. of Edward Albert Scha¨fer, a world-class physiologist Horsley’s theory originated during the same period in who promoted animal research as the basis on which which he was still studying the motor cortex in monkeys

ANCIENT TREPANATION 11 and now beginning to operate on patients with Jacksowith its emphasis on the role of the supernatural in disnian epilepsy. At this time, he took a trip to Paris, where ease states, whereas others sided with Horsley, whose he saw many of the Neolithic crania studied by Broca, emphasis was on the probable consequences of cranial who had died in 1880. In addition to archeology, Horsley fractures without recourse to terrifying demons or the enjoyed photography as a hobby, and he examined and supernatural world. took many photographs of these specimens for further Sir William Osler, one of the most respected men of study. medicine at the beginning of the new century, clearly As put by Stephen Paget (1919, p. 124), one of favored Broca’s view. Sounding very much like Broca Horsley’s biographers: himself, he told his audience: “The operation was done for epilepsy, infantile convulsions, headache, and varNever were lecturer and subject more happily suiious cerebral diseases believed to be caused by conted to each other. . . the fact that trephining was fined demons, to whom the hole gave a ready method practiced far and wide in the Stone Age found of escape” (Osler, 1923). Over the years, many people its proper exponent in him, who was both surgeon agreed that the surgery had to be linked to demonology and antiquarian. The skulls in Paris had been and probably to convulsions, although other disorders, waiting for him ever since they were trephined. such as migraine headaches and mental illnesses, Horsley recognized that the cranial holes made during might also be treated in this way (see Wakefield and the Neolithic Period did not seem to be randomly Dellinger, 1939, p. 167; Lisowski, 1967). placed. As Broca had noted, the face was always To some of these people, the weakest part of Broavoided. He even drew a composite map of the holes, ca’s theory was his belief that the surgery was largely, and it showed that the openings were centered more if not exclusively, performed on children. Late in 1879, or less above the motor cortex (Horsley, 1887, 1888). one year before he died, he was interviewed by an This was a part of the brain Horsley knew extremely astute female British anthropologist, A.W. Buckland, well. It had been and still was the subject of some of who examined the skulls in the Anthropological his most important stimulation and ablation experiMuseum with him and politely noted: ments on monkeys. He would call it the so-called One circumstance in connection with this seems motor cortex because he thought it had both motor rather difficult to explain: it is that among all of and somatosensory functions (Horsley, 1909). In the trepanned skulls hitherto discovered there has addition, Horsley had just shown the medical world not been one of a child found. Now as it is certain that this part of the brain is very likely to be damaged that some, and probably a large proportion of those or compromised in cases of motor (Jacksonian) epioperated upon died from its effects, we should lepsy, and that these seizures could be eliminated by naturally expect to find at least a few children’s surgically ablating diseased or injured parts of it. skulls thus treated. (Buckland, 1882) In short, Horsley was convinced that depressed fractures above the motor region would have caused Broca responded that children’s skulls are not as durable considerable surface pain and probably epilepsy. From as those of adults, especially if mutilated. Buckland this premise, he suggested that the tender flesh and knew this was true, but was not entirely swayed by this bone might first have been treated surgically to control defense of the theory. In fact, she noted that the skull the pain, only to find that operating on the broken skull that showed the aberrant suture growth indicative of bones also controlled the epilepsy. “Consequently the surgery early in life was still unique. Without additional operation would gain a certain reputation for the cure skulls showing abnormal suture development, and withof convulsions generally, and as such might have been out any children’s skulls exhibiting trepanations, she, for frequently practiced among savages to whom pain is one, could not accept the part of Broca’s theory that of slight consequence” (Horsley, 1888, p. 102). held that trepanation was for the young. As for Horsley’s hypothesis that traumatic injury was the initial reason for the surgery, here too one can find THE FATE OF TWO THEORIES many supporters, both past and present (Stewart, 1958; The more general theory that trepanation might have Gross, 1999). Today, it is generally agreed that the best been performed by Stone Age people for seizure disorempirical support for the fracture or trauma theory ders gained broad acceptance after Broca and Horsley comes from two sources, one old and the other new. gave their talks and saw their ideas in print. NevertheThe older data come from Peru, not Europe, Asia, or less, there was never good agreement about whose theAfrica. Many of these skulls, as noted, exhibit evidence ory did a better job explaining how the practice started of fractures and cranial injuries, and the ratio of males in the Old World. Some favored Broca’s explanation, to females in some samples is as high as 4:1 (Moodie,

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1929; Horrax, 1952; Popam, 1954; Jrgensen, 1988; Rifkinson-Mann, 1988; but see Verano, 2003). In addition, Peruvian trepanations are found most frequently on the left side of the skull, which is just what would be expected if wounds were sustained from right-handed adversaries (Stewart, 1958; Verano, 2003). Among the ancient Peruvians, treating fractures by trepanation seems to have been commonplace, although it was probably not the only reason for the surgery, so why could this not also have been true in Europe? As for the newer material, anthropologists and medical historians have studied traditional societies, whose members still practiced trepanation into the 20th century (Ackernecht, 1947; Lisowski, 1967; Margetts, 1967; Rawlings III and Rossitch Jr., 1994). They found that the natives of some South Pacific islands performed these operations to treat fractures, epilepsy, insanity, and headache, but also for preventative reasons. The operation was also found to be commonplace in Kenya and Tanzania, where it was performed for headache with or without cranial fractures (Margetts, 1967). From all indications, these surgeries were done for medical problems – not for rites or rituals alone. But while fractures and post-traumatic epilepsy were important reasons for trepanning, they were not the only reasons. Hence, there is indirect evidence to suggest that Neolithic trepanation might well have been an early intervention for treating neurological problems. Still, this is hypothetical and even modern scientists can do no more than speculate about the paradigms or the motives for these early surgeries in France and other locations thousands of years ago. In the absence of hard evidence, the theories of Broca and Horsley will probably continue to generate debate well into the future.

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ANCIENT TREPANATION Finger S, Fernando HR (2001). E.G. Squier and the discovery of cranial trepanation: a landmark in the history of surgery and ancient medicine. J Hist Med Allied Sci 56: 353–381. Furnas D, Sheikh MA, Hombergh VD, et al. (1985). Traditional craniotomies of the Kisii tribe of Kenya. Ann Plast Surg 15: 538–556. Goldsmith WM (1945). Trepanation and the “Catlin mark.” American Antiquity 10: 348–353. Gross CG (1999). A hole in the head. Neuroscientist 5: 263–269. Hilton-Simpson MW (1922). Arab Medicine and Surgery. A Study of the Healing Arts in Algeria. Oxford University Press, London. Horrax G (1952). Neurosurgery. An Historical Sketch. Thomas, Springfield, IL. Horsley V (1885). Experimental researches in cerebral physiology: on the muscular contractions which are evoked by excitation of the motor tract. Proc R Soc Lond 39: 404–409. Horsley V (1886). Brain surgery. Br Med J 2: 670–675. Horsley V (1887). Brain surgery in the Stone Age. Br Med J 1: 582–587 (Abstract of his address at the Royal Institution). Horsley V (1888). Trephining in the Neolithic period. J Anthropol Inst G Brit Ire 17: 100–106. Horsley V (1909). The function of the so-called motor area of the brain. Br Med J 2: 125–132. Horsley V, Scha¨fer AE (1888). A record of experiments upon the functions of the cerebral cortex. Philos Trans R Soc Lond B Biol Sci 179: 1–45. Hrdlicˇka A (1914). Anthropological Work in Peru, in 1913, with Notes on the Pathology of the Ancient Peruvians, with Twenty-six Plates. Smithsonian Institution, Washington. Jackson JH (1870). A study of convulsions. Trans St. Andrews Med Grad Assoc 3: 162–204. Jackson JH (1873). On the anatomical, physiological, and pathological investigation of the epilepsies. West Riding Lunatic Asylum Med Rep 3: 315–319. Jrgensen JB (1988). Trepanation as a therapeutic measure in ancient (pre-Inka) Peru. Acta Neurochir (Wien) 93: 3–5. Kaufman MH, Witaker D, McTavish J (1997). Differential diagnosis of holes in the calvarium: application of modern clinical data to palaeopathology. J Archaeol Sci 24: 193–218. Lastres JB, Cabieses F (1960). La Trepanacio´n del Cra´neo en el Antiguo Peru. Lima: Universidad Nacional Mayor de San Marcos. Lillie MC (1998). Cranial surgery dates back to Mesolithic. Nature 391: 854. Lisowski FP (1967). Prehistoric and early historic trepanation. In: DR Brothwell, AT Sandison (Eds.), Diseases in Antiquity. Charles C. Thomas, Springfield, IL, pp. 651–672. Lyons JB (1966). The Citizen Surgeon: A Biography of Sir Victor Horsley. Peter Dawnay, London. MacCurdy GG (1923). Human skeletal remains from the highlands of Peru. Am J Phys Anthropol 6: 217–329.

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Margetts EL (1967). Trepanation of the skull by the medicine-men of primitive cultures, with particular reference to present-day Native East African practice. In: DR Brothwell, AT Sandison (Eds.), Diseases in Antiquity. Charles C. Thomas, Springfield, IL, pp. 673–701. Martin G (2003). Why trepan? Contributions from medical history and the South Pacific. In: R Arnott, S Finger, CUM Smith (Eds.), Trepanation: History, Discovery, Theory. Swets & Zeitlinger, Lisse, pp. 323–345. Moodie RL (1929). Studies in paleopathology, XXIII, surgery in Pre-Columbian Peru. Ann Med Hist 1: 698– 728. Mueller MD, Finch III CS (1994). Kisii trepanation: an ancient surgical procedure in modern-day Kenya. The Explor J 72: 10–16. Mun˜iz MA, McGee WJ (1897). Primitive Trephining in Peru. Sixteenth Annual Report of the Bureau of American Ethnology, Washington, DC. Ortner DJ (2003). Identification of Pathological Conditions in Human Skeletal Remains. Academic Press, Amsterdam, Boston. Osler W (1923). The Evolution of Modern Medicine: A Series of Lectures Delivered at Yale University on the Silliman Foundation in April, 1913. Yale University Press, New Haven, CT. Paget S (1919). Sir Victor Horsley: A Study of his Life and his Work. Constable and Co., London. Piggott S (1940). A trepanned skull of the beaker period from Dorset and the practice of trepanning in prehistoric Europe. Proc Prehist Soc 6: 112–132. Popam RE (1954). Trepanation as a rational procedure in primitive surgery. Univ Toronto Med J 31: 204–211. Prunie`res PB (1874a). Sur les craˆnes artificiellement perfore´s a` l’e´poque des dolmens. Bull Soc Anthrop 9(2nd ser.): 185–205. Prunie`res PB (1874b). Sur les craˆnes perfore´s et les rondelles craˆniennes de l’e´poque ne´olithique. Comp Rend Assoc Fran Avan Sci 3: 597–635. Rawlings III CE, Rossitch Jr. E (1994). The history of trephination in Africa with a discussion of its current status and continuing practice. Surg Neurol 41: 507–513. Richards GD (1995). Brief communication: earliest cranial surgery in North America. Am J Phys Anthropol 98: 203–209. Rifkinson-Mann S (1988). Cranial surgery in ancient Peru. Neurosurgery 23: 411–416. Roberts CA, McKinley J (2003). Review of trepanations in British antiquity focusing on funerary context to explain their occurrence. In: R Arnott, S Finger, CUM Smith (Eds.), Trepanation: History, Discovery, Theory. Swets & Zeitlinger, Lisse, pp. 55–78. Romero J (1970). Dental mutilation, trephination and cranial deformation. In: TD Stewart (Ed.), Handbook of Middle American Indians. Vol. 9. University of Texas Press, Austin, TX, pp. 50–67. Rose FC (2003). An overview from Neolithic times to Broca. In: R Arnott, S Finger, CUM Smith (Eds.), Trepanation: History, Discovery, Theory. Swets & Zeitlinger, Lisse, pp. 347–363.

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Ruisinger MM (2003). Lorenz Heister (1683–1758) and the “Bachmann Case”: social setting and medical practice of trepanation in eighteenth-century Germany. In: R Arnott, S Finger, CUM Smith (Eds.), Trepanation: History, Discovery, Theory. Swets & Zeitlinger, Lisse, pp. 273–288. Schiller F (1992). Paul Broca: Founder of French Anthropology. Explorer of the Brain. Oxford University Press, Oxford. Silva AM (2003). Trepanation in the Portuguese Neolithic, Chalcolithic and Early Bronze Age periods. In: R Arnott, S Finger, CUM Smith (Eds.), Trepanation: History, Discovery, Theory. Swets & Zeitlinger, Lisse, pp. 130. Sparrow EP, Finger S (2001). Edward Albert Scha¨fer (Sharpey-Schafer) and his contributions to neuroscience: commemorating of the 150th anniversary of his birth. J Hist Neurosci 10: 41–57. Squier EG (1877). Peru; Incidents of Travel and Exploration in the Land of the Incas. Macmillan and Co., London. Steinbock RT (1976). Paleopathological Diagnosis and Interpretation. Charles C. Thomas, Springfield, IL. Stewart TD (1958). Stone Age skull surgery: a general review, with emphasis on the New World. Annual Report of the Smithsonian Institution, 1957, Publication 4314: 469–491. Stewart TD (1976). Are supra-inion depressions evidence of prophylactic trephination? Bull Hist Med 50: 414–434. Stone JL (1991). Paul Broca and the first craniotomy based on cerebral localization. J Neurosurg 75: 154–159.

Stone JL, Urcid J (2003). Pre-Columbian skull trepanation in North America. In: R Arnott, S Finger, CUM Smith (Eds.), Trepanation: History, Discovery, Theory. Swets & Zeitlinger, Lisse, pp. 237–249. Taxil J (1602). Traite´ de l’E´pilepsie, Maladie Vulgairement Appele´e au Pays de Provence la Goutette aux Petits Enfants. Robert Renaud, Lyon. Tello JC (1913). Prehistoric trephining among the Yauyos of Peru. XVIII International Congress of Americanists (London, 1912). Harrison and Sons, London 1: 75–83. Tello JC, Mejı´a Xesspe T (1979). Paracas, Segunda Parte: Cavernas y Necro´polis. Universidad Nacional Mayor de San Marcos, Lima. Verano JW (2003). Trepanation in prehistoric South America: geographic and temporal trends over 2000 years. In: R Arnott, S Finger, CUM Smith (Eds.), Trepanation: History, Discovery, Theory. Swets & Zeitlinger, Lisse, pp. 223–236. Wakefield EG, Dellinger SC (1939). Possible reasons for trephining the skull in the past. Ciba Symposia 1: 166–169. Wehrli GA (1939). Trepanation in former centuries. Ciba Symp 1: 178–186. Wilkinson RG (1975). Trephination by drilling in Ancient Mexico. Bull NY Acad Med 51: 838–850. Wilkinson RG, Winter MC (1975). Cirugia craneal en Monte Alba´n. Inst Nac Anthropol Hist Bol 12: 21–26. Yacovleff E, Muelle J (1932). Una exploracio´n en Cerro Colorado. Rev Mus Nac (Lima) 1: 30–59.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 2

Mesopotamia FREDERICK M. FALES * Dipartmento di Storia e Tutela Dei Beni Culturali (DIBE), University of Udine, Udine, Italy

THE MEASURE OF MESOPOTAMIA Foreword No treatise of ancient Mesopotamian observations on clinical neurology has yet been written, although much ground-breaking philological and interpretative work on the myriad of medical or medically related texts in cuneiform script has been performed in recent years. For the aims of the present, research-based, description of the neurological knowledge of the (comparatively little-known) society and culture which flourished from 5000 to 2000 years ago in what is now the territory of Iraq, it will thus be necessary to deal with a number of preliminary issues. First, a brief overview of the history of the region and then a general explanation of the intellectual and factual context in which medicine arose and flourished will be necessary. Only at this point will it be possible to enter into a detailed view of the clinical observations – from symptoms to diagnoses to prognoses – which the Mesopotamian medical specialists accumulated over the centuries, and which offer important findings on a number of neurological disorders, so as to draw a set of general conclusions.

Historical context Mesopotamian civilization spans some 3000 years, from the rise of the first urban-based states in the alluvial plain between the Tigris and Euphrates rivers and the creation of the earliest system of writing on clay media (late 4th millennium BC) to the disappearance of cuneiform script and its accompanying lore under the impact of Aramaic and Greek culture, at the beginning of the Christian era (Geller, 1997). Especially during the period of the first Sumerian city-states (2600– 2250 BC), the harsh conditions of the arid subtropical *

environment, which is present-day southern Iraq, tempered only by the extensive yearly floods of the Twin Rivers (albeit ill-timed in their occurrence and mutual combination), forced Mesopotamian inhabitants to create vast local networks of canals, sluices, and reservoirs, for water storage and gradual crop irrigation (Potts, 1997). The complementary activity of trade with the outlying hilly regions, in order to obtain otherwise unavailable timber and stone, crucial for large-scale building activities (Postgate, 1992), was a by-product of the earliest attempts to unify Mesopotamia under one rule, under the first Semitic dynasty of Akkad (2250–2120 BC) and the subsequent Third Dynasty of Ur (2120–2020 BC). From approximately 3000 BC, clay, the most abundant resource in the land apart from water, began to be employed in rolled lumps for the recording of simple economic memoranda through engraved pictographic signs. Quite soon, however, writing on the clay medium (by now fashioned into small regular-shaped tablets) evolved both formally – into an abstract system of signs formed by lines and triangular wedges (“cuneiform”) – and conceptually, with the notation of all language features through a combination of logograms (word-signs) and syllabograms (syllablesigns). This system, perfectly fitting for the needs of the agglutinative and monosyllabic language of the first identifiable people of Mesopotamia, the Sumerians, was later adapted to record the language of the Akkadians – a language which, like all other Semitic tongues, e.g., Hebrew, Aramaic, and Arabic, is flexive and polysyllabic. The complexity of this adaptation, especially after the dying out of Sumerian in the late 3rd millennium, brought with it a great expansion of the specialized schools for scribes (called é-dub-ba, “house of tablets”), whence we have derived, through archeological discoveries, a vast quantity of texts of

Correspondence to: Prof. Frederick Mario Fales, Chair of History of the Ancient Near East, University of Udine, Vicolo Florio, 2, I-33100 Udine, Italy. E-mail: [email protected], Tel: +39-0432-556643, Fax: +39-0432-556649.

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the learned tradition. These range from syllabaries to dictionaries, mono- or bilingual, to lists enumerating terms or describing aspects or phenomena of many different conceptual categories – among which are many features of medical interest, such as lists of plants and minerals (Cavigneaux, 1980–1983; Reiner, 1995, pp. 45–46). In its turn, the sophisticated development of the Akkadian cuneiform script engendered applications of this writing system to non-Semitic tongues in areas outside Mesopotamia, from the Hittites in central Anatolia to the Elamites in southwestern Iran. Not by chance, the earliest experiment in creating an alphabet – a script with a sign for each phoneme – was effected on the basis of cuneiform in the Mediterranean port of Ugarit during the 13th century BC (Pardee, 1997). Over time, the great wealth and intellectual fame acquired by the Mesopotamians through intensive human effort incited many foreign population groups coming from outer areas to penetrate the fertile alluvial plain and conquer its strongholds. Most of these groups then fully adapted to the local language and culture, becoming standard-bearers of the Mesopotamian intellectual tradition in their own right. This is the case of the West Semitic Amorites, who created parallel dynasties in the older Sumerian cities of the south from approximately 2000 BC onward; their unification under one rule was achieved by Hammurabi, King of Babylon (1792–1750 BC). This is also the case of the non-Semitic Kassites, who conquered Babylonia around 1600 BC, and ruled it in the name of existing tradition for some seven centuries. In its subsequent return to power over its own land, the older southern Mesopotamian population was initially aided and later supplanted by the nomadic-military groups of the Chaldeans, who finally raised Babylonia to imperial status between 612 BC and 539 BC (Brinkman, 1968; Frame, 1992). In the northern part of the alluvium, marked by rolling plains and higher (but still scarce and ephemeral) rainfall, the Akkadian population of the city-state of Assur, specializing in long-distance trade between 1900 and 1800 BC, was for three centuries under the domination of the invading Hurrians, originating from eastern Anatolia (Wilhelm, 1982). Only in the 14th century BC was this yoke shaken off, and an independent state of Assyria formed, with plans for rapid military and territorial expansion. These were carried out over the following centuries, despite periods of crisis and setback, toward the ultimate result of a “world empire,” which came to dominate the entire Near East, from Anatolia to Egypt and from Iran to the Mediterranean Sea, starting in 745 BC (Fales, 2001). The demise of Assyria in 612 BC brought about the quick takeover of the conquered areas by the Babylonian Chaldeans for a few generations, but in 539 BC the

conquest of Babylon by Cyrus, King of Persia, opened the age of foreign-based rule over Mesopotamia. Both in Babylonia and Assyria (where two cognate varieties of Akkadian, somewhat like UK and US English, were in use), the literary and erudite wisdom of ultimate Sumerian origin was preserved through the scribal schools, where extensive recopying of older works and preparation of new compendiums took place in continuous fashion (Oppenheim, 1964, p. 235f). To be sure, certain periods show particular peaks of scholarly activity. Thus Hammurabi’s age marks the debut of organized series of tablets indicating celestial or terrestrial phenomena and their ensuing positive/negative omens of divine origin, along an “if . . . then” logic that also underlies the so-called law codes of this period (Botte´ro, 1974, p. 81f). In the following Kassite age and in contemporary Assyria, the same logic began to be applied to therapeutic material (albeit proceeding from the signs/symptoms back to the cause), with the first elaboration of a true diagnostic handbook (see Health and healing in Ancient Mesopotamia). But it was during the age of the “world empire” created by the Assyrians, and specifically due to the antiquarian interests of King Ashurbanipal (668–627 BC), that the entire body of traditional literary and erudite lore from Assyria and Babylonia – including medical texts – was recopied and collected in the capital city Nineveh (Pederse´n, 1998). Thus, Ancient Mesopotamia may be ranged alongside contemporary Egypt as the seat of a multitude of wideranging intellectual experiments and developments, albeit, of course, restricted to the urban and literate elites. Nevertheless, Mesopotamian scholars did not leave us full-blown commentaries or analytical treatises of the many domains of reality that they investigated. This absence is particularly felt in the case of medicine. There is no explicit Mesopotamian definition of health, sickness, or even of treatment, and we must therefore rely on the therapeutic or diagnostic texts themselves and on letters or literary sources for supplementary contextual data (Herrero, 1984, pp. 12–17; Biggs, 1987–1990). Perhaps it is for this reason that the Greek historian Herodotus provided misleading information on the lack of medical practitioners in Babylonia, in contrast with Egypt.

MESOPOTAMIAN MEDICINE: BASIC TENETS Health and healing in Ancient Mesopotamia It is nowadays generally recognized that our knowledge of the health conditions in Ancient Mesopotamia still lacks a coherent historical-scientific framework,

17 MESOPOTAMIA and that only more data from paleo-anthropological as peopled by godly and demonic beings, structured analyses of skeletons found in archeological excavain complex groupings by rank and function, albeit with tions may change this picture in the near future (see no fixed superior rule to regulate their actions on Krafeld-Daugherty, 2002). By contrast, the vast nummankind (Botte´ro, 1987–1990, p. 205f; Farber, 1995, ber of medical texts that the Mesopotamians themp. 1896). selves have bequeathed to us are most useful in At another level, specific gods of the vast Sumerodefining the cultural awareness of these ancient peoAkkadian pantheon (most of which identified with ples toward ill-health, disease, and suffering, and the planets or main stars) were viewed as responsible their ways of coping with such realities and problems for “touching” the body and causing physical and men(Heessel, 2003, p. 7). Of course, difficulties of various tal afflictions in their displeasure, usually because a orders regarding the “translations” of such texts into a taboo had been broken or a transgression had been modern clinical framework – from actual linguistic committed (even unwittingly) against the social order. renderings to much more complex correlations of An intermediate figure known as the “personal god” thought and interpretative patterns – constitute a deficould also carry out these tasks, as described in the nite barrier for our grasp of the historically determined Babylonian poetic lament of the “Righteous Sufferer” conditions of health and illness in the Tigris-Euphrates or “Babylonian Job” (Foster, 1995, p. 298f; see Motor river valley during pre-Hellenistic antiquity. Still, it is and sensory impairments). felt that such a barrier may be to some extent overOther agents of illness, pertaining to a more popucome, also in the light of the cross-cultural challenges lar level of perception of the supernatural, holistic that modern medicine nowadays faces (see Neurologirather than theistic in foundation, were malevolent cal symptoms in Mesopotamian medical texts, below). demons and even restless spirits of ancestors (van Without question, the enjoyment of a long life of Binsbergen and Wiggermann, 1999). These demons or wellness of body and mind was an ideal of Mesopotaspirits were especially active during sleep. In contrast, mian culture. Thus, the high priestess Adda-guppi, who truly “black” magic, as performed by sorcerers and allegedly lived to the age of 104 between the mid-7th witches with the intent to cause personal bodily harm, and mid-6th centuries BC, related proudly that “my seems to have been only a late and secondary developeyesight was good, my hearing excellent, my hands ment, which however also made its way from time to and feet were sound, my words well chosen, food time into the diagnostic literature (Abusch, 1999). and drink agreed with me, my health was fine and This overall deterministic approach, according to my mind happy” (Pritchard, 1969, pp. 561, ii, 29–32). which illness was referred back to the action of exterIn point of fact, however, due to generally poor and nal supernatural “hands,” may also be traced in early unhealthy conditions (Avalos, 1996, p. 452), the rate Greek medicine (Geller, 2001–2002, p. 73; Scurlock, of mortality at birth and during infancy was extremely 2003), later to be repudiated in Hippocratic medical high, and adult life expectancy was very short by modthought, which viewed sickness without recourse to ern standards. Sickness was often recorded in texts the supernatural as resulting from an imbalance of dealing with everyday life, with possible external four basic internal humors. In recent studies, therecauses referred back to nutritional deficiencies, inadefore, a certain structural connection has been pointed quate food preservation, or hazards from water, aniout between the theoretical foundations of ancient mals, and plants (Scurlock and Andersen, 2005, Mesopotamian medicine and the inductive, empiricist pp. 13–25; also see the Akkadian verb marasu, “to be approach that caused modern medical science to gra_ sick,” Civil et al., 1977, p. 269f). Thus, for example, dually emerge from its Hippocratic heritage (Scurlock an Assyrian letter bears the following caveat: “the and Andersen, 2005, p. 12). water is dangerous in that place, the people will fall In particular, it is now increasingly sensed that the ill” (Saggs, 2001, p. 155f). supernatural “hands” indicated in the learned diagIn the scholarly collections of medical texts from nostic texts could have stood, through complex symAshurbanipal’s library (}1), signs and symptoms of bolic or metaphorical associations, for actual disease many and diverse afflictions were referred back to patterns, clustered in functional classes. Thus, for agents originating from outside the person and physiexample, a group of demons believed to be recruited cally entering in contact with his body, albeit invisibly among young persons, who had died just before or (Biggs, 1995, p. 1915f). This external etiological sphere after marriage (lilû, lilītu, and ardat lilî ), were confor the attribution of observable signs and symptoms sistently held responsible for maladies affecting the pertained largely to what we term the supernatural young, possibly including Gilles de la Tourette (unlike the Mesopotamians, who viewed it as a constisyndrome (Scurlock and Andersen, 2005, p. 434; see tuent part of reality). This vast domain was perceived Gilles de la Tourette syndrome). In cases such as

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these, we may be tempted to perceive an intellectual transition in progress, from a more general, magically oriented, attribution of illnesses to divine influence, to a more technical approach, involving the distinction and classification of disorders, named after individual supernatural agents (a practice that still persists in popular cultures today, as reflected in the Italian and Maltese nickname of shingles as “St. Anthony’s fire”).

The medical specialists: asû and āšipu The variety and complexity of these perceived etiologies implied specialized strategies for the patient’s cure, pertaining to the pharmaceutical-clinical, as well as to the procedural-magical spheres – both of which were considered potentially efficacious. Starting from the earliest medical texts written in Sumerian, the practitioner known as A.ZU (Akkadian asû) appears employed in a number of practical activities tied to healing: from setting bones, to lancing boils, to treating war-wounds, to administering herbal remedies for internal or external illnesses. A female asû is at present attested only at the royal court of Mari in the Amorite period, with uncertain functions, while a male practitioner of the same period would seem to have access to the palace harems, in order to cure cutaneous ulcers (Durand, 1988, pp. 558, 578–579). The asû’s stock-intrade seems to have been sets of jars bearing fumigants and ointments for different healing purposes (see Neurological symptoms in Mesopotamian medical texts); some of these jars have been archaeologically retrieved (Walker, 1980). The Hammurabi law code regulated the fees the asû could charge in relation to what he did and the social class of the patient, also attributing penalties in case of malpractice (Hallo, 2003, II, pp. 348–349). No direct evidence connects the asû to knowledge of human anatomy through autopsies. However, it must be recalled that Mesopotamian specialists developed, at least from Hammurabi’s time onward, a detailed cognition and classification of the internal organs (and especially the liver) of sacrificial animals, for the purpose of drawing omens from their most minute alterations; full-size clay models of sheep livers, with anatomical parts marked in writing on their surfaces, have been found in excavations from various periods (Biggs and Meyer, 1980–1983). Thus, the possibility of human post-mortem examinations should not be ruled out, and in fact some notations in medical texts seem to confirm this practice (see Neurological symptoms in Mesopotamian medical texts, below). The asû harked back to the goddess Gula, whose main temple was in the southern city of Isin (Black

and Green, 1992, p. 101). Therapeutic training and actual treatments were probably carried out here (Avalos, 1996), although the evidence is somewhat flimsy. In specific sectors of this shrine, archeological excavations have brought to light groups of skeletons showing malformations in the articulations and vertebral column (Haussperger, 1997, p. 205), as well as votive terracotta figurines of Kassite date representing various body-parts (Biggs, 1987–1990, p. 626) and the dog symbol of the Deity. Quite fittingly, in a hymn of self-praise, Gula presents herself as the embodiment of this practicing pharmacist-physician, albeit not averse to employing magic procedures: “I am the asû, I can save life/I carry every herb, I banish illness/I gird on the sack with health-giving incantations/I carry the texts which make one well/I give cures to mankind” (Lambert, 1967, p. 121; Foster, 1995, p. 232). In personal names from the later periods, on the other hand, we find invocations to Gula as an asitu, “female physician” (Black et al., 2000, p. 26). The great medical prestige of the Gula temple may be further gauged from the Babylonian comical text of the “Poor Man of Nippur” (Foster, 1995, p. 357f), in which the previously mistreated hero returns disguised as an asû from Isin and is immediately addressed with praise for his skills. The foremost practitioner in the treatment of illnesses, however, also harking back to Gula, was the āšipu. This figure has been variously described as an “exorcist,” a “magician,” and a “conjurer.” The āšipu’s textual materials pertained to omen interpretation and exorcism in various domains; his focus was the protection of the individual members of the human community from evil, through bargaining with the supernatural (Scurlock, 1999, 2003). Therapy was only one of his activities and it included, among other things, a subset of remedies to restore male potency (Guinan, 1997). Even when dealing with patients, the āšipu (apart from possibly observing the pulse) did not engage in the typical activities of the asû. His task was that of averting the influence of the “hands” which had “touched” the patient by reciting the appropriate incantations, by preparing braziers and censers, and by making libations to deities (Biggs, 1995, p. 1921). He could be assisted in his work by the barû or haruspex, concerned with the prognostication of the time of recovery. Counter to earlier views (Oppenheim, 1964, p. 290f; Ritter, 1965), it is nowadays held that there was no clear-cut opposition between the medical activities of the asû and of the āšipu, and that these two specialists worked side by side, sharing materials and methods (Avalos, 1995, 1996, p. 453; Scurlock, 1999; Scurlock and Andersen, 2005, p. 8f). This view is warranted

MESOPOTAMIA 19 for some better-known documentary contexts, such as “pharmacist-physician,” he would have relied on lists those issuing from the royal courts in Mari (18th cenof plants, which were correlated with specific illnesses, tury BC) or Assyria (7th century BC), although it and the relevant “recipes” for their therapeutical use remains to be demonstrated with regard to the entire (Herrero, 1984, pp. 17–20). span of the Mesopotamian scribal tradition (Finkel, 2000; Abrahami, 2003). Assyrian letters relate that The knowledge base of ancient the chief asû of the court prescribed phylacteries to Mesopotamian medicine be hung around the neck along with the anointment The materia medica of the asû was consistent with the of salves to cure King Esarhaddon’s fever (Parpola, worldwide folk tradition of herbal medicine, based on 1983, p. 226), thus freely mixing materia magica and practical experience in the selection and functional promateria medica. At least from one personal history, cessing of specific plant products (Majno, 1975, p. 37f). again dated to the Late Assyrian period, it may morePlants, herbs, and spices of numerous types were used, over be inferred that the same people could have offidry or fresh, and their parts (roots, shoots, stems, cially practiced both disciplines during their careers leaves, seeds, blossoms, fruits) could be ground, sifted, (Biggs, 1995, p. 1920). soaked, boiled, or grilled. Carriers or mixers such as More often it has been suggested that the bodies of beer, vinegar, honey, milk, flour, beeswax, and tallow texts pertaining to the “conjurer” and to the “pharmacistwere used, as well as locally available or imported physician” worked along different, albeit complementary, resins (cedar, myrrh, frankincense, cassia, and natural lines (e.g., Stol, 1991–1992). The main “handbook” of the turpentine) and plant alkali, obtained through proāšipu was a series known in Babylonian as sakikku cesses such as decoction and distillation. (“Symptoms”), the first of which opens with the line “If Further ingredients for healing remedies were the conjurer goes to the patient’s house” (Labat, 1953; insects (such as spiders and locusts), small reptiles augmented edition by Heessel, 2000). This series is fully (lizards), and parts or products of mammals, such as in line with Babylonian omen tradition (}1), with an a-b-c bones, horns, eggs, internal organs, and animal or pattern: the overt symptoms shown by the patient are human excreta (but this “filth pharmacy” might have described in detail, then a diagnosis with reference to been a cover for some plant names, kept secret to the the “hand” responsible for them is derived, and finally a uninitiated; cf. Ko¨cher, 1995), as well as minerals, such prognosis is offered in terms of recovery or death. The as salts, alum, and crushed stones. The patient received Babylonian scholar Esagil-kin-apli (mid-11th century BC) these varied admixtures through swallowing, enemas, assembled the “Symptoms” texts from exemplars dating tampons, and the application of lotions or salves back to Hammurabi’s time (see Geller, 2001–2002, (Oppenheim, 1964, p. 292f; Herrero, 1984, pp. 50–59). p. 73f) into a 40-tablet “canon” that was still used in the The identification of the names for this wide variety Persian period (Finkel, 1988). An older and different colof ancient Mesopotamian therapeutic components with lection of diagnostic-prognostic texts (“If you approach botanical and mineral substances to be found in the a sick man”) also circulated from the mid-2nd to the natural environment of Iraq was bravely attempted in mid-1st millennium (Stol, 1993, p. 91). the past (Thompson, 1949). Apart from the most comAs for the asû’s knowledge base, it was traditionally mon items, however, these efforts have been quesbelieved to go back to a vast series of so-called therationed (Biggs, 1995, p. 1915), due to etymological peutic texts, ordered by subsets according to different difficulties and to the obscure metaphors present in parts of the body, from head to toe. In such texts, after many names (such as our “Baby’s Breath” for the delia description of the symptoms, a detailed practical cate Gypsophila flower). This situation still causes treatment for healing was offered, while an ensuing severe limitations for the detailed study of the asû’s prognosis was provided only in rare cases (for editions therapies, and thence for a precise evaluation of their see Borger, 1967–1975: I, p. 240f, p. 528f). A Late overall efficacy. In any case, it still remains to be seen Assyrian private library from Assur, belonging to a whether the asû’s pharmacopoeia was based on an family of āšipus, however, included series of therapeuunderstanding of disease and treatment that excluded tic prescriptions alongside its vast collections of diaginfluences of the supernatural (Worthington, 2003). nostic tablets (Pederse´n, 1986: II, p. 41f). This Medical historians fare better in the realm of sympsuggests that most of the known therapeutic texts toms. Although the modern interpreter may encounter could, in fact, have been additional materials forming many uncertain items in the texts of the “conjurer,” due the backbone of the āšipu’s wide intellectual curricuto the synthetic style therein employed, moreover replete lum (Scurlock, 1999). In contrast, no actual “manual” with technical vocabulary, the basic organizing principles seems to have been available to the asû: in accordance underlying Esagil-kin-apli’s sakikku (“Symptoms”) and with his qualification as a permanently operational

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F.M. FALES

its cognate series (see The medical specialists: asû and āšipu, above) are, in point of fact, relatively clear (Scurlock and Andersen, 2005, pp. 575–677). In tablets III–XIV, an anatomical sequence was followed, with the ailing body parts forming the organizing principles of the prognoses recorded in each tablet (head–temples–eyes– nose/lips/teeth–tongue/palate–face–ears–neck/throat/arms– hands–breast/chest–abdomen/bowels–hip/inguinal region/ buttocks/anus/legs/feet). The remainder of the series (tablets XV–XL) bears forth other, and quite varied, criteria: from the length of illness (1 day–more than 1 day) to the time of day of the onset of illness, to focuses on specific symptoms (fever–no fever–pain in various places), or syndromes (seizure–stroke–enteric fever– skin lesions), or conditions (pregnancy), or health issues tied to sex/age (gynecology–pediatrics). In general, it may be observed that the vast majority of these symptoms seems to derive from direct external observations or at most from case histories; a few, however, clearly betray their origin in surgical procedures or autopsies (Scurlock and Andersen, 2005, pp. 9, 42–43, 416–417; see The medical specialists: asû and āšipu). The enlarged and updated edition of the text of “Symptoms” (Heessel, 2000) has rekindled much interest in ancient Mesopotamian health theory and practices during the last few years. No doubt, the wide variety of symptoms listed in Esagil-kin-apli’s series still show a reduced analytical focus on single diseases (Heessel, 2003). Nevertheless, a comprehensive attempt to fit such data into a workable grid of present-day illnesses was jointly undertaken by an Assyriologist and a medical expert (Scurlock and Andersen, 2005). Despite possible doubts on many vague or obscure ancient descriptions, this vast reading-out of Mesopotamian medical observations appears to have borne the most advanced results so far, in terms of competence and range. This recent work may thus act as a valid information base for the following overview of neurological symptoms and syndromes, based on this author’s personal selection of the clearest and bestdocumented cases in the available textual material.

NEUROLOGICAL SYMPTOMS IN MESOPOTAMIAN MEDICAL TEXTS The brain and the head The Mesopotamians believed that organs other than the brain (liver, heart, stomach) could be the primary seats of reason and emotion (Worthington, 2003), and seem to have equated the brain with a form of marrow peculiar to the skull. A number of non-medical texts point to the close association between the ear and the cranium in the context of mental performance, both in

intelligence and madness (Goodnick Westenholz and Sigrist, 2006). More generally, the head held a strong symbolic status for the entire person, and it was commonly perceived that afflictions of the head had negative consequences for one’s ability to think.

Headache Painful sensations in the head formed the specific object of one of the subsets of the therapeutic series (see The medical specialists: asû and āšipu above), with the title line: “If the crown of a man’s head” (Attia and Buisson, 2003; Worthington, 2005). Furthermore, a number of diagnoses in the āšipu’s handbook dealt with headaches, at times so intense as to cause reactions in other parts of the body. On the basis of the terminology and the overall description of the symptoms, it is possible to distinguish the relevant case histories between bilateral and viselike (literally “squeezing”) headaches, unilateral migraine with accompanying sensations of temple warmth, tearing, bloodshot eyes, nausea, and vomiting, febrile headaches, and, finally, intense head pain possibly deriving from abscesses, tumors, or ruptured cerebral aneurysms (Scurlock and Andersen, 2005, pp. 286, 311–314). An example from the latter category may be given, with diagnostic reference to the “ghost,” an agent consistently associated with painful headaches, neckaches, dizziness, and ophthalmological migraine: “If his temple afflicts him so that he continually cries out, his temporal blood vessels (feel like they) are pulsating greatly, (and) the seam of his head (feels like it) is open –‘hand’ of a ghost. He will die” (Scurlock and Andersen, 2005, pp. 314, 441). An intense headache resulting from a stroke (see Strokes, below) is described as follows: “If he has a stroke and then gets better, but his temples continually afflict him and he shudders – the one who holds his head has not (yet) let go” (Scurlock and Andersen, 2005, p. 329).

Motor and sensory impairments A wide technical vocabulary was employed by the āšipu to describe phenomena of muscle weakness, loss of sensation, and limb paralysis, whether in health (e.g., caused by cold water) or in disease, i.e., caused by nerve injuries, seizures (see Seizures and epilepsy, below), or strokes (see Strokes, below). Thus, we find cases describing temporary immobilization of hands and feet, paralysis sensations while emerging from the cold river water, loss of motor control in the mouth and lips, numbness and stiffness in the lower extremities, “disconnection” sensation in the trunk, weariness and heaviness in hands and feet, and limpness and flaccid paralysis in the muscles. A specific diagnostic test for paralysis resulting from a mild stroke or transient ischemic attack appears to be dealt with in the following example:

MESOPOTAMIA 21 “If he has a stroke and either his left side or his Seizures and epilepsy right side is affected and his shoulder is not Seizures are well attested in the non-medical literature released, but he can straighten out his fingers of Mesopotamia. Thus, the Code of Hammurabi preand he can lift his hand and stretch it out scribes that and he is not off food or drink – affliction by a ghost of the steppe. Recovery in three days” If a man purchases a slave or a slave woman, and (Scurlock and Andersen, 2005, pp. 328, 342). within his one-month period seizure (bennu) then befalls him, he shall return him to his seller, and the buyer shall take back the silver that he has Coma weighed and delivered. (Hallo, 2003, p. 351). The neurological condition whereby a patient cannot be aroused by vigorous visual, auditory, or painful stimuli, which we call coma, seems to have been well known to the āšipu. The first two clinical stages of coma (stupor and moaning or avoidance movements) were attributed to a spirit known as alû, as in the following case in which spastic paralysis (“tense” limbs) might also be involved: “If something like a stupor continually afflicts him and his limbs are tense, his ears roar, and his mouth is ‘seized’ so that he cannot talk – hand of an evil alû” (Scurlock and Andersen, 2005, pp. 293, 339). In non-medical literature, a full description of alû-induced coma is that of the “Righteous Sufferer” (cf. Health and healing in Ancient Mesopotamia, above): My body has donned an aluˆ-demon as one would a garment; he covered me with sleep as with a net. My eyes stare but do not see; my ears are open but do not hear. Numbness has gripped my whole body, paralysis has fallen upon my flesh . . . . Death has drawn (the curtain): it has covered my face. He (= the demon) listens to me, but I cannot answer the one who questions me. (Foster, 1995, p. 306, with variants in translation) The comatose stages, in which painful stimuli are employed to arouse the patient and are diagnostic of the severity of disease, might have been the object of the following example, entailing a double prognosis: “If he has been sick for 6 days and he does not get a respite on the seventh, they throw water on his face and he does not open his eyes – he will die. If he opens and closes his eyes at the water they throw over him and wails – he will recover” (Scurlock and Andersen, 2005, p. 548). The final stages (decerebrate posture and brain death) are described also in relation to the respiratory gasps (huqu) that reflect bilateral lower brain damage: If he has been sick with a mighty sickness for 5 or 10 days and the pupils of his eyes persist in moving downward, and huqu continually afflicts him for two days – he will die on the third day. (Scurlock and Andersen, 2005, p. 340)

Similarly, numerous purchase contracts from different periods contain warranties of 30–100 days against the slaves coming down with bennu. This term, long considered to mean “epilepsy” (Stol, 1993, pp. 5–7), is now more likely to be viewed as describing convulsive episodes, including those acquired or infectious, such as those from cysticercosis, due to the larvae of the tapeworm (Scurlock and Andersen, 2005, pp. 83–84). This type of exposure is explicitly mentioned in the following example: If his breasts continually hurt him, he stops eating and drinking a lot, he lies down a lot, and he continually jerks and shudders – bennu afflicts that person. It afflicted him either in the door or in the courtyard or at the river. (Scurlock and Andersen, 2005, p. 84) Also to be noticed in this text is the continuously recurring aspect of the seizures, which is the condition leading to actual epilepsy. Various other forms of seizure were catalogued by the āšipu. Seizures in infants, of a usually benign nature, were referred to as miqtu, “falling (spells),” focal seizures were attributed to the god LUGAL. U`R.RA, while other forms of generalized seizure (nowadays defined as petit mal, grand mal, etc.) went under the name of AN.TA.SˇUB.BA, which may be rendered as “(that which has) fallen from heaven” (Stol, 1993, pp. 7–9). A further diagnostic attribution may be effected solely, and with no small difficulty, on the basis of the associated symptoms. Thus, a description of a grand mal seizure runs as follows: If his eye flutters, his lips come apart, spittle flows from his mouth, his hand, his foot, and his torso thrash around like (those of) a slaugh tered sheep – AN.TA.SUB.BA – seizure afflicts him. (Scurlock and Andersen, 2005, p. 317) Of particular interest to neurologists is the recording of the well-known “aura” (unfamiliar odors, sensory illusions, hallucinations) that signals an oncoming seizure:

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F.M. FALES If, when a confusional state comes over him, his torso feels heavy and stings him, and afterward it comes over him and he forgets himself – (this  is) AN.TA.SUB.BA – seizure. If this happens in the middle of the day – it will be difficult for him. (Scurlock and Andersen, 2005, p. 321)

Complex disorders associated with seizures were also recorded. For the weakness or paralysis associated with a postictal state, the āšipu gave a consistent attribution to the “hand” of the Sun-god Sˇamasˇ, a deity often connected with altered mentation (Scurlock and Andersen, 2005, pp. 318, 431). In the following example, a complex disorder beginning with a focal seizure, then developing into a generalized seizure, and finally leading to a state of exhaustion is recorded, through consecutive “permutations” between the various responsible supernatural agents:   If the god LUGAL.UR.RA turns into AN.TA.SUB. BA (and then) turns into the “hand” of Ištar – (it is) the “hand” of Ištar. To save him, . . . (Scurlock and Andersen, 2005, p. 448; cf. Cranial trauma, below)

Cranial and spinal cord trauma CRANIAL

TRAUMA

In a society that frequently engaged in armed disputes and outright battles or wars, the severity of head lesions was well known. Evidence for cranial wounds has been retrieved in various Ancient Near Eastern archeological contexts through paleo-anthropological analysis (Krafeld-Daugherty, 2002). This evidence is generally consistent with the data from Mesopotamian non-medical texts, which speak of “hitting” with clubs or sticks, “stabbing” with metal weapons, “shooting” with arrows, and “striking” with bare hands (cf. Civil et al., 1977, pp. 71–84). A visual example of a cranial injury and its neurological consequences is attested in a series of limestone bas-reliefs from Ashurbanipal’s palace in Nineveh, depicting the pitched battle between Assyrians and the troops from hostile Elam on the Ulai river (653 BC). In one detail of this vast realistic limestone mural, we see the Elamite king Teumman being hit squarely on the head with a mace, while in an adjacent scene – relevant to a later moment – he is shown on one knee alongside a bowman, surrounded by many Assyrian soldiers. A caption placed above the scene reads “Teumman, in a deranged state, said to his son: ‘Raise the bow!’” (Gerardi, 1988, p. 30); in other words, the daze resulting from the blow made him believe a solitary last stand was possible.

In the āšipu’s handbook, consistent with its inner principles, cranial wounds are attributed to the influence of diverse divine or demonic “hands,” often on the basis of matching diagnoses for non-traumatic disorders. For example, the Moon-god Sin was viewed as responsible for facial illnesses, such as herpes simplex (including its possible neurological reflexes, such as Bell’s facial paralysis). The Moon god was also considered the agent of any traumatic injury to the facial nerves, as in the following case, which shows a remarkable insight into the resulting facial deformity: If he was wounded on the side of his face and his mouth is turned to one side and his skin smoothes out and falls flat against his skull, and spittle flows from his nose/mouth – “hand” of the god Sin. He will die. (Scurlock and Andersen, 2005, pp. 223, 292, 478) Similarly, Isˇtar, albeit directly connected to wounds due to her nature of goddess of warfare, was invoked as an agent of injuries to the eighth cranial nerve, as well as paresthesias and seizures, as in the following case: If he was wounded on his skull, and consequently, his ears do not hear – hand of Ištar. (Scurlock and Andersen, 2005, p. 309) Elsewhere, we may observe a passage of agency from Isˇtar to other deities: If he was wounded on his head and consequently he twists – he was entrusted by Ištar to the twin gods. (Scurlock and Andersen, 2005, p. 475) This diagnosis would seem to underscore the complications of cranial trauma (“twisting”), due to the wellattested connection of the “twin gods” with high fever accompanied by convulsions (Scurlock and Andersen, 2005, pp. 486–487). A case of fatal gastrointestinal hemorrhage following a head injury is also connected to these gods: If he was wounded on his head, and, consequently, he produces dark blood – hand of the twin gods. He will die. (Scurlock and Andersen, 2005, p. 309)

SPINAL

CORD TRAUMA

Mesopotamian civilization provides the first historically recorded visual evidence of the consequences of spinal cord injury. This is in a detail from a further series of Assyrian bas-reliefs, relevant to Ashurbanipal’s hunting for lions in his game park. The scene shows quite realistically a lioness pierced by various arrows in her vertebral column, and thus forced to drag her paralyzed hind limbs and paws, while the forelimbs are still capable of

MESOPOTAMIA

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Fig. 2.1. Assyrian wall-relief (age of Ashurbanipal). A lioness wounded in the vertebral column. British Museum. From Perrot and Chipiez, 1884, fig. 268.

movement (Fig. 2.1). Similar scenes also apply to humans: in the already quoted scene of the battle on the Ulai river (see Cranial trauma, above), a detail shows an Elamite soldier, wounded in the back as well as in the groin by arrows, whom a comrade is forced to drag by the arm, since he is incapable of leg movement. The remarkable depictions of the Assyrian warartists of the fact that localized lesions in the vertebral column could lead to paraplegia also find some parallels in the āšipu’s handbook, as in the following case: “If his limbs become limp and he excretes blood, he was wounded from behind. He will die.” Additionally, we find this statement, showing another complication of spinal cord injury: If he was wounded on his spine and, as a consequence, he is stopped up so that his excrement cannot come out – hand of a murderous ghost. He will die. (Scurlock and Andersen, 2005, pp. 107, 309)

Possible brain tumors and abscesses In view of the many recurring symptoms and causal elements in the āšipu’s neurological diagnoses, the possible presence of brain tumors may only be suspected, with much remaining uncertain. The following case may be considered: If a falling spell falls upon him and it has been falling upon him for one year and as its sign it comes over him – it is a worrisome situation. If the AN.

 TA.SUB.BA – seizure (cf. Cranial and spinal cord trauma) comes closely spaced and in the middle of the day – it will be (increasingly) difficult for him. (Scurlock and Andersen, 2005, pp. 326–327) Of course, this is merely a description of a long-standing seizure disorder, and the hypothesis of a brain tumor may be brought forth merely on the basis of the slowly progressive nature of this illness.

Strokes The āšipu’s handbook used a specific term for stroke, mišittu, which allows us to set apart the diagnoses of likely cerebrovascular episodes from others in the neurological section. Examples of possible mild strokes or strokes with associated headache have been given above (see Headache and Motor and sensory impairments, above). Of interest is the āšipu’s recording of strokes in relation to neurologic loss on one side of the body, and to diminution of muscular control in specific body parts (facial, arm, hip and leg symptoms). The following is a positive prognosis for a stroke that has weakened the limbs: If it is difficult for him to bend either his hand or his foot, and he has had a stroke – he will get well. (Scurlock and Andersen, 2005, p. 330) A negative prognosis leading to permanent deficit is, in contrast, the following one, relevant to a stroke with consequences on multiple body parts:

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F.M. FALES If his face twitches, his torso is powerless, he lets his right hand drop and is unable to lift it, and he drags his foot – hand of a stroke. Even if he lives for a long time, he will not straighten up. (Scurlock and Andersen, 2005, p. 330)

Pediatric neurology A number of neurological diseases affecting infants can be found in a specific omen series (called šumma izbu, from the title-line, “If a foetus . . .”) regarding malformations at birth. A possible case of neurofibromatosis, with description of the relevant skin lesions and neurological complications, such as tumors of the nerve trunk or spinal cord, seems to be attested in one of the examples from this series: If a woman gives birth and there is a piece of flesh set upon the child’s head like a turban and its base is constricted and the child continually falls down, his left eye is blind, his left hand and foot are weak and his teeth have erupted, – then . . . (Scurlock and Andersen, 2005, p. 394) As for the material from the āšipu’s handbook, the following case could refer to cerebral palsy, with paraplegia, seizures, and mental retardation also involved:

infants suffering seizures. This is revealed in the following example: Recitation for the infant continually shuddering, wailing, jerking, and having confusional states. To calm him – the relevant ritual: (you will) clean a (branch) of dogwood-tree exactly at sunset, and say the following words: “may the evil dew of the stars not get close to you, may only pure and clean dew fall upon you!” (Farber, 1989, pp. 62, 192–196)

Possible basal ganglia disorders Mesopotamian medical specialists noted movement disorders, such as chorea, because of their impressive features. One is described in this example, with reference to the demon Sˇulak, elsewhere associated with cranial trauma and stroke-like symptoms: If the patient is sick and his ears ring and his right hand and foot jump to the left, and his left  hand and foot jump to the right – hand of Sulak. He will not recover; he will die. (Scurlock and Andersen, 2005, p. 334) Another case is described at length as follows:

If an infant of 1, 2, 3 or 4 years writhes in contortion so that he is unable to get up and stand, he is unable to eat bread, and his mouth is “seized” so  that he is unable to talk – sperm of Sulpaea. He will never straighten up. (Scurlock and Andersen, 2005, p. 331)

If an affliction afflicts him while he is going along the road, and when it afflicts him he makes his hands and feet writhe in contortion against the earth, his eyes are dark, his nostrils are contracted, and he eats his garments – sperm of  Sulpaea. (Scurlock and Andersen, 2005, p. 335)

The specific agent called “sperm (or spawn) of (the god) Sˇulpaea” was also responsible for illnesses that would correspond to floppy baby syndrome. It is of interest to note that, at least in one such case, in which an infant did not “wail or cry or stiffen up” since birth, the āšipu prescribed euthanasia by drowning, so that the household should not “be scattered” (Scurlock and Andersen, 2005, p. 332). A further case in which a baby’s neurological illness was viewed as a bad omen for the whole family is the following, perhaps referring to a contagious disease, such as meningitis:

An interesting case involves what might have been Parkinson’s disease, which the āšipu believed to derive from poisoning:

If the infant is breast fed for 1 or 2 months and then falling spells fall upon him and his hands and his feet are immobilized – hand of a god was born with him. Either his father or his mother will die at his foot. (Scurlock and Andersen, 2005, p. 326) From non-medical literature, it is known that specific soothing (lullaby-like) recitations were performed for

If his head, his hands, and his feet, all tremble at once and his words hinder each other in his mouth, that person has been fed a dirty substance. (Scurlock and Andersen, 2005, p. 337)

Gilles de la Tourette syndrome? The typical jerking movements and the uncontrollable verbalization, often with obscene connotations, that mark Gilles de la Tourette syndrome might have been described in the following case: If he continually cries out, “My insides, my insides!” he continually raises his pelvic region, confusional states come over him, and when they come over him, he continually talks in a frightful manner – hand of ardat lilî. (Scurlock and Andersen, 2005, p. 337)

MESOPOTAMIA The link with the demon ardat lilî should indicate that a young person – often a victim of this syndrome – was involved (see Health, below).

Neurological diseases of infectious origin RABIES Rabid dogs and the lethal effects of their bites are frequently attested in the non-medical literature of Mesopotamia. The code of laws of the city of Eshnunna (19th–18th centuries BC) prescribes that If a dog becomes rabid and the ward authority informs its owner, but he does not watch over his dog so that it bites a man and causes his death, the owner of the dog shall pay 40 shekels of silver. If it bites a slave and causes his death, he shall pay 15 shekels of silver. (Hallo, 2003, p. 335) Astrological omens also included rabid dogs among the negative consequences of phenomena in the sky: If in the 12th month the moon is eclipsed – the king of Elam will die, and dogs will become rabid and bite humans. The bitten man or woman will not survive. (Wu, 2001, p. 36) Finally, a Babylonian incantation provides a succinct image of the dog’s lethal bite, with metaphors drawn from the realm of childbirth: From his teeth flows death; in his mouth is carried his semen; wherever he bit, he left behind his child. (Finkel, 1999, p. 214) In contrast, the āšipu’s handbook seems to have only one, albeit detailed, reference to the consequences of rabid dog bite. The symptoms, neurological and other, include “spinning face,” “tense limbs,” depression, troubled words which are soon forgotten, short breath, fever, stiffness in the joints, pain in the limbs and neck muscles, excessive salivation, mood swings, and terrible dreams in which the patient visualizes the dead. The length of the illness is described as approximately 3 months (Scurlock and Andersen, 2005, pp. 22–23).

TETANUS Tetanus seemed to be quite frequent in Ancient Mesopotamia, due to agricultural work being carried out barefoot or barelegged in environments probably heavily laden with tetanus spores. Thus, it is not surprising that this affliction was characterized by a diagnostic term of its own, šaššatu. It is described as follows in a literary text:

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Šaššatu afflicts that person’s limbs like a snake whose head a man has beaten. He does not eat good bread, he does not drink good water, he does not sleep good sleep. He spends every day in woe. He cannot turn his limbs; they feel as if they had been cut apart the way a lying rush bends its neck. (Scurlock and Andersen, 2005, p. 67) The neurological consequences of tetanus, and specifically incontrollable muscle spasms caused by its neurotoxin, are described in a number of entries in the āšipu’s handbook. The following one is the most eloquent: If a person’s muscles are stiff from his neck muscles to his heel, his eyebrows are knitted, and his jaws feel as if they were pressure – šaššatu (Scurlock and Andersen, 2005, p. 67)

CEREBRAL

MALARIA

The Mesopotamian alluvial plain, subjected to yearly flooding by the Twin Rivers, comprised (as it still does today) many temporary or permanent marshy tracts, in which mosquitoes undoubtedly thrived. “He must not go into the lowlands by the river or the la’ibu-disease will infect him (ila’ibšu)” – thus runs an Assyrian warning, in which (through the connection of both the verb and the disease name to the notion of “infection”) we might have an allusion to the possibility of contracting malaria (Scurlock and Andersen, 2005, p. 36). The typical cycle of malaria affliction, with recurring febrile spikes and alternating days of respite, would seem to be described in the following case: If he is sick for six days and on the seventh he gets well, on the eighth day he is sick and on the ninth he gets well, on the tenth day he his sick and on the eleventh he gets well and his illness has a turn for the worse – the āšipu shall not make a prognosis for his recovery. (Scurlock and Andersen, 2005, p. 67) The following case may illustrate some of the consequences of cerebral malaria, viz., the ocular bobbing and the forcible closing of the mouth: If, when it comes over him, his left/right eye makes (bobbing movements like) a spindle when it spins, and his right/left eye is full of blood, he continually opens his mouth and he bites his tongue – the god LUGAL.GIR.RA afflicts him. (Scurlock and Andersen, 2005, p. 37) Other cases, always with reference to the god LUGAL. GI`R.RA, mention the spinning of the head, trembling hands, growling like a dog, and nystagmus (“his eyes jerk”) (Scurlock and Andersen, 2005, pp. 36–37).

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F.M. FALES

CONCLUSIONS Among the signs and symptoms observed by Mesopotamian medical practitioners, those associated with disorders of the nervous system prove to be among the most focused, due to the rich technical vocabulary employed and the characterizations of the clinical picture. Further, as shown above, the ensuing diagnostic sections refer back – more than anywhere else in the sakikku collection – to a recurring and quite restricted set of supernatural causal agents or “hands,” to the extent that it may be asked whether these names of gods or demons responsible for neurological disorders had not become, over time, mere labels for a technical pinpointing of the disorders themselves (see Health, below). This view becomes even more plausible if one takes into account some descriptions of neurological symptoms, in which one supernatural agent is said to “turn” into another, of different name and nature, thus indicating the onset of different phases of the illness (Scurlock, 2003, p. 13; see Seizures and epilepsy and Cranial trauma). Mesopotamian diagnostic texts, in connection with other records, some medical and some non-medical, offer remarkable insights into the lives and sicknesses of these people – their fears, illnesses, sufferings, and destinies (by the prognostication of recovery or death). Environmental factors, work habits, and armed conflicts, i.e., the everyday issues of an ancient society in an arid habitat, form the overall historical backdrop to this vast clinical picture, which also includes gods, demons, and other supernatural entities. All of these forces might have represented true objects of belief and even fear, and they were generally perceived as influences capable of penetrating the human body and radically altering its health, if not properly assuaged. It is in this complex intellectual and psychological context that the clinical-neurological observations of Ancient Mesopotamia are to be placed, as an important stage in the extended itinerary that has led us to our present knowledge of mankind and its maladies.

REFERENCES ´ propos des fonctions de l’asuˆ et de Abrahami P (2003). A l’a¯sˇipu: la conception de l’auteur de l’hymne sume´rien de´die´ a` Ninisina. Le Journal des Me´decines Cune´iformes 2: 19–20. Abusch T (1999). Witchcraft and the anger of the personal god. In: T Abusch, K vd Toorn (Eds.), Mesopotamian Magic: Textual, Historical, and Interpretative Perspectives. Styx, Groningen, pp. 83–121. Attia A, Buisson G (2003). E´dition du texte “Si le craˆne d’un homme contient de chaleur, deuxie`me tablette.” Le Journal des Me´decines Cune´iformes 1: 1–24. Avalos H (1995). Illness and Health Care in the Ancient Near East. The Role of the Temple in Greece, Mesopotamia, and Israel. Scholars Press, Atlanta.

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MESOPOTAMIA Finkel IL (2000). On late Babylonian medical training. In: AR George, IL Finkel (Eds.), Wisdom, Gods and Literature. Studies in Assyriology in Honour of W.G. Lambert. Eisenbrauns, Winona Lake, IN, pp. 137–223. Foster BR (1995). From Distant Days: Myths, Tales, and Poetry of Ancient Mesopotamia. CDL Press, Bethesda, MD. Frame G (1992). Babylonia 689–627 BC: A Political History. Nederlands historisch-archaeologisch instituut te Istanbul, Leiden. Geller MJ (1997). The Last Wedge. Zeitschrift der Assyriologie 87: 43–95. Geller MJ (2001–2002). West meets East: early Greek and Babylonian diagnosis. Archiv fu¨r Orientforschung 48–49: 50–75. Gerardi P (1988). Epigraphs and Assyrian palace reliefs: the development of the epigraphic text. Journal of Cuneiform Studies 40: 1–35. Goodnick Westenholz J, Sigrist M (2006). The brain, the marrow, and the seat of cognition in Mesopotamian tradition. Le Journal des Me´decines cune´iformes 7: 1–10. Guinan A (1997). Auguries of hegemony: the sex omens of Mesopotamia. Gender & History 9: 462–479. Hallo WW (Gen. Ed.) (2003). The Context of Scripture, vols. I–III. Brill, Leiden. Haussperger M (1997). Die mesopotamische Medizin und ¨ rzte aus heutiger Sicht. Zeitschrift der Assyriologie ihre A 87: 196–218. Heessel NP (2000). Babylonisch-Assyrische Diagnostik. Ugarit-Verlag, Mu¨nster. Heessel NP (2003). Reading and interpreting medical cuneiform texts: methods and problems. Le Journal des Me´decines cune´iformes 3: 2–9. Herrero P (1984). La The´rapeutique Me´sopotamienne. E´ditions Recherche sur les Civilisations, Paris. Ko¨cher F (1995). Ein Text medizinsicher Inhalts aus dem neubabylonischen Grab 405. In: RM Boehmer, F Pedde, B Salje (Eds.), Uruk- Die Gra¨ber. Philipp von Zabern, Mainz, pp. 203–216. Krafeld-Daugherty M (2002). Archa¨ologie, Philologie, und Anthropologie: eine Synthese. In: O Loretz, KA Metzler, H Schaudig (Eds.), Ex Mesopotamia et Syria Lux: Festschrift fu¨r Manfred Dietrich zu seinem 65. Geburtstag. Ugarit-Verlag, Mu¨nster, pp. 245–287. Labat R (1953). Traite´ akkadien de diagnostics et pronostics me´dicaux, I–II. Acade´mie Internationale d’Histoire de Sciences, Paris. Lambert WG (1967). The Gula Hymn of Bullutsa-rabi. Orientalia 36: 105–132. Majno G (1975). The Healing Hand: Man and Wound in the Ancient World. Harvard University Press, Cambridge, MA, London. Oppenheim AL (1964). Ancient Mesopotamia: Portrait of a Dead Civilization. University of Chicago Press, Chicago-London. Pardee D (1997). Alphabet. In: EM Meyers (Ed.), The Oxford Encyclopaedia of Archaeology in the Near East. Oxford University Press, Oxford, vol I, pp. 75–79. Parpola S (1983). Letters from Assyrian Scholars to the Kings Esarhaddon and Assurbanipal: Part II, Commentary and

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Appendices. Butzon & Bercker Kevelaer, NeukirchenVluyn. Pederse´n O (1986). Archives and Libraries in the City of Assur: A Survey of the Material from the German Excavation, I–II. Almkvist & Wiksell, Uppsala. Pederse´n O (1998). Archives and Libraries in the Ancient Near East, 1500–300 BC. CDL Press, Bethesda, MD. Perrot G, Chipiez C (1884). Histoire de l’Art dans l’Antiquite´: II. Chalde´e et Assyrie. Hachette, Paris. Postgate JN (1992). Early Mesopotamia. Routledge, LondonNew York. Potts DT (1997). Mesopotamian Civilization: The Material Foundations. The Athlone Press, London. Pritchard JB (1969). The Ancient Near East. Princeton University Press, Princeton, NJ. Reiner E (1995). Astral Magic in Babylonia. The American Philosophical Society, Philadelphia, PA. Ritter K (1965). Magical-expert (= a¯sˇipu) and Physician (= asuˆ): Notes on Two Complementary Professions in Old Babylonian Medicine. In: HG Guterbock, T Jacobsen (Eds.), Studies in Honor of Benno Landsberger on his Seventy-Fifth Birthday. University of Chicago Press, Chicago-London, pp. 299–321. Saggs HWF (2001). The Nimrud Letters, 1952. British School of Archaeology in Iraq, London. Scurlock JA (1999). Physician, Exorcist, Conjurer, Magician: A Tale of Two Healing Professionals. In: T Abusch, K vd Toorn (Eds.), Mesopotamian Magic: Textual, Historical, and Interpretative Perspectives. Styx, Groningen, pp. 69–79. Scurlock JA (2003). From Esagil-kin-apli to Hippocrates. Le Journal des Me´decines cune´iformes 3: 10–30. Scurlock JA, Andersen BR (2005). Diagnoses in Assyrian and Babylonian Medicine. University of Illinois Press, Urbana–Chicago, IL. Stol M (1991–1992). Diagnosis and therapy in Babylonian medicine. Jaarbericht Ex Oriente Lux 32: 42–65. Stol M (1993). Epilepsy in Babylonia. Styx, Groningen. Thompson RC (1949). Dictionary of Assyrian Botany. The British Academy, London. van Binsbergen W, Wiggermann F (1999). Magic in history. A theoretical perspective, and its application to Babylonian medicine. In: T Abusch, K vd Toorn (Eds.), Mesopotamian Magic: Textual, Historical, and Interpretative Perspectives. Styx, Groningen, pp. 1–33. Walker CBF (1980). Some Mesopotamian inscribed vessels. Iraq 42: 85–86. Wilhelm G (1982). Grundzu¨ge der Geschichte und Kultur der Hurriter. Wissenschaftliche Buchgesellschaft, Darmstadt. Worthington M (2003). A discussion of aspects of the UGU series. Le Journal des Me´decines cune´iformes 2: 2–13. Worthington M (2005). Edition of UGU 1 (=BAM 480 etc.). Le Journal des Me´decines cune´iformes 5: 6–43. Wu Y (2001). Rabies and rabid dogs in Sumerian and Akkadian literature. Journal of the American Oriental Society 121: 32–43.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 3

Neurology in Ancient Egypt GEORGE K. YORK, III 1 * AND DAVID A. STEINBERG 1 Department of Neurology, University of California at Davis; Fiddletown Institute, Fiddletown, CA, USA

INTRODUCTION Neurology, as a systematic study of diseases of the nervous system, did not exist in Ancient Egypt and we have no evidence that the Egyptians had any conceptions of the nervous system as a discrete organ. Nevertheless, Egyptian doctors made careful observations of illness and injury, some of which involved the nervous system. Egyptian medicine was a compound of rational, magical and religious elements. Egyptian physicians used a combination of medications, physical manipulation, and prayers and incantations to treat the sick and injured. Their medical practices were specialized and hierarchically organized. Though no extant writings tell us of specialists devoted to the nervous system, Herodotus tells us that there were specialists of the head. Nevertheless, the role of the physician in society, and the conditions for which people consult a physician, have not changed materially since the time of the pharaohs. While ancient Egyptian medical writers did not connect symptoms with nervous system pathology, their observations of symptoms now known to be due to neurological disease make their explanations interesting to modern neurologists. For general descriptions of ancient Egyptian medicine, see the studies of Sigerist (1951 pp. 216–373) and Nunn (1996). We use the hieroglyphic translations of Nunn (1996) and Breasted (1930). Latin and Greek translations are our own.

METHODOLOGY There are two types of historical investigations of ancient Egyptian neurology, studies of Egyptian ideas about the signs and symptoms of neurological disease and attempts to apply modern diagnostic techniques to the patients of antiquity. Unfortunately, the medical ideas of the Egyptians are opaque to modern scholars,

*

and we learn little of Egypt from giving ancient illnesses modern names. Historians of neurology recognize the gulf between them and their subjects yet try to glimpse the medical models of the past. Our intuitions about Egyptian medical ideas are based on recognizable symptoms and can be judged by the same standards as any scientific or medical hypothesis. There is symmetry between the unknown future and the unknowable past—the advance of scientific neurology and the understanding of ancient medical theories demand the same analytic techniques. Other perspectives on this topic can be found in the commentaries of Karenberg and Leitz (2001) and York (2002). Only a few medical papyri survive and it is safe to assume that this represents a small percentage of those that once existed. Not only does the small sample size introduce errors when their contents are generalized to global ideas about Egyptian neurology, but any departure from randomness introduces additional potential errors. For example, papyri stored in royal libraries are more likely to be preserved than those in a provincial temple, yet the contents of the latter may be more representative of the general societal understanding of the nervous system. See Sigerist (1951, p. 298) for other types of sampling errors in Egyptian medicine. Regardless of the number of documents available for evaluation, any understanding of their contents requires a translation of the words into modern terms. The meaning of words in historical documents presents the greatest challenge to recreating a contemporary understanding of Egyptian medicine (Steinberg, 2002). By writing about the history of medicine one potential difficulty is avoided. That is, medical science begins with observations of human anatomy and disease that have presumably remained stable over historical intervals. Modern understanding of health and disease allows us to imagine some aspects of ancient medical thinking.

Correspondence to: George K. York, III MD, Fiddletown Institute, 21201 Ostrom Rd., Fiddletown, CA 95629, USA. E-mail: gkyork@ ucdavis.edu, Tel: +1-209-476-3236, Fax: +1-209-245-5409.

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We have nothing left of ancient Egyptian theories of the brain, if indeed they had any such theories, but we can see outlines of practical medicine in ancient Egyptian diagnosis and treatment. The paucity of evidence about ancient Egyptian neurology makes any certain knowledge of it impossible, yet our imperfect understanding of Egyptian diagnosis helps to engender an appreciation of a professional continuity spanning five millennia.

SOURCES Modern scholars have three sources of information about ancient Egyptian medicine: papyri, inscriptions, and mummified remains. Some papyri treat medical subjects and are therefore termed medical papyri, but these texts do not necessarily segregate magical, religious and empirico-rational elements. Most of our information about ancient Egyptian neurology is derived from two of these so-called medical papyri, the Edwin Smith Surgical Papyrus and the Ebers Papyrus. The Egyptologist Edwin Smith bought the papyrus that bears his name from a local dealer in Luxor in 1862. He was not able to translate it himself, and his heirs donated it to the New York Historical Society; it now resides in the library of the New York Academy of Medicine. The noted Egyptologist James Henry Breasted published a monumental translation of it in 1930 (Breasted, 1930). Breasted considered that the papyrus was a 17th century BCE transcription of an archaic text that dated to 3000–2500 BCE. The 17th century scribe added explanatory material to the archaic text as a gloss for later readers, and a third scribe added other sources. Breasted speculated that the Old Kingdom original might have been written by the illustrious Imhotep, architect and physician, but there is no evidence to support this contention. The Edwin Smith Surgical Papyrus is devoted to the assessment and treatment of injuries, such as those that might occur in the course of battle. This has led many commentators to the opinion that it was a manual for military surgeons (Breasted, 1930; Sigerist, 1951; Nunn, 1996), although it is also possible that the cases could have stemmed from industrial (building) accidents. It is unlike the other medical papyri in lacking incantations, magical explanations and specific references to healing deities. This feature makes it more like the empiricorational texts of later antiquity. By contrast, the nearly contemporaneous Ebers Papyrus uses an aggregate of explanatory elements to treat a variety of internal illnesses (Ebbell, 1937). In this regard, it gives a broader sense of ancient Egyptian medical practice. A number of medical papyri from the Ramessid period have survived, including the Berlin Medical Papyrus,

the Carlesberg VIII Papyrus, the Chester Beatty VI Papyrus, and the London Medical Papyrus. These writings treat a number of topics, but only the Berlin Papyrus contains a description of an arguably neurological nature. Sigerist (1951, pp. 298–318) and Nunn (1996, pp. 24–41) provide detailed discussions of the provenances and contents of these medical papyri. Other papyri also contain items of medical interest, though they apply mainly magical treatments and are therefore called magical papyri. For example, the Chester Beatty V and Leiden Papyri offer remedies for headache. James Breasted published a collection of inscriptions in five volumes that contain a number of medical inscriptions, one of which contains a description of a patient who had a stroke (Breasted, 1906–1907). In addition, Herodotus of Halicarnassus, writing in Greek, described Egyptian culture of the 5th-century BCE in the context of the conflict between Greeks and Persians. He contributed brief comments on Egyptian neurology.

EGYPTIAN PHYSICIANS AND SURGEONS Documents and papyri indicate that the Egyptians recognized a distinction between physicians, priests and magicians. Both the Ebers Papyrus and the Smith Papyrus instruct the physician (swnw), or the priest of Sekhmet, on palpating the pulse. The Ebers Papyrus also mentions that a magician might do the same thing (Breasted, 1930, p. 104). Funeral inscriptions tell that, even in the Old Kingdom, Egyptian physicians occupied a hierarchy of official positions, including overseers, inspectors and chiefs (Jonckherre, 1958). Palace physicians were even more stratified. In his 5th century BCE history, Herodotus says that there were Egyptian physicians for the eyes, head, teeth and belly (Herodotus II, 84; see Herodotus, 1920, pp. 368–369). This degree of specialization is borne out by inscriptions that tell of dentists and proctologists (Nunn, 1996, pp. 117–119). Though no descriptions of specialized surgeons have survived, Breasted (1930, pp. 6–9) distinguishes the Egyptian physician who recites recipes for healing potions from the Egyptian surgeon who uses mechanical appliances or processes to treat the injured. The same person might prescribe pharmacological remedies, probe wounds, and recite incantations; even so, Breasted felt it proper to describe the Edwin Smith Papyrus as a surgical document.

MEDICAL PRACTICE IN ANCIENT EGYPT Egyptian physicians of all ranks had access to medical texts, which followed a set formula. In these papyri, the discussion of an illness began with the title, usually naming the major symptom with which the physician must

NEUROLOGY IN ANCIENT EGYPT

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contend. A description of other symptoms followed. The medical writer then gave a verdict, telling whether the physician would treat the condition. Sometimes the verdict contained a prognosis, but often enough this was implied rather than stated. If the physician would contend with the injury or illness, the text would then describe the treatment. Treatment might include drugs, bleeding, prayers, ointments, fumigations and incantations. Egyptian physicians used empirical methods of inspection and palpation in order to arrive at a diagnosis. They tested movement, gait, sensation, sight and hearing. They also asked the patient to make certain movements, observing what the subject could and could not do. No statement of discrete pathophysiological principles has survived, but we know that they compounded their own remedies according to strict prescriptions. Remedies were given orally or rectally. We have no evidence of systematic theories of disease in Ancient Egypt, but the ancient Egyptians recognized the connection between the heart and the blood vessels. They knew that the vessels carried blood and air from one place to another. In similar passages in the Ebers Papyrus and the Berlin Medical Papyrus, medical writers enunciated the principle of wekhedu (whdw), which Steuer (1948) has called a pus-making principle. This material is contained in food and expelled in feces. When it builds up in the body, disease and death result. The physician tested for the presence of whdw by taking the pulse, and used purging and enemas to treat and prevent its accumulation. Closely related to the concept of wekhedu is the treatment of the metu, undefined anatomical structures which include blood vessels, nerves and tendons. The metu can become irritated, stiff, tired, hot, swollen and painful, and Egyptian physicians used a variety of measures to soothe, quiet and refresh them. Of particular importance was to treat the metu by releasing the wekhedu rectally; hence the importance of enemas in ancient Egyptian medicine. For a further discussion of metu, consult Nunn (1996, pp. 44–49) and Sigerist (1951, p. 352).

Papyrus also states that skull fractures produce a softening of the frontal bone as is seen in a child before he matures, showing that the Egyptians were familiar with the anterior fontanelle. For a fuller discussion of Egyptian terms pertinent to the anatomy of the skull, see Nunn (1996, pp. 49–50). Open skull fractures allowed Egyptian surgeons to see the brain, which they called the ais, the marrow or viscera of the skull. They further described hemispheric convolutions, which the Old Kingdom author of the Smith Papyrus compared to the corrugations formed on molten copper. The New Kingdom scribe who copied the papyrus added a comment that the original author meant the slag that the coppersmith removes from copper before pouring molten copper from the crucible into a mold (Breasted, 1930, p. 173). He added that the living brain pulsates. However, as Sigerist (1951, p. 353) points out, the fact that the Egyptians had a word for the brain does not imply that they had a conception of its function. Soldiers, embalmers and cooks knew about brain tissue, but this does not mean that they attached a specific function to it. The Egyptian pharmacopoeia used the brains of animals in compounding remedies, in which circumstance the brain is called amen. However, this word is not found referring to the human brain in health or disease. Thus the ancient Egyptians had two words for the brain, but neither presupposes knowledge of its function (Iversen, 1947). A number of cases in the Edwin Smith Papyrus describe spinal injuries. The papyrus uses the word tjes to refer to the vertebrae, and clearly distinguishes between vertebral fractures and dislocations (Breasted, 1930, p. 328). The Egyptians did not identify the spinal cord as independent of the bony vertebrae, although they did distinguish between skull and brain, but they did describe the consequences of cervical cord injuries. In a patient with an open skull fracture, the Egyptian surgeon describes both nh, spinal fluid, and ntn.h, the meningeal membranes (Breasted, 1930, p. 172).

NEUROANATOMY

Egyptian medical writers observed a number of symptoms that modern physicians recognize as the result of neurological disease. We should not assume that the ancients thought the same about patients with these symptoms as moderns do, but neurologists are interested in the ways in which past physicians looked at such signs as unconsciousness, quadriparesis, hemiparesis and dementia (see Karenberg and Leitz, 2001). Embalming and mummification have left us with rich sources of information on Egyptian material culture, though only the well-to-do could afford these

The Egyptians had words for the skull and some parts. The word djennet denotes the skull in general. The occipital bone is designated by the word ha, and the zygomatic arch is called gema. The parietal bone is called paqyt; Case 7 of the Edwin Smith Papyrus says that if the paqyt is breached, the leathery tepau is seen. Tepau has been variously interpreted as the falx cerebri (Westendorf, 1992), the cranial sutures (Breasted, 1930), or the frontal sinus (Chapman, 1992). The Smith

SYMPTOMS OF NEUROLOGICAL DISEASE

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G.K. YORK AND D.A. STEINBERG

elaborate and expensive practices. Egyptian embalmers were careful to preserve the heart after death, whereas they typically removed and discarded the brain. Such cavalier treatment of the brain suggests that the ancient Egyptians had no real conception of brain function, or of the primacy of the brain in cognition, though certainty on the subject is not possible (Finger, 2000, pp. 15–19). Nevertheless, fragmentary descriptions of unconsciousness, paralysis, and dementia exist. The oldest extant description of medical care is found on the inscription from the tomb of the 5th dynasty vizier and architect Weshptah, dated c. 2455 BCE. According to this inscription, written by the architect’s son, the pharaoh Neferirkare Kakai inspected a new building and praised its beauty to the court. According to Breasted’s translation of the inscription: “His majesty saw him, that [he] heard not” (Breasted, 1906–1907, vol., 1, pp. 111–113). This illness caused great fear among the onlookers, and Weshptah, still alive but not hearing, was brought before the court. Court physicians were present, and the pharaoh called for medical writings to be consulted. The writings indicated a mortal illness, which caused the pharaoh to grieve for his friend. Breasted interpreted this inscription as saying that Weshptah suffered a stroke, and that he “heard not” because of unconsciousness (Breasted, 1930, p. 3; Rowling, 1961). In the Smith Papyrus, a number of causes lead to the inability to speak, denoted by the word dgm-y (Breasted, 1930, pp. 296–297). For example, in patients with facial fractures, the writer attributed speechlessness to the inability to open the mouth because of pain. In a patient with an open fracture of the temporal bone, on the other hand, the patient made no reply because of unconsciousness. Thus, Egyptian surgeons recognized circumstances in which patients were alive, but unconscious from head injury or perhaps stroke. Cervical spinal cord injuries, as might be seen in battle injuries or accidents, lead to quadriplegia, and the Smith Papyrus includes this malady. In a description of traumatic cervical myelopathy, the Old Kingdom author says that the paralyzed person hmy his limbs, meaning not knowing his arms and legs (Breasted, 1930, p. 325). This “not knowing” can also be rendered “unconscious of,” in the sense of “unaware of,” a body part. In other words, Egyptian surgeons observed that a neck injury caused paralysis of the limbs, which they called an unawareness of them. Breasted calls attention to a parallel construction that used the same word to denote “not knowing myself” in a non-medical context. In The Story of Sinuhe, a masterpiece of ancient literature, the Egyptian-born Syrian prince Sinuhe returned to the land of his birth. Ushered into the presence of the pharaoh,

Fig. 3.1. The hieroglyphic words from The Story of Sinuhe that Gardiner translates as “I lost consciousness in his presence,” literally “I did not know myself” (Gardiner, 1916, p. 96).

he faints from fear and excitement. A.H. Gardiner comments that when Sinuhe says he lost consciousness, he literally says “I did not know myself” (Gardiner, 1916, p. 96) (Fig. 3.1). That is, the Egyptian word hmy, meaning not knowing oneself, is used to denote both paralysis and unconsciousness. The eighth case in the Smith Papyrus describes a patient who has been smashed in the temple, yet without an external mark. Palpation of the area reveals swelling, yet the patient is able to walk. The Old Kingdom writer described the patient “shuffling with his sole, on the side of him having that injury of the skull . . .” (Breasted, 1930, pp. 203–204). The New Kingdom commentator, in glossing this text, amplified the description of a shuffling gait by saying that the patient’s sole drags, his foot is feeble, his toes are contracted into the ball of the foot, and they walk fumbling to the ground. This seems to describe hemiparesis, though it is ipsilateral to the injury. After consulting with physicians, Breasted interpreted this passage as showing a contre-coup injury. This line from the Smith Papyrus is one of the bestknown passages of ancient literature. Some observers claim that it shows that the ancient Egyptians understood lateralization, or at least that injury to one side of the brain produced unilateral weakness. Breasted translated the line as saying that the unilateral weakness was ipsilateral to the injury. However, this passage should be read cautiously. There is no evidence that the author of the Smith Papyrus connected weakness or paralysis with the brain in any way, and any assumption to the contrary is speculative. This case also contains the only known disagreement between the Smith Papyrus’s two authors concerning the cause of the physical findings. The original author says that the hemiparesis is due to being smitten by something external, presumably a blow of some sort. In glossing the text, the New Kingdom scribe corrects this impression, saying that the external force is a god or the personification of death. Breasted says that this gloss represents a debate between an empirico-rational surgeon and a physician with magico-religious tendencies (Breasted, 1930, pp. 212–213). The Ebers Papyrus contains a passage translated by Ebbels as stating: “As to perishing of the mind and forgetfulness: it is breath of the activity of the reciting priest that does it; the breath enters into the lung several times, and the mind becomes confused through it.”

NEUROLOGY IN ANCIENT EGYPT 33 Some authors contend that this passage describes however, the patient developed a fever, the surgeon dementia (Boller and Forbes, 1998; Halioua and Ziskind, declared the patient untreatable. 2002). Halioua and Ziskind write that, since breath The Ebers Papyrus is composed of 877 consecutive corrupts the vessels, this passage refers to a vascular paragraphs, which treat a variety of unrelated subjects, dementia. A perishing of the mind could refer to proand evidence suggests that it had a number of difgressive dementia, particularly when tied to forgetfulferent authors. It contains about 900 specific remedies ness, but the accumulation of whdw in the mtw cannot for a variety of conditions, of which 13 are devoted be equated with vascular disease. Hence this interpretato the treatment of headache (Karenberg and Leitz, tion is also speculative. 2001). Paragraph 250 is translated as: “Another [remedy] for suffering in half the head. The skull of a catfish, fried in oil. Anoint the head therewith” PALEOPATHOLOGY OF THE NERVOUS (Ebbell, 1937). SYSTEM It is hard to avoid interpreting this description of Modern investigators have found evidence of neurologisuffering in half the head, or meret in the ges-tep, as cal disease in surviving texts, inscriptions, paintings, migraine. The writer does not elaborate on any migraisculptures, and human remains. Some of this evidence nous accompaniments, so that the diagnosis remains is highly ambiguous, but other parts are convincuncertain. In the Beatty V Papyrus, a “spitting mouth” ing. Head and neck injuries and their complications have sign appears in conjunction with the sign for headache, not changed much since the ancient Egyptians described which Karenberg and Leitz (2001, pp. 912–913) state is the consequences of being smashed in the head. A search possibly a migrainous accompaniment. Temporal headfor headache remedies has occupied physicians since antiaches associated with eye disease appear in the Ebers quity. We can find suggestions of stroke, epilepsy and Papyrus, and pain in the back of the head associated poliomyelitis in ancient Egyptian sources. Modern diagwith head injury appears in the Smith Papyrus. noses of these illnesses differ markedly from ancient The direct application of a remedy to the painful diagnoses, but the recognition that they require treatment area is a time-honored, though often unsuccessful, connects ancient and modern healers. remedy for headache. Furthermore, Egyptian treatThe Edwin Smith Papyrus gives a convincing ments for headache show the inextricable intertwining description of closed head injury with hemiparesis. of what modern physicians would consider magical, The Old Kingdom surgeon describes a smash on the religious, and rational approaches. For example, in side of the head with nothing but swelling at the site, the Leiden Papyrus, severe head pain is treated by both associated with skew deviation of the eyes and ipsilatincantations and prayers (Karenberg and Leitz, 2001, eral hemiparesis (Breasted, 1930, pp. 201–212). He also pp. 913–914). This conflation of elements makes little describes a patient with traumatic cervical myelopathy, sense to modern neurologists, but it epitomizes Egypin whom a cervical dislocation produces quadriparesis, tian medicine. involuntary erection, urinary incontinence, abdominal After the conquest of Egypt by Persia in 525 BCE, the distension, and conjunctival injection. Injury to a difPersian emperor Cambyses II became pharaoh of Egypt. ferent part of the neck produces seminal emission The Greek historian Herodotus, writing almost a century rather than urinary incontinence (Breasted, 1930, later, compared Cambyses’s cruel reign with the more pp. 323–332). benevolent regime of his father. He wrote, “. . . for The complications of head and neck injuries, partiindeed he is said to have been afflicted from his birth cularly open fractures, were usually fatal in the prewith that grievous disease which some call sacred. It is antibiotic era, and the Smith Papyrus describes two no unlikely thing then that when his soma was grievously feared complications. Case 3 described neck stiffness affected his phrenes too should be diseased” (Herodotus in a patient with a gaping wound of the head with perIII, 33; see Herodotus, 1921, pp. 42–45). Though Camforation of the skull (Breasted, 1930, pp. 125–131). Such byses was Persian, not Egyptian, and the description is open wounds invite meningitis, should the patient in Greek, commentators often characterize this passage survive the initial injury. In Case 7, a patient with an as depicting epilepsy in Ancient Egypt (Temkin, 1971; open skull fracture penetrating the bone and separating York and Steinberg, 2001). the sutures is described as having “the cord of his The Berlin Papyrus is a compendium of mathematimandible” contracted, and shuddering exceedingly. cal and medical knowledge, and the medical section Most commentators believe that this case describes closely parallels some sections of the Papyrus Ebers. tetanus, which the Egyptian surgeon undertook to treat One paragraph gives a recipe for “fumigation for drivby applying hot objects to the mandible, in order to ing out a taking of one side of his face and the corner relax the muscle (Breasted, 1930, pp. 175–182). If, of his mouth.” Two commentators have interpreted this

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as Bell’s palsy (Westendorf, 1992; Nunn, 1996, p. 92). The Egyptian words are not found in uniquely medical contexts, but rather are words in common use and are appropriated for medical use. The Ebers Papyrus contains a description of a patient who “suffers in his shoulders and his fingers tremble” (Ebbell, 1937). Modern scholars view this as a description of Parkinson’s disease (Alamovitch and Danziger, 1995; Halioua and Ziskind, 2002). These same investigators contend that the tremor is caused by a pathogenic substance called setet, which travels through the vessels and can be driven out by a particular remedy. Again, the description could be of Parkinson’s disease, though this is not at all certain, and the ancient Egyptians made no connection between any pathogenic substance and tremor, parkinsonian or otherwise. As mentioned above, most commentators interpret the illness of the 5th dynasty vizier Weshptah as stroke, because he was abruptly affected by an illness that caused him not to hear the pharaoh’s words of praise. With no other evidence than a single sentence in a worn inscription that is over 4500 years old, this interpretation is necessarily unverifiable. Being suddenly afflicted with an illness that renders the patient insensible, yet still alive, does suggest some type of stroke, but beyond this the inscription is silent. Nunn (1996, p. 77) describes a funerary stela from the 18th or 19th dynasty in which the subject, a man named Roma, is depicted with a withered leg and an equinus deformity of the foot. In the relief carving, the man with the wasted leg carries a staff, which Nunn says is to be used as a cane (Fig. 3.2). Since the leg is grossly shortened, Nunn joins other commentators in saying that Roma had been afflicted with poliomyelitis in his early childhood. Others have claimed that this stela depicts congenital clubfoot, which causes shortened limb length more often than does poliomyelitis. In addition, a recent examination of the mummified remains of Siptah, a pharaoh of the 19th dynasty, who ruled from 1194 BCE to 1188 BCE, found a deformed left foot, which is attributed to polio (Callender, 2006). In studying the skeletal remains of ancient Egyptians, modern investigators have found evidence of bony erosion and exostosis of the skull, which are characteristics of an underlying meningioma (Hussein, 1949–1950; Pahl et al., 1987). We have no documentary or physical evidence that ancient Egyptian physicians recognized or treated meningiomas, and incidental meningiomas in healthy adults are a common finding. Derry described the skull of an Egyptian man with an orbito-frontal circumference of 66 cm, well above the 99th percentile for adults (Derry, 1912–1913). This

Fig. 3.2. The early New Kingdom stela of the gatekeeper Roma, showing him with a wasted and shortened right leg. Item AEIN 134. Ny Carlsberg Glyptotek, Copenhagen. Photographed by Ole Haupt.

indicates the presence of macrocephaly. Derry interpreted this as a sign of compensated hydrocephalus, since the patient would have developed the skeletal abnormality during childhood yet lived to the age of 30 years. The findings, however, are equally consistent with benign macrocephaly, which has many causes, and no brain tissue remains by which to differentiate the two conditions. Observers have attempted to discern the presence of pathology in the subjects of ancient statuary, under the assumption that these figures accurately reproduce the features of the individual being honored. For example, one group of investigators examined two statues of Akhenaten, pharaoh from 1378 BCE to 1362 BCE (Cattaino and Vicario, 1999). These portray Akhenaten as having a narrow face, hollow cheeks, lowered eyelids and an open mouth. His body is shown with a long, thin neck, gynecomastia, a protuberant abdomen and thin forelegs. They interpreted these images as showing myotonic dystrophy. There is no clear evidence that these statues aimed to be naturalistic portrayals of Akhenaten, and most commentators now believe the representations were an artistic convention of the Amarna Age (see Redford, 1984; Aldred, 1988). Another group examined mummy portraits that were painted during the Roman Era in northern Egypt and correlated them with the skulls of the individuals portrayed (Appenzeller et al., 2001). They found one young man with both facial and bony features of

NEUROLOGY IN ANCIENT EGYPT progressive facial hemiatrophy. They also found evidence of skew deviation of the eyes and papillary abnormalities in the portraits, though they did not find any associated bony abnormalities. Assuming that these diagnoses are correct, and that the individuals had other symptoms associated with the primary conditions, they claimed that they also had focal epilepsy, hemiplegic migraine, and autonomic dysfunction. No corroboration from other sources was provided.

COMMENTARY ON THE SIGNIFICANCE OF NEUROLOGY IN ANCIENT EGYPT Signs and symptoms of neurological disease can be found in ancient texts and sources, including those of Ancient Egypt. However, we have only an unclear understanding of how Egyptian physicians themselves organized their observations. Even if our sampling of sources and our translations of the ancient Egyptian language are accurate, our study of ancient Egyptian neurology is colored by modern medical concepts. This leaves ancient Egyptian medicine, as conceived by the Egyptians themselves, cloaked in uncertainty. We also have evidence that Egyptian physicians and surgeons practiced a recognizable form of medicine that had some empirical and rational basis. However, we have no indication that these ancient practitioners attributed any function to nervous tissue, nor that they connected pathology of the nervous system with anything they saw in their patients. Therefore, we cannot say that the ancient Egyptians had any meaningful neurology. At the same time, modern physicians feel a strong connection to physicians in the past and can plausibly claim to be filling a similar role in society. It is natural to identify with past physicians, even those in antiquity, as a justification for the importance of medicine. Modern specialists are especially attracted to Ancient Egypt, with its own specialization and strict ranks of social order for various physicians, but it would be wrong to read too much into Egyptian medical practices. We know little of their theories, values or perspectives, and our knowledge of their medicine is so fragmentary that we dare not assert a certain understanding of it.

REFERENCES Alamovitch S, Danziger N (1995). Neurologie. EstemMedline, Paris. Aldred C (1988). Akhenaten: King of Egypt. Thames and Hudson, London. Appenzeller A, Stevens JM, Kruszynski R, et al. (2001). Neurology in ancient faces. J Neurol Neurosurg Psychiatry 70: 524–529.

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Boller F, Forbes MM (1998). History of dementia and dementia in history: an overview. J Neurol Sci 158: 125–133. Breasted JH (1906–1907). Ancient Records of Egypt; Historical Documents from the Earliest Times to the Persian Conquest, Collected, Edited and Translated with Commentary by James Henry Breasted. University of Chicago Press, Chicago, IL. Breasted JH (1930). The Edwin Smith Surgical Papyrus: Published in Facsimile and Hieroglyphic Transliteration with Translation and Commentary in Two Volumes. University of Chicago Press, Chicago, IL. Callender G (2006). The cripple, the queen and the man from the north. KMT 17: 49–63. Cattaino G, Vicario L (1999). Myotonic dystrophy in ancient Egypt. Eur Neurol 41: 59–63. Chapman PH (1992). Case seven of the Smith Surgical Papyrus: the meaning of tpÅw. J Amer Research Centre Egypt 29: 35–42. Derry DE (1912–1913). A case of hydrocephalus in an Egyptian of the Roman period. J Anat Physiol (London) 47: 436–457. Ebbell B (1937). The Papyrus Ebers. The Greatest Egyptian Medical Document. Levin & Munksgaard, Copenhagen. Finger S (2000). Minds behind the Brain. A History of the Pioneers and their Discoveries. Oxford University Press, Oxford. Gardiner AH (1916). Notes on the Story of Sinuhe. Librairie Honore´ Champion, Paris. Halioua B, Ziskind B (2002). Me´dicine au temps des Pharaohs. E´ditions Liana Levi, Paris. Translated by DeBevoise MD (2005). Medicine in the Days of the Pharaohs. Belknap Press of Harvard University Press, Cambridge, MA. Herodotus (1920). Herodotus, Books I–II, with an English translation by A.D. Godley. Harvard University Press, Cambridge, MA. Herodotus (1921). Herodotus, Books III–IV, with an English translation by A.D. Godley. Harvard University Press, Cambridge, MA. Hussein MK (1949–1950). Quelques specimens de pathologie osseuse chez les anciens E´gyptiens. Bulletin de l’Institut d’E´gypte 32: 11–17. Iversen E (1947). Some remarks on the terms “mm” and “ais.” J Egypt Archaeol 33: 47–51. Jonckherre F (1958). Les Me´decins de l’E´gypte Pharaonique; Essai de Prosopographie. Fondation E´gyptologique Reine Elisabeth, Brussels. Karenberg A, Leitz C (2001). Headache in magical and medical papyri of ancient Egypt. Cephalalgia 21: 911–916. Nunn JF (1996). Ancient Egyptian Medicine. University of Oklahoma Press, Norman, OK. Pahl WM, Asaad E, Khattar NY, et al. (1987). Macroscopic and radiological aspects of tumors of the skull in Ancient Egyptians – Part 1. Human Evolution 2: 329–363. Redford DB (1984). Akhenaten, the Heretic king. Princeton University Press, Princeton, NJ.

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Rowling JT (1961). Pathological changes in mummies. Proc R Soc Med 54: 409–415. Sigerist H (1951). A History of Medicine. Volume 1. Primitive and Archaic Medicine. Oxford University Press, Oxford. Steinberg DA (2002). Limits of historical and scientific knowledge. J Hist Neurosci 11: 49–54. Steuer RO (1948). Whdw. Aetiological principle of pyaemia in Ancient Egyptian medicine. Bull Hist Med Suppl 10: 1–34.

Temkin O (1971). The Falling Sickness. Second edition, revised. Johns Hopkins University Press, Baltimore, MD. Westendorf W (1992). Erwachen der Heilkunst: die Medizin ¨ gypten. Artemis und Winkler, Zu¨rich. in Alten A York GK (2002). Getting started: objectives and justifications in the history of neurology. J Hist Neurosci 11: 63–66. York GK, Steinberg DA (2001). The sacred disease of Cambyses II. Arch Neurol 58: 1702–1704.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 4

Neurology in the Bible and the Talmud MOSHE FEINSOD * Faculty of Medicine, The Technion – Israel Institute of Technology, Haifa, Israel

INTRODUCTION The Bible (The Hebrew Bible; Old Testament; Tanach) and the Talmud are the canonized writings of the historical, religious and cultural creations of the Jewish people, assembled over many generations from, roughly, the 14th century BCE to the 6th century CE on a continuum. It is evident, however, that during this process many other manuscripts and scriptures were excluded, and most of them lost. The Bible is the most essential foundation of the Jewish religion, cultural heritage and national identity, as well as one of the cornerstones of Western civilization. This is the major reason for the continued interest, scrutiny and research associated with it. The first attempts at a systematic study of the medicine in the Bible (Old and New Testaments) were awakened by the Reformation (Bartholin, 1672). But it was only in the second half of the 19th century CE that scholars, especially in Germany, established a scientific approach to the study of the Bible and the Talmud, recognizing the continuity of these two creations. The study of medicine in these old texts was but one aspect of this flourishing discipline. Dr. Julius Preuss (1861–1913), a physician well versed in the Jewish Holy Scriptures, as well as in Semitic and classic languages, published in 1911 his magnum opus – Biblisch-Talmudische Medizin (Preuss, 1978), which is still the authoritative work on the subject. Fred Rosner (1978) edited and translated this book into English in 1978. Since then, many scholars have unraveled more bits of information and had new insights. The present chapter will deal with the neurological observations and many related insights found in the Bible and the Talmud.

NEUROLOGY IN THE BIBLE Two main processes are to be recognized in the formation of the Bible. The first is evolutionary. Until reaching *

its final form and being “sealed” and canonized by a rabbinical committee on the eve of the 2nd century CE, this heritage, in the form of rules, histories, poetry and exalted prophecies, underwent a process of transmission from one generation to another in verbal versions, and only later in written forms. We have evidence of different versions and approaches coexisting. The second process is that of omission. From the Talmud and the Bible itself, we may learn of books that, for one reason or another (theological as well as political), were omitted from the canonized and later sanctified final form. Most of these books were lost and only a few from the Hellenistic period survived either in Hebrew (e.g., the Dead Sea Scrolls) or in Greek translations under the collective name The External Books or Apocryphes (e.g., the Book of the Maccabeans). The Biblical style may pose difficulties. In his classical book, Mimesis, Auerbach (1953) stresses the laconic account of the Biblical story and the externalization of only so much of the phenomena as is necessary for the purpose of the narrative, all else left in obscurity; the decisive points of the narrative alone are emphasized, and call for interpretation that is completely antagonistic to the lengthy and detailed Homeric style. Many dramatic events are recounted in no more than two to three sentences. Researchers, especially physicians who try to dig out details, and to reconstruct a clinical situation from these fragments, may find themselves tempted to depend on unfounded interpretations and possibly to be carried beyond the factual sphere. The language also may pose major problems. Hebrew was spoken and developed for over a millennium, but it became a dormant language for nearly two millennia. During the last century it has been revived, albeit sometimes at the expense of an arbitrary translocation of a word or term from a deep layer into a new significance. Research and opinions that are based on translations,

Correspondence to: Moshe Feinsod MD, Faculty of Medicine, The Technion – Israel Institute of Technology, Efron Street, Haifa 31096, Israel. E-mail: [email protected], Tel: +972-522-378-798, Fax: +972-4-8264105.

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especially from other translations, should be regarded with caution. Even if Hebrew is one’s first language, and the landscapes of the Bible are one’s daily surroundings, there is still a challenge in attempting an unbiased examination. The Bible has been translated into every language, and sometimes there are several versions of the same language. It was elected here to refer to the most popular English translation – The Authorized King James Version. The Bible, especially in its historical chapters, is dotted with many accounts of bodily injuries during battles, skirmishes, murder, or slayings during coups d’etats. But in most instances, the report is limited to “and he pierced him and he died,” sometimes with elusive identification of the injured organs. Diseases are mentioned, but again in vague terms. Treatment of wounds was known, as is evident from the prophet’s lament “From the sole of the foot even unto the head there is no soundness in it; but wounds, and bruises, and putrefying sores: they have not been closed, neither bound up, neither mollified with ointment” (Isaiah 1:6). But in no case is there a description of even an attempt to treat the injury. Physicians are mentioned only twice – as embalmers in Genesis 50:2 and in an unspecified form in Jeremiah 8:22: “Is there no balm in Gilead; is there no physician there . . . ?” Indeed, all of the penetrating injuries resulted in death, without any instance of recovery and without any report of an attempted treatment. Instances of recovery from disease are mentioned, but the cure was heavenly intervention. As the region of today’s Israel was under Egyptian influence in early Biblical times, it is plausible to assume that this was reflected in the medical concepts and treatments, although no hard evidence is available.

Peripheral nerve injury The first injury of neurological nature is described in Genesis 32:24–33. And Jacob was left alone; and there wrestled a man with him until the breaking of the day. And when he saw that he prevailed not against him, he touched the hollow of his thigh; and the hollow of Jacob’s thigh was out of joint, as he wrestled with him. And he said, Thy name shall be called no more Jacob, but Israel: for as a prince hast thou power with God and with men, and hast prevailed. And as he passed over Penuel the sun rose upon him, and he halted upon his thigh. Therefore the children of Israel eat not of the sinew (Gid Ha-Nashe) which

shrank, which is upon the hollow of the thigh, unto this day: because he touched the hollow of Jacob’s thigh in the sinew that shrank. Hoenig (1977), in a thorough discussion based on medical considerations and traditional Jewish commentaries, concluded that Jacob appears to have sustained neurological injury to his sciatic nerve, as well as musculoskeletal damage to his hip. These injuries caused a temporary limping gait. Jacob probably sustained a neurapraxia of the sciatic nerve. The differential diagnosis of his musculoskeletal hip injury includes hip dislocation, fracture, soft tissue trauma, and articular pathology. The identification of Gid Ha-Nashe with the sciatic nerve seems sound. In Arabic, the sciatic nerve is called Irq el-nashe. The Talmud provides specific instructions for the removal of the sciatic nerve from the flesh of slaughtered animals, as instructed in Genesis 32:32.

Head injuries Head injuries were regarded in antiquity and for many centuries afterward as a grave event that sooner or later turned out to be fatal. It is only in the last two centuries that the subject emerged as a formidable clinical and scientific challenge, and the prognosis was entirely changed only in the last decades. The three head injuries recounted in the Bible occurred in the 12–10th centuries BCE, but continue to excite the free imagination, as well as the disciplined examination of the reader. The first description of a head injury is reported in Judges (4:21–22; 5:26–27). The defeated fugitive Canaanite general Sisera accepts the shelter offered by Jael the Kenite, and after he falls asleep in his exhaustion she strikes a tent nail into his temple with a hammer. Then Jael Heber’s wife took a nail of the tent, and took an hammer in her hand, and went softly unto him, and smote the nail into his temples, and fastened it into the ground: for he was fast asleep and weary. So he died . . . Sisera lay dead, and the nail was in his temples . . . she smote off his head, when she had pierced and stricken through his temples. For the post-Biblical reader (in English, as well as in Hebrew medical terms, since the Middle Ages) the temple, or raqqah in Hebrew, is the flat part of the head between the forehead and the ear, or the squama of the temporal bone. The identification of the temple with the raqqah is the accepted view in the vast majority of translations of the Bible, as well as in the famous etching by Rembrandt. They all refer to the temples, ignoring the Hebrew Biblical text in which the word is expressed in its singular form.

NEUROLOGY IN THE BIBLE AND THE TALMUD 39 According to Rozelaar (1988), who based his arguAnd if so be that the king’s wrath arise, and he ment on the praise of the beloved girl from the Song say unto thee, Wherefore approached ye so nigh of Songs (4:3) – “Thy temples are like a piece of a unto the city when ye did fight? Knew ye not that pomegranate within thy locks” – the Biblical raqqah they would shoot from the wall? Who smote Abiis the open mouth, because in the temple there is no melech the son of Jerubbesheth? Did not a resemblance to a piece of pomegranate, which is wet woman cast a piece of a millstone upon him from and red, while the open mouth satisfies the demands the wall, that he died in Thebez? Why went ye of the erotic song. If so, the tent’s nail went into nigh the wall? Sisera’s open mouth and killed him by injuring the The third case, and the most famous, of head injuries in lower medulla and upper spinal cord through the now the Bible is the story of David and Goliath (Samuel I, popular trans-oral approach to the craniovertebral junc17:49–51): tion. If we look into The Antiquities of the Jews by Josephus Flavius (1900), we find that the accepted renAnd David put his hand in his bag, and took dering in the first century CE was that “while he was thence a stone, and smote the Philistine in his asleep, Jael drove with a hammer an iron pin through forehead, that the stone sunk into his forehead; his mouth and cheek and pierced the ground.” and he fell upon his face to the earth. So David The second reported head injury occurred while prevailed over the Philistine with a sling and Abimelech and his army were besieging, during a tribal with a stone . . . Therefore David ran, and stood feud, the strong tower of the city of Thebez (Judges upon the Philistine, and took his sword . . . and 9:50–54): slew him and cut off his head therewith . . . And a certain woman cast a piece of a millstone upon Abimelech’s head, and all to break his skull. Then he called hastily unto the young man his armour bearer and said unto him. Draw thy sword, and slay me, that men say not of me, A woman slew him . . . After taking the lower city, Abimelech approaches close to the gate of Thebez’s tower to set it on fire, but the fragment of the upper millstone thrown from above crushes his skull. He remains conscious with enough mental power to judge the implications of death by a woman on his reputation. Still, he knows that his condition is hopeless, and therefore he asks to be slain by his armor bearer. This comprehension seems well founded. As implied from the Edwin Smith Papyrus of the 16th century BCE (Sigerist, 1951), as well as from the writings of the famous French Renaissance surgeon Ambroise Pare´ (1951), there was practically no change in the fatalistic attitude toward severe cranial injuries over this long expanse of time. In these two documents, there are descriptions of head injured people who are conscious and without motor deficits, but nevertheless succumb to what most likely is meningitis. It is implied in the Mishnah (2nd century CE) that a tear in the meninges will lead to inevitable death, whereas a traumatic skull defect per se may be compatible with life. Yadin (1963) pointed out that the military lesson from Abimelech’s injury became part of the official military practice even 200 years later, as implied from the fear of King David’s generals:

According to the Biblical story, the stone sank into Goliath’s forehead. But in Jonathan’s Aramic translation, the “stone sank through the orbit.” The “interpreter” Rabbi, David Kimchi, explains that the stone could go into Goliath’s head only because of entering at an angle below the helmet. This kind of fronto-basal penetrating head injury occurs even nowadays, in spite of protective helmets. Like Abimelech, Goliath does not die immediately, but David ensures his death by beheading him. It seems that the idea of a heavily-armored Philistine giant conquered by a youth armed with a sling inspired the artists (Michelangelo, Donatello, Rembrandt, etc.) but was difficult for certain others to accept. Hence, a “medical” explanation was sought. In 1983, the Rabins hypothesized that Goliath harbored multiple endocrinological neoplasia Type 1 (Rabin and Rabin, 1983). Pituitary macroadenoma produces acromegaly and gigantism, together with visual field defects. The latter enabled David to approach the giant. These authors placed a pancreatic tumor in Goliath’s abdomen, but could not decide whether it excreted gastrin or insulin. Other authors also gave Goliath, seriously and even “undoubtedly,” macroadenoma, which not only made him acromegalic with defective visual fields, but also caused nearly every possible complication (Shapiro and Mintz, 1990; Sprecher, 1990). Be it hypoglycemia or hyperacidity, it seems that Goliath was unable to be at his best on that fateful morning. The aforementioned learned explanations leave us with important unanswered questions, since acromegalics (not giants) suffer from myopathy and muscle

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weakness, and since, according to the Bible, Goliath was but one of several Philistine giants. Was the Philistine condition so desperate that the only one they could send to the crucial battle as their representative was such an endocrinological and visual cripple? It may be of interest to note that neurosurgeon Harvey Cushing, in a letter to medical historian Fielding Garrison dated 29 June 1925, questioned whether the son of the family of giants (Samuel II 21:20) to which Goliath belonged was, in fact, acromegalic, because, according to his experience, men with this condition do not procreate. As for David, being inexperienced in armor and heavy weaponry, he chose the sling, with which he was accustomed. This was a thoughtful decision, as the sling was used in regular armies to hit the enemy and cause disorder in his lines, even before the actual clash. In the Assyrian army, as depicted in the relief of Sancheriv’s siege of Lachish (British Museum), the slingers are positioned even behind the archers, because their range was the most distant. A sling’s stones can cause serious injuries, and the sling is even used nowadays in civil riots (Yadin, 1963). Those who theorized various diseases in Goliath might not have appreciated that an accomplished warrior could sling a smooth stone some 80–100 m with good accuracy. As mentioned in Judges (20:16), “every one could sling stones at a hair breadth, and not miss.” A stone injury from a sling could be serious and possibly lethal, even to a soldier without a rare endocrinological disorder (Yadin, 1963; Feinsod, 1997). A deadly atlanto-occipital injury is reported in Samuel I 4. Eli, the 98-year-old heavy and blind grand priest, waited for the report of a battle between the Philistines and the Israelites, one into which his two sons took the sacred ark of God. He sustained the disastrous news about the defeat and the death of his sons but, “when he made mention of the ark of God, that he fell from off the seat backward by the side of the gate, and his neck broke, and he died: for he was an old man, and heavy” (Samuel I 4:18). The translation belittles the accuracy of the original. The Hebrew text specifies that the fall caused a fracture of the atlanto-occipital joint, for which Hebrew has a specific term, mafreket, which contains as its root, perek (a joint). The Talmud deals with spinal injuries in a more detailed form.

Hand dominance Hand dominance is referred to twice in two instances that occurred in the Tribe of Benjamin, though hundreds of years apart. The first (Judges 3: 12–30) concerns the

slaying of Eglon, the Moabite King that the children of Israel had to serve, by “Ehud the son of Gera, a Benjamite, a man left handed; And Ehud put forth his left hand, and took the dagger from his right thigh, and thrust it into his belly.” The king’s guardsmen searched for arms on one side only, relying on the assumption that all people are right handed. Ehud could, thus, conceal his dagger to be used by his able left hand. Many generations later, the Tribe of Benjamin was engaged in a bitter war against the rest of the Israelites. The initial victories of the Benjamites were due to their elite fighters: Among all this people there were seven hundred chosen men left handed; every one could sling stones at an hair breadth, and not miss. (Judges 20:16) We have no clue to explore whether left-handedness was prevalent in this particular small tribe and whether there were some familial traits. The phenomenon is not mentioned anywhere else in the Bible. It should be noted that the Septuagint (the ancient translation of the Bible into Greek) and the Vulgate (the translation of the Bible into Latin by the Catholic Church) explained that these warriors were amphoterodexioi and could fight equally with both hands (ita sinistra ut dextra proeliantes). In modern terms, they were ambidextrous. The Talmud also mentions left-handedness, but in another context.

The association between right hand paralysis and loss of speech The agony of the exiles from Judea on the rivers of Babylon, after the destruction of the Temple and Jerusalem (586 BCE), are expressed in Psalms 137. In this chapter we find: If I forget thee O Jerusalem let my right hand lose its cunning. If I do not remember thee let my tongue cleave to the roof of my mouth; if I prefer not Jerusalem above my chief joy. (Psalms 137:5,6) Halpern taught that this oath, said at every Jewish wedding at the pinnacle of the ceremony, is a reflection of the common observation that people suffering paralysis of the right arm typically are unable to speak (Halpern, personal communication). Benton (1971) followed in a paper stating that this is a Biblical description of motor aphasia and right hemiplegia. The poet of the psalm had little knowledge of the brain dysfunction behind the affliction, but for the modern reader it may be a far call from the ancient history of aphasia and stroke.

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Epilepsy

NEUROLOGY IN THE TALMUD

Several scholars have claimed that there are a few epileptic episodes depicted in the Bible. Oddly, all happen to involve prophets. There are several instances where a person fell on his face during an epiphany, prophecy, or while getting a message from God (cf. Abraham, Moses, Bileam). It has been argued by some that they were epileptics or, at least, had an epileptic episode. Nevertheless, Kottek (1988) rightfully points out that one cannot assume that the phrase falling on the face signifies epilepsy. This expression could reflect an unsuccessful attempt to translate a Hebrew idiom – one signifying humility before a superior while bowing. Indeed, it also appears in the Bible in several nonreligious instances. King Saul “fell down naked a whole day and a whole night” (Samuel I 19:24), while joining a group of prophets. In an episode that seems like mass hysteria, King Saul was likely experiencing extreme ecstasy, and not status epilepticus (Rosner, 1975; Preuss, 1978). Additionally, we read that the prophet Bileam was “falling into a trance, but having his eyes open” (Numbers 24:4,15). The words “into a trance” actually do not appear in the Bible; the phrase is an addition by the translators. Thus, it is also difficult to accept Bileam as an epileptic prophet. Other assumptions, such as falling under the influence of drugs, can be accepted with just as much certainty (Kottek, 1988). Common to all of the above-mentioned episodes is the act of falling, which may fit with the ancient concept of “the falling sickness.” Yet the Talmud uses a different term, either because of the evolution of the Hebrew or because of the development of a different concept of this disease. In a scholarly but short article, Altschuler (2002) claims that the prophet Ezekiel had temporal lobe epilepsy. His analysis of the book brings out all that he thinks are the necessary ingredients for this diagnosis – extreme religiosity coupled with aggressive and pedantic prophecies, concern with the minute details of the temple, repetitive hypergraphia, and criticism of women’s sexual behavior, multiple fainting spells, and sticky personality. His diagnosis is open to debate. Several assumptions seem to be quite subjective, but the subject certainly deserves further study (Ross, 1978). Since Preuss, there have been many attempts to identify psychiatric and medical diagnoses from hints in the Bible. Although such speculations go beyond the scope of this review, more can be gleaned about neurological problems from the Talmud.

Whereas the Bible is an assembly of ancient Jewish law, historical heritage, prophecies, literature and poetry that were concluded at the eve of the 2nd century CE, the Talmud is the record of oral rabbinic discussions of Jewish law, ethics, customs and history that developed at a later period. It is comprised of two components that are historically separate, the Mishnah and the Gemara. The Mishnah is the first written assembly of Jewish law, which is an interpretation and expansion of the Biblical statement laws. The rabbinical opinions, debates and discussions that were held for about four centuries were assembled, edited, and “sealed” around 200 CE by Rabbi Yehuda the President (of the Sanhedrin – the supreme assembly of rabbinical sages) in Tiberias. The Mishnah is made of six parts and attempts to cover all the aspects of religious and mundane life from as many points of view as possible; its style is very accurate and concise. The ever changing complexities of life, together with the establishment of Jewish academic traditions, brought the rabbis of Palestine and Babylon to reinterpret the implications of the laws. Following the reduction of the Mishnah, they analyzed, elucidated and discussed that work, and investigated the legal implications of every statement on every aspect of life. Each statement is accurately defined and compared with other, even remote, statements, and analyzed in a dialectical exchange between two or several disputants. Many of these definitions are based on acute observation of medical or physiological phenomena. For example, the definition of dawn, for the practice of the matinee prayer, is based on recognizing the transition from rod to cone vision. “Just when one can discern between white and pale blue, between a wolf and a dog” (B.T. Brachot 9b, see below). In fact, two Talmuds were assembled. One was by the sages of the dwindling Jewish population of Northern Palestine, and it was edited and “sealed” around 400 CE as the Jerusalem Talmud. The other was the product of many schools of the thriving Jewish population of Mesopotamia, and it is a much bigger volume. It was edited and “sealed” toward the end of the 6th century CE under the name Babylonian Talmud (B.T.). It continues to be the basic legal source of the traditional Jewish culture. As for Jewish law and thinking, the Bible, the Mishnah and the Gemara are historically and conceptually on a single continuum. The Mishnah is made of six “orders,” each containing 7–12 tractates. Each tractate deals with a certain subject and its legal and rational ramifications. The Gemara is logically built and printed (in a fixed order)

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around the Mishnah. The major part of the Gemara is a legal analysis. This starts with a legal statement made in the Mishnah, which is then compared with other statements and thoroughly analyzed and accurately defined – thus building a legal system that covers every aspect of life. The quotations from the Mishnah are marked traditionally by the name of the tractate and the sentence number, while those from the Talmud (Babylonian Talmud) are identified by the name of the tractate, the leaf number, and its side (a or b); see Fig. 4.1. During most of the Mishnaic and Talmudic eras, Eretz-Israel (Palestine), Egypt and Mesopotamia (Babylon), i.e., the three major Jewish concentrations, were under Roman and Byzantine control. The dominating culture of these powers was Hellenistic, with its major cultural centers in Alexandria, Rome, and later Constantinople. The rabbinical attitude toward the study of Greek culture is ambiguous. On one hand, there is rejection (B.T. Baba Kamma 82b) but, on the

other hand, there is permission to study “Greek wisdom” when it is neither day nor night (B.T. Menahoth 99b). In fact, the Mishnah and the Talmud are dotted with stories of discourses between Rabbis and a legendary forum, “the Sages of Athens;” people were even allowed to enjoy Homer (who is mentioned by name). Many Greek words and terms in scientific, medical, agricultural, and political affairs were incorporated into Hebrew, and many Jews in Alexandria and Palestine adopted Greek names. Some probably even attended Hellenic medical schools. Galen, who visited Palestine in 166 CE, criticized the Jewish physicians for their adherence to the laws of Moses rather than to Plato. He also mentioned the Jewish physician, Rufus of Samaria, possessor of a valuable library (Geller, 2003). The earliest surviving Hebrew medical treatise, the Book of Assaph Harophe (Assaph the Physician), makes extensive use of Hippocratic and Galenic concepts and materials (Muntner, 1951; Ross, 1978; Rosner, 1993). If there were other

Fig. 4.1. A typical Babylonian Talmud page. At the center is the Mishnah statement surrounded by the Gemara comments.

NEUROLOGY IN THE BIBLE AND THE TALMUD works or treatise written in Hebrew or by Jewish physicians, they were not canonized and thus lost. It should be remembered that the Talmud is not a medical book. Yet it reflects, even if unintentionally, amazing medical knowledge in subjects that have bearing on the legal system that encompassed every aspect of life, as elaborated and discussed over generations. A major part of the medical knowledge stems from the strict observance of the religious dietary restrictions, which required anatomical and pathological dissections after the ritual slaughter. Rabbi Rav recounts that he had stayed for 18 months with the shepherds and herdsmen to learn which afflictions cause permanent damage and which are transient and followed by recovery (Sanhedrin 5). The richness of Hebrew anatomical vocabulary would induce the Renaissance anatomist Vesalius to use it in his famous anatomical plates of 1543. During the later Talmudic era, the Persian kingdom, rising again in the North, clashed with the Byzantine Empire. Despite the stream of Greek scholars fleeing to Persia and translating texts on medicine and other sciences into Pahlavi, Persian medicine never got far beyond the stage of magic spells, and there are no signs of Hellenistic or Indian-Aryan developed medicine and surgery (Garrison, 1933). In contrast, the passages in the Talmud that refer to demons and the use of incantations, charms, amulets and weird concoctions (B.T. Gittin) may reflect the Persian influence. The use of these magical and seemingly illogical treatments by medical persons may explain the ambivalence of the Talmud toward the medical profession. On the one hand, it honors the grand Rabbis that practiced medicine, but, on the other hand, it states: “The best of physicians to [will inherit] Hell” (Aminoff, 1998). It was only after the Arab invasion in 638 CE that medicine flourished in Persia and Central Asia, and became a forerunner of “Islamic Medicine,” in which Jewish physicians played a substantial role.

The brain After being asked a not so clever question by a student, Rabbi Yehuda the President (2nd century CE), reacted: “I assume that he does not have a brain in his head” (Yevamoth 71:9 and later in B.T. Nashim 9a). The Talmud brought up and used this slighting remark to initiate a lengthy discussion concerning the ethics of teacher–student relationships, and the respectful and warm attitude that students deserve. From a neurological point of view, one is tempted to think that this unique passage is a distant reflection of the contemporaneous Galenic concept of the brain as the seat of the rational soul (Ross, 1978; Rocca,

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2003). This is a definite conceptual change – in the Bible, morals, feelings, and wisdom are associated with the kidneys, heart, and adrenals. The brain as an organ is mentioned otherwise only in a tractate discussing whether it is edible, being compared to the bone marrow (B.T. Psachim 84b).

Head injuries The sages addressed the effects of head injuries in cattle. Rabbi Shmuel “the Physician” discussed the occurrence of post-traumatic skull defects (Hulin 42). It is stated that a skull defect per se does not endanger an animal’s life, but a torn or punctured membrane (meaning the meninges) is considered a harbinger of imminent death, and the slaughtering of the animal improper. It may well be that the skull defects were the consequences of head injuries that were complicated by chronic osteomyelitis, with softening or resorption of broken or detached cranial bones. Thus, the examination of the membranes was an attempt to learn just how deep the injury went. This mortal blemish attracted further attention (e.g., B.T. Hulin 11a, 45a; Nashim 48a). The echo of the Biblical story of Abimelech’s head injury and the ancient Egyptian knowledge that a traumatic cerebrospinal fluid leak is a fatal condition may be heard in these discussions.

Headache, including migraine Among the various ailments discussed in the Talmud, suffering from headache was considered one of the more serious ones. Rabbi Rab said that he can tolerate “any illness but not intestinal disease, any suffering but not pain in the heart, any pain but not a headache, any evil but not an evil wife” (B.T. Shabbath 112). The Talmud, which otherwise encourages visiting the sick, warns not to call upon a person while he is suffering from a headache (B.T. Nedarim 41a). Being tormented by headache, an eminent rabbi cried out: “Behold what the generation of the deluge (the source of all evil) brought upon us.” An interesting observation is that of Rabbi Judah of Sichnin, who held that if one of two twin sisters has a headache, the other feels it too (Rosner, 1975). One can only speculate whether he was witnessing familial migraines or menstrual headaches, which may occur concomitantly in sisters, or perhaps both types of headaches. The only given underlying causes of headaches are the blowing into the foam of beverages or an excess of wine. Rosner (1975) points out that the legendary drunk Persian king in the Biblical story of Esther is named Achaverosh, which is jokingly interpreted hachash berosh – the victim of headache. The only

44 M. FEINSOD physical treatments mentioned for headache are rubbing kfia, which means the act of imposing something the head with wine, vinegar, or oil; therapies also recomagainst the will of the person. mended in the writings of Greco-Roman physicians. Epilepsy is regarded as a serious disease that may Of course, a more universal treatment for many ailcause serious injuries, such as falling into water or fire. ments was distraction, especially by occupying oneself Rabbi Judah the President instructed that, because of with the study of the Torah (Bible, Talmud, etc.) (B.T. this danger, nearly all of the sacred commandments – Eruvin 54a), which is “an ornament of grace unto thy like the rules of the Holy Shabbat – should give way head” (Proverbs 1:9). for the care of the afflicted. In the Talmudic section Gittin, there is a section on In spite of this serious approach, there is no descripfolk medicine with incantations, charms, amulets and tion of the clinical picture of the disease and loss of weird concoctions for various disorders. One of these consciousness. That is, convulsions and associated pheconditions is tsalcha or tsilochtha, which, according nomena are not mentioned. It is recognized, however, to the medieval commentators, is equivalent to the that the attacks may come on periodically, and in some hemicrania of the ancients. The various bizarre treatcases even at predictable times. The sages knew that ments may point either to the severity of the condition the disease may appear at any age and can even be or to the ineffectiveness of other remedies. The identiregarded as one of the inborn defects. A form of epification of tsalcha with migraine, as was done in modlepsy is recognized in which the afflicted person is ern Hebrew, rests on hints like the following – “for fully conscious, and it was known that an attack could tsilchata smear the blood of a wild rooster on the painmake one temporarily insane and irresponsible. ful side of the head” (B.T. Gittin 62b). There is no As for the etiology, some Talmudic sources lay mention, however, of other characteristics of the pain. the blame on an attack by an evil spirit or a demon. One is referred to Preuss (1978) and Rosner (1975) for Others state that the offspring of immodest sexual further discussions. intercourse in public, or in the light of the candle, or following hasty sex after coming out of the lavatory, Tremor may suffer from epilepsy. The sages, along with the Hippocratic physicians, were aware that there may be Trembling, as a result of emotional anxiety, is menhereditary factors in the disease. The Talmud states: tioned in the Bible and the Talmud. The latter also “A man should not marry a woman of a family with states that women may shake or tremble when menses epileptics . . . .” Kottek (1988) assumes, in certain concommences (B.T. Niddah 63b). texts, that three cases within a generation is the Tremor as a neurological symptom is brought up in defining number. the Talmud in the context of old age, a condition that The social status of the epileptic was rather low. If a barred the Levites from further Temple service. Rabbi slave merchant omitted to mention that a servant or the Chanina used the phrase “until they begin to tremble” – slave was epileptic, the purchase could be invalidated. rathath – in this way (B.T. Chulin 24b). It is quite tempting And, if a woman hid the condition before marriage, to regard the tremor as a sign of Parkinsonism or a related the husband had the right to divorce her and deprive neurogenerative condition, but there is no mention of her of her dowry. Feelings of aversion or disgust other signs of movement or cognitive disorders. Theretoward an epileptic husband were also considered fore, the association of the tremor with an extrapyramidal acceptable causes for divorce. Epileptic priests were disorder remains speculative, and diagnosis of idiopathic deemed unfit to serve in the Temple, even if the senile tremor seems more plausible. attacks were separated by days and, as some suggest, even if they could be foretold. Epilepsy As for treatments, there is mention of an amulet Epilepsy is referred to in many ancient early cultures, (kame’a) that is permitted to be worn even on the Sabincluding those of the Acadians, Egyptians and Greeks. bath, not only by the epileptic but also as a preventive Hippocrates refuted the concept of this condition as measure by others. It is not stated whether it was a divine and stated that it is a natural disease caused written amulet or a suspended root, as Galen had by problems involving the brain. In general, the advised. It is also not clear if it were specific for epiTalmud accepts the concept of an “organic” disease, lepsy or a more general sort of panacea. although the brain is not considered the origin of this A transitory condition that may resemble epilepsy, disease, and the disease is not given a specific name. one in which the patient is suddenly seized by confusion The Talmud stresses the involuntary nature of the epiand illogical decisions, experiences dizziness, and may leptic attack by naming the person afflicted by epilepsy be unable to speak, is mentioned in both the Babylonian as Nikhpe. This term is derived from the Hebrew noun and the Jerusalem Talmud (Tractate Brachot). As the

NEUROLOGY IN THE BIBLE AND THE TALMUD age and general condition of the affected person are not mentioned, today’s reader is free to speculate whether to regard it as an epileptic equivalent (Rosner, 1975), or perhaps as a vascular event.

Handedness The Bible records left-handedness as an objective, noteworthy, observable fact. The Talmud’s definition of the phenomenon is that the left-handed person (itter) is the one who writes with his left hand (B.T. Shabbath 103a). The Bible describes the left-handed person as having no control over his right hand (itter yad yemino), whereas the Talmud shortened the denomination to itter, not mentioning the limb. A left-handed man is allowed to wear the phylacteries on his right arm, instead of on the left as ordained. Ambidextrous people have to wear them, like most people, on the left arm (B.T. Menachot 37a). The Talmud regards a left-handed layman as ordinary and fit, but a left-handed priest is not allowed to serve in the Temple. The sages are split about the ambidextrous. According to Rabbi Judah, the equality of strength results from abnormal weakness of the right arm, but other scholars thought that in such cases the left hand may simply be exceptionally strong (B.T. Bechorot 45b).

Spinal diseases and injuries The relief from the palace of Assyrian King Assurbanipal (7th century BCE) depicting a dying lioness with paraplegia, due to an arrow piercing her thoracic spine (McHenry, 1969), reveals that spinal injuries and the resulting paralysis were recognized since antiquity. The Talmudic sages were well acquainted with various spinal conditions, which helped them decide whether particular cattle were healthy enough to be slaughtered for food. Severe spinal injury was considered to be imminently life endangering, and such animals were thus disqualified. Rabbi Jacob held that an injury of the spinal cord is fatal. The editor of the Mishnah, in an original observation much ahead of his time, stated that it is fatal (by causing paralysis) only when the injury narrows the width of the spinal canal by more than one-half of its transverse diameter (Hulin 3:1). A sheep in the house of Rabbi Habiba was dragging its hind legs. Said Rabbi Yemar: it is suffering from “shigrona” [sciatica or rheumatic condition]. To this [Rabbi] Ravina objected: perhaps the filament of the vertebral column [spinal cord] is disrupted? They examined the sheep post mortem, and found it according to Ravina. (Hulin 51a)

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This is probably the only case on record in ancient literature where a diagnosis of a spinal lesion was made during life and then verified with a post-mortem examination (Leibowitz, 1960). Rabbis Yemar and Ravina were aware of the differential diagnoses of limping or weakness of the hind limbs that can result from spinal injury or from chronic degenerative conditions – shigrona. Rosner (1975) pointed out that the term shigrona was used also to describe back pain or pain in the hip joints. In such cases the recommended treatment was rubbing fish brine over the painful area. Rabbi Levi added to the aforementioned discussion that he saw a person who suffered from tremor of the head, and he even remarked that the man must be suffering from softening of the spinal cord. Abaya added that such cases were not necessarily fatal, but the patients lost their reproductive functions. According to Biblical law, the first born of edible animals should be sacrificed. The sages decided that only healthy animals can be used for the ritual, hence their interest and widening knowledge of birth defects. This knowledge was applied also to human cases, again in order to rule whether the newborn was viable. In tractate Niddah 24a, a condition was brought up for deliberation. “If one aborted a creature that had two backs and two spinal columns, Rab ruled: In the case of a woman it is no valid birth.” Antigonus stated that, any (firstling of cattle) that had two backs and two spinal columns was unfit for the Temple service. Thus, these sages probably saw “spina bifida aperta” and various forms of meningomyelocele. Extreme scoliosis was also recognized, exemplified by a case mentioned in the same tractate, where the spinal column of a newborn was so crooked that it resembled a double column.

Cranial surgery There are many passages in the Talmud that indicate that various surgical procedures were performed, and that certain herbs and plants were used to reduce pain (Feldman, 1986; Aminoff, 1999; Levinger and Blickstein, 2000). Geller (2003) and Levinger and Blickstein (2000) suggest that, as cranial trephination was widely practiced at the time, it was also known to the Talmudic scholars. A passage in the Mishnah provides specific evidence for this. The tractate Ohalot 2:3 discusses (not for medical purposes) the size of the piece of bone to be removed and refers to the trepan, the surgical instrument used for opening the skull. The passage even differentiates between the size of the drill or gimlet of the physicians and a larger one of the carpenter. The latter’s size is defined in another Mishnaic tractate (Kelim 17:12) as the size of a sela, a specific piece of

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money coined by the emperor Nero, or the size of an Italian coin, the fundion. In a recent detailed article, Weinberg (2006) made a notable attempt to clarify a Talmudic passage (B.T. Ketubot 77b) that describes the surgical treatment of a repulsive affliction of the scalp. The affliction, ra’atan, is referred to in several other tractates and its definition using today’s terminology presents a very difficult, if not an unattainable, challenge (Rosner, 1993). It exemplifies some of the problems encountered in the interpretation of ancient texts, especially those in which medical situations are mentioned en passant in nonmedical writings and for non-medical purposes. In this particular case, the affliction was painful, disfiguring, and repulsive, and its discharge was swarmed by flies. The article depicts the preparation for surgery, which begins by soaking the diseased area with an abundant amount of a mixture or infusion of herbs that was used either to cleanse and expose the eroded skull or to soften it. Tongs were used for taking out some pieces of bone, while other pieces and some diseased tissue were scraped to remove the organisms (Rosner, 1993) in those diseased tissues. The operator is given an important directive – to be extremely careful not to injure the meninges. Damaging these membranes, as discussed earlier, carried a mortal danger. It is evident from this Talmudic passage that surgery of the head and its problems were, in fact, well known even to non-medical scholars. But what was ra’atan? The evidence suggests that ra’atan was not meningitis, which is an acute mortal condition. Weinberg correctly dismisses a number of other diseases and disorders. What seems to me a tempting suggestion is that ra’atan could have been a chronic frontal sinusitis resulting in a discharging osteomyelitis eroding the anterior and posterior walls of the frontal sinuses. This erosion enabled the removal of pieces of skull by tongs. The pus could have been infested by flies and maggots. This condition may be the ancient source of the popular Jewish legend praising the wisdom of Moses Maimonides, the great medieval philosopher and physician, who saw a worm crawling on the brain during surgery. He removed it gently by enticing it with a succulent leaf, thereby not causing any additional harm.

Titus’ tinnitus The Great Revolt against Rome (66 CE) was practically terminated in the year 70 CE by the fall of Jerusalem and a terrible massacre. The city and the Temple, the holiest site for the Jewish faith, were desecrated and burned to the ground. The treasures of the Temple were ransacked and carried to Rome to be displayed

in the triumphant procession, and many Jews were exiled from their land. The hatred of the conquered toward the Roman general Titus Flavius Vespasianus (30–81 CE), who inflicted the national tragedy and humiliation, was expressed by wishing him a long-lasting neurological agony (B.T. Gittin 56b). According to the story, a gnat entered Titus’ nostril while he was having some wine, and it picked at his brain for 7 years. One day Titus was passing near a blacksmith’s shop and the noise of the sledgehammer silenced the gnat. Titus thus said, “Here is a remedy,” and the blacksmith was brought to hammer daily, for which he was paid handsomely. To the Israelites, Titus said, “be content to see your enemy in his suffering.” After 30 days, the gnat became accustomed to the noise and resumed pecking. After Titus died, his skull was pierced and a growth resembling a sparrow (passer domesticus) was found. It had a brass-like orange color and black–gray specks, and weighed about 30 g. Another extra-Talmudic version (Bereshit Raba) describes the lesion growth as resembling a dove weighing about 360 g (Katz, 1997). There is no mention of the intracranial location of the lesion. Both versions are, of course, no more than myths or legends. In fact, there is no evidence in Roman historical sources that Titus suffered from any chronic ailment. He became Emperor in 79 CE and died 2 years later after a short, probably infectious illness. Hippocrates and Galen both recognized tinnitus. Dan (2005) provides a summary of Greco-Roman knowledge of the affliction and the explanation of the symptomatology, which was then associated with imbalances among the humors. The Talmudic description of tinnitus resembling the buzz of a mosquito, and its relief by external noise, are consistent with modern descriptions and are helpful in its diagnosis. It is quite tempting to identify the bird-like abnormality as a cerebello-pontine-angle tumor (Katz, 1997). There is no evidence, however, that post-mortem explorations of the contents of the skull were practiced at that period. The description of the growth in the first version may resemble a huge tumor; the later version is purely imaginary. It may well be that even further research of Talmudic and extra-Talmudic sources may not provide a definitive answer to this tempting enigma.

CONCLUSIONS In the Post-Talmudic Era, Jewish scholar-physicians became an important part of Islamic medicine’s endeavor to preserve and develop the Greco-Roman medical heritage. The spread of Jewish communities all over medieval

NEUROLOGY IN THE BIBLE AND THE TALMUD Europe made the Jewish physicians an important link between Islamic medicine and the developing Christian medical schools and institutions. As all of these men were rabbinic scholars, as best exemplified by Maimonides, they were not mere conveyers but carried with them also the Biblical and Talmudic legacies, which may have provided them with distinctive points of view that clearly merit the attention of modern scholars.

REFERENCES Altschuler EL (2002). Did Ezekiel have temporal lobe epilepsy? Arch Gen Psychiatry 59: 561–562. Aminoff I (1998). “The best of doctors to Hell” (a study from the source of the Sages). Harefuah 134: 740–747. Aminoff I (1999). Talmudic lipectomy. Harefuah 136: 323–325. Auerbach E (1953). Mimesis. The Representation of Reality in Western Literature. Princeton University Press, Princeton, NJ. Bartholin T (1672). On diseases in the Bible: a medical miscellany. (Translated from the Latin by J. Willis. Edited with an introduction by J. Schioldann-Nielsen and K. Sorensen.) Acta Hist Sci Nat Med 41: 1–147. Benton AL (1971). A Biblical description of motor aphasia and right hemiplegia. J Hist Med Allied Sci 442–444. Dan B (2005). Titus’s tinnitus. J Hist Neurosci 14: 210–213. Feinsod M (1997). Three head injuries: the Biblical account of the deaths of Sisera, Abimelech and Goliath. J Hist Neurosci 6: 320–324. Feldman D (1986). Health and Medicine in the Jewish Tradition. Crossroads Publishing, New York. Flavius J (1900). The Antiquities of the Jews. Routledge, London. Garrison FH (1933). Persian medicine and medicine in Persia. Bull Hist Med 1: 129–153. Geller MJ (2003). Hippocrates, Galen and the Jews: renal medicine and the Talmud. Am J Nephrol 22: 101–106. Hoenig LJ (1977). Jacob’s limp. Semin Arthritis Rheum 26: 684–688.

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Katz Y (1997). Did a mosquito kill Titus? Harefuah 133: 653–655. Kottek SS (1988). From the history of medicine: epilepsy in ancient Jewish sources. Isr J Psychiatry Relat Sci 25: 3–11. Leibowitz JO (1960). Traumatic (?) paraplegia as reported in the Talmud. Med Hist 4: 350–351. Levinger U, Blickstein I (2000). Surgery in the Talmud. Harefuah 138: 75–77. McHenry LC (1969). Garrison’s History of Neurology. Charles C Thomas, Springfield, IL. Muntner S (1951). The Antiquity of Asaph the Physician and his Editorship of the Earliest Hebrew Book of Medicine. Baltimore, MD. Pare´ A (1951). The Apologie and Treatise of Ambroise Pare´. Falcon Educational Books, London. Preuss J (1978). Biblical and Talmudic Medicine. Translated and edited by Fred Rosner. Sanhedrin Press. New York. Rabin D, Rabin PL (1983). David, Goliath and Smiley’s people (Letter). N Engl J Med 309: 992. Rocca J (2003). Galen on the Brain. Brill, Leiden, Boston. Rosner F (1975). Neurology in the Bible and Talmud. Isr J Med Sci 11: 385–397. Rosner F (1978). Julius Preuss’ Biblical and Talmudic Medicine. Sanhedrin Press, New York. Rosner F (1993). The illness “ra’atan” (insect in the brain?). Korot 10: 157–161. Ross JM (1978). Epilepsy in the Bible. Dev Med Child Neurol 20: 677–678. Rozelaar M (1988). An unrecognized part of the human anatomy. Judaism 45: 97–101. Shapiro R, Mintz A (1990). (Letter; comment). Radiology 176: 288. Sigerist HE (1951). A History of Medicine. Oxford University Press, New York. Sprecher S (1990). David and Goliath (Letter). Radiology 176: 288. Weinberg A (2006). A case of cranial surgery in the Talmud. J Hist Neurosci 15: 102–110. Yadin Y (1963). The Art of Warfare in Biblical Lands: In the Light of Archeological Study. McGraw-Hill, New York.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 5

The Greco-Roman world AXEL KARENBERG * Institute for the History of Medicine and Medical Ethics, University of Cologne, Cologne, Germany

INTRODUCTION The Greco-Roman world lasted for almost 1500 years and stretches from the first written Greek texts to the fall of the West Roman Empire. Political events and scientific developments suggest a division of the vicissitudes of neurological thought in this period as follows: 1. 2. 3. 4.

the pre-Hippocratic phase in Archaic Greece (8th to 6th centuries BCE) the Hippocratic period during the “Golden Age of Greece” (5th to 4th centuries BCE) the Alexandrian epoch during the Hellenistic period (3rd to 1st centuries BCE) medicine in the Roman Empire (1st to 4th centuries CE)

Each of these periods is characterized by particular ways of seeing structure, function and illnesses of the brain, spinal cord and nerves. There are also multifarious transitions, both within the Greco-Roman world as well as to preceding and succeeding cultures. In early Greek medicine we detect, for example, elements of Egyptian medicine; conversely, ancient concepts imprinted themselves in various ways onto Medieval and Early Modern thinking. This overview focuses on neuroanatomy, neurophysiology and disorders of the nervous system. All technical terms and the general frame of reference are modern, not historical. The term “modern” is employed in pre-modern historical periods to facilitate comprehension, but is done so knowing that projecting backwards must be done with caution. The guiding principles of modern science – the formulation of testable hypotheses, controlled experimentation, and observer objectivity – are largely the achievements of later generations and their application to the ancient neurosciences would be premature. From this perspec-

*

tive, many old theories regarding brain function and the nature of scientific evidence are decidedly speculative and dubious. In this early phase of medicine it was also impossible to classify illnesses morphologically or etiologically. Instead various clusters of symptoms and signs were summarized to define different kinds of diseases. It is for this reason that ancient terms, such as “epilepsy” and “apoplexy,” bear only a slight resemblance to the modern versions. In short: it is critical to keep in mind when studying ancient neurology that Greco-Roman science differs fundamentally from modern science.

PRE-HIPPOCRATIC CONCEPTS: MYTHOLOGICAL, LITERARY AND PHILOSOPHICAL SOURCES As in many other cultures, the early Greeks understood health and illness as divinely bestowed. The myths Homer, Hesiod and other poets recited contain numerous healing deities, including the sun god Apollo and the centaur Cheiron. Promoted to his position as the central healing god before the 6th century BCE, Asklepios knew the medical arts. Soon thereafter the cult of Asklepios appeared and special temples, asklepieia, were built for the droves of pilgrims seeking cures. Almost 500 of these temples have been found across the Mediterranean (Steger, 2004). The best known are in Epidaurus (south of Corinth), on the island of Aegina, and in Athens (Fig. 5.1). Exactly who visited these places with what neurological disorders is known only by fragments from recovered inscriptions. Reports carved in stone tell of the successful treatment of many chronic illnesses including blindness, speech disorders and paralysis. This is a typical example of one such engraving:

Correspondence to: Prof. Dr. med. Axel Karenberg, Institute for the History of Medicine and Medical Ethics, University of Cologne, Joseph-Stelzmann-Straße 20, D-50931 Cologne, Germany. E-mail: [email protected], Tel: þ49-221-478-5266, Fax: þ49-221-478-6794.

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Fig. 5.1. Temple of Asklepios in the Greek city of Troizen, built about 400 BCE. View of the Hall of the Diseased. Institute for the History of Medicine and Medical Ethics, University of Cologne, Germany.

Demosthenes, legs paralyzed. He came to the temple borne on a stretcher and walked around using two canes. When he fell asleep in the sacred hall he saw a face: he dreamt the god decreed that he remain in the holy area for four months after which time he would be healed. Hereupon he emerged inside of four months . . . healed. (Herzog, 1931, p. 33) The central element of this description is the dream. Asklepios appeared in a dream and performed miracle cures or communicated needed prescriptions, while the supplicant slept. We cannot doubt that many spiritual cures took place in this setting, but (as in the example above) every detail of what actually happened remains unknown, thus inviting endless speculation (Edelstein and Edelstein, 1945, pp. 142–145; Krug, 1984, pp. 134–141). The earliest reflections on rudimentary anatomical knowledge are literary and stem from the time of the Homeric epics (c. 800 BCE). Although fragmentary, these passages evidence an impressive clarity as regards personal observation (Grmek, 1991, pp. 17–38). We read in the Iliad of a warrior’s injury, his helmet and head pierced by a spear: And the brain spurted forth from the wound along the socket of the spear all mingled with blood. There then his strength was lossed . . . (Homer, 1976, p. 253)

Likewise, the head trauma of another warrior is described with gruesome realism (Homer, 1976, p. 191): “. . . and clean through passed the spear of bronze beneath the brain, and clave asunder the white bones . . . a black cloud of death enfolded him.” Homer used the Greek word enkephalos for brain, a word which remains part of modern medical terminology (e.g., encephalon, encephalitis). Yet “Homeric neuroanatomy” did not establish much more than that the brain sat within the cranium, and the spinal cord within the backbone (Souques, 1936, p. 12). With the awakening of scientific curiosity at the dawn of the 5th century BCE, pragmatic everyday knowledge gave way to a process of systematic discovery. Investigations into the fundamental nature of matter and the search for rational explanations were characteristics of every Greek thinker until Socrates; these are known as the pre-Socratic philosophers (Longrigg, 1993, pp. 47–103). Two groups of pre-Socratics are of import to the history of neurology. The Ionic natural philosophers took their name from Ionia, an area on the west coast of modern Turkey. These men reduced everything in the cosmos to basic elements. Thales (first half of the 6th century BCE) concluded that water was the most basic element; his pupil Anaximander (c. 610–546 BCE) believed that all matter was made of water and earth fused by the sun. A third substance, air, was taken as fundamental by Anaximander’s disciple Anaximenes (c. 585–526 BCE). Another Ionian, Heraclitus of Ephesus (c. 544– 480 BCE), considered fire a central cosmic element. A second group of scholars resided primarily in the western part of Greater Greece, in lower Italy near the present-day town of Crotone and in Sicily. These philosophers “packaged” these four elements together. Pythagoras (c. 570–490 BCE) hypothesized that everything on earth, including the human body, was made of water, earth, air and fire. Empedocles of Agrigentum (c. 490–430 BCE) is credited with finally shaping the cosmogenic theory of the four elements. By the 4th century BCE these elements were associated with two pairs of fundamental qualities: water was associated with cold and moistness, earth with cold and dryness, air with heat and moisture, and fire with heat and dryness. This arrangement laid the basis for the Hippocratic theory of medicine. The Pythagoreans also formulated additional, specialized questions regarding the nature of man: how do the sensory organs transmit their messages to the human mind? What governs our ability to move about? Historians have reconstructed some of the answers given to these questions in ancient times (Solmsen, 1961). Alcmaeon of Crotona (c. 570–500 BCE), author of a book titled On Nature and possibly a student of Pythagoras, is

THE GRECO-ROMAN WORLD 51 said to have removed animal eyeballs, thereby discovering Greece and supposedly died at the advanced age of 89 what later became known as the optic nerve. He also pos(or perhaps even 109) in Larissa, a city in Thessalia not tulated similar “passages” or “channels” for the ears, far from Mt. Olympus (Pinault, 1992). nose and tongue (Clarke and O’Malley, 1968, p. 3): “All The collection of writings which bears his name, the the senses are related in some way to the brain so that if Hippocratic corpus, contains more than 60 texts on it is moved or if it changes its position, they are blunted anatomy, physiology, internal medicine (including because the passages by which sensation occurs are neurology), gynecology, and surgery. It also contains blocked.” In all probability, Alcmaeon connected only dietetics and prognostics and, importantly, medical thesensory functions to the brain. ory and ethics. Most of these pieces were written Diogenes of Apollonia (c. 460–390 BCE), another between 430 BCE and 350 BCE, although several pre-Socratic philosopher, saw the pneuma as the body’s stem from a later period. This collection thus represents cosmic breath, and thus as a vital, fundamental princithe core of the medical literature from Greece’s Golden ple. He then produced a sketchy description of a vascuAge, a period that also gave us democracy, the birth of lar system, yet one that neither distinguished between tragedy, and notable advances in the graphic arts. Yet artery and vein, nor posited a circulatory system. the “Hippocratic question” – which texts were actually He also placed the brain at the center of sensory activauthored by the man himself and which ones by others – ity, with blood vessels assuming the function of “pasremains unanswered even today. The famed “Father of sage-ways.” Through these channels life-giving Medicine” remains an author without a clearly defined pneuma could be transported to the brain to enable set of writings (Lloyd, 1991). perception and cognition. In Diogenes’ view, organs This historical background explains why the contriand limbs were also animated via the pneuma; illnesses butions of various Hippocratic physicians to ancient were a direct consequence of disturbances within this neurology seem inconsistent and even contradictory. transport system. The founder of philosophical atoOne author described the brain as “double” and mism, Democritus (c. 460–370 BCE), also assigned the divided in half by a membrane. Another maintained brain an important role, especially as concerned his that the front part of the skull contained more brain explanation of hearing (Soury, 1899, pp. 72–101). mass than the back. They were aware of the continuThus, the principle that guided Alcmaeon and those ous link between brain and spinal cord, yet the periphwho followed him was that of a carrier system within eral nerves (neura) were not clearly differentiated the body, one that transported sensory data from the from ligaments and tendons (Souques, 1936, p. 39). outer world to the brain via the sensory organs by means The clearest presentation of what we today would of a hypothetical, intracorporeal pneuma. To the modrecognize as brain functions can be found in an anonern reader, ideas like these often appear enigmatic and ymous text on epilepsy titled The Sacred Disease. The bizarre, assuming they can be understood at all. Yet author not only proclaimed his belief in pre-Socratic these ideas, along with others, such as that of the fundatenets, but ascribed an even more comprehensive role mental elements, were important. For it was with their to this organ: help that the physiological processes and pathological I hold that the brain is the most powerful organ conditions of the brain and nerves were explained. of the human body, for when it is healthy it is an interpreter to us of the phenomena caused by HIPPOCRATIC NEUROLOGY: THE BRAIN air, as it is the air that gives it intelligence. Eyes, IN HEALTH AND DISEASE ears, tongue, hands and feet act in accordance with the discernment of the brain . . . Wherefore Hippocrates is both a historical figure and a myth. We I assert that the brain is the interpreter of conknow he was born around 460 BCE into a medical sciousness. (Hippocrates, 1959, p. 179) family on Kos. That he came from a family with a medical tradition is typical of the entire Greco-Roman He then states that the brain is the locus of all feelings, period, for neither education nor occupation were all perception and all moral judgment: regulated by law in any way. It was on this island off the Ionian coast that Hippocrates practiced what he Men ought to know that from the brain, and from had learned from his father, amongst others, for a the brain only, arise our pleasures, joys, laughter time. He also taught medicine to students for a fee and jests, as well as our sorrows, pains, griefs and, according to Plato and Aristotle, in this way and tears. Through it, in particular, we think, established the great reputation of the Kos school of see, hear, and distinguish the ugly from the beaumedicine. After many years as a wandering physician, tiful, the bad from the good, the pleasant from the Hippocrates spent the final years of his life in northern unpleasant . . . . (Hippocrates, 1959, p. 175)

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Closing in the tradition of the pre-Socratics, the author put forward that all of this was possible because the brain is in contact with external air via the mouth and nose; furthermore, pneuma flows into the brain through blood vessels. In addition to this discussion of brain function, nervous system pathology was fundamental to the “Hippocratic Enlightenment.” Many texts detail attempts to rationally explain diseases without recourse to magical or religious interpretations. A new theory of disease and differentiated descriptions of individual illnesses are accordingly considered the most impressive accomplishments of the Hippocratic epoch. The impact of this history of thought about the brain is most clearly indicated in The Sacred Disease, which begins with the following words: I am about to discuss the disease called “sacred”. It is not, in my opinion, any more divine or more sacred than other diseases, but has a natural cause . . . The fact is that the cause of this affliction . . . is the brain . . . These things we suffer all come from the brain, when it is not healthy, but becomes abnormally hot, cold, moist or dry, or suffers any other unnatural affection to which it was not accustomed. (Hippocrates, 1959, p. 139) From this perspective, supernatural powers no longer played a dominant role. The essential starting point of all considerations was now the doctrine of humors that appeared very early in Hippocratic medicine. The four cosmic elements (air, water, earth and fire), as well as their related qualities (moisture, cold, dryness and warmth), were associated in a doubly dichotomous system with four bodily fluids (blood, phlegm, yellow bile and black bile) and projected onto the inner workings of individuals. Health was seen as the harmonious blending of these four humors (eukrasia) and illness as a disturbance within this balance (dyskrasia). What had previously been known as the “sacred disease” now appeared as a somatically determined disturbance (Temkin, 1971, pp. 51–56). The actual causes of this condition, still unknown to Greek physicians, were now associated with external, observable factors such as age, gender, and climate. The patient’s innate disposition, diet, and life experiences were also thought to play important roles (Fig. 5.2). The history of another neurological disorder, apoplexy, may facilitate access to this understanding of disease. Stroke features prominently in Hippocratic texts (Clarke, 1963a; Karenberg and Moog, 1997). It was defined as a sudden loss of consciousness accompanied by paralysis of the entire body, often leading to death. The cause was assumed to be congestion of the head with “cold and moist” phlegm or “cold and dry”

Fig. 5.2. The doctrine of the four elements, qualities and humors with later expansions.

black bile. One of these elements interrupted the flow of pneuma to the brain. The condition could be influenced by environmental factors, including season and time of day. These were considered “macrocosmic” factors. Patient factors, such as age and disposition (what the Greeks called the “microcosmic” factors), were also of great importance. Hippocratic therapies were constructed on this theoretical framework. Either the body was freed of excess fluids by blood letting, a purge, an emetic, or some other means, or the disorder was treated by its opposite: e.g., “cold” diseases such as epilepsy or apoplexy by a “warming” diet or “warm” herbs. The goal of treatment in both cases was to restore the natural balance of humors and qualities. Humoral theory also played a critical role in the treatment of cranial wounds. The Hippocratic physician often left open cranial wounds alone, but might have a hole drilled if he believed that the blow to the skull led to the accumulation of blood and other noxious humors in the head. The author of On Head Wounds feared that these harmful fluids could contribute to the generation of dangerous “pus” (Hippocrates, 1999). This dramatic situation could be obviated, at least in some cases, by trepanation. Finally, the Hippocratic texts also mention other illnesses that we now consider neurological: headaches, migraines, speech disorders, and various palsies of cerebral or spinal origin (Rose, 1994, pp. 245–246). In many cases, however, profound differences between

THE GRECO-ROMAN WORLD ancient and modern conceptions of disease make placing descriptions from the Hippocratic collection into modern diagnostic categories difficult and even dangerous. Thus it must remain an open question whether tetanus, rabies, mumps encephalitis, postdiptheric paralysis, and other conditions should be recognized as definable diseases, as some authors have maintained (Souques, 1936, pp. 68–93; Ritter, 1969). During Hippocrates’ long life, classic Greece saw the development of a new concept of disease. Observations at the bedside (kline), a speculative, but rational etiology, subtle prognostics, and a treatment based on knowledge and experience were henceforth critical characteristics of the medical arts (techne). Ancient neurology profited from these developments. Yet the anatomical basis of neurological theory and practice remained a “black box” during the Hippocratic era. Decisive discoveries regarding the structure of the brain and nerves would follow in the next significant period of ancient neurology.

NEUROANATOMY IN ALEXANDRIA: NEW INSIGHTS INTO THE STRUCTURE OF THE NERVOUS SYSTEM The systematic dissection of humans first began some 50 years after Hippocrates’ death. This procedure represents an extraordinary, epoch-making development for cultural and medical history in general and for the history of research into the nervous system. At the end of the 4th century BCE, the scientific and medical center of the Greek world shifted to Alexandria, a city founded by Alexander the Great after conquering Egypt in 331 BCE. The factors that led Alexandria to become a true “city of science” within a few years have been extensively analyzed (von Staden, 1989, pp. 1–31). Political and financial patronage by the ruling Ptolemaic dynasty constituted a kind of state sponsored research program. The open, accepting atmosphere created a “melting pot” and drew scholars from the entire Greek world including mathematicians Euclid and Archimedes, as well as astronomers Ptolemy and Aristarchos. These researchers also enjoyed the use of excellent scientific institutions including a botanical garden, a zoological collection, and the library in which the Hippocratic texts had been compiled. Alexandria was an ideal place for anatomical research for other reasons. Legal limitations, religious taboos, and moral constraints regarding dissection played a smaller role here than in the Greek motherland. The ancient yet still practiced cult of mummification might have also played a role. In any case, these conditions permitted the first known dissection of human bodies. It is likely that vivisection was also carried out on criminals sentenced

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to death. The matter of human vivisection, however, remains uncertain, despite the survival of a lively ethical discussion of the pros and cons of the procedure (Leven, 2005, cols. 407–409). The start of empirical research into neuroanatomy is linked with the names of Herophilus and Erasistratus, both physicians. Unfortunately their writings are lost. Yet their insights and doctrines were preserved in the work of later authors, principally Galen. Herophilus (c. 330–250 BCE) came from Chalcedon in Bithynia, a small city on the Bosporus. After training as a physician, he went to Alexandria (Fig. 5.3). The list of his accomplishments is long and impressive (von Staden, 1989). One of his first acts was to confirm the partition of the brain into cerebrum (enkephalos) and cerebellum (parenkephalis), which Aristotle had established in animals. Herophilus was probably aware of six pairs of cranial nerves, what we today would identify as II, III, V, V3, VII þ VIII and XII. He also described a few of the cerebral sinuses including the confluens sinuum, which to this day is known as the torcular Herophili. Herophilus also observed another section of the cerebral vascular system in animals: the retiform plexus, a symmetrical arrangement of arteries at the base of the skull. This structure, not present in humans, was of decisive importance in late ancient and medieval theories of brain function. Herophilus’ studies of the inner cavities of the brain became the point of departure of a long tradition in this field: he took the rearmost (what we call the fourth) ventricle to be the most important by virtue of its position between the cerebellum and the spinal cord, and because he saw in this cavity a kind of “command center” for the human body. He then described in detail the base of this ventricle and noted its similarity to a pen made from reed, observations that survive in anatomical

Fig. 5.3. The first dissection by the Alexandrian physician Herophilus. Idealized relief by Paul-Franc¸ois Niclausse from 1955. Paris, Nouvelle Faculte´ de Me´decine. Institute for the History of Medicine and Medical Ethics, University of Cologne, Germany.

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Latin as calamus scriptorius. Herophilus found that the inner surfaces of every cerebral cavity are covered with small vascular tracks, which reminded him of fetal chorion. This was the origin of the term choroid plexus. Herophilus is frequently credited as the first to differentiate between motor and sensory peripheral nerves. Although this is probably true, he failed to distinguish fully between nerves, tendons and ligaments, which he lumped together as “nerve-like parts.” Still, he inferred that motor nerves extend exclusively from the brain and spinal cord. Herophilus’ younger contemporary, Erasistratus (c. 320–c. 245 BCE), also investigated the nervous system by means of methodical (vivi-)section of animals and humans, and is recognized as a founder of comparative neuroanatomy. By examining the cerebellum of various species, he noted a correlation of size with the ability to run quickly. He similarly correlated intellectual ability with the complexity of convolutions, and thus explained the prominent position of the human mind using anatomical arguments (Longrigg, 1981). Although Herophilus assigned the brain ventricles preeminent physiological meaning, from his earliest days Erasistratus viewed the dura mater as the control center, and thus the origin of nerves. At the end of his life, he corrected himself and made the brain central. He also postulated that motor and sensory nerves carried out their functions by means of special psychic pneuma. The following excerpt gives a lively impression of neuroanatomical studies in Alexandria at this time: We viewed also the structure of the (human) cerebrum, and it was bipartite as in all other animals, and there were ventricles lying there, elongated in form. The ventricles were united by a perforation at the point of contact of the parts. From this point a passage led to the so called cerebellum, where there was another small ventricle. Each of the parts had been partitioned off by the meninges. For the cerebellum had been partitioned off by itself, and also the cerebrum, which is similar to the jejunum and has many folds; and the cerebellum, even more than the cerebrum, was provided with many convolutions . . . And the outgrowths of the nerves were all from the brain; and by and large the brain appears to be the source of the nerves in the body. For the sensation that comes from the nostrils passed to the member through the apertures, and also the sensations that come from the ears. And outgrowths from the brain went also to the tongue and the eyes. (Rocca, 2003, p. 39)

Unfortunately, no surviving texts indicate how this knowledge of the inner structure of the nervous system was applied to actual patients or nervous diseases generally. We have only a single passage where Erasistratus mentions that stroke is caused by an accumulation of “cold and icy phlegm” that blocks the nerve origins in the brain (Garofalo, 1988, p. 125). The Alexandrians Herophilus and Erasistratus established a new vision of medicine as a profession. In addition to acting as physicians in the Hippocratic sense, the physician was now also a scientist. The opportunity to study human anatomy via dissection established a new basis for knowledge of the brain and nerves. In this regard one may justly speak of an “epistemological revolution” (Vegetti, 1996, p. 81), even if human dissection were no longer possible and this singular “window of opportunity” closed shortly after these two pioneers died. In hindsight, the “discoveries” of the Alexandrian scientists may appear banal and well-nigh self-evident. In order to fully appreciate the enormous significance of the Alexandrians’ work, it must be placed within the context of the ancient debate on the central organ of the human body. The head or the heart?

THE MILLENNIAL DEBATE ABOUT THE “REGENT PART” The debate over the organ that controls and coordinates the human body traverses the entire span of ancient medicine and philosophy (Rose, 1993). As shown, preSocratic philosophers had already localized a kind of sensorium commune within the human body. At that time, however, there was a serious opposing school of thought, one represented by Empedocles and his students. They believed the ruling principle (hegemonikon) lay in the thorax, in the blood, or in the heart itself. This debate sharpened after the 4th century BCE. Even Hippocratic writings provide evidence for both positions. The author of the text The Sacred Disease favored the brain and is therefore considered encephalocentric, whereas the author of a later treatise titled On the Heart favored the heart and is counted among the cardiocentrics (Harris, 1973, pp. 83–96). This controversy prompted two of the most important ancient philosophers to search for an answer. Plato (428/7–349/8 BCE) divided the issue of sensory function from that of the operations of the mind or soul. The latter interested him far more than the former (Solmsen, 1961). In his late dialogue, Timaeus (Plato, 1975), he advocated a tripartite division of the non-material soul within the body (45a–b, 69d–70a, 70d–71b). The “rational” soul resided in the head, the “emotional” in the heart, and the part of the soul that is subject to appetites for food and

THE GRECO-ROMAN WORLD 55 drink and all other wants was planted in the subecho of this past controversy. It is not difficult to imadiaphragmatic area (Plato, 1975, pp. 101 and 181–187). gine that the heart–brain issue was as divisive then as Nowhere, however, does Plato definitively describe the brain death is today in some parts of the world. brain as the hegemonic organ. He merely acknowledged that the sensory organs are in the head and that perception THE SYNTHESIS OF ANCIENT is linked to the brain. NEUROSCIENCES IN ROME: GALEN ON Aristotle (384–322 BCE) was much clearer. Although THE BRAIN AND NERVES a student of Plato, he took the opposing view, particuThe four centuries that separate the end of the Alexanlarly in his History of Animals and Parts of Animals. drian golden age from the beginning of Galen’s career He viewed the heart as the seat of perception, thought, saw few new anatomic or physiologic advances. In memory, and feeling, as well as the source of all bodily addition to not being able to perform human dissecmovement. Based on a great number of animal dissections, this intermission in fundamental research can tions, his physiological schema still gave the brain an be traced back to two sources (Gourevitch, 1996). First, important role (Clarke, 1963b). Because it is the coolest these centuries marked a period of cataloguing and and moistest body part, its prime function must be to systematization of knowledge already assembled, a temper the heat from the heart. This is also why it is time of cultural transfer from the declining Greeks to so extraordinarily large and has numerous blood vessels the ascending Romans. An initial highpoint in this on its surface. This odd and erroneous theory is more development are the Roman encyclopedists Celsus plausible when one takes into consideration additional (1st century CE) and Pliny the Elder (23/24–79 CE), arguments Aristotle used to establish his doctrine. He both of whom wrote in Latin. Second, interest in the first reviewed the tradition: the Mesopotamians, Egypclinical and therapeutic aspects of medicine markedly tians, and Jews had all considered the heart the “acropoincreased: the pulse theory, pharmacological treatlis of the body.” Further, the beating heart of a fetus, ments, and surgical problems were of serious concern the cor punctum saliens, was the earliest sign of unborn to many physicians at this time. Within medicine, varlife. The heart lies in the center of the body, warms us, ious sects emerged, each with a particular doctrine or moves us, and contains vital blood. In contrast, the brain methodology. For example, the Dogmatists further lies at the periphery of the body, feels cold, and was developed medicine based on theory, while the Empiriconsidered insensitive and bloodless. Finally, as a zoolocists did so via observation and experience. The Methgist Aristotle argued that some primitive animals can odical sect developed their own reductionistic concept move and perceive, even though they lack brains. and repudiated the doctrine of the humors. Continued Aristotelian doctrine was very convincing to the interest in age-old pneuma by the Pneumatists gave rise Greeks of his day, and to generations that followed to newer theories of its nature and function. them. Many physicians, including the famous Diocles Several representatives of these medical sects are of of Carystos, Praxagoras of Kos (both 4th century importance to the history of neurology (Creutz, 1934). BCE), and Chrysippus, are counted among believers Aretaeus (1st century BCE), who like most physicians in it, and they interpreted neurological disorders as in the Roman world came from the Greek part of the originating from the heart and blood vessels. This Empire, was familiar with contralateral paralysis and background clarifies the importance of the discovery explained this phenomenon anatomically by a decussaof nerves by the Alexandrian school. One qualification, tion of the nerves above the spinal cord. One should however, must be mentioned: the theory of the suprenote, however, that he possibly owed this knowledge macy of the brain, suggested by Herophilus’ and not to observations of his own, but to an unknown anaErasistratus’ anatomical results and physiological tomic text. hypotheses, was neither immediately convincing nor Aretaeus also clearly differentiated various kinds of very popular to some groups. Stoics and Epicureans, headaches: to name two important factions, still clearly favored If someone has transient headache from a short the cardiocentrist approach. It was Galen, whose ideas lasting cause, even if it continues for several will be described in the next section, who finally days, then we call it cephalalgia. If the headache brought this ancient discussion to a preliminary end. has been present for quite some time, then we Traces of the heart–brain controversy can be found speak of cephalea . . . Others have pain only on throughout the history of European thought. William the right or the left, the pain is confined to the Shakespeare picked up on this old question in The region of the temple, the ear or even the eyebrow Merchant of Venice when Portia asks: “Tell me where or the eye, or the pain divides the nose, as far as is fancy bred, Or in the heart, or in the head?” The the middle of the face, into two equal parts. The international debate regarding brain death is also an

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A. KARENBERG pain does not move to the other side, but remains Alexandrians. It was Galen who described and named confined to a certain part of the head unilaterthe corpus callosum and the fornix, the pineal gland, ally. This headache is called heterocrania. the lamina quadrigemina, and the infundibulum (Rocca, (Koehler and van der Wiel, 2001) 2003, pp. 113–167). Following his teacher Marinus of Alexandria, Galen identified seven pairs of cranial Aretaeus described apoplexy and paralysis, epilepsy, nerves (today known as II, III, V2, V3, VII þ VIII, hysteria, and vertigo with equal precision (Aretaeus, IX þ X þ XI, XII) and parts of the sympathetic ner1856; Ilberg, 1923). We also find a similar spectrum vous system. On the other hand, his conjecture that the of diseases in Celsus’ compilation On Medicine sensory nerves are softer and end in the soft cerebrum, (Celsus, 1935–1938). The most detailed and accurate whereas the harder motor nerves trace back to the descriptions of clinical situations are, however, those harder cerebellum and the spinal cord, was incorrect. of Soranus of Ephesus (c. 100 CE) of the Methodical Galen’s most well-known experiments include his sect. His treatises On Acute Diseases and On Chronic transections of the spinal cord, which he described in Diseases survive in a later Latin version and contain detail in his On Anatomical Procedures (Galen, 1956, systematically conceived sections covering topics p. 221). Lesions from above the first to below the third including stroke, tetanus, rabies, dizziness, and epicervical vertebra resulted in respiratory failure, quadriplelepsy (Caelius Aurelianus, 1950). Moreover, they also gia, and then death in animals. Incisions under the sixth contain what might be the first attempt to distinguish cervical vertebra likewise resulted in paralysis of every between flaccid and spastic palsies. limb, as well as of the thorax muscles, but left the control The highpoint and final chapter of Roman medicine of the diaphragm intact. He further observed that transbelongs to Galen, who is recognized as the most imporverse sectioning or hemisectioning of the spinal cord tant physician of later Antiquity. He combined learning resulted in the loss of feeling and touch below the lesion. from books with his own observations, which he Using the same procedure, Galen experimentally declared the epistemological basis for all knowledge. clarified the role of the recurrent laryngeal nerve in Galen deliberately coined the word “autopsy” (literally: voice production (Spillane, 1981, p. 21). He demonto see for oneself). His anatomic methodology was larstrated in public that an animal’s cries during vivisecgely innovative, but limited by the religious and legal tion were suddenly muted after one pair of nerves in restrictions of his day to animals. His interest in morthe throat had been tied or severed. This finding helped phology was, however, merely the initial stage of explain why after being operated upon for goiter two establishing an understanding of living functions. His patients had lost their voices: vivisections of animals are the finest physiology in the ancient world. This is why today Galen’s name is justly linked in medicine to “the birth of experimentation” (Finger, 2000, p. 39). Galen (129–c. 210 CE) was born into a distinguished family in the Greek city of Pergamon near the west coast of Turkey. He was well taught in philosophy before spending several years acquiring a comprehensive education in medicine in various cities of the Roman Empire, including Athens and Alexandria. After working as physician to gladiators in his home town, he moved to Rome. He quickly became the leading physician of his day, serving Marcus Aurelius and his successors at the imperial court. Neither the exact year of his death nor the location of his grave are known. He authored several hundred works, about half of which have survived. Galen was extremely critical of the many medical sects of his day, and he unfailingly relied on Hippocrates as the highest authority. Galen preferred non-human primates, particularly Barbary apes, for his systematic dissections, because their brains appeared to him most like the human brain. Galen’s neuroanatomy also included deep brain structures, and in this context he moved well beyond the

A surgeon while operating for deep glandular swellings of the neck . . . without realizing what he was doing tore through the recurrent nerves. As a result, he rendered the patient voiceless, though the boy was cured of his glandular trouble. Another person operating on another boy in a similar way, left his patient with half a voice as a result of injury to one of the recurrent nerves. These results seemed perplexing to everybody, because it was seen that although neither larynx nor the trachea was injured, the voice was profoundly affected. But when I demonstrated to them the vocal nerves, they ceased to be bewildered. (Finger, 2000, pp. 43–44) These and other experiments convinced Galen of the decisive role of the brain as control center and ultimate source of all nervous impulses. Hence, although he valued Aristotle highly for his biology, he rejected the cardiocentric doctrine completely: For the supposition that the encephalon was formed for the sake of the heat of the heart, to cool it and to bring it to a moderate temperament,

THE GRECO-ROMAN WORLD is utterly absurd, since in that case Nature would not have placed the encephalon so far from the heart. Rather, she either would have entirely surrounded the heart with it, as she has with the lung, or would at least have placed it all down in the thorax, and she would not have attached the sources of all the senses to it. (Galen, 1968, p. 387) Galen’s own theory of brain function was no less speculative, however, and his explanation is considered one of the more difficult parts of the Galenic corpus. It is also nothing less than one of the greatest challenges ancient medicine offers today’s neurologist (Siegel, 1976; Rocca, 2003, pp. 171–244). Platonic philosophy and Alexandrian physiology are equally present, as are the results of Galen’s own dissections and experiments. Without at least some familiarity with this theoretical context, most neurological notations of any kind made before 1700 remain virtually incomprehensible. In Galen’s system (Fig. 5.4), the decisive medium of brain function is psychic pneuma (or animal spirit), a concept mentioned by Erasistratus. This “first organ of the rational soul” originated in an elaboration process from the vital pneuma (or vital spirit), which built up in the heart and was funneled to the brain via the arteries. Yet psychic pneuma (or its preliminary stage) also reached the ventricle system via the nose and openings in the ethmoid bone. The location of the transformation of pneuma from vital to psychic was primarily thought to be the retiform plexus, the arterial rete mirabile at the base of the skull, which Herophilus had seen in animals and whose existence Galen had confirmed in many animal dissections. The “refined” psychic pneuma was stored in the ventricles and

Fig. 5.4. Galen’s theory of brain function.

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reserved as a kind of “fuel” for the transmission of motor and sensory data between the brain and the body. When a ventricle was cut, the escaping psychic pneuma led to stupor or death, and Galen took this as conclusive proof of his doctrine. Galen’s system offered a decisive advantage over preceding theories. Supplementing with the Hippocratic doctrine of the four humors, he employed this pneuma-based encephalocentric physiology to explain neurological conditions. Apoplexy, paralyses, and other disorders were the result of noxious humors blocking the ventricles or parts of them. Galen also thought epileptic fits could come from the brain, were it to become too dry or moist. It remains unclear whether Galen believed the origin of neurological disorders was exclusively in the ventricles or sometimes in the cerebral substance itself, and this may reflect the fact that many of his treatises were lost in his own lifetime to fire. In his surviving works, one does not find clear statements or a formal theory of localization of higher functions in the brain. This considerable task would occupy physicians and philosophers after Galen’s death – individuals who would cite and lavish praise on Galen. From the 3rd century on, organization, classification, delineation, and expansion of the thoughts of a few classical authors, Galen high among them, would be the chief and continuing goals of medicine.

CONCLUSIONS As this brief synopsis has shown, the main themes of Greek and Roman views of the nervous system and its disorders can still be traced and understood, even if most medical texts from this period are lost or have been preserved only in suspect form. In this context it is important to note that those physicians who actually left written records would represent an elite group seeking to spread their views. Traditional medical doctrines in no way represented a binding standard or even a complete set of guiding principles for any group of ancient physicians. Further, from another perspective, the history presented here exhibits a certain distortion, as it emphasizes the rational approach. Ancient medicine did not, however, progress consistently “from myth to logic.” In fact, there is evidence that just the opposite occurred: the Asklepieion on Kos, for example, a center for spiritual and religious healing, was constructed a century after Hippocrates worked there! It is closer to the truth to observe coexistence and competition between rational and non-rational medicine over many centuries. Social factors also played a decisive role. As a rule, only patients from the upper classes had the means to

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consult a physician versed in philosophy and the medical science of the day. The majority of those afflicted with neurological disorders set their hopes on spiritual or magical cures that were offered in abundance by numerous healers, including individuals with no formal training. A good example of such dubious methods is the treating of epileptic fits with the blood of a gladiator or of an executed man (Moog and Karenberg, 2003). Many other folk medicine therapies will remain forever unknown, as no extant source recounts them. Still, everyone associated with medicine in the Greco-Roman world would agree with the following statement from The Sacred Disease: Each disease has a nature and power of its own; none is hopeless and incapable of treatment. (Hippocrates, 1959. p. 183)

REFERENCES Aretaeus (1856). The Extant Works of Aretaeus the Cappadocian. Edited and translated by F Adams. Sydenham Society, London. Caelius Aurelianus (1950). On Acute Diseases and On Chronic Diseases. Edited and translated by IE Drabkin. University of Chicago Press, Chicago, IL. Celsus (1935–1938). De Medicina, 3 vols. Edited and translated by W Spencer. Heinemann, London. Clarke E (1963a). Apoplexy in the Hippocratic writings. Bull Hist Med 37: 301–314. Clarke E (1963b). Aristotelian concepts of the form and function of the brain. Bull Hist Med 37: 1–14. Clarke E, O’Malley CD (1968). The Human Brain and Spinal Cord. A Historical Study Illustrated by Writings from Antiquity to the 20th Century. University of California Press, Berkeley, CA and Los Angeles, CA. Creutz W (1934). Die Neurologie des 1–7. Jahrhunderts n. Chr. Eine historisch-neurologische Studie. Thieme, Leipzig. Reprint 1966, Bonset, Amsterdam. Edelstein E, Edelstein L (1945). Asclepius. A Collection and Interpretation of the Testimonies, 2 vols. Johns Hopkins Press, Baltimore, MD, vol. 2. Finger S (2000). Minds behind the Brain. A History of the Pioneers and their Discoveries. Oxford University Press, Oxford and New York. Galen (1956). On Anatomical Procedures. Translation by Ch Singer. Oxford University Press, Oxford. Galen (1968). On the Usefulness of the Parts of the Body, vol. 1. Translated by MT May. Cornell University Press, Ithaca, NY. Garofalo I (1988). Erasistrati Fragmenta. Giardini, Pisa. Gourevitch (1996). Wege der Erkenntnis: Medizin in der ro¨mischen Welt. In: MD Grmek (Ed.), Die Geschichte des medizinischen Denkens. Antike und Mittelalter. Beck, Mu¨nchen, pp. 114–150. Grmek MD (1991). Diseases in the Ancient Greek World. Johns Hopkins University Press, Baltimore, MD and London.

Harris CRS (1973). The Heart and Vascular System in Ancient Greek Medicine. From Alcmaeon to Galen. Clarendon Press, Oxford. Herzog R (1931). Die Wunderheilungen von Epidauros. Ein Beitrag zur Geschichte der Medizin und der Religion. Dieterich’sche Verlagsbuchhandlung, Leipzig ( ¼ Philologus, Supplementband XXII, Heft III). Hippocrates (1959). The Sacred Disease. Hippocrates with an English translation by WHS Jones. Harvard University Press, London and New York. Hippocrates (1999). On Head Wounds. Edition, translation and commentary by M Hanson. Akademie Verlag, Berlin. Homer (1976). The Iliad, vol. 2. With an English translation by AT Murray. Harvard University Press, Cambridge, MA. Ilberg G (1923). Das neurologisch-psychiatrische Wissen und Ko¨nnen des Areta¨us von Kappadokien. Zschr ges Neurol Psychiat 86: 227–246. Karenberg A, Moog FP (1997). Die Apoplexie im medizinischen Schrifttum der Antike. Fortschr Neurol Psychiatr 65: 489–503. Koehler PJ, van der Wiel TWM (2001). Aretaeus on migraine and headache. J Hist Neurosci 10: 253–261. Krug A (1984). Heilkunst und Heilkult. Medizin in der Antike. Beck, Mu¨nchen. Leven KH (2005). Antike Medizin. Ein Lexikon. Beck, Mu¨nchen. Lloyd GER (1991). The Hippocratic Question. In: GER Lloyd (Ed.), Methods and Problems in Greek Science. Cambridge University Press, Cambridge, pp. 194–223. Longrigg J (1981). Erasistratus. In: Dictionary of Scientific Biography, vol. 3. Charles Scribner and Sons, New York, pp. 382–386. Longrigg J (1993). Greek Rational Medicine. Philosophy and Medicine from Alcmaeon to the Alexandrians. Routledge, London and New York. Moog FP, Karenberg A (2003). Between horror and hope. Gladiator’s blood as a cure for epileptics in ancient medicine. J Hist Neurosci 12: 137–143. Pinault JR (1992). Hippocratic Lives and Legends. Brill, Leiden. Plato (1975). Timaeus. With an English Translation by RG Bury. Harvard University Press, Cambridge, MA. Ritter G (1969). Die Neurologie in der hippokratischen Med¨ berblicks. Nervenarzt 40: 327–333. izin. Versuch eines U Rocca J (2003). Galen on the Brain. Brill, Leiden. Rose FC (1993). European Neurology from its beginnings until the 15th century. An overview. J Hist Neurosci 2: 21–44. Rose FC (1994). The neurology of Ancient Greece. An overview. J Hist Neurosci 3: 237–260. Siegel RE (1976). Galen on Psychology, Psychopathology, and Function and Diseases of the Nervous System. Karger, Basel. Solmsen F (1961). Greek philosophy and the discovery of the nerves. Museum Helveticum 18: 150–197. Souques A (1936). E´tapes de la Neurologie dans l’Antiquite´ grecque. Masson, Paris.

THE GRECO-ROMAN WORLD Soury J (1899). Le Syste`me Nerveux Central, Structure et Fonctions. Histoire critique des the´ories et des doctrines. Carre´ et Naud, Paris. Spillane J (1981). The Doctrine of the Nerves. Chapters in the History of Neurology. Oxford University Press, Oxford. Steger F (2004). Asklepiosmedizin. Medizinischer Alltag in der ro¨mischen Kaiserzeit. Steiner, Stuttgart. Temkin O (1971). The Falling Sickness. A History of Epilepsy from the Greeks to the Beginnings of Modern

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Neurology, 2nd edn. Johns Hopkins Press, Baltimore, MD and London. Vegetti M (1996). Zwischen Wissen und Praxis. Die hellenistische Medizin. In: MD Grmek (Ed.), Die Geschichte des medizinischen Denkens. Antike und Mittelalter. Beck, Mu¨nchen, pp. 81–113. von Staden H (1989). Herophilus. The Art of Medicine in Early Alexandria. Cambridge University Press, Cambridge.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 6

After Galen: late Antiquity and the Islamic world ¨ L A. RUSSELL * GU Texas A&M University System Health Science Center, College Station, TX, USA

A tradition broken and unbroken. (Owsei Temkin, 1962)

INTRODUCTION The period following Galen (d. 200 AD) suffers from a historically flawed perspective, which in turn affects interpretations of the early developments relevant to neurology. A commonly held view is that after Galen medicine declined and anatomical curiosity was put on ice, only to be thawed with Vesalius’ Fabrica (1543). His dissections, exemplified by numerous illustrations, such as that of the brain, signaled the beginning of “modern scientific anatomy” (O’Malley, 1965; Cunningham, 1997). In such a view, a period over a millennium that encompasses Late Antiquity–Byzantine and Islamic civilizations, as well as the Medieval Latin West, is regarded as having made hardly any significant contribution to medical knowledge. The cause is attributed to the crushing authority of “Galenism” in medical thinking, which had emerged in late Antiquity. With redactions and paraphrases in textbooks, the ambiguities and uncertainties of Galen had been removed, leaving “dead book” knowledge, a frozen structure that allowed little change (Ullmann, 1978). With lack of dissection, Galen’s errors were perpetuated when “simple, direct observation” would, it is assumed, have revealed them (Patten, 1992). Furthermore, both the Byzantine and the Islamic periods are regarded largely as historical relay stations: the former for preserving and passing on the Greek and Hellenistic legacy via Syriac to the Arabic/Islamic world; the latter via Arabic to the medieval Latin West. This role of transmission, though important in itself, has served to divert attention from the achievements that were made during this period. *

Scholars have increasingly shown that starting in Late Antiquity (4th century), followed by the Islamic civilization, important changes were taking place “even as the participants themselves claim to be maintaining past tradition” and “these changes in turn come to be seen as part of that tradition” (Nutton, 2004). Conversely, when the Renaissance figures, such as Vesalius, were claiming to break with the past, they were still maintaining Greco-Arabic tradition (Siraisi, 1987, 1990; Russell, 1994a; Cunningham, 1997). To properly understand and evaluate developments pertaining to the brain, nerves, and related disorders, we need to identify and distinguish the changes from what is perceived as tradition. It is also essential to recognize that our knowledge of these periods is incomplete. There are gaps in the existing records due to loss, as well as present inaccessibility in print of important works that still remain unpublished in libraries.

The first Renaissance Two key developments can be singled out between the 9th and the 12th–13th centuries with profound consequences for the history of science in general and the history of neurology in particular. Between the middle of the 8th and the 10th centuries, all the extant available Greek and Hellenistic works were resurrected through translations initially into Syriac, followed by more accurate versions into Arabic in Baghdad under the ‘Abba¯sid dynasty. They were brought together and given a new lease of life through an unprecedented translation movement (Gutas, 1998). If the Renaissance is broadly defined as the “rebirth” of Greek knowledge, then one can argue that it is in this intellectually (so-called) “frozen” period that the first “Renaissance” took place.

Correspondence to: Professor G.A. Russell, PhD, Texas A&M University System Health Science Center, Department of Humanities in Medicine, College of Medicine, 102 Reynolds Building, College Station, TX 77843-1114, USA. E-mail: russell@medicine. tamhsc.edu, Tel: +1-979-845-6462, Fax: +1-979-845-8634.

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The Arabic translations into Latin in the 12th century, including original Arabic works, through largely bilingual Jewish and other interpreters, laid the ground for the Italian Renaissance, which thus represents the second “rebirth” with its own unique features (Lindberg, 1978, 1992). Without the Arabic one, however, and its subsequent influences, the 15th-century Latin Renaissance in the sciences and philosophy would have been inconceivable in the way it occurred, and the form it took, including the responses elicited even by its rejection of the Arabic translations of Greek works. Neither movement, however, was a product of merely accessing “preserved” knowledge through translations, whether directly from the Greek or Arabic sources (Russell, 1994a, 2002; Saliba, 2007). What can clearly be established is that the transmission to the West embodies the culmination of a millennial evolution, during which medical and other knowledge neither suffered a “catastrophic decline,” nor remained static. Starting in Late Antiquity, Galen’s legacy was modified conceptually as well as in style, in ways ranging from subtle to dramatic through commentaries. It was broadened in content (beyond Galen) with additional influences through encyclopedias (with case descriptions and pharmacopoeia). In the Islamic period, the cumulative knowledge was systematized with critical responses, corrections, and novel interpretations. The “doubts about Galen” undermined the Galenic authority in specific areas, such as vision, at times diverging significantly from the Greek and Hellenistic traditions. In fact, an entirely new paradigm was initiated in visual optics, out of which a concept of fundamental and lasting importance emerged for neurology. The “point to point correspondence theory” of image formation in the eye (Ibn al-Haytham/Alhazen: 960–1040 AD) paved the way for the anatomical principle of functional projection (in modern terms, “mapping”), which is usually attributed to Descartes in the 17th century. In this chapter, some of the key areas (in Late Antiquity and the Islamic periods) relevant to “neurology” will be outlined by: (1) identifying the developments after Galen; (2) considering to what extent the features of the inherited “Galenism” were modified in the Islamic period (using selected examples, rather than a repetitive account of all the variations); and (3) focusing on the divergence from the established tradition that initiated a paradigm shift, pointing the way to Descartes and beyond.

LATE ANTIQUITY: EMERGENCE OF GALENISM Late Antiquity (2nd–7th century) marks the gradual emergence of an enduring medical system, which has been labeled as Galenism (Temkin, 1973). Based on Galen, it came to embody a theory of comprehensive explanatory power of the body in health and disease

together with a substantial range of clinical applications and therapeutics. Galen’s views acquired an undisputed authority through simplification and redactions of his texts, with no challenging alternatives (Nutton, 2004). There were, however, arguments over interpretations of Galen’s texts, as well as attempts to harmonize Galen with Aristotle, Plato, and other influences. Such activities expanded Galenic knowledge that ultimately affected interpretations of the brain function and the senses, as well as related disorders. The Late Alexandrian medical curricula had expanded to the Hippocratic texts by adding the synopses of Galen’s so-called 16 books that were collectively referred to as the Summaria Alexandrinorum. Through these texts, abridged for memorization, read in a specific order and explicated by means of lectures and commentaries, a didactic Galenic canon emerged. By the 5th century, the Alexandrian syllabus offered a cogent and well-structured overview of Galenic medicine, encompassing anatomy, humoral physiology, pathology (general diseases pertaining to the whole body, as well as diseases specific to individual parts, ordered from “head to toe”), and therapeutics, extending to dietetics/nutrition and hygiene. As medical training was based on reading texts with a teacher, medicine came to be defined in terms of specific books (Iskandar, 1976). Furthermore, in the medical compendia that developed between the 4th and 7th centuries, the attempts to present a succinct account of a particular topic, through paraphrases, also led to the disappearance of ambiguities and qualifications in Galen, replacing the practical and empirical side of his works with the dogmatic. At the same time, however, such encyclopedic works as those of Oribasius of Pergamum (c. 325–400 AD), Aetius of Amida (fl. 530 AD), and Paul of Aegina (Alexandria, c. 630 AD) introduced other sources than those of Galen, frequently with direct quotations from original texts (Nutton, 2004; Pormann, 2004). In Aetius, for example, we find a description of ventricular localization of cognitive function by a Byzantine physician, Posidonius (4th century AD), that is the only extant record (Aegineta, 1846; Aetius, 1935). More importantly, it presents a view that is different from Galen.

Medicine and philosophy: priority of the brain With the gradual separation of theory and practice, two developments are particularly significant for discussions of brain function and the senses. Galen’s emphasis on the need for a physician to understand some philosophy came to be interpreted as a need for greater training in logic and theoretical content of medicine. In the commentaries on Aristotle, a growing overlap emerged between philosophy and medicine (Westerinck, 1964; Cunningham, 1986).

AFTER GALEN: LATE ANTIQUITY AND THE ISLAMIC WORLD 63 Some of the Aristotelian commentators had a fairly the front part [meros] of the brain has been extensive acquaintance with Galen, either directly harmed, the imaginative faculty alone is injured; through his own works or indirectly through tradition. when the middle ventricle [ koilia: “hollow”] of Their knowledge of medical concepts, and specifically the brain has been harmed, there occurs a perGalen’s anatomy, influenced their interpretations of version of the cognitive faculty, while the back the senses, particularly vision, as in the case of Alexanof the brain has been harmed below the der of Aphrodisias (198–211 AD). The reconstruction occiput, the faculty of memory is destroyed, of Aristotelian views, using Galen, was combined also, and with it the other two are also completely as in the case of Philoponus in the 6th century, with a destroyed. (Bk. VI, 2) Neoplatonist perspective. This meant that in accounting In locating the three functions, Posidonius’ use of two for the primacy of the brain over the heart, the empiridifferent terms, “part” (meros) and “hollow space” cal evidence from clinical cases and Galen’s animal (koilia), led scholars to argue that he specifically vivisection could be utilized to argue for the brain as names only one ventricle (the middle) associated with the central organ of the body controlling the senses a function (cognitive). He depicts the other two sites (Westerinck, 1964; Clarke and O’Malley, 1968; Todd, as “anterior and posterior parts,” and not as ventricles 1984; Sorabji, 1986). of the brain (Wolfson, 1935; Pagel, 1958; Green, 2003). Nemesius in his On the Nature of Man (De natura hominis) also uses the two terms with some degree of Localizing brain function: ventricles ambiguity in locating the senses in the anterior “venOne consequence of the confrontation of Galenic, tricles” but the intellect in the “middle part” and memAristotelian, and Neoplatonist views, and the assimilaory in the “back of the brain” (Pagel, 1958; Clarke and tion of clinical material into philosophy, was the localiO’Malley, 1968; Kemp, 1996; Green, 2003): zation of the cognitive functions in the ventricles (i.e., . . . the senses have their sources and roots in the the “hollow spaces”), which was not in Galen. front ventricles of the brain, that those of the Although his views varied in different works, in faculty of the intellect are in the middle part of locating sensation, intellect, and voluntary motion in the brain and those of the faculty of memory in the brain, Galen did not express a clearly defined venthe hinder part of the brain. . .[also] the soft tricular theory. The psuché was present throughout nerves of sensation descend from the middle part “the actual body of the brain [cerebrum]” and “not just and from the front ventricles (“hollows”) of the in any of the ventricles,” with the pneuma serving as its brain, while the motor nerves proceed from the “primary tool” (Galen/May, 1968, 1978; Todd, 1984). posterior ventricle (“hollows”) and the marrow For example, Galen had described the damaging effects of the spine. (Nemesius, 1955, pp. 341–342. Telof injury being progressively more serious from the fer renders the term “koilia” as “lobes” and “parts” anterior to the posterior ventricles, but he did not assoinstead of as ventricles) ciate the injuries to the ventricles with the different cognitive functions (Pagel, 1958; Green, 2003). Although its origins remain unclear, there is sufficient Such an association has been traced to the 4th-century evidence that the concept of a tripartite ventricular locaByzantine physician Posidonius, and his contemporary, lization of function emerged in Late Antiquity. The Nemesius of Emesa, a Syrian physician and bishop. In explicit references to “medical writers” in St. Augusdescribing the harmful effect of “phrenitis” on the brain, tine’s account in his Literal Meaning of Genesis (401 Posidonius, as reported by Aetius (in De Re Medica), AD) suggest that it was already current in some form identifies both the losses of specific functions (deriving among physicians by the end of the 4th century: from Galen’s observations) and their related sites: . . . the medical writers point out that there are . . . there are those who have been harmed in the three ventricles in the brain. One of these, which imaginative faculty alone, but their cognitive is in the front near the face, is the one from faculty and memory are preserved; or the cogniwhich all sensation comes; the second, which is tive faculty alone has been injured, but the imain the back of the brain near the neck, is the ginative faculty and the memory are preserved; one from which all motion comes; the third, or there is harm to both the imaginative and which is between the two, is where the medical the cognitive faculties, but the memory is prewriters place the seat of memory. Since moveserved; but when memory perishes in the case ment follows sensation, a man without this seat of feverish afflictions, both the cognitive and of memory would be unable to know what he imaginative are altogether destroyed. Thus when ought to do if he should forget what he has done.

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G.A. RUSSELL Now, the medical writers say that the existence of these ventricles has been proved by clear indications of cases in which these parts of the brain have been affected by some disease or pathological condition. For when sensation, motion, or memory of motion is impaired, there was a clear indication of the function of each ventricle, and by applying remedies to these different ventricles physicians determined which parts needed healing. (Augustine, 1982, II, pp. 18–19)

What is attributed to “medical writers” is the site of the three ventricles on the basis of clinical evidence and the identification of their functions as sensation, motion, and memory. No specific mention is made of the intellect, and the memory is placed in the middle ventricle. The variations indicate the lack of a consistent or a fully developed theory. Some scholars have emphasized the role of the Christian Patristic tradition in the emergence of ventricular theory. The early church fathers turned to the Greek and Hellenistic sources to resolve their concerns as to whether the “soul” (not the Aristotelian psuché) could be distributed throughout or concentrated in certain parts of the body. As articulated by such theologian-physicians as Nemesius, since the “soul” was not a corporeal substance, it could not be identified with body parts. Yet it was joined to the body (as sunlight to the air). The Platonic tradition combined with the clinical evidence from Galen, showing loss of specific function with damage to parts of the brain, provided a compromise. The “soul,” itself could not be localized, but its functions could be “housed” in particular sites in the brain. As an intermediary for the non-corporeal “soul,” the “pneumatic hollow spaces” of the ventricles seemed to be more appropriate than Galen’s substance of the brain (Pagel, 1958; Harvey, 1975). The infusion of the metaphysical “soul” into the physical concept of psuché (as a function of the brain and pneuma) initiated a complex dichotomy. The ventricular theory illustrates the attempt, from impairment, not only to define normal function but also to identify its site. This represents a critical step in the development of localization of brain function, going beyond that of Galen.

THE ARABIC/ISLAMIC PERIOD Galenism defined, modified, and questioned The art of physic is a philosophy which does not tolerate submission to any authority, nor does it accept any views or yield to any dogmas without proper investigation. (Rhazes: Doubts Concerning Galen [Kita¯b fi’l-shuku¯k ‘ala¯ Ja¯līnu¯s])

A key figure in the dissemination of Galen and Galenism was “ Hunayn ibn Isha¯q al-iba¯dı¯ (807–877 AD; ˙ Latin, Johannitius), a Nestorian Christian, who together with his collaborators provided remarkably accurate Syriac and Arabic translations of Greek works. In fact, those who initiated translations from Greek and Hellenistic works were largely Nestorian, and those who subsequently contributed to medical knowledge were Christian, Zoroastrian, Jewish, and Muslim. They came from various ethnic and linguistic backgrounds, and a vast geographical area extending from Central Asia and Persia, via North Africa to Spain. The result was a synthesis of diverse influences where Arabic served as the common medium of communication analogous to Latin in the West. At his death, H “unayn’s translations included 95 titles into Syriac and 34 into Arabic of Galen’s works alone, thus making almost the entire Galenic corpus available to physicians (Meyerhof, 1926). Galen became incorporated into the Arabic/Islamic and subsequently western medical tradition through “unayn’s versions. An extant list by H H “unayn Ibn Isha¯q himself gives an idea of what texts were of ˙ initial interest at the time and why. First, the titles are given in the order that they were expected to be read according to the medical curriculum at the School of Alexandria (Meyerhof, 1926). Second, most of the translations were specially commissioned, indicating the familiarity of the Syriac physicians with the synopses of Galen’s texts in the Summaria Alexandrinorum (Bergstra¨sser, 1925, 1932; Iskandar, 1976; Ullmann, 1978). For example, Yuh anna¯ ibn Ma¯sawayh (d. 857 AD; ˙ ˙ 17 years old, Latin, Mesue) commissioned “ Hunayn, then to translate nine of Galen’s books, specifically on anatomy and anatomical procedures, because of his interest in the brain. He was a personal physician to the ‘Abba¯sid caliph, al-Ma’mu¯n, and chief physician at the hospital in Baghdad. Ma¯sawayh, as reported by Ibn al-Qift¯ı (d. 1248 ˙ ¯), not only kept “Barbary ˙ apes” AD; Ta’rikh al-hukema _ (like Galen) for anatomical investigation but appears to have considered even vivisecting his own “idiot” son’s brain to understand the cause. I have a long face, a high cranium, a broad forehead, and blue eyes. And I was endowed with intellect and a memory for everything that takes place within my hearing. The daughter of alTH “ayf urī was my wife, the mother of my son, and the most beautiful woman whom I had ever seen or heard of, but she was stupid and simple-minded, neither making sense in what she said, nor comprehending what was said to her.

AFTER GALEN: LATE ANTIQUITY AND THE ISLAMIC WORLD So her son received all of our bad qualities and none of our fine attributes; and if it had not been for the sultan interfering with what did not concern him, I would have dissected this son of mine while living, just as Galen dissected humans and [Barbary] apes, so that I might learn by means of his dissection (tashrı¯h) the causes of his stu˙ pidity, and he would have been released from his condition in this world. Furthermore, I would have won acclaim for her family by recording in my book the structure of his body, the pathways of his arteries, veins and nerves, described as a science. But the sultan prevented that. (Ibn al-Qift¯ı /Lippert, 1903, pp. 390–391; Savage˙ Smith, 1995, p. 83) Ma¯sawayh was not unique in his keen interest in ˙ Galen’s treatises on dissection. And contemporary records show no legal or religious prohibition (Savage-Smith, 1995). Apart from occasional textual evidence of direct observations, however, Galen’s On Anatomical Procedures in 15 books seems to have provided a vicarious hands-on dissection experience for physicians, and it has in fact survived in its entirety only in Arabic translation. An extremely detailed and long description of the ¯ lı¯ibn al-‘Abba¯s alstructure of the brain is given by ‘A Maju¯sı¯ (Haly Abba¯s; d. 994 AD) in his Complete Book of Medical Art, Kita¯b ka¯mil al-sina¯‘a al-t¸ibbīya; (1985; _ displays a thoroughly see also De Koning, 1903), which rational approach to medicine, devoid of any metaphysical concepts (Russell, 1994b). Translated partially by Constantine the African (d. 1087) as Pantegni, then in its entirety by Stephen of Antioch (1127) as Regalis dispositio, and printed in 1492 in Venice, it was one of the most influential books in medicine, until it was overshadowed by Avicenna’s Canon of Medicine (Harvey, 1975; Ullmann, 1978; Burnett, 1994). The Pantegni, for example, served as a channel for the transmission of new terminology directly from Arabic, some of which is still in use at present, such as the “pia mater” (umm al-raqīq) and “dura mater” (umm al-ja¯fī ) (Strohmaier, 1970). A close textual comparison of Haly Abba¯s with Galen on the brain has revealed definite signs of independent observation (sinus occipitalis, pericranium) in spite of his dependence on Galen (De Koning, 1903; Wiberg, 1914; Russell, 1994b). Haly Abba¯s also describes cutting into the brain of a living animal and then closing it up again, whereby the temporary loss of sensation and motion are restored. Although this account derives from Galen (De placitis Hippocratis et Platonis, VII.3), Haly Abba¯s uses it to distinguish the pneumatic “animal spirits” (al-arwa¯h), produced by the body, _

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from the immaterial “soul,” which he relegates to the province of philosophy as outside the physician’s concern (Harvey, 1975; Burnett, 1994). A significant case of concrete deviation from Galen occurs in Ibn al-Naf ¯ıs’s (d. 1288 AD) critical commentary on the anatomy sections of Avicenna’s Canon. Ibn al-Naf ¯ıs disputes, on the basis of firsthand observation, Galen’s notion of invisible pores in the interventricular septum of the heart. Indeed, the heart has only two cavities, one of them filled with blood, on the right side, and the other filled with pneuma, on the left. There is definitely no passage between these two, for otherwise the blood would pass to the place of the pneuma and would degrade its essence. And [furthermore] dissection (tashrı¯h) refutes what they said, for the septum (ha¯jiz)˙ between the two ventricles is much thicker than elsewhere. (Savage-Smith, 1995, Sharh Tashrı¯h al˙ Iskandar, ˙ Qa¯nu¯n, WMS.Or. 51, fol. 357b; also 1967, fol. 54b) The implications of this observation, which Ibn alNaf ¯ıs developed in detail, constitutes a major change from Galen’s concept of “ebb and flow” to a circular movement of blood between the heart and the lungs. Although not taken up in the Islamic world, its influence on specific Renaissance figures in the West has been an on-going debate (Iskandar, 1967, 1974; Jacquart, 1996). “ Hunayn also provided a convenient outline of the Galenic medical system in two of his own works. The Questions on Medicine for Students (al-Masa¯’il fī alt¸ibb li’l mutaallimīn) (1980) was designed primarily as a simple handbook with lucid definitions and didactic style to provide students with a concise introduction to medical theory and practice (including the use of medicaments/pharmacopoeia). Written in the form of questions and answers, it also served for examining physicians as licensed to practice. Widely circulated, “ Hunayn’s concise summary influenced the content and organization of subsequent medical writings in Arabic, starting with Rhazes (Zakariyya¯ al-Ra¯zı¯, ca d. 925–933 AD) (H “unayn Ibn Isha¯q, 1980). Theory, for example, came to be seen only˙ as a means to enhance clinical utility or practice. The medieval physicians also became acquainted with Galen initially through H “unayn Ibn Isha¯q’s ˙ works, which were translated into Latin much earlier than those of Galen. The Masa¯’il may in fact have been the first Latin translation of an Arabic medical treatise (as Isagoge by Constantine the African) in the latter part of the 11th century and used at Salerno, as part of the standardized theoretical curriculum (the

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articella) at medical schools (Jacquart, 1986; Siraisi, 1987; Burnett, 1994; Newton, 1994; Nutton, 2004). What is outlined on “nerves” in the Masa¯’il is treated in detail in “ Hunayn’s second work, the Ten Treatises on the Structures of the Eye, its Diseases, and their Treatment (Kita¯b al-‘ashr maqa¯lat fi al-‘ayn) (1928), which also contains the oldest extant schematic drawings of the eye. He starts with the nature and structure of the eye, and devotes the second treatise to the nature and uses (function) of the brain, and the third to the “pneuma.” Written over a period of 30 years (830–860/870), and based largely on Galen’s De usu partium, and De placitis Hippocratis et Platonis, “ Hunayn’s Ten Treatises is neither a slavish reproduction nor a summary of Galen’s differing views, with which he was thoroughly familiar (Galen, 1968, 1978; Eastwood, 1982; Rocca, 2003). It rather presents a logically coherent view, updated by the post-Galenic developments, with some differences of interest. The brain is regarded as one of the four principal organs, with the heart, liver, and the testicles. The heart–brain dichotomy is bypassed by an emphasis on two parallel yet interdependent systems. The heart is the source of life and natural warmth; the brain is the source of sensation and voluntary movement, as well as the cognitive powers. The teleological approach is exemplified in “ Hunayn’s discussion of “the cold nature of the brain” (a concept that goes back to Aristotle) to counteract the natural heat produced by brain activity. The brain performs its tripartite functions of “sensation (al-hiss), voluntary movement (al-hareka al_ by itself ira¯d “iyya) _and judgment (al-siya¯siyya),” either or by means of the nerves that originate from the brain and the spinal cord. Closely following Galen, “ Hunayn identifies the seven pairs of cranial nerves, and distinguishes between “soft” (sensory) and “hard” (motor) nerves. From the brain, “the power of sensation and the power of motion proceed through the nerves into all the sensory and motor organs.” The senses are viewed hierarchically with emphasis on sight as “the most delicate” (H “unayn, 1928). On nerve transmission, “ Hunayn presents a unified doctrine that is not explicitly stated in Galen. Taking up the question of whether the nerves convey the “substance” or the “force” of the “pneuma” from the brain, he argues in his treatment of vision that only the optic nerve is hollow and conveys the pneuma itself. All other nerves conduct a “force” or power (quwwa) via the pneuma, not the substance (H “unayn, 1928). What Galen had considered only for the motor nerves, carrying from the brain to the muscles a “power” (dynamis) or an “alteration” which “does not reside in the nerve itself,” “ Hunayn generalizes to all except the optic nerves (Eastwood, 1982).

We also find in “ Hunayn the elements of a clearly articulated ventricular localization of cognitive function. “The act of thinking,” which is “effected by the brain itself,” involves “the power of imagination (al-takhayyul), reflection (al-fikr) and recollection (al-dhikr).” These functions are mediated by the “psychic spirit” or pneuma in the ventricles, which are four in number: . . . two cavities in the anterior, one in the posterior part and one in the intervening space between anterior cavities and the posterior one . . . Through the pneuma in the posterior cavity, movement and the act of recollection are accomplished; through the pneuma in the anterior part of the brain, sensation and imagination; and through the pneuma in the middle part of the brain, reflection. (H “unayn, 1928, pp. 17–18) Subsequently, Rhazes provides a schematic illustration of the position of the ventricles by a drawing which consisted with four circles (De Koning, 1903).

The function of the vermis and the pineal gland Furthermore, “ Hunayn also provides a description of the role of the “vermis” (choroid plexus) in the transmission of the pneuma between the ventricles, which is usually attributed to Qusta¯ ibn Lu¯qa¯’ (864–923 AD) ˙ Wilcox, 1987). As “ (Pagel, 1958; Harvey, 1975; Hunayn states, the pneuma passes from the anterior ventricle to the middle, and from there to the posterior cavity by way of a canal between the two cavities. But this canal is not always open, for it contains in its hollow something resembling a worm by which it is blocked until Nature intends to admit the animal spirit from the middle to the posterior cavity. When she intends to move it on, she withdraws that worm like (structure) and gives passage to such (quantity) as she wishes to let pass; after that she returns it to its place. (H “unayn, 1928, p. 18) The “valve” action is regarded by some historians as an important development in the ventricular theory, by adding a dynamic element to a static model (Pagel, 1958; Clarke and Dewhurst, 1972). ¯ l ¯ı ibn al-‘Abba¯s al-Maju¯sı¯ (Haly Abba¯s) consid‘A ered this “valve” action in the passage from the middle to the posterior ventricle as being complex in nature, including, besides the vermis, also the pineal gland (an idea that was originally rejected by Galen). The vermis is

AFTER GALEN: LATE ANTIQUITY AND THE ISLAMIC WORLD an elevation that stretches along the longitudinal direction of the passage . . . [and] looks like a big worm . . . made up of many parts . . . like that of links in a chain . . . its one end begins behind a body of a glandular substance which looks like a fir cone and the other end stops at the beginning of the posterior ventricle. He further gives a detailed description of its action: [the worm] also alters its shape, in that the end which touches the posterior ventricle of the brain in the region where the overlying membrane borders on it, the worm [vermis] is curved upwards and thin; after that it continues little by little to increase and become broader/thicker, until its ridge reaches the interval between the nates and becomes one with them (same height or width); thus when extending in the longitudinal direction, the worm, will fill out the latter so as to make a totally safe enclosure; when contracting behind (in a posterior direction) it pulls along with its convex end, and thus the channel opens . . . for in proportion as the worm contracts, the channel opens because by contracting and retreating the worm is shortened in length and increased in breadth . . . till it assumes the likeness of the shape of a ball; when its contraction is insignificant, the opening of the channel will be small, but when its contraction is great, the opening of the channel will likewise be large . . . (De Koning, 1903, p. 284) For Zakariyya¯’al-Ra¯zı¯ (Rhazes) the pineal gland served “as the guardian and gate keeper of the system, controlling the flow from the anterior and middle ventricles to the posterior one.” The essential similarity of this view of the pineal gland to that of Descartes in the 17th century has been pointed out by historians (Pagel, 1958; Clarke and Dewhurst, 1972; Harvey, 1975; Green, 2003; Martensen, 2004).

Sources for neurology Starting with “ Hunayn ibn Isha¯q, the material relevant to ˙ of source: (1) the specianeurology is found in two kinds lized encyclopedic works on medicine, including surgery, as well as on natural philosophy (the sciences), and (2) treatises dealing with specific medical subjects. Some of these were written in response to individual patients in order to deal with their clinical conditions, ranging from problems of memory/recall to brain fevers and asthma. The encyclopedic compendia evolved largely between the 9th and the 11th centuries from those of loosely compiled, disparate materials into systematically organized and unified reference works by Zakariyya¯ al-Ra¯zı¯ ¯ lı¯ ibn al-‘Abba¯s al-Maju¯sı¯ (Rhazes, d. 925/933 AD), ‘A

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(Haly Abba¯s, d. 982/995 AD), Ibn Sina¯ (Avicenna, d. 1037 AD), and Ibn Rushd (Averroes, d. 1198 AD). They presented medicine as logically coherent both in theory and practice (Russell, 1994b, 2002). For example, Abu¯ al-Qa¯sim al-Zahra¯wı¯’s (Abulcasis/Albucasis, c. 939–1013 AD) influential book on “surgery” (Kita¯b al-Tasrīf), with illustrations of surgi_ cal instruments, constitutes only the last part of his 30-volume work on medicine. It includes neurological disorders (epilepsy, migraine/headaches, facial palsy, partial paralysis or localized numbness, stroke), head and spinal injuries along with surgical treatments largely by cauterization (although used with caution as a last resort), and instruments specific to brain and nerve disorders (such as cranial drills that avoid puncture of the “dura mater”) (Albucasis, 1973). The encyclopedic compendia also reflect the progression in the medical background of the physician from the Syriac theological tradition to a philosophical one, which is epitomized by Avicenna (Russell, 2002). His Qa¯nun fī al-t ibb (before 1015 AD), in its Latin translation as the _Canon of Medicine, served as a textbook at medical schools beyond the 17th century and “ultimately revolutionised the content of medicine and the allied sciences” (Siraisi, 1987). These works brought together cumulative knowledge of the brain, spinal cord, and the nerves, as well as related diseases from extensive pre- and post-Galenic sources. Organized according to Galenic principles, they first introduced the fundamental anatomical systems of the body (bones, muscles, nerves, arteries, and veins), followed by the “compound” parts (the liver, heart, brain, and sensory and generative/reproductive organs). In the Canon, Avicenna treats the anatomy and function of the brain in the general account of the principal “actions” of the body (Bk I), and then in the sections on diseases (Book III) starting with those of the head, brain, nerves, spinal cord, and the sensory organs (Gruner, 1930; Shah, 1966). Avicenna’s second compendium, the Shifa¯’ (Sufficientia) on natural philosophy (the sciences), is an attempt to encompass total knowledge as a “cure” (shifa¯’) for “diseases” of ignorance. The treatment of the brain, nerves, and the spinal cord is largely taken from the Canon. It also contains his important synthesis of Galen and Aristotle (especially Book II, 6, Kita¯b al“ Haya¯wa¯n; Latin: Liber de Anima), which resolved the dichotomy of the brain and the heart as the principal organs in two parallel systems (Musallam, 2004).

Ventricular localization Avicenna described the mechanism of brain function in terms of “internal senses” (al-hiss al-batina) with spe˙ cific locations in the lateral, middle, and_ the posterior

68 G.A. RUSSELL ventricles. They were distinguished from the external similar Medieval diagrams, which predate Mansu¯r, ˙ senses (sight, hearing, smell, taste, and touch), which have been a subject of much discussion (O’Neill, were thought to occur peripherally via the nerves as 1969; Russell, 2004/2002). extensions of the brain itself. The internal senses were The nervous system: a hydrostatic model defined as the powers (quwa¯) of the “mind” (nafs/ psuyche´) which Avicenna considered as the highest The doctrine of [animal] Spirits, to explain the integrative principle, unifying the diverse operations animal functions and their Diseases has been of the brain (Kita¯b al-Naja¯t). The internal senses so readily and universally receiv’d from the organized sensory information in five ways. The first Days of the Arabian Physicians (and higher) organization constitutes the “pooling of the senses” down to our present Times, that scarce one (al-hiss al-mushtarak; translated into Latin as “sensus (except here and there, a Heretick of late) had _ communis”) where information from one sense is called this Catholic Doctrine into question . . . conjoined with information from other senses. This (Cheyne, 1733) enables sensory information from different modalGreco-Arabic attempts to understand the structure ities to be integrated. Second, this sensory montage and function or “uses” of the brain, the nerves, the is then preserved as an “image” (khaya¯l), enabling senses, and their related disorders were based not awareness to continue independently of sensory experionly on anatomy and clinical experience but also on ence. The third function is “editorial,” in terms of analogies with contemporary physics, especially selectively separating and combining these images (alapplied mechanics and hydrostatics. They drew on a musawwira/al-mutakhayyila) and also ideas (al-mufak_ Without this editorial control of sense impreslong tradition, both empirical and written, of the conkira). struction of water clocks, through such influential sions or record, experience would be unintelligible. treatises as the Pneumatics of Philo of Byzantium The fourth function (al-wahmiya) gives meaning (2nd century BC), the Mechanics of Hero of Alexan(ma’na) or significance (good, bad, pleasant, unpleadria (1st century BC) and Pseudo Archimedes, of much sant) to what is conveyed by the external senses. The later origin. fifth function is to conserve in memory ( ha¯fizd “a) the Under the ‘Abba¯sids, with a formal application of meanings (ma’a¯ni) of experience, which_ can then mechanics and hydrostatics, the combined legacies of be recalled. Avicenna further emphasizes that these centuries-old Greek, Hellenistic, and Sassanid Iranian internal powers function in qualitatively different traditions of the construction of water clocks were ways. The “editorial” and “associative” functions are further developed with trick vessels, fountains, and dynamic, ordering sensory material to give it meaning. related automata (hiyal) in the works of the Ba¯nu¯ MuThe other three (sensory pooling, representation _ sa¯ brothers (10th century) and al-Jazarı¯ (13th century), of images, memory) are static principles, which receive along with utilitarian devices. The successful operation and conserve (copies of) sensory information. of water clocks depended upon achieving a constant Avicenna’s detailed theory transformed the static rate of discharge of water from a reservoir involving doctrine of localization of cognitive functions in the valves and a closed loop system, operated by a feedback ventricles into a dynamic process (Avicenna, 1952, control (Hill, 1978; Ba¯nu¯ Mu¯sa, 1979; Hassan and Hill, 1956). 1986). The analogies with mechanical actions provided The fully developed form, in which the ventricular a coherent explanatory power to the “pneuma” theories, theory influenced the West, was largely that of Avicenna, as well as some consistency to clinical practice. The which was significantly expanded from the earlier mechanisms that created automata were of particular versions. His major contribution is, however, greater to relevance. Although associated with Descartes in the psychology than to neurology (Avicenna, 1952, 1956, 17th century, the usage of such models had become a 1972; Clarke and Dewhurst, 1972; Harvey, 1975). significant factor in the development of rational, An increasing emphasis from the 10th century mechanistic and quasi-mechanistic explanations of the onward on teaching anatomy directly from Galen, nervous and sensory systems of the body. rather than from the Alexandrian synopses of his In the description of the ventricles and nerve conworks, led also to individual works on anatomy. One duction, one can identify the mechanism of the hydrosuch text, known as the Tashrīh-i Mans urī or Mansu¯r’s static model. The “pneuma,” as the sensory and Anatomy (c. 1394–1409 AD), uniquely_ contains _fullnervous medium, was contained within the “cavities” page schematic illustrations of the Galenic systems of the brain, the ventricles, which served as reservoirs. of the body, which include the nerves, along with the bones, muscles, veins and arteries. Their origin, It was in continuous flow, unless blocked, from one as well as their relationship to, and influence on, ventricle to the other. The transmission of the pneuma

AFTER GALEN: LATE ANTIQUITY AND THE ISLAMIC WORLD between the ventricles was regulated by means of a stopcock or valve action, as in automata, to either allow or block the flow. Whether this function was given to the “worm-like structure,” the “vermis” (i.e., the choroid plexus), or the pineal gland as the “gate keeper,” the mechanism remained the same of alternately opening and closing the passage as needed through which the pneuma flows – for example, from the middle to the ¯ lı¯ ibn al-‘Abba¯s posterior ventricle (H “unayn ibn Ish a¯q; ‘A al-Maju¯sı¯). It was forced through ˙the nerves by the pulsating action of the brain. The cranial and peripheral nerves (like the blood vessels) were a network of conduits or pipes, extending from the brain and the spinal cord to all parts of the body. Here it should be mentioned that the Galenic “vital spirit” (arising from the heart) was replaced in Arabic by “animal spirit” for the “pneuma” as the medium of the nervous system. It was due to a mistranslation of the Greek “pneuma zo¯tikon” as “animal spirit” (ru¯h hayawa¯nī) (Ullmann, 1978). Transmitted into _ ˙directly from Arabic, “animal spirits” remained Latin in use until the 17th century, as exemplified by Descartes (Clarke and O’Malley, 1968, 1978).

Sensation: tactile mechanics Both sensory and motor nerves produced their effects through the flow to the sense organs or the muscles of “animal spirits” or “pneuma,” so rarefied and subtle that it was otherwise undetectable. Such a theory gained meaning, as well as explanatory power from analogies with the mechanics of projectiles and impact. The sensory nerves were characterized by a “tactile” approach, which explained awareness in terms of mechanical contact, as with a blind man’s stick. Whether direct, as in touch (skin contact), or at a distance as in sight, sensory awareness was achieved by means of contact (Russell, 1996). What made contact possible was the network of sensory nerves as tactile extensions of parts of the brain and the spinal cord. The sensory nerves were described as “soft,” and could receive “imprints” or impressions upon contact ¯ lı¯ ibn al-‘Abba¯s al-Maju¯sı¯ in De Koning, 1903). (‘A For example, the “hollow” optic nerve conveyed the visual pneuma from the brain to the eyes (crystalline humor and pupil) to contact via the air and gain an impression of the visual object. Such sensory awareness consisted of holistic impressions, which were received complete, all at once, also analogous to the Aristotelian imprint of the form of the signet ring on wax (Russell, 1996). The motor nerves were believed to be hard, similar to rigid conduits, in which the transmission or “propulsion” of the pneuma was faster than in the compliant sensory nerves (H “unayn ibn Isha¯q, 1928, ˙

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1980). The mechanical principle thus helped explain the speed of transmission of the pneuma (or its power) to the muscles and the rapidity of voluntary movement.

Clinical applications Hydraulic analogies were applied in clinical cases. The common denominator in causal explanations of brain disorders was obstruction of flow. Any interruption or “break in continuity” of nerve conduction had clinical or functional consequences. It could result from a number of factors that included internal obstruction, excess fluid (humors), severing a nerve, or bursting a vein (as outlined in “ Hunayn ibn Isha¯q’s Masa¯’il). Depending ˙ the function of the ventrion the severity of the damage, cles could be impaired individually or all together. For example, any obstruction in the ventricles due to overaccumulation of humors (originating elsewhere) could cause epilepsy or apoplexy; in the spinal cord and the nerves, it could lead to paralysis or stroke (Harvey, 1975; Manzoni, 1998). In the first book of his ZH “a¯d al-Musd “a¯fir (translated into Latin as the Viaticum, subsequently retranslated into Hebrew, then Latin in 1333 AD), Ibn al-Jazza¯r made the observation that, depending on the site of the retention of excess fluid, the symptom of paralysis could be quite different. He associated paralysis of the right side of the body with loss of speech (aphasia in modern terms), and excess fluids on one side of the head; whereas with the excess fluids in the spinal cord, only movement was impeded without impairing speech (Viaticum, 1515, Bk I, ch. 23, fol. 147 in Karenberg and Irmgard, 1998). The accumulation of excess phlegm, if the open passages between the brain and nose were blocked, also led to pathological conditions, exemplified by certain cases of “fevers” which affected the brain, such as “fara¯nı¯tis/qara¯nı¯tis,” from the Greek, phrenitis (H “unayn ibn Isha¯q, Isaac Israeli), or “meningitis” (sirsa¯m) (al-Ra¯zı¯). ˙ Peccant material in the head did not drain, resulting in convulsions, delirium and death (Ibn al- Jazzar/Bos, 2000; Smith, 1981). Rhazes (1955-1971) describes treating this condition by venesection in his casebook of private notes, which was posthumously put together by his students to constitute the massive Kita¯b al-Ha¯wī f ī’al-tibb (Liber Conti˙ from “sirsa¯m” _ suffering nens). He divided the patients into two groups. He applied bloodletting only to one group, using the other as a control, and recorded his observations, thus providing an early example of a clinical trial (Iskandar, 1990, 1997. For his medical works, see Meyerhof, 1935; Bernburg, 1994). Among his numerous independent clinical observations, for which no known precedents exist, Rhazes also related the loss of sensation or movement to the

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slowing down or interruption of flow in the sensory and motor nerves due to excessive cold. The remedy to warm the chilled nerves by “fiery coloured old red wine, taken neat” (Meyerhof, 1935; Harvey, 1975) is of great interest, suggesting that the warmth would be generated by some means other than the transfer of heat by contact. In a work written as a regimen of health for a patient suffering from asthma (al-rabw), Maimonides (1138– 1204 AD) ascribes the cause to the excessive amount of fluids from the brain, which blocked the passages to the lungs (filling in the bronchial tubes), resulting in severe distress (Bos, 1994; Maimonides, 2002). The increased quantity and sluggishness of the phlegm in old age affected the brain. Ibn al-Jazza¯r explained, in response to an old man suffering from an inability to remember (or retain what he learned), that new memories could no longer be established in old age, just as a frozen surface does not take on the imprint of a seal (Ibn al-Jazza¯r, 1995). Cataracts in the eye were also believed to occur because of the accumulation of matter between the crystalline humor and the cornea (rather than being the actual opacity of the lens itself). Since sight was somewhat restored by couching, it was thought that they impeded the flow of the pneuma from the crystalline humor to the pupil, blocking the continuity of nerve “contact” with the visual object (H “unayn ibn Ish a¯q, ˙ 1980; Eastwood, 1982; Russell, 2000). Although these principles concerning the pneuma were not entirely consistent, these examples illustrate the considerable flexibility of explanatory reference provided by the analogies. This may be one factor in their longevity extending into the 17th century (Clarke, 1978; Lonie, 1981). Using the same analogies, physicians were able not only to differentiate neurological symptom and their sites, but also to make new diagnostic observations that might not have been previously noted.

light to prevent damage to sight). The analogy that Rhazes used for his “new” explanation was that of a float, which regulates the amount of water flow by increasing or reducing the opening at the mouth of a reservoir so that neither too much nor too little reaches the garden (Pines, 1954; Iskandar, 1981; Russell, 1996). In criticizing Galen under the influence of Hippocratic clinical observation, or Aristotle and the Aristotelian commentators, physician-philosophers like Rhazes were beginning to undermine established tactile theories of neural awareness and sensation. In a brilliant series of arguments, for example, Avicenna brought together evidence from diverse sources, including Galen’s ocular anatomy, to reveal the logical absurdity and weaknesses of the existing explanations in vision. His contemporary, Ibn al-Haytham (965–1040 AD; Latin, Alhazen), however, went further. Through his extensive researches on the physics of light and vision, he was able to provide a comprehensive new theory that totally destroyed the viability of Greek and Arabic explanations of visual sensation based on indivisible copies, imprints and holistic impressions. His theory had profound consequences for neurology which have not been noted.

A PARADIGM SHIFT: THROUGH DEVELOPMENTS IN THE PHYSICS OF LIGHT AND VISION

Doubts against Galen?

Truth is sought for itself but the truths are immersed in uncertainties . . . therefore . . . whoever investigates the writings of ‘scientists’ has the duty, if learning the truth is his goal, has the duty to make himself an enemy of all that he reads and, applying his mind to the core and margins of its content, attack it from every side. He should also suspect himself as he performs his critical examination of it, so that he may avoid falling into either prejudice or leniency. (Ibn al-Haytham: Doubts against Ptolemy [al-Shuku¯k ala¯ Batlamyus] )

The hydraulic model also accommodated arguments against established explanations of function. Rhazes, in his substantial Doubts Concerning Galen (Kita¯b fı´lShuk uk ‘ala¯ Ja¯linu¯s), raised the question that, when one eye is closed, if the dilatation of the pupil of the open eye were due to the internal pressure or impact of the increased amount of visual pneuma transferred to it, as Galen claimed, how was it that both eyes dilated or narrowed together with changing conditions of light? Galen’s explanation derived from his teleological view of why parts of the body, such as the eyes, were in pairs. Rhazes instead emphasized the mechanical nature of the change in the size of the pupils of both eyes in relation to the amount of incoming light (increasing in dim light to enable vision to occur and decreasing in bright

In mapping the geography of the brain/mind, the key concept of point-to-point correspondence in anatomical projection emerged out of studies of the visual system. Its origin is usually attributed, at least in part, to Descartes’ (1596–1650) re-projection of the retinal image to the pineal gland via the optic track (Polyak, 1957). Prior to Descartes, Kepler (1571–1630) had established that an inverted image was formed in the eye by means of the lens focusing the rays of light from each point on the surface of the object to a corresponding point on the retina (Lindberg, 1976). Both Kepler and Descartes were, however, using a punctate model of mapping that had already been introduced by Ibn al-Haytham (965–1040), one of the most important figures to emerge in the history of early modern science.

AFTER GALEN: LATE ANTIQUITY AND THE ISLAMIC WORLD His Optics (Ibn al-Haytham, 1989), the Kita¯b al-Mana¯zd “ir (c. 1027), represents a painstakingly empirical investigation, in seven books, of the properties of light (rectilinear propagation, reflection, radial dispersion, and refraction) as distinct from vision (what makes objects visible, the conditions under which vision in stages occurs). Ibn al-Haytham brought together ocular anatomy and the physics of light for the first time to explain vision in stages as the outcome of (a) the formation of a punctate image in the eye, based on the principle of point-to-point correspondence by light reflected from the surface of the visible object, and (b) its conduction through the optic nerves to the chiasma for binocular integration and finally (c) to the anterior part of the brain for its interpretation (for full details, see Russell, 1996). The Kita¯b al-Mana¯zd “ir became the most influential text on visual optics in the West, through its Latin translation (De Aspectibus, late 12th/early 13th century), to be widely diffused through its subsequent printed version (the Opticae Thesaurus, 1572) (Lindberg, 1976; Sabra, 1983, 1989).

Ibn al-Haytham’s new ‘visual image’ theory Ibn al-Haytham’s theory emerged out of his concern, as stated at the beginning of his Optics (1989), to determine the essential properties of light (dd “aw’) and vision (ibsar¯) independent of the particular instances of time, place,_and circumstance. To achieve this, he reduced complex issues to a series of closely interrelated simple studies, systematically subjecting each problem to a detailed analysis of its variables under controlled conditions, and applying “experimental testing methods” usually associated with 17th-century science natural philosophers (Russell, 1996). His approach is exemplified by the series of experiments on the rectilinear propagation of light, where he used a dark room with an aperture in a thick wall to provide a columnated source of light. The visualized beam of light between the aperture and its projection onto the opposite wall was first checked for linearity with a rule. With additional checks, using an occlusion procedure, he found that light was disrupted only within the linear path. Occlusion within other paths (such as curvilinear) had no effect (Optics, I, ii). He also investigated whether (or not) light traveled in straight lines at all times (dawn, noon, dusk), from different sources of light (sun, moon, lamp), or under varying conditions (dust, smoke). Using specially constructed instruments with variable openings, Ibn al-Haytham demonstrated that light traveled in straight lines between the visible object and the eye, and that it is dispersed from every point on the surface of an object along straight lines (Optics, I, ii, iii). The simple principles he formulated are fundamental to vision: that, “any object to be visually perceived must

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be either self-luminous or illuminated” from a light source, and that we see “ordinary” (i.e., unpolished, rough, non-luminous) objects by the dispersion/radiation (ashraqa) of light, where some light stays “fixed” (thabata) and some is reflected in all directions from every point on their surfaces along straight lines. From smooth and polished surfaces, however, light is reflected only in predictable directions (i.e., at equal angles of incidence and reflection) (Ibn al-Haytham, 1989, I, iii; also 1968, Le Discours de la Lumie`re). The principles of reflection from polished surfaces were established prior to Ibn al-Haytham. That non-luminous and unpolished surfaces reflect light to be visible was a counterintuitive concept unique to Ibn al-Haytham. Ibn al-Haytham also explained refraction (at both plane and curved surfaces) on the basis of the density of the transparent medium through which light travels, becoming reduced in a denser medium (air to water) and increased in a rarer medium (glass to water) (Rashed, 1978; Sabra, 1964, 1983, 1989). Ibn al-Haytham applied this principle to the transparent parts of the globe of the eye as refractive surfaces, with different densities (Russell, 1996). With these fundamental findings, Ibn al-Haytham established beyond any doubt that (a) what comes to the eye is light, not the copies or impressions of objects, and (b) the constant invariant principles underlying the behavior of light also apply to the eye, the properties and structural organization of which he described in optical terms. This was a total divergence from traditional views.

The point-to-point correspondence in image formation Ibn al-Haytham’s theory of point-to-point correspondence in image formation emerged out of multiple projection of light sources in dark rooms with minimal apertures. In investigating how several separate light rays simultaneously passed in straight lines through a small aperture without interference, despite their intersection, or without affecting the transparent medium through which they traveled, Ibn al-Haytham observed that the image formation on a wall in a dark chamber had a direct correspondence to the light sources. With several lamps positioned separately on a horizontal plane in front of a double-winged door leading to a dark room (al-bayt al-muzd “lim; Latin, camera obscura), Ibn al-Haytham noted that, when the vertical slit opening was reduced to a minimal size, patches of light appeared on the wall behind the doors, corresponding to the number of lamps. If a lamp on the left side were occluded, only the corresponding light patch disappeared on the right side of the wall facing the aperture. When the opaque screen was removed, the patch of light was restored in exactly the same

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place (Ibn al-Haytham, 1989, I, vi, 115–116, p. 90). With such observations, he demonstrated not only the principle of point correspondence but also the importance of the size of the aperture. The multiple projection via a vertical reduction slit provided Ibn al-Haytham with sufficient empirical grounds upon which to anchor his theory of corresponding point projection of light from the surface of an object to form an image within the eye.

Image formation in the eye In considering the eye analogous to a dark chamber, the size of the pupil as its aperture presented Ibn alHaytham with major difficulties. He was fully aware from his experiments that a point-to-point correspondence could only be obtained by a minimal opening that served to exclude the multiple light rays from each point on the surface of an object, and allowed only one ray to pass through. A wide aperture produced multiple representations of each object point, whereby the pattern of rays would be degraded and lost as an image (see Fig. 6.1A and B). How does the eye with its large pupil then form a punctate image? In the absence of a pinhole, Ibn al-Haytham’s solution derived initially from the mechanics of impact rather than refractive optics. Although he described the crystalline lens as a biconvex refractive body, he was unaware of its point-focus function in the eye. On the basis of experimental observations in mechanics, he had concluded that only the impact of perpendicular pro-

Fig. 6.1. Light projection via an aperture (A) and a pinhole (B). In (A), the single point source of light is represented by multiple rays; in (B), the single point source is represented by a single ray.

jectiles was forceful enough to penetrate a surface. The oblique ones, with equal force and from an equal distance, were deflected. Similarly, the solution to the problem of multiple rays and the pupil of the eye, was in the choice of the perpendicular ray alone. There could only be one such ray from each point on the surface of the object that could penetrate the layers of the eye, and these “single” rays would preserve the order of their points of origin. In this way, there would be a point-to-point correspondence between the visible object and the image in the eye (see Fig. 6.2), as all incidental or oblique rays would be excluded. His proposal was in effect an alternative method to the pinhole of reducing the multiple rays from each object point to a single one (Russell, 1996). Ibn al-Haytham did not put forward an inflexible theoretical position on image formation in the eye. Rather, he continuously developed his hypotheses as his empirical optical acquaintance expanded. Upon discovering that incidental rays carried visual information to the eye, he modified his theory to incorporate them. For example, he noted that a small object, such as a needle or a pen, held close to the temporal corner of one eye while the other eye is shut, can be seen even though no perpendicular line could be drawn from the object point in this position to the surface of the eye. Again, a small object such as a needle, placed close to one eye, while the other is shut, did not hide an object-point lying directly behind it on the common line (axis) drawn from the center of the eye. He further noted that the needle appeared to be wider but transparent, enabling one to see behind it. Fine marks put on the wall were fully visible and not occluded by the needle, when close up. Since the object point in these cases could only be seen by an oblique ray, he concluded that it must be due to refraction (Sabra, 1983; Russell, 1996). In the absence of any concept of a focusing lens, Ibn al-Haytham proposed an ingenious theoretical solution

Fig. 6.2. Schematic representation of Ibn al-Haytham’s concept of image formation in the eye, using the principles of perpendicular and incidental rays, and refraction, as follows: (Axis) indicates a perpendicular line on which all the transparent parts are centered; (P) the perpendicular, (I) the incidental to the surface of the eye, (Lens) the biconvex crystalline lens.

AFTER GALEN: LATE ANTIQUITY AND THE ISLAMIC WORLD which, though incorrect, enabled him to incorporate refraction at the cornea and the anterior and posterior surfaces of the lens. By including only those incidental rays that are refracted to pass through the centre of the eye, he was able to exclude all other (i.e., the more oblique) incidental rays and thus maintain a point-to-point correspondence in image formation. Ibn al-Haytham now had to resolve the additional problem of image inversion (both horizontal and vertical), which would have been at variance with “normal” perception of the external world. He had already described the biconvexity and the forward position of the lens in the globe of the eye. By means of refraction at the posterior surface of the lens, the intersection of the rays at the center of the eye is prevented (see Fig. 6.2), and an upright image through the vitreous is projected to the cavity of the “hollow” optic nerve (Ibn al-Haytham, 1989, Bk. I, vi; Bk. II, iii).

Anatomical re-projection of the punctate image Preserving both the order of its corresponding points and upright orientation, the image from each eye is then conveyed to the chiasma by the transparent sensory “pneuma” (al-jism al-hass) via the separate filaments in _ nerve. In Galenic anatomy, the the channel of the optic chiasma, or the “common nerve” (al-‘asaba al-mushtaraka), was formed by the two optic_ nerves coming together. Ibn al-Haytham used the chiasma to resolve the problem of diplopia, or double vision, by assuming an exact matching of the sensory information from each eye. The separate punctate patterns were superimposed on the “common nerve” and, if they made a perfect match, fused into a single image which was then conveyed via the optic tracks to the anterior part of the brain (Ibn alHaytham, 1989, Bk. I, vi; Bk. II, ii, iii). This notion of image fusion derived from Ibn al-Haytham’s observation of the critical role of eye movements for binocular integration. To maintain the correspondence of the two ocular images, equal convergent as well as conjugate eye movements were essential during changes of gaze from one object to another or even in different areas of the same object. For example, when the observer looked at the visible object, by directing the pupil toward it, the axes of the two eyes converged at some point on its surface; when the observer moved his eyes over the visible object, the two axes moved together over every part of its surface. When the two images were spatially misaligned, i.e., by having the observer fixate an object with one eye while manually deviating the other eye, double vision was produced, due to the difference in the positioning of the two images in the eyes.

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In the re-projection of the image to the anterior part of the brain, Ibn al-Haytham did not identify a specific site. He fully recognized, however, that the ocular punctate image (i.e., sensory input) is only an essential preliminary stage for further complex processes in its subsequent perception as a 3-dimensional object in the external world, to which he also devoted a substantial part of his work (Ibn al-Haytham, 1989, Bks II and III). A conceptually similar solution was proposed by Descartes to the problem of how two retinal images could create a single picture of the visual world. Descartes assumed, however, that the two images were conveyed to the brain separately. They were fused not in the chiasma but in the pineal gland, which served as a site for the convergence of all sensory information. (Here Descartes provided a further mechanistic explanation for the complex multi-sensory integration of Avicenna’s “sensus communis” [al-hiss _ al-mushtaraka] in the anterior ventricles.) Although the extent to which Descartes was influenced by Ibn al-Haytham has yet to be established, there is no doubt that the Latin translation of the Optics and its printed edition (1572) served as a springboard for all studies in vision between the 13th and the 17th centuries (Lindberg, 1978, 1992). Ibn al-Haytham’s theory of point-to-point correspondence formed the basis of subsequent attempts to find a topological representation of external objects in the eye (the retinal surface with Kepler) and in the brain (the pineal gland with Descartes and ultimately in the cortex with Munk). His serial reprojection of the punctate image in the eye, chiasma, and brain can be regarded as dramatic precursors of the principles in neurology of sensory “mapping” and hierarchical anatomical organization of sensory information from simple to complex.

CONCLUSIONS After Galen, there were significant modifications in Late Antiquity and fundamental changes in the Islamic period. A balanced perspective on the history of neurology depends on the recognition that (a) some of the Greek and Hellenistic concepts, as received by the West, were modified or totally transformed in Islamic civilization, and (b) their formative influence extended well beyond the Medieval Period of Arabic transmission into the Renaissance and the 17th century. The increasing emphasis on the primacy of the brain initiated the beginnings of ventricular localization of function in Late Antiquity, which was developed into a theory in Islamic civilization and transmitted to the West via Arabic. Following the unprecedented translation movement in 9th-century Baghdad, the cumulative Greek and Hellenistic knowledge of the brain, nerves, and senses from diverse sources was brought together

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in the logically unified Arabic medical compendia of encyclopedic proportions. Their Latin versions became standard texts at medical schools. An important element of this synthesis was the critical approach to the ancient heritage, frequently articulated as “doubts against Galen,” by independent minds like Rhazes, Avicenna, Averroes and others, which resulted in divergence from accepted views and in new diagnostic observations. The oldest extant diagrams relevant to neurology, with the eye (H “unayn ibn Ish a¯q), the ventricles ˙ (Rhazes), the visual system (Ibn al-Haytham) and the nerves, date from this period. These schematic illustrations, remaining within Galenic anatomy, served as models for the Medieval Latin West (Russell, 1997). Furthermore, their development of coherent descriptions of the motor and sensory systems, and related clinical disorders, by analogy with the mechanisms of hydraulic automata, exemplify some of the explanatory methods associated with the 17th century. Finally, Ibn al-Haytham’s theory of point-to-point correspondence in vision provided the basis for the emergence of a key concept in neurology of functional brain maps. In showing that what is sensed is not the object itself, but a punctate optical “image” due to light reflected from the surface of the object to the eye, Ibn al-Haytham’s revolutionary approach to vision was a paradigm shift that destroyed the viability of the Greek tradition of holistic forms and tactile sensory impressions, and created the fundamental transition to a corresponding point theory of image formation. Due to Ibn al-Haytham, an understanding of vision increasingly required a synthesis of anatomy with the physics of light. Subsequently, the visual enquiry shifted from the global question of “how do we perceive the external world by the sense of sight?” to specific concerns arising from the implications of Ibn al-Haytham’s “optical” image in the eye: (a) the preservation of a point-to-point correspondence between object and image; (b) image inversion and the veridical (upright) perception of the object; (c) the unity of perception, or the binocular fusion of the two separate images, one from each eye and (d) the anatomical projection of the retinal maps to various brain centers. The fact that these became central issues extending to Descartes and beyond underscores the unique legacy in neurology of Ibn al-Haytham’s brilliant insight into the formulation of a punctate sensory map, which anatomically re-projected and served more complex sensory functions.

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internationale d’histoire des sciences, No. 8, Paris, pp. 480–487. Polyak S (1957). The Vertebrate Visual System. Chicago University Press, Chicago, IL, ch. iii, especially pp. 147–152. Pormann P (2004). The Oriental Tradition of Paul of Aegina’s Pragmateia. EJ Brill, Leiden, pp. 1–8, 17, 19, 67–77. Rashed R (1978). Lumie`re et vision: L’application des mathe´matiques dans l’optique d’ ibn al-Haytham. In: R Taton (Ed.), Roemer et la Vitesse de la Lumie`re. Paris, pp. 19-44, especially, 30–44. Rhazes (1955–1971). Kita¯bu‘l-Ha¯wı¯ fi’t¸-T¸ibb (Continens) of Rhazes. Encyclopedia of Medicine by Abu’l Bakr Muhammad Ibn Zakariyy’a¯ ar-Ra¯zı¯. Da¯’iratu’l-Ma’a¯rif-l˙ Osmania, Hyderabad-Deccan, 23 vols. Rocca J (2003). Galen on the Brain: Anatomical Knowledge and Physiological Speculation in the Second Century AD. EJ Brill, Leiden. Russell GA (1994a). Historical introduction: the age of Arabic. In: GA Russell (Ed.). The “Arabick” Interest of the Natural Philosophers in Seventeenth-Century Britain. EJ Brill, Leiden, pp. 1–17. ¯ lı¯ ibn alRussell GA (1994b). The anatomy of the eye in ‘A ‘Abbas al-Magusi a textbook case. In: C Burnett (Ed.). Pantegni and Related Texts. EJ Brill, Leiden, pp. 247– 265. Russell GA (1996). The emergence of physiological optics. In: R Rashed (Ed.), The Encyclopedia of the History of Arabic Science. Routledge, London, pp. 672–716. Russell GA (1997). Ebn Ilyas. In: E Yarshater (Ed.), Encyclopedia Iranica, Vol. VIII, Fasc. i, pp. 16–20. (Reprint. In: E Yarshater (Ed.) (2004). The History of Medicine in Iran. Columbia University, Encyclopedia Iranica Foundation, New York, pp. 96–100.) Russell GA (2000). The optics of Ptolemy and the “passions aroused” in the “groves of the academe.” ISIS 93(3): 556–561. Russell GA (2002). Greek medicine in Persia. In: E Yarshater. (Ed.), Encyclopedia Iranica Vol. IV, Fasc. 10: 342–457. Reprint. In: E Yarshater (Ed.) (2004), The History of Medicine in Iran. Columbia University, Encyclopedia Iranica Foundation, New York, pp. 30–46. Sabra AI (1964). Explanation of reflection and refraction in Ibn al-Haytham, Descartes, and Newton. In: Actes de Dixie`me Congre`s Internationale d’Histoire des Sciences. Ithaca, NY, 1962, Paris, I, pp. 551–554. Sabra AI (1966). Ibn al-Haytham’s criticisms of Ptolemy’s Optics. J Hist Phil 4:145–149. Sabra AI (1983). Ibn al-Haytham. In: CC Gillespie (Ed.), DSB, VI, pp. 189–210. Sabra AI (1989). The Optics of Ibn al-Haytham. Books I-III on Direct Vision. Vol. II. Introduction (especially pp. Liii-Lxii) and Commentary. The Warburg Institute, London. Saliba G (2007). Islamic Science and the Making of the European Renaissance. MIT Press, Cambridge, MA. Savage-Smith E (1995). Attitudes toward dissection in medieval Islam. J Hist Med 50: 67–110, especially pp. 83 (translation slightly modified) and 102.

AFTER GALEN: LATE ANTIQUITY AND THE ISLAMIC WORLD Shah MH (1966). The General Principles of Avicenna’s Canon of Medicine. Book 1 with a Summary of Books 2–5. Karachi. Siraisi N (1987). Avicenna in Renaissance Italy. The Canon in Medical Teaching in Italian Universities. Princeton University Press, Princeton, NJ, chs. i, vii. Siraisi N (1990). Medieval and Early Renaissance Medicine. An Introduction to Knowledge and Practice. University of Chicago Press, Chicago, IL, pp. 137–188. Smith WD (1981). Implicit fever theory in Epidemics 5 and 7. In: WF Bynum, V Nutton (Eds.), Theories of Fever from Antiquity to the Enlightenment. Medical History Supplement, No. 1. Wellcome Institute for the History of Medicine, London, p. 8. Strohmaier G (1970). Dura mater, pia mater: die Geschichte zweier anatomischer Termini. Clio V: 201–216. Temkin O (1973). Galenism. The Rise and Fall of a Medical Philosophy. Cornell University Press, Ithaca, NY and London. Todd RB (1984). Philosophy and medicine in John Philoponus’ commentary on Aristotle’s De Anima. In:

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 7

Neurological conditions in the European Middle Ages WALTON O. SCHALICK, III * University of Wisconsin, Madison, WI, USA

INTRODUCTION Traditionally, medicine in the Middle Ages (approximately from 500 CE to 1500 CE) has been described as intellectually stagnant and practically chaotic (Sait et al., 2004). Such assertions are particularly true for medieval neurology. The image offered is that Western knowledge of neurologic medicine was confined to the sort of butchery conveyed in the Song of Roland, in which combatants are cloven down to the spine, or, as in one scene, a figure is quartered by horses tied to his limbs, so that “his every nerve was stretched and torn” (Moncrief, 1919, verse CCXLV). Certainly, there are exceptions that prove this historiographic rule, though these are infrequent (Finger, 1994; Gorji and Ghadiri, 2002), but the typical characterizations stem from a lack of familiarity with the primary sources and a very long shadow dating from the castigations of Renaissance scholars. Neither the stagnant nor the chaotic attribute is accurate. Medieval scholars were vibrantly creative in their intellectual explanations for what we would today identify as neurophysiology and pathophysiology. In addition, many practical innovations continue to affect us, ranging from the invention of medical universities to that of eyeglasses, from medical licensing to pharmaceutical regulation and prescriptions, from laicization to an overall process of medicalization. Nevertheless, it is unquestionable that medicine and neurology in the Middle Ages were rather different than today. For us to speak of a discipline of “neurology,” largely a construct of the 19th and early-20th centuries, is inappropriately anachronistic. Furthermore, both the intellectual content and the social context in which neurologic conditions were described, as we would consider them today, appear somewhat foreign, and yet they were consistent and appropriate to their own time.

*

This chapter will present a summary of the development of medicine as it relates to neurologic conditions from the fall of the Roman Empire to the Renaissance in Western Europe. In characterizing “medieval” medicine, it is important to note that the changes embraced by the Renaissance came to different parts of Europe at different times. Thus late-13th-century Italy was experiencing elements decidedly post-medieval, while parts of England and Germany were still “medieval” into the 15th century. The Middle Ages were far from homogeneous. What follows is thus at best a series of broad strokes which will require finer brushes to fill in.

THE SETTING The Early Middle Ages (c. 500–c. 1000) The starting point for any broader discussion of medieval medicine must be its connection to, and at times dependence upon, ancient medicine. As the authors of preceding chapters have shown, ancient medicine was both wide and deep in its traditions. The Hippocratic and Galenic traditions of learning provided an extraordinary fund of knowledge to be used in the healing of those with neurologic conditions (Temkin, 1973 and Nutton, 2004). What distinguishes the ancient medical context from the medieval was access to texts and the capacity to read them. The texts were almost universally written in Greek, a language that was in general lost to the Western medieval world for many centuries, and the manuscripts were largely destroyed after the fall of the Roman Empire. The period of segue, from roughly 500 to 1000, has often been styled “the Dark Ages,” because metaphorically the light of that knowledge, conveyed by books from Antiquity, was extinguished with the pillaging and burning of libraries during the incursion

Correspondence to: Walton O. Schalick, III MD, PhD, University of Wisconsin, 1300 University Avenue, #1410, Madison, WI, 53706, USA. E-mail: [email protected], Tel: +1-608-262-6760, Fax: +1-608-265-0486.

80 W.O. SCHALICK, III of “barbaric” tribes into the Latin West. As far as medabbess, her condition, perhaps migraine headaches with icine is concerned, scholars have repeatedly debunked auras, may have been interpreted as visions, although this characterization, beginning with Loren MacKinney scholars disagree (Singer, 1955; Sweet, 2006). (1937), although the darkling image remains. Rather, Socially, these different groups could come into early medieval medicine was simply different in form market-oriented conflict. Thus, the physician and the from what we are accustomed to, paying greater attenpriest could join together against the magical healer tion to practical rather than theoretical impact, and (sorcerer or magician), in order to maintain a “rationoffering a greater emphasis on oral rather than literate ality” in the explanation of disease (Flint, 1989). transmission of knowledge (Garner, 2004). For neurological conditions, as for all of medicine, orality The High Middle Ages (c. 1000–c. 1200) offered its own challenges. Intriguingly, such orality What distinguished the high from the early Middle Ages may provide an explanation for the odd substitution was a growing access to translations from Arabic, and of the Anglo-Saxon word for “shoulder” where the occasionally Greek, into Latin. In places, including the word “brain” should be in one 10th-century text (McIlmonastery of Monte Cassino in southern Italy, the plains wain, 2004). And while many remedies would today of Moorish Spain, and the cathedral school at Chartres in seem to have a decidedly magical, oral flare to them, northern France, scholars came in contact with copies of such as the requirement to tie a herbal remedy for works by Galen, Hippocrates and eventually Arabic headache to the head with a red fillet while murmuring authors (Portman and Savage-Smith, 2007). What folrhythmic words of healing, some interventions problowed was a geometric rise in the number of texts early ably were efficacious, such as the use of opiates for scholars could read and begin to digest. pain or cupric salts for infections (Bruyn, 1989; As in all translational activity, there was a great deal Cameron, 1993; van Arsdall, 2002; Schalick, 2003). of confusion over the meaning of terms originally in Identification of seeming continuity with today can Greek or Arabic, which had no Latin translation or also be found in the spinal surgeries of the 13th ceneven meaning (Jacquart, 1994; McVaugh, 2002). It is tury, whose origins were undoubtedly earlier (Deshaies a curious linguistic feature of the word “paralysis” that et al., 2004). Indeed, at times ancient and medieval it existed since the Anglo-Saxon as a word, having non-neurologic interventions were so efficacious as to been borrowed from the Latin via Old French, but then change the environment. One plant was farmed out had to be re-borrowed in the 16th century into Middle of existence because of its utility as an abortifacient English (Oxford English Dictionary online edition, (Riddle, 1992; Riddle and Estes, 1992). www.oed.com). Early medieval medical knowledge was broadly Thus, in order to help delineate meaning where little ensconced in three contexts: religious, lay medical, existed, teachers began to appear. Some were in catheand popular. At times the boundaries between such dral schools, originally mandated by Charlemagne in contexts are blurred, but by and large, monastic or 789 to help generate an inchoate bureaucracy. The focus eventually cathedral-centered medicine had a highly litof these early medical scholars was understanding mederate and more theoretical focus than the largely illitericine as one component of God’s universe, for its theoreate, oral and apprenticed structure of the lay medical tical side rather than its practical (Burnett, 1984). provider, which was distinct from the non-structured Others appeared at the new lay school of medicine popular medicine, largely by virtue of concentration at Salerno in the 10th century and beyond. In Salerno, and rudimentary training (Jaritz, 1990). attention to practical implications was given equal Intellectually, the more religious context, which here and at times even greater weight than theoretical prerefers to Catholicism, took its authority not only from mises. It was here that the first Latin European textthe Church, but from the scant copies of ancient medbook of medicine was likely created, the Articella ical texts remaining within the walls of monasteries (Jordan, 1990). and churches. Thus, monks and nuns tended other reliSimultaneous with this growth of teaching was a gious figures with paralyses, headaches, epilepsy, senspecialization of medical practitioners. Thus the “physory impairments, central infections, and a wide sician” separated from the surgeon and from the pharvariety of what we would consider neurological condimacist at an increasing rate by the mid-12th century. tions, all within a religious framework (Skinner, 1997; In addition, the West saw a growing number of Montford, 2004). For one monk, the tending led to modinstitutions, hospitals, leprosaria, and the like with a erated despair when he was paralyzed in 9th-century considerable mission for the provision of centralized France without hope of terrestrial cure, but with surety care, previously provided only in the home or in monof heavenly salvation (MacKinney, 1937). For others, asteries (Kealey, 1981; Bowers, 2007). like Hildegard of Bingen (1098–1179), an 11th-century

NEUROLOGICAL CONDITIONS IN THE EUROPEAN MIDDLE AGES

The late Middle Ages (c. 1200–c. 1500) In many ways, as an outgrowth of the rise of translated texts and a valuation of learning, universities, a medieval invention, appeared in Bologna and Paris and then throughout Europe. These centers of learning soon incorporated medicine on faculties devoted to the subject, and subsequently accreted books in libraries and students from all over Europe. With an increasing number of scholars came an acceleration in the assimilation of translations, to the point that by 1300 scholars shifted from merely assimilating to actually absorbing and transforming the works they read. This new stage, largely focused on the works of Galen and Hippocrates, has been called “The New Galen” by some modern historians (Garcı`aBallester, 1998). Coincident and dependent upon this refashioning of antique knowledge, university doctors (in this chapter, I will use “doctor” to refer to university-trained medical doctors, because the term emphasizes their academic affiliation; the term “physician” is historically a very complex one in English [Bylebyl, 1990]) began to assert their learning in the marketplace, harnessing the political power of royal and ecclesiastical courts to support them. What emerged was a professional pyramid, later to be described by Vesalius, which would have influence well into the 20th century and beyond in Europe and the United States, with the doctors surmounting surgeons, pharmacists, and a bevy of lesser practitioners (Schalick, 1997). Also by 1300, Europe witnessed the rebirth of human anatomy, housed in the universities, first in the south of Europe, and eventually in the north. Not since the days of Erasistratus and Herophilus during the 2nd century BCE in Ptolemaic Egypt had the human body been divided up for learning. But while it was slowly accepted again, the students and faculty participating in the dissections were using these events largely to demonstrate the texts of Galen, which they were so vigorously absorbing. Anatomy had not yet reached the stage of critical observation it would achieve in the Renaissance and Early Modern periods through which the shortcomings of Galenic (neuro-) anatomy would be highlighted (Lind, 1990; Park, 2007). Finally, Western Europe experienced a process of “medicalization.” Some previously religious explanations and systems were given over wholesale to, or at least affiliated with, medical interpretations. This process could also happen with lay, secular activities that were not heretofore medical (McVaugh, 1997; Schalick, 1997). Thus, leprosy, a condition previously “diagnosed” by priests, who also controlled the care of those with the condition, by 1300 fell under the authority of

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the learned doctor to diagnose, evaluate and palliate (Demaitre, 1985, 2007). Similarly, doctors increasingly were asked to prescribe cosmetic prescriptions (Schalick, 1999). And doctors began appearing at the courts of the elite amidst growing efforts to endow institutions of learning (universities) and care (hospitals). The result was a series of interrelated changes that gave social power both to doctors and to medicine as a collective entity. Certainly, neurological conditions played a role in these processes (McVaugh, 1981). And it is intriguing to note that, despite the growing textual authority of the learned doctor, the more practical surgeon could make fundamental clinical observations with long-term validity. As an example, a 13th-century Italian oculist was experienced and observant enough to recognize that a pupil that is fixed and dilated will not benefit from couching for the cataract (Reeves and Taylor, 2004).

PATHOLOGIES OF NEUROLOGICAL CONDITIONS From an intellectual point of view, medieval theories of the causes of neurological disease were highly varied. The term “pathology” was coined pathologia in 1554 by the Renaissance Galenist Jean Fernel in his Universa Medica (Fernel, 1656). Consequently, it was not a term that existed in the Middle Ages. Rather, the concept of disease causation was folded into a broader sense of etiology of diseases, as well as of “prognosis,” that ancient and medieval harmonium of the natural course of an individual’s condition from inception to termination (Grmek, 1998). In the Modern Era, we link therapy to diagnosis. In Antiquity and the Middle Ages, therapy was more concretely linked to prognostica, as Hippocrates’ popular treatise thereon observed (the physician is able to “carry out the treatment best if he knows beforehand from the present symptoms what will take place later”) (Kibre, 1985, p. 200). Understandably, this idea is blended into the modern association with the label or diagnosis of a condition, but that intermediate step was not so necessary in the Middle Ages. If pathology means a system of etiologies of disease (and here I refer to Fernel’s anticipation that the cause is Aristotelian and efficient), which is distinct from therapeutics, physiology, semiology/diagnosis and simple nosology, “neuropathology” in the Middle Ages was highly variable, and may be considered as “neuropathologies.” Medieval neuropathologies changed with time, with the absorption of increasing texts from Antiquity and the Arabic world, as well as with geography, gender and socioeconomic status. The pathologic etiology of

82 W.O. SCHALICK, III neurological diseases for the serf in the field differed phlegm, or even by motions of the nerves, Saintfrom that of the baroness at court, from the Arabic Amand came to the conclusion that its phlegmatic trader and from the elite physician. Magical elements components make it a chronic condition distinct from among Norse seafarers differed from magical etioloparoxysms. Consequently, it must be caused by gies of the Franks, and from those of early medieval vapors ascending into the head, much more dynamipeasants (Bragg, 1997). cally (Pagel, 1894, pp. 94–96). The resulting refineOne pathology is typified by the elite medical concepment of terminology came along with a refinement tualizations of disease. As suggested by the Parisian of disease identity and meaning through iterative medical scholar Jean de Saint-Amand (c. 1230–1303), questioning (McVaugh, 1981). “disease is a situation other than the natural and the The nerves could have an elemental place in the way cause of harmful [bodily] actions” (Pagel, 1894, p. 200). physicians explained a large variety of physiologic and Following the dictates of Hippocrates, Galen, Avicenna pathophysiologic processes, though not always of a and a host of other Ancient and Arabic authors, medieval modern neurological variety. Thus in Salerno, the tradiLatin doctors saw disease stemming from: (a) an imbaltion of the famed “Salernitan Questions” considered the ance of the four humors (blood, phlegm, yellow/red bile, nerves as instrumental in prematurity. However, their and black bile), (b) an obstruction of the flow of the bodily role was not “neuronal” as we would consider it today, spirits, (c) a disturbance of the four Elements, (d) or of but rather to transfer blood from the mother’s liver to the Qualities, (e) a disruption of the Members, (f) an irrethe fetus. In other settings, nerves, difficult for mediegularity of Energies, (g) of Operations, or (h) of Spirits. val scholars to distinguish physically from tendons, Collectively, these variables formed the “Naturals,” could behave like “sinews.” In answering why some peoalterations of which could also restore health, as guided ple sleep with their eyes open, scholars suggested that by a physician. the nerves in the upper eyelids were sometimes too short Dominant among the Naturals, in terms of etiologic (Lawn, 1979, p. 19). Ironically, in the very next question explanations by university physicians, was humoral (Lawn, 1979, pp. 19–20), a response to why some talk imbalance and alteration of the body’s (or body part’s) in their sleep, “nerve” re-attached to a more modern normal quality (hot, cold, wet or dry), also known as neuro-sensory function: in being blocked, the vital complexion. Thus these variables were the Aristotelian spirit conveyed in the nerve detours, thus innervating material causes of disease. The efficient causes both the “fantasy cell” of the brain and the lungs were alterations in the six Non-naturals: Air (which and resulting in a stimulation of the voice (Lawn, could include: Seasons/Stars, Winds, and Place), Food 1979, p. 15). And in still other settings, it was clear that & Drink, Exercise & Rest, Sleep & Waking, Fasting the nerves were the fundament of the senses (Lawn, & Fullness, and Accidents of the Mind. Such altera1979, p. 4). tions resulted in the imbalance of one or more of the The anatomic association of the nerves played an Naturals. The efficient cause of too little sleep would increasingly important role from the 13th century result in a surfeit of phlegm, the material cause, and onward. That salience came from a conflict of authoria subsequent runny nose. In such a clearly Galenic conties. Galen, the quintessential source of medical knowlstruction, neurological disease was a result of one of edge in the Middle Ages, argued that the nerves arise the Non-naturals. from the brain and that the brain therefore was the The trick with medieval humoral explanations was primary organ, especially in neurological conditions. that they were not always unitary. Thus, the paucity In contrast, Aristotle, the paragon of philosophers, of sleep and surfeit of phlegm, rather than causing described the heart as the central organ with a strong a runny nose, could just as easily result in epilepsy. influence on nerves, motion and sensation. The Galenic Scholastic physicians struggled with such overlapping encephalocentrism ran into the Aristotelian cardioetiologies and, in so doing, sought new nosologic centrism in the late medieval universities, because both clarity. Saint-Amand, for example, thought epilepsy authors were being newly translated into Latin and was a sudden condition that must occur from a flux only slowly absorbed. The contesting authorities stimuof a gross (rather than fine) humor opening a path lated a great deal of creative theorizing. for the flow of spirits in the cerebral ventricles. But By the 14th century, for example, the philosophically at the same time, he felt that the nerves, rooted so minded physician, like Gentile da Foligno (d. 1348) in securely in the brain, must play a role in epilepsy, northern Italy, took theorization about nerves and their perhaps in the physical movement of the nerves. By properties to a reductive extreme. If the heart were struggling with how it was that epilepsy comes and hot, but the brain cold, how was it that blood vessels goes so quickly, which would be difficult if it were and nerves did not cancel each other out (“resist” caused simply by a thick, lethargic material like each other) in proximity? Foligno created a concept

NEUROLOGICAL CONDITIONS IN of “co-alteration,” which allowed body parts of different humoral complexions to co-exist in the same anatomy (the hand for example). Not only did co-alteration allow for co-existence, but it came to explain why the hand could be so discerning in perceiving different temperatures, textures, etc. That is, co-alteration became one more explanation for sensation, though still rooted in the nerves (French, 2001, pp. 94–95). In similarly scholastic terms, Jean de Saint-Amand explained the dissipation of bodily virtues using strokes and the sensitivity of nerves as models to explain how nerves can be damaged through evaporative coldness (Karenberg and Hort, 1998). The dissolution of the [neural] virtue occurs in two ways: either it is evaporated or extinguished . . . , and it ought to be noted that . . . because heat, which is the instrument of virtue, doubly fails either because its matter is evaporated or dispersed, and so it does not have anything in which to conduct, or it is evaporated by a stronger conductor, just as a greater flame extinguishes a lesser, because it assumes the matter of the lesser flame. And thus wine causes paralysis because by assuming or consuming the moistness of the natural heat, the heat is weakened and so it cools the member and especially the neural members, because the nerves are of a cold complexion . . . The [body’s] heat however is extinguished on account of many humors as in stroke or similar conditions or on account of the tightening of the spiritual members . . . (de Saint-Amand, 1549, p. 374) Elite practitioners writing for elite patients sometimes used the medium of the consilium, an exchange of letters in which the physician “prescribed” a regimen for an unseen patient. One of the first authors of this genre, the redoubtable Taddeo Alderotti of Bologna (1223–1295) wrote several treatises on memory loss and psychological conditions, the cures for which made prominent use of purgatives (Giorgi and Pasini, 1997, nos. 1, 22, 102 and 103). But some of these authors wrote about “diseases of the nerves,” including paralyses. Thus Ugo Benzi (1376–1439), one of the most prominent physicians of his day, included at least four consilia on this subject, most frequently attributing the cause of the paralysis to the brain with humoral mediation. In one case, a colleague sent Ugo a letter about one of the colleague’s patients, a great lord of Malateste who had endured 35 days of left-sided paralysis with fever and bedwetting. The ultra-specialist’s (Ugo’s) opinion concurred with the referring physician, “. . . and I share the precepts . . . , the suspect cause returns to me because it is not without a great harm in the brain . . . .” Ugo recommended alum of

THE EUROPEAN MIDDLE AGES 83 feather and roses, but, ever the cautious practitioner, equivocated on the prognosis (Lockwood, 1951, pp. 254–255). Baverius de Baveriis (d. 1480) was a papal physician to Nicholas V (1397–1455) and wrote another set of consilia. In one letter for a certain Petronius, he offered a differential diagnosis of paralytic conditions that make a patient non-responsive (aphasic). This included catalepsy, epilepsy, hysteria and syncope. But he ultimately concluded that paralysis with aphasia was a condition of weakened nerves caused by a bad complexion of the moist humor. Consequently, although he was dubious of absolute cures, he recommended a diet “entirely directed toward heat and dryness. And likewise choose air that is hot and dry, and if it is not naturally so, it may be achieved with fire from wood of good odor” (Baverius, 1489, fo. 119r). He also offered a host of pharmaceuticals, including a “sponge infused in the strongest vinegar” placed under the nose (Baverius, 1489, fo. 119v). The tension between cardio- and encephalocentrism, that is between Aristotelian and Galenic (patho-) physiology, could also lead to practical consternation. Thus, Jean de Saint-Amand argued that Aristotle’s cardiocentrism was wrong in the care of paralysis, because, “according to him, in paralysis we ought to place a plaster over the heart, whence, according to him, the nerves originate. We however, place the plaster over the neck because it is here that the roots of the nerves begin” (Pagel, 1894, p. 25). According to Saint-Amand, Galenic encephalocentrism also explained the intractability of paralysis. “The nutrient of the nerves is a thickly viscous humor and on account of its abundance it causes a blockage [in the nerves] and thus paralysis, which blockage is why it is so difficult to cure” (Pagel, 1894, p. 215). Nevertheless, doctors continued to offer cures by experimentum, that is by experience. Thus in one 15th-century manuscript, preserved at the Vatican, a medical author penned a brief recipe to combat epilepsy employing wine and blood distilled for nine days (Pal Lat, 1229, fo. 49r). It should be noted that most academic physicians were cautious in their designation of the cause of a disease, recognizing that any particular sign or symptom could be caused by many diseases stemming from even more causes. Many an academic debate started with just this point. In trying to resolve the dispute between Galen and Aristotle on the origins of the nerves, university physician Taddeo Alderotti acknowledged their material, Galenic origin in the brain, but then appealed to their Aristotelian “origin” functionally in the heart, since that is the origin of the raw spirit, which would be disseminated by the nerves (Ottosson, 1984).

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W.O. SCHALICK, III Often, though not always, despite the seemingly (encephalocentrism) (d’Abano, 1548, fos. 58–59). In ephemeral nature of such discussions, the physicians addition, he argued that nerves motivate muscles were referring to very concrete perceptions of (d’Abano, 1548, fo. 82r), but did not distinguish conditions – a meningitic fever is a disease of excess between nerves and tendons. On another topic of disheat in the head; blood is hot and moist; therefore a cussion by Galen and Aristotle, Peter also argued with meningitic fever is the result of an excess of blood in Galen that pain was a symptom and not a disease the head. Therapy frequently followed in a logical (d’Abano, 1548, fos. 107r–108r). fashion from the interpretation of the particular But while the great theoreticians argued such subtleimbalance. ties, more practically oriented healers, often trained in It is also valuable to note that, in the pre-modern an apprenticed model of medicine distinct from the uniworld, as was described above, diagnosis took a backversities, had a less theoretical and more fluid patholseat to prognosis, for a variety of reasons, largely genogy, usually based on specifics and anatomical erating from the marketplace. However, around 1300 location in particular. The specific versus the systemic diagnosis began to take a stronger position in the phywas quintessentially suggested by texts, which charactersician’s armamentarium (McVaugh, 1997). ized disease a capite ad calcem – the head-to-toe It is important to recognize that a harbinger of the description of diseases by anatomic location. Headache decline of Galenic (physiologic) pathology was the rise was less the result of a humoral imbalance and more of patho-anatomy from the 13th century onward. An the potential nature of the head, distinct from the heart example is the Galenic attribution of idiopathic epilepsy or foot, and therefore prone to “neurologic” conditions. to a surfeit of phlegm in the brain. Sixteenth-century Its therapies were similarly practical. The Anglo-Saxon patho-anatomies found no such phlegm and provoked Herbarium (c. 1000), a highly practical text, argued that questioning of the Galenic doctrine. The empiricism that mandrake root, a member of the nightshade family with would arise in the Renaissance undercut the discriminasome narcotic efficacy, should be used tive scholasticism, which had helped clarify spasm from 1. for headache and for sleeplessness, take the rigor, tremor and palpitation (McVaugh, 1981). juice and smear it on the face, and use the It is ironic that this rise of pathoanatomy should be plant in the same way to relieve headache. so overwhelming to neurological theories, given that You will be surprised at how quickly sleep medieval neuropsychophysiology and pathology had an will come. intrinsic anatomic element to them, namely the cerebral 2. for earache, take the juice of the same plant ventricles. In this explanatory system, the brain has a mixed with oil of spikenard and put it into number of ventricles (usually presented as three, the the ears. You will be surprised at how quickly two lateral ventricles being treated as a single entity, it cures.. . . often with further internal divisions), between which 5. again, for nerve spasms, take one ounce by flowed the animal spirit. That spirit was the most weight from the body of this plant and pound refined of the digested derivatives of food, processed it into powder. Mix it with oil and then smear in the liver and heart, and disseminated to the parts of it on whomever has the aforementioned conthe body. A final processing took place in the Galenic dition. (van Arsdall, 2002, p. 206) version of the theory in the rete mirabile, a network of vessels in the head found in some animals, but not Within the rubric of organized medicine, another recognized to be missing from humans until the 16th practically oriented pathology was that of the surcentury. As Galen’s work was established with little geon, coucher for cataracts, hernia therapist, boneaccess to human dissection, his theories were consesetter, or the like. For such practitioners, cause (i.e., quently influenced by animal anatomy, as in this case. the generator of decision for therapy) was a simpler From the rete mirabile, the animal spirit then passed concept usually conveyed by a post hoc ergo propter through the ventricles and along the nerves and sensory hoc understanding. Thus, the cranium broke because organs (e.g., the eyes), allowing for sensation, fantasy, of the falling tree. For such pragmaticians the memory, sensitive and rational imagination, and so on cause was less material than the fact that the (Park, 1988; Kemp and Fletcher, 1993; O’Neill, 1993a, b). cranium was broken and must be re-joined. IntriguSo, Pietro d’Abano (c. 1257–c. 1315), known as the ingly, there is compelling evidence that medieval Conciliator for his efforts at reconciling medicine people survived such head wounds, especially from (Galen) and philosophy (Aristotle) through his book weapons. What is less clear is how much the medieval of the same name, discussed the origin of the nerves, surgeon or physician altered the natural history of the whether from the heart or the brain. He sided strongly cranial or traumatic brain injury (Anderson and with Galen that the nerves came from the brain Hodgins, 2002).

NEUROLOGICAL CONDITIONS IN THE EUROPEAN MIDDLE AGES Religious pathology included sin, divine testing, divine punishment, and the unknowable act of God. Using any of these precepts, priests and religious figures could explain epilepsy, paralysis, sensory impairments and a host of other neurologic conditions, including cognitive disorders. In addition to the doctors’ theories of chronic neurological conditions, religious explanations helped people with disabilities and those caring for them to understand their conditions. Thus, the devil could cause a crippling pain, the loss of faith in a patron saint could cause the reoccurrence of blindness, or unrepentant sinning could cause insanity. Simultaneously, the Catholic Church’s ministrations to those with disabilities were significant and were even symbolized by the bishop’s crosier as a support to the infirm. Sustenance came from the divine as well. Appeals to saints for miracle-based cures were common, though variable with time, place and condition. In this role, religious healing was an economic competitor of lay medical “cures” (Finucane, 1997; Moog and Karenberg, 2003; Metzler, 2006). Even the non-ecclesiastic “holy,” like the flagellants during the plague, held a salutary power – their blood was thought to prevent or cure blindness. But the orthodox were not the only religious groups to use such pathologies (Kroll and Bachrach, 1986). Unlike pathology proper, prognosis could be used especially well by heretics, for example, to anticipate when a patient would die and offer conversion to a heretical point of view immediately prior to the patient’s death, making the conversion irreversible (Pegg, 2001). For this reason, magical causes also displayed great diversity during the Middle Ages. Thus AngloSaxons believed in the malicious intervention of elves and elf-shot, the arrows that transmitted diseases to the brain or spine, which we would largely consider infectious today. Certainly the succubus and incubus provided a malevolent etiology. And in Arabic as well as lay Western cultures, the Evil Eye conveyed any variety of conditions from opthalmia to blindness to death. At times, magical pathologies came into conflict with rational medical and religious pathologies. The result was a kind of proto-professional competition for patients. But at other times the three co-existed without authorial comment in many texts of the Middle Ages (Flint, 1989). In a sequence of remedies in the Anglo-Saxon Leechbook of Bald, the reader is encouraged to cure pain by way of a herb to rebalance the humors, a prayer to appeal to God’s power of healing, and a magical charm, which worked by means of its red color (Cockayne, 1864). And in the list of uses of mandrake root above, a sixth appears on the list:

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“If anyone perceives any grievous evil in the home, take the mandrake plant to the center of the house – as much as one has of it – and it will expel all the evil” (van Arsdall, 2002, p. 206). But folk pathologies were largely, though not exclusively, represented in a combination of the religious and the magical. Within the confines of society, pathology increasingly throughout the Middle Ages had to be distilled into the framework of medico-legal causation. This was one of the facets of the “medicalization” of society. Thus, in the event of a brawl in which a reveler died following head blows from several assailants, identification of which blow killed the victim could mean the difference between life and death of another person. Mental conditions too could have legal implications for inheritance in the form of diagnoses of madness (Turner, 2000). And neurological conditions could provide explanations for accidental death, which otherwise might have been considered homicide. So in 1378, the centenarian Robert Wylewes, canon of Missenden monastery in England, was sitting in his wheelchair by a fire. Robert was “lame and feeble.” His servant was preparing Robert’s meal and left him unattended. Robert rolled into the fire, sustaining dramatic and fatal facial burns and could not get out of the flames because of his disability, but the servant was judged blameless (Boatwright, 1994, p. 83). A final definition of neuropathology is a retrospective one. What causes of disease can we identify today that existed in the Middle Ages? This in itself is a large topic, but paleoanthropology on the remains of humans from 500 to 1500 has yielded data about infections such as congenital skeletal defects, spinal tuberculosis, trauma, cancer, and nutritional deficiencies, among others. Most of these conditions exist today. Similarly, diseases we have that medieval people might not have had include neurological complications of human immunodeficiency virus/autoimmune deficiency syndrome (HIV/AIDS) and perhaps multiple sclerosis (Finger, 1998). While some historians have argued that retrospective diagnosis is a difficult or even useless task, in some studies it has spurred and supported creative intellectual, social and cultural historical studies (McCormick, 1998; Graumann, 2000; Leven, 2002).

NEUROLOGIC CONDITIONS AND SOCIAL RESPONSES Many medieval neurologic conditions would be clustered under the rubric of disability today. Such an umbrella term did not exist during the Middle Ages. But we can see an important aspect of “disabling” conditions by retrospectively collecting data about them.

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W.O. SCHALICK, III Ideas about and experiences of disability during the veracity of that epithet. Some famous figures with disMiddle Ages varied dramatically (Covey, 1998; Stiker, abling conditions, including Hermann von Reichenau 2000). The conceptualization and experience of disabil(1013–1054) (also known as Hermann “the Lame” ity by a serf with a lower-extremity paralysis in 12thbecause of a congenital lower-extremity impairment), century England were notably different from that of were born into the nobility and went on to positions a 15th-century Italian duke with a speech impediment, of great intellectual productivity denied to the poorest or an 11th-century German nun with depression. In medieval peasant. Hermann was educated at an abbey addition, the social expectations of medieval people and became a well-known chronicler, poet, musician, were rather different from those today in the West. and mathematical astronomer. Teresa de Cartagena As a consequence, the following survey will be at best (1415/1420–?), who became deaf as a child, as a nun an overview. 20 years later wrote Arboleda de los Enfermos (“Grove Medieval neurodisability originated from many of the Infirm”), possible only because her family was medical conditions and social situations. Given that wealthy enough to have her tutored. King Baldwin IV some studies report nearly 50% of children died before of Jerusalem (1161–1185) was a child when he conage 21, death was a fiercely regular occurrence in the tracted leprosy with a consequent neuropathy, and yet home and community. During the Middle Ages, nearly he continued to fight in crusades before his death at a third of the inhabitants of a cemetery in York, UK around age 24. Another leper, this one very poor, lived were children. Parasites were frequent, suggested by in Venice and spent much of his life begging on the archeological studies of cesspits. Accidents were a reg14th-century streets. The Old Norse Landnámabók ular occurrence. Hunger and starvation were probably (“The Book of Settlement”) of the 12th century refers common in the full life of a medieval rural person; to a certain Bjargey Valbrandsdo´ttir, wife of Ha´varðr conditions of nutritional deficiency, such as rickets, Halti (“the Lame”). In the 10th century, Adso Deruenwere also common. Still, infectious diseases were probsis, in his Life of St. Walbert, refers to a man “. . . havably the most common cause of death. But death was ing been made lame by ruptured nerves” (Goullet, only an extreme (Dyer, 1990). 2003, p. 84). A famous 12th-century woman with a Owing to scant “record-keeping” and the inevitable potentially disabling condition, the mystic Hildegard ravages of time on original sources, it is difficult to of Bingen had perhaps scotomatous visions. Rather generate any kind of accurate epidemiologic statistics than impairing her vision while toiling in the fields, of disabling conditions during the Middle Ages. We these images became a religious experience, which know that tuberculosis (meningitis, other infections transformed both her individual relationship to God of the Central Nervous System and compression injuand also those influenced by her writings. As well as ries from spinal TB), plague (headache and weakness class, religion, race, and gender certainly altered the from systemic infection), and leprosy (neuropathy, experience of disability. today the most common global cause of neuropathy), The world around the medieval person was potenamong others, were infectious diseases that could have tially disabling at all times. In one example, a medieval left survivors with long-term disabilities of both a neufisherman netting a torpedo fish became paralyzed in rologic and a musculoskeletal nature, as attested to by his upper extremities (Thorndike, 1923, pp. 905–906). both archeological and textual evidence. Data derived The often-analyzed Hippocratic Aphorisms explained from miracle records at the shrines of saints suggest how winds from the south make one deaf. In addition a range of symptomatic/diagnostic conditions with disto the vagaries of nature, accident, happenstance, and abling features, including blindness, deafness, mutism, bad fortune were clearly agents of disabling etiology. a variety of paralyses, and leprosy (Finucane, 1997; More frequently, etiology was attributed to witchcraft Demaitre, 2007). or evil magic, as when King Alfred the Great was While we have only the barest sense of epidemiolenjoying his wedding night and was attacked by a ogy for medieval disabling conditions, we can gather severe pain. that disabilities were common enough both to provoke notice, and yet often to deny total “otherness” by the When, therefore, he had duly celebrated the degree of accommodation and integration invoked by wedding . . . and after the feasting which lasted society at large. The experience of disabilities by medday and night, he was struck without warning ieval people is only now beginning to be elucidated. in the presence of the entire gathering by a sudBiographically, we know any number of figures with den severe pain that was quite unknown to all disabling conditions. Henry the Minstrel, 15th-century physicians. Certainly it was not known to any chronicler of William Wallace of Scotland, was known present . . . nor to those up to the present day as “Blind Henry,” though not all scholars agree to the who have inquired how such an illness could

NEUROLOGICAL CONDITIONS IN THE EUROPEAN MIDDLE AGES 87 arise . . . [It continued for] many years without their role as “others.” During the Black Death in remission, from his twentieth year up to his for1347–1348, some castigated the “cripples” and “the tieth and beyond. Many, to be sure, alleged that mutilated poor” as the cause of the epidemic, along it had happened through the spells and witchwith Jews and the wealthy (de Chauliac, 1974, p. 773). craft of the people around him; others, through Intriguingly, disability could be as “othering” a characthe ill-will of the devil, who is always envious teristic as non-Christian religion or social status. Simiof good men; others, that it was the result of larly, as charity provoked almsgiving, some beggars some unfamiliar kind of fever; still others in 13th-century Paris disguised themselves as disabled thought that it was due to the piles, because he people to generate more alms. When they were discovhad suffered this particular kind of agonizing ered, as might be expected, a more general backlash irritation even from his youth. (Keynes and against all beggars ensued (Farmer, 2002). Lapidge, 1983, pp. 88–89) Despite these changes at the social level, some doctors advertised their unique strengths in the face of a But magical and religious explanations were widemedicalizing market demand. Impairments and disabilspread and promulgated by ecclesiastical doctrine. As ities fell increasingly under the care of elite doctors a consequence, the role of relics and saints’ shrines in and surgeons, but this segue was not without conceptual miraculous cures of disabling conditions is undeniable. complications at the level of boundaries – between the Increasingly into the 13th and 14th centuries, a pronatural and the other than natural (i.e., the pathological). cess of “medicalization” provided another explanatory In the 15th century, for example, the Medical Faculty of system. This was hardly to the extent of the medicalithe University of Paris provided a set of recommendazation of the 19th and 20th centuries, but still signifitions for artificially improving memory (De memoria cant. Jean de Saint-Amand, the 13th-century doctor, artificialis, NLM Schullian 516, fo. 34r). Thus the dividfor example, prescribed a drug for scrubbing on the ing line between neuroaugmentation and medical therpalate, which then attracted phlegm from the head, apy was complicated then as now, as it was in other thereby healing someone of an “aphasia.” spheres of medicine (Schalick, 1999, 2005). Neurological deviations also revealed shifts in theory Theodoricon has a special property: if one scrubs amongst the scholastics. Some focused on the normathe palate with this drug, it attracts phlegm from tive, ignoring the deviant. In this camp was the great the head and for this reason it is good in noninterpreter of Aristotle, Thomas Aquinas (c. 1225– arousability. Here is an example of this action: 1274). He characterized the more standard. But other I was called to a woman who was already lost scholastics favored systems of reason, following according to the common wisdom; it was at the Aristotle, but not necessarily Aquinas. Into this camp end that I had restored [her] ability to talk for a fell William of Auvergne (d. 1249), Peter John Olivi moment. I scrubbed her palate with this substance, (1248–1298), and others. They advanced theories that and also placed there a little diacastoreum. The were more adept at dealing with exceptional cases rather patient recovered her speech, made her testament than the normative. In particular, cases of the neurologiand died. (de Saint-Amand, 1581, fo. 217) cally developing child, the insane, or potentially the At times, neurologic conditions demanded caution on disabled emerged as explainable in a non-Thomist model the part of the learned doctor. Thus, Avicenna, an (Boureau and Semple, 1994; Montford, 2004). 11th-century Arabic physician widely studied in Latin Finally, marketplace changes also altered the nature translations in Europe, noted that celery was contraof the social relationship to disability. The handicapindicated in epileptics, as it could cause status epileptiping nature of some impairments in the social milieu cus. But one condition could also induce another prevented those with paralyses from being admitted disabling one. According to Taddeo Alderotti, the to some hospitals, as, for example, at Valenciennes, 13th-century Bolognese physician, diarrhea could France. In contrast, specialized institutions for those induce stuttering or stammering (Siraisi, 1981). with disabilities, such as the Quinze-Vingts founded Similarly, chronic, untreatable conditions of a disby Louis IX for 300 blind people in Paris, and imitators abling nature could be a cause to withhold certain in five other cities, or the plethora of leprosaria in the kinds of charitable care. Thus, the Hospital of St. John 13th century, enhanced the association of charity with the Baptist in Oxford did not accept people with disability (Farmer, 2002). chronic or untreatable conditions, including people The massacre of the lepers in 1321 is emblematic of a who had intractable epilepsy (Rubin, 1989). dramatic social change, during which the poor infirm, People with neurologic disabilities themselves could who previously were looked upon with charity and godly be identified as etiologic agents of disease, enhancing compassion, now became an object of derision and fear

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of their diabolic association. And the 1351 French ordinance against those begging, who were sains de corps (of healthy body), altered the nature of the public and governmental relationship with the disabled yet again. Similarly, in the early- to mid-13th century, Bracton, the great English legal scholar, made those who feigned cognitive illness accountable to the full extent of the law. This shifting social response was further complicated by institutional changes. On the one hand, state-sponsored care expanded institutionalization as a medium of aid to the disenfranchised, although adumbrated with shorter stays, whereas on the other hand, the fears and suspicions engendered by the Plague suggested institutional responses of a less compassionate nature. Thus the 1351 French ordinance was reproduced in 1367, 1389, 1395, 1412 and 1450 with expanding punishments. And with each edict, the language became more precise about the mechanisms for falsifying disease and disability (Schalick, in press). In addition, children were used, and sometimes mutilated, in order to feign disability for begging (VincentCassy, 2003). In one case recounted in the Journal d’un Bourgeois de Paris in 1449, a group of heretical “caı¨mans,” murderers and thieves, “confessed to have mutilated children, to have carved out the eyes of one, to have cut off the arms of another or the feet or of others more or less” (Tuetey, 1881, p. 389). In closing, far from being stagnant and chaotic, medieval “neurology” was vibrant and increasingly coordinated. From the bases laid by the textually sophisticated physicians in refining diagnostic terminology, in controlling market dynamics, in rejuvenating intellectual structures, like anatomy and the universities, the Middle Ages became a critical foundation for the “advances” of the Renaissance and Early Modern Periods, when observation and eventually experimentation would be added into the academic enterprise that would become modern neurology.

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Pegg MG (2001). Corruption of Angels: The Great Inquisition of 1245–1246. Princeton University, Princeton, NJ. Portman P, Savage-Smith E (2007). Medieval Islamic Medicine. Edinburgh University Press, Edinburgh. Reeves C, Taylor D (2004). A history of the optic nerve and its diseases. Eye 18: 1096–1109. Riddle JM (1992). Contraception and Abortion from the Ancient World to the Renaissance. Harvard University, Cambridge, MA. Riddle JM, Estes JW (1992). Oral contraceptives in ancient and medieval times. Am Sci 80: 226–233. Rubin M (1989). Development and change in English hospitals, 1100–1500. In: L Granshaw, R Porter (Eds.), The Hospital in History. Routledge, London, pp. 41–59. Sait N, Tu¨re U, Pait TG (2004). History of spinal cord localization. Neurosurg Focus 16: 1–6. Schalick WO (1997). Add One Part Medicine to One Part Surgery and One Part Pharmacy: Jean de Saint-Amand and the Development of Medieval Pharmacology in Thirteenth-Century Paris. PhD dissertation, Johns Hopkins University, Baltimore, MD. Schalick WO (1999). The face behind the mask: medical cosmetology and physiognomy in thirteenth- and early fourteenth-century Europe. In: S Sakai, S Kuriyama (Eds.), Images of the Body: Proceedings of the 22nd International Symposium on the Comparative History of Medicine – East and West. Ishiyaku EuroAmerica, Tokyo, pp. 295–312. Schalick WO (2003). To market, to market: the theory and practice of opiates in the Middle Ages. In: M Meldrum (Ed.), Opioids and Pain Relief: A Historical Perspective. IASP Press, Seattle, WA. Schalick WO (2005). [Disability in the] Medieval West. In: GA Albrecht, J Bichenbach, D Mitchell, et al. (Eds.),

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 8

The development of neurology and the neurological sciences in the 17th century HANSRUEDI ISLER* Private practice, Hochhaus zur Schanze, Zürich, Switzerland

INTRODUCTION This chapter is not an exhaustive account of the major contributors to neurology in the 17th century. It focuses on how systematic brain research originated at the University of Oxford, along with a new name, “neurology,” and a first textbook, namely Willis’s book Cerebri Anatome, The Anatomy of the Brain (Willis, 1664). It also shows how Willis completed his neurology with two more textbooks anticipating the subjects of the future clinical specialty, neurology. These innovations were based on the rich tradition of neurological and neuroanatomical observations from Classical Antiquity through Late Renaissance, and the successive intellectual revolutions initiated by Paracelsus, Vesalius, Copernicus, Kepler, Galilei, Francis Bacon, and William Harvey. The political and religious background was: first, the English Civil War, where Oxford was the pivot, then the execution of King Charles I, Cromwell’s Puritan Commonwealth, and the Restoration – in effect, a world turning head over heels (Malcolm, 1997). As for the dynamic intellectual background of the new specialty, neurology, it was a by-product of the conflict between “Ancients,” Aristotelian scholastics and partisans of Galenic humoral pathology, and “Moderns,” enthusiasts of Bacon’s experimental science and Harvey’s physiological medicine at the University of Oxford (Jones, 1936; Carre´, 1949). Like many of his friends, Willis was a religious and political conservative, but a “Modern” in his scientific work. It should be noted that Bartolomeo Eustachi (1520–1574) anticipated a sizeable part of Willis’s findings in his Tables of 1552. But they lay hidden in the Vatican Library and were not published until 1714 (Morton, 1970; Meyer, 1971).

*

SPECIFIC PREREQUISITES FOR THE RISE OF NEUROLOGY There were specific precedents that favored the formation of neurology in mid-17th-century Oxford. Some were the explanation of neurological diseases as brain diseases by Carolus Piso, the biochemical fermentation doctrine of van Helmont, the energetic view of nerve and muscle action of Gassendi, and the non-Cartesian tripartite soul as described by Gassendi and van Helmont. The widespread reception of van Helmont’s and Gassendi’s doctrines in England, the arrival of Sylvius’s anatomy in Oxford, the neuropathology and neurovascular dye injections of Wepfer, and the discursive and liberal climate of the burgeoning Royal Society, which favored experiments, inventions, and teamwork, also influenced events in England and abroad. An additional factor was the inductive method of Thomas Willis, the founder of English epidemiology and biochemistry, about whom collateral information can be found in other chapters in this volume (see Bentivoglio and Mazzarello, Ione, Isler, Lanska (movement), Millett, Rose, Stahnisch, Storey, Tyler, Williams, Zanchin).

The cerebral explanations of neurological diseases by Carolus Piso (Charles Lepois, 1563–1633) Piso (1618) explained epilepsy, migraine, and hysteria as cerebral diseases, thus paving the way for future developments in neurology and brain research (Fig. 8.1). He was a successful clinician, and not much hampered by traditional taboos since his patient, the Duke of Lorraine, had founded a medical faculty for him. His book on diseases of 1618 was widely known and

Correspondence to: Hansruedi Isler MD, Private practice, Hochhaus zur Schanze, Talstrasse 65, CH-8001 Zu¨rich, Switzerland. E-mail: [email protected], Tel: +41-3611359, Office: +41-2102898.

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Fig. 8.1. Carolus Piso (Charles Lepois), 1563–1633, Lorraine, France, explained epilepsy, migraine and hysteria as brain diseases, based on autopsies, and described complex migraine aura (Piso, 1618).

quoted up to the late-18th century (Piso, 1785). He rejected the dogma of the uterine origin of hysteria, which had been handed down from Ancient Greece, and described hysteria in men. He found a “flood” of serous liquid at the base of the brain in autopsies of his patients with epilepsy, hysteria and migraine, and mistook these post-mortem changes for the cause of the diseases. But he was a precise observer who gave a perfect description of migraine with complex aura in a young girl who felt a numbness wandering across the fingers and up the arm before the onset of headache. He also described a prodrome of his own migraine, febricula, a little fever. Similar non-aura prodromes were sufficiently documented only in 2000, with the help of hand-held computers given to patients, who noted whatever they experienced before an attack.

The biochemical fermentation doctrine of van Helmont, inventor of “gas” Jan Baptist van Helmont (1577–1644), a Fleming at Brussels, created a whole medical and chemical science of his own (Fig. 8.2). After intense studies he said that university medicine was not even able to provide a cure for a simple toothache, and turned to alchemy, mysticism, the Kabbala, and the chemistry of Paracelsus. This led him to believe in the philosophers’ stone, and in the then famous weapon-salve, which cured wounds when the weapon that had inflicted them was anointed with the salve. He accepted these popular delusions without great difficulties, side by side with his own strictly scientific

Fig. 8.2. Jan Baptist van Helmont (1577–1644), Brussels, discovered gas, invented its name, and created early biochemistry, mixing hard science with mysticism.

methods (Pagel, 1982). He combined Paracelsian spagyrics (analysis, from the Greek spáô, and synthesis, from the Greek ageírô) with quantitative control of mass balance (Newman and Principe, 2002). He was convinced that life processes are chemical processes, and he was probably the leading chemical researcher of his time and the main source of information and inspiration for Robert Boyle (Partington, 1961, pp. 209–243, 486–549). He tried to quantify the ingredients and products of his experiments, and achieved major advances, including his creation of the term “gas” out of the Greek word chaos. He identified gas sylvestre, carbon dioxide, and gas pingue, methane (Partington, 1961, pp. 209–243). The twin of “gas” was “blas,” equivalent to the Chinese qi, an energy flowing in the human body and moving it. Van Helmont also introduced ferments as protagonists in his biochemistry. Despite his mysticism, van Helmont convinced later researchers of the feasibility of scientific studies of biochemistry and autonomous life processes, and his influence on Willis’s fermentation biochemistry can hardly be overestimated.

Gassendi’s energetic view of “animal spirits” and nerve and muscle action Pierre Gassendi (Petrus Gassendus, 1592–1655), of Digne (Provence) and Paris, was a humanist, pious Catholic priest, assiduous astronomer, and an experimental physicist (Brundell, 1987). He revived the atomism of Epicurus and his epistemology. As a teenage teacher of philosophy, he grew disenchanted with the prevailing Aristotelian

DEVELOPMENT OF 17TH CENTURY NEUROLOGY scholastic formalism and replaced it with the pragmatism of Epicurus, whose philosophical school had survived all others in Ancient Greece (Diogenes Laertius, 1980, p. 538). Gassendi (Fig. 8.3) later also replaced the prevailing natural philosophy of Aristotle with the atomism of Epicurus. He coined the term molecula, our “molecule,” a diminutive mass for small bodies composed of a few atoms. Both Leibniz and Locke later used his Epicurean epistemology and logic to escape from the Scholastic Aristotelian system. Locke’s sensualism, which held that nothing is in the mind that has not been in the senses, was derived from Epicurus (Diogenes Laertius, 1980, pp. 560–561, 568; Locke, 1987, pp. 100–118) through Gassendi’s annotated bilingual edition of that text (Gassendi, 1658, Vol. V, pp. 1–166) and Willis’s Oxford lectures (tabula rasa: Dewhurst, 1980, p. 66). Gassendi, like everybody else up to the mid-18th century, believed that Galen’s spiritus animales (animal spirits) carried out the functions of nerves. But unlike most others, he said that they had nothing to do with the spirit of wine; rather, their nature was more akin to flame and light. This energetic view of nerve function was the closest possible approximation to the chemical–electric concept developed from the mid-18th century to the 19th century. He also compared muscle action to the explosion of gunpowder, ignited only by a small spark (quoted in Willis, 1667, pp. 6–11). Both similes were taken up by Willis as part and parcel of his new neurology (Willis, 1664, 1667, 1672; Isler, 1965, 1968; Hughes, 1991).

Fig. 8.3. Pierre Gassendi (Petrus Gassendus), Digne (Provence) and Paris, 1592–1655, replaced Aristotelian scholasticism with Epicurean atomism and logic, held that animals have a material soul, able to learn, and described the “animal spirits,” the hypothetical carriers of nerve action, as something akin to light.

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The three parts of the soul of man in Gassendi and van Helmont: anti-Cartesian psychology and anthropology, accepted by theologians Descartes explained the impossibility of causal interaction of body and soul (as would Hughlings Jackson over 200 years later, (York, 1999)), because the res extensa (the dimensional thing, the body) and the res cogitans (the thinking thing, the soul) belonged to incompatible categories. He then proceeded to bridge the gap by placing the seat of the soul in the pineal gland, from whence it could regulate the flow of animal spirits in the ventricles and nerves. Descartes believed that the soul exists only in humans, while animals are mere automata without a soul. The soul, une et indivisible (one and indivisible), exists only in man. Gassendi, in contrast, said that anybody could see that animals are capable of sensation, spontaneous movement, and limited cogitation. He concluded that they must have these abilities because they have a soul, albeit not an immortal soul, and he elaborated the traditional concept of three parts of the soul, the vegetative in man, animals, and plants, the sensitive in man and animals, and the rational soul, which exists only in man. This concept had come from Aristotle through Albertus Magnus and Thomas Aquinas, and it was far more widely accepted in the 17th century than Descartes’ exclusive model of the one indivisible soul. Van Helmont also believed in a version of a soul of three parts. It justified the comparative anatomy, the animal experiments, and the hypotheses of central nervous functions, which Willis and his teams used in their brain research, whereas Descartes’ anthropology was hardly compatible with these methods and with attempts at brain localization beyond the pineal gland and the ventricles. Gassendi collected his astronomical observations in tables over 30 years, attempted to prove a theory of inertia, corresponded in Latin with Galileo, van Helmont, Kepler, Kircher, Scheiner, and many other researchers, wrote the biographies of Tycho Brahe, Copernicus, and Regiomontanus, and described a persisting foramen in the ventricular septum of the adult heart (Gassendi, 1639). His collected Latin works were published 3 years after his death, with a clearly commending imprimatur of Louis XIV, proving that there were no cogent objections by those Catholic zealots who had contrived against Descartes (Gassendi, 1658). Only the original Latin texts can serve as reliable reference, since there is no useful text in French (Darmon, 2000) or any other modern language. Gassendi’s doctrine of the three parts of the soul in man was tolerated by the religious critics, who also failed to suppress his rehabilitation of Epicurus, despite the canonized condemnation of Epicurus by church fathers.

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Obviously the prelate Gassendi was able to pass nearly unscathed through clerical scrutiny, an ability we find again in the Anglican hero, Willis, whose version of the three parts of man’s soul was also accepted by the clergy of his church.

The reception of van Helmont and Gassendi in Oxford The medical reform movements of the 1650s in England were closely associated with the disputes and conflicts between conservatives among Anglicans, Presbyterians, and Puritan sectarians, and their radical antagonists within the same confessions (Elmer, 1989). For the liberal segments, following new ideas in the study of nature, and especially in chemistry, was a part of religious life, and the pious van Helmont became popular among them, while most orthodox seventeenth-century theologians adopted the opinions of Pierre Gassendi, which held that animals were endowed with a lower, subtle material soul (Henry, 1989). The works of both van Helmont and Gassendi were widely read in Oxford, Cambridge, and London in the 1650s. The Oxford physician Walter Charleton (1620–1707), an early member of the Royal Society (Partington, 1961; Bodemer, 1974), enhanced their popularity in these years. He translated some of van Helmont’s works into English in 1650, when new alternatives of learning were sought (Bodemer, 1974, pp. 192–194). He spread the natural philosophy and epistemology of Gassendi through his: Physiologia Epicuro-Gassendo-Charltoniana: or, a Fabrick of Science Natural, Upon the Hypothesis of Atoms, Founded Repaired Augmented

By

His anatomical lectures became famous and Leyden students felt that only Sylvius could really explain dissections. One student, the Dane Thomas Bartholinus, incorporated Sylvius’s lecture notes in the re-edition of his father Caspar’s anatomy textbook of 1641, with due credit (Beukers, 2000). Another student, William Petty, was captivated by Sylvius’s brain anatomy and comparative anatomy, and imported the method into Oxford in 1650. There he instructed Willis in dissection, neuroanatomy, and comparative anatomy (Partington, 1961; Dewhurst, 1980).

Wepfer’s neuropathology and cerebrovascular dye injections of 1658 Johann Jakob Wepfer (Schaffhausen, Switzerland, 1620– 1695) reformed the anatomy and pathology of the cerebrovascular system by introducing the dye injection of cerebral vessels in human autopsies (Wepfer, 1658) (Fig. 8.4). He also gave many classic descriptions of neurological disorders (Wepfer, 1727, 1787; Major, 1978). His book of 1658 was quoted at length by Willis (1672).

The Vertuosi and the Royal Society In 1648, several followers of Francis Bacon’s experimental science were appointed to Oxford chairs by the victorious Puritans, who wanted to break up the Scholastic front of the Royalist dons, of whom some were bodily carried out of their college lodgings. The newcomers called themselves the Vertuosi, after the members of Italian learned societies. They established a culture of free discussions and experiments, and brought in new philosophies and research theories from the continent (see above, van Helmont, Gassendi, Charleton). These ideas, and the custom of the Vertuosi of working in teams, shaped the brain

Epicurus Petrus Gassendus Walter Charleton

London, 1654 (Partington, 1961, pp. 467–468).

The neuroanatomy of Sylvius, brought to Oxford by Petty Franciscus de le Boe¨ Sylvius (1614–1672), professor of medicine at Leyden, promoted Harvey’s circulation doctrine and had his experiments replicated. He described the Sylvian fissure and the aquaeductus Sylvii, which bear his name (Sylvius, 1663), and observed that some tremors occur at rest, others only during movement. He explained diseases in terms of acid–alkali imbalances in the body, causing a pathological effervescence, noting that, if this occurred in the animal spirits (the humor resembling wine-spirit that activates the nerves), it induced epileptic seizures.

Fig. 8.4. Johann Jakob Wepfer (1620–1695), Schaffhausen, Switzerland, investigated human brain arteries by dye injection, and improved neuroangiology and the pathologic anatomy of stroke (1658). He founded experimental toxicology (1679), and described a series of neurological diseases of the head (1727, 1787).

DEVELOPMENT OF 17TH CENTURY NEUROLOGY research of Willis and also formed the basic pattern of the Royal Society, founded by the Vertuosi, and among them Willis, in 1660 (Hoppen, 1970). Many Vertuosi were uomini universali, universal men, such as Robert Hooke, who became their curator of experiments and promoted microscopy, Robert Boyle, and William Petty, who designed (invented) catamarans for the Navy, among other projects, and first met Willis in a chemical research group. Petty was representative of his fellow Vertuosi. He became Professor of Music, Surveyor of Ireland, created “political statistics,” and wrote his Political Anatomy of Ireland in 1672, uniting sociology with anatomy (Hoppen, 1970), much like his fellow Vertuoso Christopher Wren, who combined brain anatomy with monumental architecture. This was a climate of such openness that even laymen took part in autopsies.

The inductive method of Thomas Willis, founder of English epidemiology and biochemistry Willis wrote in his first book on fermentation and fevers of 1659 that he compared his clinical observations to one another, and adapted general notions from particular events. This enabled him to find out types of epidemic fevers, and to distinguish typhus from typhoid. It also helped him to define sexual hormones, and much later, diabetes mellitus. The same method resulted in the development of his neurology, as outlined in the preface to Cerebri Anatome (Anatomy of the Brain) (Willis, 1664).

HOW NEUROLOGY CAME TO BE Willis: practicing physician, biochemist, Anglican hero, founder of neurology, businessman Thomas Willis (1621–1676) grew up on a farm near Oxford, studied arts and medicine in nearby Christ Church College as a batteler or poor student servant of Canon Iles, and had to help the Canon’s wife in the preparation of medicines (Aubrey and Dick, 1960). His medical studies were interrupted when he served as a Royalist volunteer during the siege of Oxford in the Civil War. In June 1646 Oxford was taken by the troops of Parliament, and the university resumed its functions. In December 1646, Willis graduated Baccalaureus of Medicine, after a long absence from formal scholastic medical training. His humanist training for the BA and MA must have been much more complete, to judge from his Latin style and classical metaphors (Willis, 1664, 1681, praefatio/preface). He then attended country markets as a wandering doctor, already in close connection with early protagonists of the “New” experimental science, which William

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Harvey, among others, had propagated in the university during the siege by his demonstration of the circulation of the blood in a dog. Starting in 1648, a group of the future founders of the Royal Society, who called themselves the Vertuosi, assembled in Oxford. They began to do extracurricular research on chemistry and medicine in small teams. Willis soon joined them. Their habitual teamwork became typical of Willis’s own research, as was their open-mindedness about exploring topics foreign to the scholastic curriculum.

Assembling neurology, 1664–1672: brain anatomy, neuropathology, neuroangiology, neurophysiology, clinical neurology, and neuropsychiatry Willis’s Sedleian Lectures (Dewhurst, 1980) contain topics that were fully developed later, not only in Cerebri Anatome, but also in Pathologiae Cerebri et Nervosi Generis Specimen of 1667, and in “our psychology,” announced by Willis in 1664 and published in 1672 as De Anima Brutorum, meaning “Of the Soul of Animals,” the first coherent textbook of neurophysiology, neuropathology, and neuropsychiatry. The introductions to these books, Willis’s remarks on his publication program, and the notes from his lectures, outline a master plan for research on neurology developed from the anatomical experiences with Petty, and from Petty’s suggestions for comparative anatomy, which Willis implemented. The plan evolved through the joint chemical, anatomical and medical research activities with groups of Oxford Vertuosi, and through their descriptions in Willis’s Sedleian Lectures. That this research was done by small teams was well known and openly declared by Willis. He has been wrongly accused of publishing the results of his associates in his books without contributing much more than his name. Comparison of the Latin style of his books from 1659 to 1676, and of his expressions of enthusiasm for observation and research, shows that he was the author of these texts throughout, except for the illustrations and their legends. Repeated testimonies of his leading collaborator, Richard Lower, show that Willis had Lower’s unswerving loyalty (Lower, 1665; Dewhurst, 1983), and that Willis closely directed the joint research work and performed the autopsies on his own patients (Hughes, 1991) (Fig. 8.5).

1664: CEREBRI ANATOME Introducing neurology: teamwork Cerebri Anatome: cui accessit nervorum descriptio et usus (Anatomy of the Brain followed by the Description and Use of the Nerves) (Willis, 1664) was the first monograph devoted exclusively to the brain,

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H. ISLER first proved in many animals sacrificed for this purpose (Willis, 1664, 1681, preface, tables 9–13, fig. 1). Millington, a physician (later renowned as a botanist), served as his critic in frequent discussions. Wren (doctor of laws, professor of astronomy, pioneer of intravenous injection, blood transfusion, and splenectomy, and from 1666 the architect of St. Paul’s and 51 churches in London) applied his spatial know-how and drew the illustrations of the brain (Willis, 1664, 1681, preface, tables 1–8).

Methods of dissection and comprehension

Fig. 8.5. Thomas Willis, title page of De Anima Brutorum, reprint of 1676. The third neurological monograph by Willis appeared in 1672. It was a textbook of neurophysiology and neuropathology including the important psychiatric diseases. Together with Cerebri Anatome of 1664 and the book on convulsive diseases of 1667 it contained the main topics of the new discipline, neurology.

spinal cord, and peripheral nerves (Meyer, 1971). It was the first part of Willis’s triad of neurological works, and it introduced the Greek neologism neurología, later translated into English as “neurology” by Samuel Pordage (Willis, 1681, 1683, 1684). Willis calls neurología institutum nostrum, meaning “our project” or “our establishment,” and he refers to neurología nostra in later books (Willis, 1672, ch. 13). He writes that he had invented bold hypotheses to explain the parts and offices of the soul (as Sedleian Professor of Natural Philosophy he had to lecture on Aristotle’s De Anima) but grew ashamed of them, and turned to the study of natural anatomy (instead of that of Galen’s and Aristotle’s texts), “especially by opening heads and studying their contents.” He says that as he had not enough time, and perhaps not enough wit, for the work of developing this anatomy, and building up a physiology and pathology of these parts, he made use of the help of others: Richard Lower (1631–1691), Thomas Millington (1628–1704), and Christopher Wren (1632–1723). Lower, “a most skilful anatomist, was so industrious that hardly a day went by without some dissection,” and they had soon seen all of the brain and its appendages. As they went on to study the peripheral nerves, Lower “indefatigably followed their branches to the most hidden places, and drew the exact schemes of their course” (the original meaning of neurología), making sure that no line was in his drawings unless

The book begins with instructions for dissection in order to display the brain’s hidden parts without misleading artifacts. Earlier anatomists had dissected the brain in situ, but Willis took it out of its bowl and cut it from base to vertex (Dewhurst, 1980). The human brain was so complex and convoluted that it was much easier to study the hidden parts in the brains of animals, and animals had to serve when human brains were unavailable. Some deficient brains of congenital feebleminded humans also allowed easier access. Willis gave practical instructions on how to reach the deeper structures in normal human brains without losing the connections. When he described structures such as the fornix, he interpreted them both as static elements holding the hemispheres together and as highways for the animal spirits communicating with distant parts of the brain. Galen’s animal spirits had been assumed as the agents of the activities of the nervous system since classical antiquity. Willis adopted Gassendi’s similes of flame or light for the animal spirits, and he illustrated their activities by using a great variety of metaphors that brought him closer to modern descriptions of brain function than anybody before the mid-18th century. He was most fond of optical similes. Canguilhem (1955, pp. 57–78) concluded that these interpretations of the spiritus animales led directly to Willis’s concept of reflex action, and he found some of Willis’s metaphors still in use in 20th-century textbooks. Neuroangiologic studies were based on the new technique of cerebrovascular dye injection, introduced by Wepfer (1658) and developed by Wren, a pioneer of intravenous injection and blood transfusion. From these studies and from animal experiments, Willis concluded that emotions modify the circulation through the innervation of the arteries of the vagus and intercostal (sympathetic) nerves. The venous sinuses serve as heating and regulating devices for the distillation of the animal spirits. The anastomoses at the base of the brain, the “circle of Willis,” could compensate for the occlusion of one carotid artery, as found in the

DEVELOPMENT OF 17TH autopsy of a man who died of an abdominal tumor without any symptom of stroke, despite an old carotid obliteration (Willis, 1664, ch. 7).

Descending and ascending functions, interactions of faculties, and of souls Willis’s view of brain function was dynamic and connective. He saw the uses of the structures he described as connecting the cortex with the oblongata for movement, and the oblongata with the cortex for sensation (Willis, 1664, ch. 11). He localized memory in the cortex, and the sensorium commune, the center for the senses, in the striate bodies. Sensory impressions were carried to the striate, spreading like wavelets in water. When a sensory impression reached the cortex, it could raise another one that had been stored there, or elicit a related intention (appetitus), or a local movement. In this way memory and phantasy could interact. In man, the immortal, immaterial rational soul moved the material sensitive soul, using its capabilities as it wished. Instead of Descartes’ âme une et indivisible Willis adopted Gassendi’s model of the human and animal soul, in which humans and animals share two corporeal, material, and hence mortal souls. The lowest one, vegetative and vital, is in charge of the unconscious functions of the inner organs, and consists of the flame-like vital spirits in the blood. The middle one, the anima brutorum or animal soul, consists of animal spirits, enabling animals and man to move and sense, and to perform acts of simple reasoning and remembering. As for the highest soul, it is reserved for humans, being immaterial and immortal, and it accounts for the faculties of higher reasoning and human understanding. Willis was close to the Archbishop of Canterbury and two Bishops of Oxford. Although he trespassed into theological matters by including the soul in his anatomy, he was not persecuted by his Church for the presumption to explain human behavior and understanding with the help of animal experiments and dissections.

The role of the ventricles, and their discharge through the nose The central brain functions had been erroneously placed in the ventricles by medieval authors, and by Descartes. But Willis proposed that the source of all brain activity is the cortex, and that the pathways from and to the cortex are limited to the white matter and the nerves. The common cold, catarrh, had been traditionally explained as draining of the watery contents of the ventricles through the pituitary gland. Schneider (1660) had proved that there was no opening or duct to allow the passage of mucus from the pituitary to

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the nose. Lower’s studies confirmed it (published later; Lower, 1670). Willis agreed but held that a passage from the ventricles to the nose could be opened by disease. (It is well known today that trauma or other lesions can cause liquorrhea through the nose.) Willis still believed that the ventricles drain into the pituitary through the infundibulum (funnel; in Pordage’s version “tunnel”). He found no further passages leading away from the pituitary, and concluded that it must drain into veins: an evidence-based hypothesis of internal secretion (Willis, 1664, ch. 12).

Connections of the brain and cerebellum. Conscious and automatic activities The structures that ascend upwards serve as sensory connections; those descending downwards serve as motor ones. The animal spirits are created only in the cortex of the brain and cerebellum, serving for spontaneous or involuntary functions, outwards for locomotion, inwards for the apprehension of sensible things (Willis, 1664, ch. 13). Hence, the white striae (strips) in the striate body were seen as descending and ascending, “as if they were tracts from the brain into the oblong marrow,” and back, as if they were paths for the spirits into the brain, serving the common sensorium (prôton aisthêterion) and “the first instincts of local motion.” The first and second cranial nerves creep backwards at the base of the brain, in order to enter behind the striate bodies. The latter were often found softened in chronic paralysis. The medullary striae are crosslinks of the striates; all brain structures have such transverse connections. Choroidal infoldings (plexus choroidei) are always found in the ventricles, receiving the excessive serum that could not be received or contained by the glands (Willis, 1664, ch. 14). There are by-passages to and from the cerebellum. The passions (affections) of the sensitive soul disturb the praecordia and the entrails, and move and distort the face. The natural instincts from the praecordia and the entrails, such as hunger, are transmitted to the brain, where they elicit appropriate responses: hunger, for example, prompting the newborn to suck. The animal spirits flow from the brain and cerebellum into the medulla oblongata for the command of movements, and they spring back from there into the pathways for the sensory acts. There is a continuous exchange of the spirits between the brain and most of the organs of sense and spontaneous movement, except those that perform their actions not incited by intention, but either by the instincts of nature or by the blind impulse of passion: they are exchanged in the cerebellum. The bypass through the three pairs of

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connections of the cerebellum with the oblongata is necessary to avoid disturbing the sensorimotor mainstream of spirits by those conveying the impulses of the instincts and passions, of which the person is not aware. The perfectly regular arrangement of the cerebellar lamellae and medullary branches is suitable for the regular sorting and distribution of the spirits “without any driver” (= automatic; Willis, 1664, ch. 15, p. 118). Since the cerebellum is similar in all warm-blooded animals and in man, its duties have to be very similar and regular, as in the regulation of respiration and heartbeat.

A new view of the cranial nerves The cranial nerves were arranged into a new system (it was to become standard prior to Soemmerring’s system of the late-18th century, which is still in use). The olfactory, optic, oculomotor, trochlear, trigeminal, and abducens pairs were described almost as they are in present textbooks, with an emphasis on connections to the innervation of thoracal and abdominal organs, believed to serve automatic functions. The seventh was called the auditory pair but it was divided into two branches, a soft one for hearing and a harder one for the muscles of the face. The eighth was called the vagus, or the wandering pair, with many thoracal and abdominal branches for automatic, unconscious functions (Willis, 1664, chs. 23–24). It corresponded to the 10th of our current order. These visceral extensions were matched by the “intercostal nerve” (Willis, 1664, chs. 25–29), later known as the sympathetic system. The 9th and 10th pairs were responsible for the movement of the tongue (Willis, 1664, ch. 29) whereas sensory functions, including taste, belonged to the 5th, the trigeminal nerve. The accessory nerve, currently the 11th (sometimes called N. accessorius Willisii), was described as the spinal accessory nerve.

Establishing the autonomic nervous system, and the vasomotor function The autonomic nervous system had been explored and exhibited in precise tables by Bartolomeo Eustachi (1520–1574) in 1552, but his plates were only discovered 150 years later and not published until 1714 (Morton, 1970). Before 1664 and up to 1675, Willis and his teams were immersed in combining information from widely distant fields of clinical and autopsy observations, comparative anatomy, and animal experiments. Their experimental cerebellar surgery regularly damaged the medulla and its autonomic functions, which they then attributed to the cerebellum. Based on Willis’s erroneous but fertile speculations about the autonomic

functions of the cerebellum, they succeeded in mapping and interpreting correctly the cervical, thoracic, and abdominal ganglia and branches of the vagus and “intercostalis” (sympathetic) nerves. Richard Lower (1631– 1691) did the painstaking dissections and drawings, and Willis (1664) acknowledged this in his foreword. Eustachi and Willis were the only anatomists who clearly distinguished the vagus from the sympathetic trunks, which had been mistaken as one complex from Galen through Vesalius and up to Willis (Meyer and Hierons, 1965; Spillane, 1981). Lower and Willis ligated and then cut the vagus nerve in a living dog, recognizing its cardiac depressor function. Willis also believed that the nerves extending to the trunks of the arteries constricted them like loops, but in the first volume of his last book, the Pharmaceutice Rationalis of 1675, he reversed this model and stated that a mechanical effect of nerves on vessels was not possible – the constriction could only be caused by animal spirits and “instincts” (excitations) conveyed to them through the nerves. (For more details on the exploration of the autonomic nervous system, see Spillane, 1981, pp. 89–94.)

The rich publication history of Cerebri Anatome Willis’s account of the anatomy of the brain and nerves, and of the complete autonomic nervous system, together with its cardiac and vasomotor functions, became widely known. His publications obtained immediate international attention, as Cerebri Anatome came out in four editions in 1664, two in London and two in Amsterdam. It was translated into English in 1681 and was reprinted twice, and the Latin original was reprinted 11 times in the collected works, between 1676 and 1720.

THE BOOK ON CONVULSIVE DISORDERS Epilepsy, hysteria, hypochondria, and the blood–brain barrier In 1667 Willis published his book on convulsive disorders, Pathologiae Cerebri et Nervosi Generis Specimen in quo Agitur de Morbis Convulsivis. It was his first book on clinical neurology. Here he defined the blood–brain barrier that he had studied after dye injections in the cerebrovascular system (Willis, 1667, ch. 1). He classed epilepsy, hysterical and hypochondric disorders, and generalized spasmodic disorder, as well as scurvy, under convulsive disorders. As he saw it, they were generally caused by explosive particles affecting the animal spirits in the brain. These abnormal components were usually kept out by the blood–brain barrier, which could be breached by hereditary or acquired

DEVELOPMENT OF 17TH damages. In his exposition of the explosive mechanism of muscular movement, Willis quoted Gassendi, who compared the induction of movement with the ignition of gunpowder by a mere spark. Epilepsy and hysterical and hypochondric disorders had been grouped together from Aretaios to Le Pois, but Willis tried to reinforce the doctrine of their cerebral origin by his theory of pathogenic explosive particles. He described what was to be known later as Jacksonian epilepsy, and confirmed its cerebral origin, despite the initial peripheral symptoms. He defended the cerebral origin of hysteria against the traditional dogma of the ascension of the womb. He also opposed the theory of its origin from disturbed respiration, an idea promoted by Nathanael Highmore, a fellow Oxford anatomist and the eponymist of the maxillary sinus (antrum Highmori).

Parkinson’s disease anticipated Willis described a generalized or interrupted spasmodic disorder. This was a history of slowly increasing coarse tremors, akinesia, painful muscle tension, labored gait with bent body and propulsion, hypersalivation, and death by pneumonia. He explained the muscle tension by bad coordination of antagonists. Referring to the same case in 1672 (Willis, 1672, II ch. 9), he used the term “akinesia” in Greek. The clinical picture was clearly that of Parkinson’s paralysis agitans. James Parkinson would later put these and other signs together in his famous pamphlet of 1817.

“Scurvy,” a medley of syndromes The extensive account of what Willis called scurvy contained various diseases that he ascribed to metabolic disorders. The remedies for them were mostly herbal infusions, which might even have had some effect on the more specific scurvy from C-avitaminosis, recognized later by James Lind.

DE ANIMA BRUTORUM: A TEXTBOOK OF NEUROPHYSIOLOGY AND NEUROPATHOLOGY In 1672 Willis published De Anima Brutorum, the book he had announced at the end of Cerebri Anatome in 1664 as “our psychology.” It came in two parts, “the first physiological, the second pathological.” Its dependence on Gassendi was more explicit than in the earlier neurological books. The first part was to complete the physiological arguments of Cerebri Anatome and of the book on convulsive diseases, confirming the theory of the material soul contained in the nervous system as the link

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between the human rational soul and the body. The second, “pathological” part covered neurological and psychiatric diseases. Together with the book on convulsive diseases (Willis, 1667), De Anima Brutorum encompassed the principal topics of clinical neurology.

The physiological part: the functions of the corporeal soul in man and animals The anima brutorum, the animal soul or corporeal soul, is the material, mortal part of the soul of both humans and animals. It carries out the functions of the nervous system in the service of the immortal human soul, the anima rationalis, the rational soul.

From earlier views of the animal soul to comparative anatomy The book begins with a review of the writings of previous authors on the nature of the soul. Willis follows the doctrine of Epicurus and Gassendi, where the animal soul consists of atoms (Willis, 1672, I chs. 1–2). He classifies the animals as bloodless, cold-blooded and warm-blooded ones, terrestrial or aquatic. He describes the anatomy of the wasp (after Malpighi), the oyster, the crayfish, the earthworm, amphibia, birds, and four-footed animals, focusing on respiration and the configurations of their hearts (Willis, 1672, I ch. 3). Willis explains the ways and means of their corporeal soul. The light-like soul in the nervous system (anima sensitiva) arises out of the flame-like soul in the blood (anima vegetativa). It consists of the animal spirits, which are often wrongly compared to the spirit of wine; they are more like the rays of light in the air (light was believed to be corpuscular). They perform various functions in the brain through nerve-like ducts and medullary tracts. As an example, the partly ablated brain of a sheep is shown and explained (Willis, 1672, I ch. 4). The corporeal soul forms its own body and grows with it. The duration of the body depends on this soul, and on its inborn obligation to protect itself and to propagate its species. The genital humor (semen) is not generated from the brain but from blood (there was a widespread belief that semen was generated from the nervous system). Venereal imaginations can give rise to swelling of the genitals, and turgid genitals can in turn give rise to venereal imaginations (Willis, 1672, I ch. 5; the passage reflects Willis’s approximation to internal secretion as a feedback loop; see Willis, 1659, 1664; Isler, 1968, p. 67f). Animals have varying degrees of cognition. Birds win their mates, marry as it were, make nests better than human architects, and bring up their young by natural instinct. But higher animals, such as dogs, horses, and monkeys, have effective memory func-

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tions: they can learn. Wild animals, such as foxes, learn to hunt from each other and they have been observed hunting with tricks that they learned from experience (Willis, 1672, I ch. 6).

and much later by Freud in his Psychopathology of Everyday Life (Freud, 1904). This passage also opens the way to the mainstay of Willis’s psychopathology, namely that only the animal soul is subject to disease.

The animal soul and the human rational soul

The human brain is used exclusively by the animal soul

The achievements of the material soul of animals and man are compared with those of the human rational soul. The material soul can only perceive simple sensory impressions, whereas the human rational soul is capable of the most elaborate abstractions up to measuring inaccessible objects solely by their shadow, and mastering algebra and geometry. It is able to understand, examine, invent, perform stupendous things, and to create – “moreover the human mind looks at itself by reflex action, thinks of itself thinking, and hence recognizes its own existence which cannot be perceived by sense, nor by phantasy . . . ” (Isler, 1968, pp. 178–179). This was to become Locke’s “reflection,” later called “apperception.” Thus, the material soul of animals can produce only simple intentions to act, and only within the set limits of an animal species. Willis cites Gassendi and the leading Greek philosophers, authors who defined this limitation. The rational soul cannot perform animal functions, since the sensory and motor functions are corporeal and conducted by specific parts of the body. Gassendi wrote that the corporeal soul is the immediate subject of the rational soul, and performs the acts of sensation and motion under its direction. Willis states that imagination, the central function of the animal soul, is the throne of the rational soul. Quoting Gassendi, he compares the human rational soul to a king, who needs to be present in his court but does not personally carry out what he orders. To the twofold cognitive faculties, the intellect and the imagination, correspond the motivating forces: intention (appetitus), will (voluntas), and sensual motivation (appetitus sensitivus). The rational soul is not subject to cupidity or affective aversions. Such base motives can move the corporeal animal soul, whereas the rational soul may be moved by loftier values, such as the contemplation of the true and good, and chiefly that which is the sum of both. Sometimes the animal soul usurps the throne of the rational soul, which may then restore its regiment again and torment itself for its guilt. Religion provides the remedies for such conflicts. Willis had to explain these proportions and balances of power to ensure that theologians could accept the following passages, where he introduces unconscious motivation of everyday behavior, a notion taken up later by Locke as madness in normal man “in the steady calm course of his Life” (Locke, 1987, p. 395),

Comparative anatomy (anatomia comparata), established elsewhere by Willis (1664), showed little difference between the brains of higher animals and man, except for size; Willis concludes that the human brain is used exclusively by the corporeal animal soul. He illustrates this with table 6, the partly ablated brain of a sheep (Willis, 1672, I ch. 4), and table 8, a comparable view of a human brain (Willis, 1672, I ch. 7).

Passions of the animal soul: psychology of unconscious emotions Passio animi was one most important term in Galen’s medical psychology. The animal soul has its passions or affective states, it can be steady or troubled. If it is troubled, it may compromise the rational soul. Once the sensitive soul is in disorder, the disorderly animal spirits also perturb the blood flow. The trouble is always caused by objects that promise good or bad, which may affect the corporeal soul, as it is united with the body, and governed by the rational soul. These passions are either physical, or metaphysical, or corporeal. The merely physical passions are sympathetic or antipathetic. The metaphysical passions are religious acts, such as devotion, piety, and the fear of God. These will affect the imagination, and soon the circulation and the heartbeat. The moral passions, which we call corporeal, will arise from the priority given by the animal soul to the urgings of the body, with which it is so closely united that it may betray its service to the rational soul: the favorable urgings, lust, and the adverse, pain. The animal soul has these two-fold affections: expanding in lust, or withdrawing into itself in sadness or pain. All other passions derive from these basic ones. Here Willis explains hidden influences of unconscious emotions, writing: Sometimes less beautiful things, which any healthy man would despise, carry this psyche away, and captivate it as if ensnared by sorcery; as some lost in love, even if they see better choices, and approve them, still follow the worse; the reason of it is, that the sensitive soul secretly enters into friendships with some things, of which the affected are not aware, and keeps them inseparably and firmly.

DEVELOPMENT OF 17TH CENTURY NEUROLOGY In the original: cujus ratio est, quod anima sensitiva amicitias, quarum affecti haud conscii sunt, cum rebus quibusdam secreto init, easque inseparabiliter ac firme colit. Pordage (Willis, 1681) misread affecti as affectus and missed the point in his translation. Willis goes on to discuss unexplained phobias of cats, eels, and toads, which undoubtedly result from hidden enmities (inimicitiae) of the sensitive soul (Willis, 1672, I ch. 8). He expands these elements of emotional corporeal psychology to cover topics including sensory and imaginary motives for love and hate (Willis, 1672, I ch. 9).

The senses in general: from Willis’s to Locke’s sensualism Here (Willis, 1672, I ch. 10) Willis states omnis scientia fit a sensu, meaning “all knowledge comes from sense,” another form of Aquinas’s nihil est in intellectu quod non prius fuerit in sensu. Locke’s anthropology and psychology, as outlined in his Essay Concerning Human Understanding (Locke, 1987), has been qualified as “probably departing little in his beliefs from any of the specific teachings of Willis” (Diamond, 1971), as recorded from Willis’s Sedleian Lectures by Locke himself (Dewhurst, 1980) and as expanded in the three neurological books (Willis, 1664, 1667, 1672). Locke’s sensualism followed Willis’s declaration quoted above. Specific topics of De Anima Brutorum, such as the limited senses of an oyster (Locke, 1987, p. 148) and the difference between stupidity and foolishness (op. cit., p. 160), occur throughout Locke’s Essay. Locke’s concept that ideas that are not induced from the senses arise from reflection obviously reflects Willis’s concept of reflex action evoking memories from the cortex. The influence of these concepts on philosophical anthropology and psychiatry up to the early-19th century is profound (Cranefield, 1961; Leibbrand and Wettley, 1961; Isler, 1968).

The special sensory systems Touch: qualities such as heat, cold, soft, hard can be distinguished by this sense, and there may be different nerve fibers for heat and cold. Gentle stimulation may evoke pleasure, whereas violent sensation that corrugates the fibers will bring pain (Willis, 1672, I ch. 11). Taste: this is conveyed by the fifth and ninth nerves, the latter also moving the tongue. There are nine simple savors – sharp, bitter, salty, acid or tart, astringent or biting, sour, sweet, oily, or without taste. Willis has quite complex chemical and corpuscular explanations for the savors (Willis, 1672, I ch. 12).

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Smell: this is a more prominent and subtle sense than touch or taste, as it perceives objects from a distance, through very tenuous exhalations of objects. It is less developed in humans than in animals. The olfactory nerve fibers are densely woven in the (laminae cribrosae) in the nasal cavity, and join the olfactory bulbs. Taste usually requires prior olfactory discrimination (Willis, 1672, I ch. 13). Hearing: this belongs to the soft branch of the seventh nerve. The configuration of the inner ear and its membranes is appropriate for the separation of sounds of different pitch (Willis, 1672, I ch. 14). Seeing: light becomes visible immediately at great distances; this cannot be done by the corpuscles of a flame, its particles must be much more subtle, like an extremely subtle flame. Seeing requires the collaboration of the external and internal parts of the eyes. The muscles must work exactly together to avoid double vision. The configuration of the eye and the quantity of its liquors determine its focus, which may be displaced in a deformed eye. The eye is compared to a camera obscura, where all objects of a hemisphere are depicted on a white wall. The visual impressions are received not by the optic nerve, but by the retina, and conveyed through the optic nerve to the sensorium commune (Willis, 1672, I ch. 15).

Sleep and waking Wakefulness prevails when the animal spirits can move about and perform their functions freely. Sleep is an affection of the animal soul, induced by habit, by increased irrigation of the cortex by nourishing substances or by exhaustion of the animal spirits. The parts of the nervous system that serve movement and conscious sensation go to rest, and the unconscious vital functions continue, while the flame or combustion in the blood is enhanced. Dreams result from spontaneous and uncontrolled activities of detached parts of the animal soul, often reproducing their customary activities in waking life.

THE PATHOLOGICAL PART: NEUROLOGICAL AND NEUROPSYCHIATRIC DISORDERS These include headache, sleep disorders, waking coma, nightmare, vertigo, stroke, paralysis, delirium, phrenesy (frenzy), melancholy, madness, stupidity or foolishness, and even gout and colic (because these painful states affect the nervous system).

Headache The first two chapters contain descriptions of migraine (without the name), its (non-aura) prodrome, fames canina, a dog-like hunger, also seasonal and time-table

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periodicities, and a categorical denial of any constitutional predisposition. Willis even introduces the first effective migraine drug, coffee (Willis, 1672, II ch. 2). He also describes chronic headache without underlying disease, lasting for decades, resistant to every treatment, as in the famous case of Anne Conway the philosopher. One of his various pathophysiologies is suggestive of Wolff’s (1948) vasomotor theory of migraine: when the blood supply to the head is obstructed, the blood rushes to the head in greater quantity, and distends and corrugates the membranes, causing local pain (Willis, 1672, II ch. 1).

Sleep and related disorders (Willis, 1672, II, chs. 3–8) Here Willis postulates that narcotic particles, similar to opium, can be generated by the body. His traditional Latin terms (from the Greek) provide a coma scale of increasing severity: ●

lethargus or somnolence, can be waked (serum on cortex) ● coma, worse, cannot be waked (disorder also below cortex) ● carus, worse still, sensory deprivation (disorder deeper in white matter) ● apoplexy, worst, obstruction of the spirits, compression of nerves. In the second paragraph of chapter 3, Willis (1672, II) clearly describes narcolepsy. It is a disease in which people “always fall asleep, in the middle of their walking, or while they are eating, or doing anything else.” He states that this is not a slothful habit but a disease (see Willis, 1681).

Excessive waking and coma vigile (ibid. ch. 5) These disorders are caused by chemical alterations of the animal spirits, such as by overindulgence in coffee. In some cases, the limbs are thrown about in the bed. Opiates are often ineffective; mild remedies to correct the chemical imbalances may help more.

Incubus, or nightmare (ibid. ch. 6) This is not caused by the devil, as believed by superstitious people, but has natural causes. The involuntary vital processes, such as respiration, are disturbed by incongruous matter intruding into the cerebellum.

Vertigo (ibid. ch. 7) This rotating giddiness is provoked by rotation of the body, or by traveling in a carriage or boat, by internal disease, or as a disease of its own (ch. 7). It is caused by animal spirits that are chemically altered or

diverted from their ordinary activities in the nerves. The animal spirits then brawl tumultuously within the brain, or move about in a disorderly fashion, which induces vertigo or the circular whirling of the objects. Vertigo is often associated with diseases of the head, including acute headache, epilepsy and others. It can be caused by wine, gin, tobacco smoking, and smearing with mercury (for syphilis). Treatment consists of avoiding such substances, and using various (usually bland) medicaments.

Apoplexy (ibid. ch. 8) This topic is discussed in ch. 8 and is contradictory. Willis quotes a page from the cerebrovascular pathology of stroke by “the famous Wepfer” of 1658, where hemorrhage and ischemia are presented as causes. He first agrees with Wepfer’s theses, but then goes on to add some modifications, contrary to Wepfer’s ischemia as a cause of stroke. He holds that suppression of blood flow cannot cause stroke, since the four supplying arteries are so well connected that compensation follows the occlusion of one or two of them. He cites one case of his own, where autopsy showed long-standing occlusions of both the right carotid and vertebral arteries without any symptoms during life. Starting from these premises he falls back on the concept of the materia morbifica, pathogenic matter, which occupies the passages of the animal spirits and stops them from performing their functions – an ancient concept from Galen and Avicenna. He describes the case of an elderly churchman who fell down while praying, unable to speak or move, with labored breathing, and expired shortly thereafter. At autopsy, the brain, the ventricles, the heart, and the rest of the body were found intact, except for the lungs, which were filled with a frothy liquid. Willis concludes that the brain must have been occupied by a pathogenic matter that was too tenuous to be recognized. However, from his own careful description we may safely infer that the patient died because of acute pulmonary edema, not of stroke.

De paralysi: of the palsy (ibid. ch. 9) Chapter 9 shows how readily Willis accommodates divergent observations in his theoretical framework. Here paralysis is explained as a disorder of the striatum, the medulla oblongata, the spinal cord, or the nerves. Paralysis can affect motor and sensory functions jointly or separately. This leads him to the conclusion that, while most nerves conduct both functions, their fibers may serve either motor or sensory functions, predominantly or separately.

DEVELOPMENT OF 17TH CENTURY NEUROLOGY He notes frequent paralysis in chronic spasmodic disease, using the term “akinesia” (in Greek) in what was to become Parkinson’s disease 150 years later, referring by page number to a detailed case history (Willis, 1667, ch. 9, p. 115). Paralysis spuria, spurious, false or “bastard palsy” (Willis, 1681), is described and explained as a specific disorder. Willis states: . . . when they get up in the morning they are able to walk steadily, to wave their arms in all directions, and to lift weights, but before noon, when the spirits that had flowed into the muscles are nearly exhausted, they can barely move neither hand nor foot. I am now treating a prudent and honest woman who has been subject for several years to this spurious palsy, and not only in her limbs, but also in her tongue; she speaks freely and unhindered for some time but after long speeches, or when she delivers them in a hurry or labouriously, she suddenly clams shut like a fish, and cannot bring out a grunt, unless she recovers the use of her voice after one or two hours. In this kind of spurious paralysis which rather comes from a defect or weakness of the animal spirits than from an obstruction, one may suspect that not only the spirits themselves, as to their quantities and their original particles, are faulty; but moreover sometimes the weakness and impotence of the local movement depends to some extent on the defect of the explosive component (copula explosiva) that is everywhere infused into the motor fibres from the blood. This is not only an unmistakable clinical description of myasthenia gravis, but also a correct interpretation of the disease as a defect in a local chemical constituent necessary for the induction of muscle action. Myasthenia is sometimes called the Erb–Goldflam disease. In his history of myasthenia, Keynes (1961) wrote that it should rather be called the Willis–Goldflam disease. Willis further describes a combination of paralysis and insanity, which has been accepted as the earliest description of general paralysis by Vinchon and Vie (1928), Kelly (1948), Cranefield (1961), and Morton (1970). He also mentions improvement in some insane and mentally deficient patients after a fever (Isler, 1968). The chapter also contains detailed treatment proposals of traditional Galenic character, aiming at the elimination of pathogenic matter from the body. There are also some case histories with reports of autopsies and brain dissections, one of a three-years-old boy.

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De delirio & phrenitide: of delirium and frenzy Here (ibid. ch. 10) various forms of agitated behavior are described, with or without delusions or fever, and interpreted as disorders of the animal spirits.

De melancholia: of melancholy This disorder is addressed in chapter 11 (Willis, 1672, II). Melancholy is caused by changes in the chemical properties of the animal spirits, induced by changes in the internal combustion in the blood. Along with the other Oxford proponents of “nitrous air,” needed for both fire and respiration, Willis (1670) believed that this forerunner of oxygen is used in a burning process in the blood, and that the blood produces the animal spirits by distillation. But it can also be caused by reaction to life events, such as insane love. The morbid animal spirits go astray from their regular pathways in the brain and establish new and unusual connections, resulting in morbid and fearful notions and ideas. Melancholic patients often see unimportant small things magnified “as in a microscopic glass,” and are unable to detach themselves from them (Willis did use microscopes). In accord with this psychosomatic view of melancholia, Willis proposes both behavior therapy, getting the patients interested in creative tasks of everyday life, and somatic treatments for the elimination of pathogenic matter. The latter is largely traditional Galenic therapy, complemented with more recent iatrochemical items. There are purges, emetics, bloodletting, and many polypragmatic remedies, including “modern” iron preparations. He has doubts about the value of usual bloodletting from hemorrhoidal veins (drawing blood away from the head), but he thinks that this may help, “if the patients are firmly persuaded that it will help.”

De mania: of madness Willis gives a clear description of melancholy and mania changing into each other in chapter 12 (Willis, 1672, II). He uses the ancient simile of burning wood, which may emit either smoke or flame. His casebook (see Dewhurst, 1964, 1981) shows that he had observed and noted what is now called bipolar disease in his patients in 1650. Madness is caused by morbid changes of the animal spirits in the brain in the same way acid of salt or vitriol is changed into aqua fortis (aqua regia, which dissolves gold) by the admixture of nitrous acid. This stygian liquor causes errors of judgment, which can result in absurd behavior. Treatment, except for strict discipline with confinement and even “strokes,” lean diet, and no strengthening drugs for violent patients, follows the same general

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pattern as melancholy: evacuation to eliminate pathogenic matter, assorted drug combinations (St. John’s wort is only one among many components), and behavior therapy to keep non-violent patients continuously occupied with light work, exercise, or entertainment.

ebri Anatome, with its figures by Wren and Lower, the book on convulsive diseases, and De Anima Brutorum.

De stupiditate, sive morosi: of stupidity, or foolishness

The new neurology was firmly based on the evidence of neuroanatomy, pathologic anatomy, compared anatomy, and clinical experience. The teams of highly qualified collaborators even ensured something approaching peer review. But their interpretations relied on the ancient imaginary animal spirits as carriers of function, and on unsupported analogies with elementary chemical experiments. This resulted in an audacious pathophysiology of neurological disorders, and equally audacious conclusions about the pathways of motor, sensory, and vegetative brain functions. In retrospect, surprisingly many of the far-fetched theses hit the mark, and the entire construct of hypothetical brain functions established a new pattern of discovery. Willis arrived at a comprehensive view of neurology that enabled him to determine basic principles such as localization of brain functions (despite major mistakes), reflex action, autonomic vegetative function, the role of the cortex in movement, sensation and memory, the role of the white matter as a conveyor system, the blood–brain barrier, and the safeguard function of the Circle of Willis. Aware of the general pattern of neurology, he recognized and recorded typical neurological disorders that had not been sufficiently described before: in present terms, myasthenia gravis, Parkinson’s disease, general paralysis (improved by fever), narcolepsy, restless legs, and complex partial seizures. In the same style he explained mental diseases as brain diseases, long before Gall and Greisinger, and kept theology out of his psychiatry. Willis was not the last neurologist, by a long way, who comprehended the nervous system with the help of his own science fiction. In the early 20th century Edinger confessed that he owed the success of his Vorlesungen of 1904 to the fact that he was “ignorant enough to erect a building in precise outlines, from material which in reality was only available in fragments” (quoted from his unpublished memories in Meyer, 1971). Needless to say, this continues up to our time and beyond.

Here, defects of the animal soul deprive the rational soul of the necessary substrate for its functions (ch. 13). Those beset by foolishness learn simple things quite deftly and quickly, and keep them firmly in memory but by deficient judgement combine or divide their notions badly, and worse infer one from the other and behave and speak most ungainly or ridiculous, and move the bystanders to laughter. To the contrary, the stupid, because of a defect of imagination, memory, and judgement, comprehend neither well nor quickly, nor argue well, and above all, not like the former, prattling and gesticulating, but flat and fatuous, behaving as in an asinine way. This differentiation was reproduced in Locke’s Essay of 1700 (1987, p. 160f), and hence remained influential in psychiatry up to the 19th century (Leibbrand and Wettley, 1961). Cranefield (1961) valued Willis’s definition as “a seventeenth century view of mental deficiency and schizophrenia.”

IMPACT, REACTION, AND PARTIAL SURVIVAL OF WILLIS’S NEUROLOGY Neurology as a bestseller: right place, right time In the mid-17th century, favorable conditions for a new view of the nervous system came together at the University of Oxford. Oxford General Practitioner and Professor of Natural Philosophy Thomas Willis managed to combine these factors, and so created the new discipline of neurology. He immediately marketed his product as a bestseller. The publication history gives evidence of neurology’s planned distribution and successful reception. Cerebri Anatome (Willis, 1664) came out in four editions in 1664, two in London (one as a pocket book) and two in Amsterdam. Willis’s Latin books were all re-edited several times in England and on the Continent, and his collected Latin works were published in 11 editions in Geneva, Lyon, Amsterdam, and Venice between 1675 and 1720. There were three London editions of the posthumous English translation of the collected works by Samuel Pordage in 1681, 1683, and 1684. The collected works in Latin and the translation always contained Cer-

Serendipity from both evidence and unsupported theory

Survival of Willisian brain research despite justified criticism The fictitious edifice of animal spirits and violent chemistry underlying Willis’s neurology served to bring his results into context, but its imaginary character could not escape the attention of critical minds, even during his lifetime. In 1669, the great Danish anatomist and geologist Stensen (Nicolaus Stenonis) published a discourse on

DEVELOPMENT OF 17TH CENTURY NEUROLOGY the anatomy of the brain, where he exposed the amount of ignorance in recent brain research (Stenonis, 1669). He criticized Willis for his inadequate evidence and fanciful ideas, and his audacious descriptions of brain tracts and their directions toward and away from the cortex. Stensen then despaired of the possibility of understanding the brain, took Roman Catholic holy orders, and was made Bishop of Schwerin. Stensen’s critical attitude was continued by many exponents of the medical mainstream in the 18th century, including Boerhaave and Haller. In London, Thomas Sydenham, Willis’s contemporary and rival in practice, belittled the value of anatomy for medicine, of brain research, the microscope, and Willis’s complicated system of medicine. He introduced a simplified, more botanical nosology. His Puritan empiricism, as opposed to Willis’s unsubstantiated theories, went into the mainstream of medicine in Britain during the Enlightenment. The development of brain research continued after Willis died in 1676. Raymond Vieussens published his Neurographia Universalis, the second monograph on neuroanatomy, in 1685. He acknowledged his dependence on Willis, and extended his research. Humphrey Ridley’s Anatomy of the Brain, in English, followed in 1695. And Willis’s comparative anatomy was extended to the higher primates by Tyson’s “Orang Outang” of 1699. But critical and adverse attitudes in mainstream medicine held back further development of neurology and brain research in the 18th century. Still, Georg Ernst Stahl (1660–1734) in Halle accepted not only the chemistry of Willis but also his concept of the soul governing the body in health and disease. His “animist” school and its “vitalist” successors continued the brain research initiated by Willis up to the 19th century, mapping brain tracts with their directions and connections, and discussing reflex action as a mechanism of brain function. This line of research, where the soul was partly replaced by Lebenskraft or vital force, produced major advances in neurology, with Unzer, Prochaska, Reil, and, finally, Johannes Mu¨ller, who reintegrated the soul in his physiology, a turning point for 19th-century science. This indirect influence of 17thcentury neurology on 19th-century neurophysiology must be taken into account by historians of neurology.

REFERENCES Aubrey J, Dick OL (Eds.) (1960). Aubrey’s Brief Lives. Secker and Warburg, London. Beukers H (2000). The Sylvian fissure. In: Peter J. Koehler, George W. Bruyn, John MS Pearce (Eds.), Neurological Eponyms. Oxford University Press, Oxford, pp. 50–55. Bodemer ChW (1974). Materialistic and neoplatonic influences in embryology. In: AG Debus (Ed.), Medicine in Seventeenth Century England. University of California Press, Berkeley, pp. 184–213.

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Brundell B (1987). Pierre Gassendi/From Aristotelianism to a New Natural Philosophy. D. Reidel, Dordrecht. Canguilhem G (1955). La Formation du Concept de Re´flexe aux XVIIe et XVIIIe sie`cles. PUF, Paris. Cranefield P (1961). A seventeenth century view of mental deficiency and schizophrenia: Thomas Willis on stupidity or foolishness. Bull Hist Med 35: 291–316. Carre´ MH (1949). Phases of Thought in England. Clarendon Press (OUP), Oxford. Darmon J-C (2000). Philosophie e´picurienne et litte´rature au XVIIe sie`cle: retour sur quelques proble`mes de me´thode symptomatiques. In: A McKenna, P-F Moreau (Eds.), Libertinage et Philosophie au XVIIe sie`cle. Publications de l’universite´ de Saint-E´tienne, Saint-E´tienne, pp. 11–35. Descartes R (1637). Discover de la me´thode. Layden, Ian Maire. Dewhurst K (1964). Willis in Oxford: some new Mss., In: Proceedings of the Royal Society of Medicine, vol. 57, p. 682 ff. Dewhurst K (1980). Willis’s Oxford Lectures. Sandford, Oxford. Dewhurst K (1981). Willis’s Oxford Casebook. Sandford, Oxford. Dewhurst K (1983). Richard Lower’s Vindicatio/A Defence of the Experimental Method. Sandford, Oxford. Diamond S (1971). Introduction to Willis T (1683) Two Discourses Concerning the Soul of Brutes. . .Scholars’ Facsimiles & Reprints, Gainesville, FL. Diogenes Laertius (1980/1925). Lives of Eminent Philosophers (Greek and English, trans. by RD Hicks), 2 vols. Loeb Classical Library, Harvard University Press, Cambridge, MA, pp. 528–677. Elmer P (1989). Medicine, religion and the puritan revolution. In: R French, A Wear (Eds.), The Medical Revolution of the 17th Century. Cambridge University Press, Cambridge, pp. 10–45. Freud S (1904). Zur Psychopathologie des Alltagslebens. S. Karger, Berlin. Gassendi P (1639). Elegans de septo cordis pervio observatio. In: S Pinaeus (Ed.), De Integritatis et Coruptionis Virginum Notis. Lugduni Batavorum (Leyden), apud Franciscos Hegerum et Hackium. English translation: in: Henry J (1939) Bull Hist Med 7: 429–457. Gassendi P (1658). Opera omnia. Lugduni (Lyon), L Anisson, IB Devenet (Eds.), VI vols. Facsimile: Gassendi P (1964) Opera omnia, F. Frommann Verlag, Stuttgart-Bad Cannstatt. Henry J (1989). The matter of souls: medical theory and theology. In: R French, A Wear (Eds.), The Medical Revolution of the 17th Century. Cambridge University Press, Cambridge, pp. 87–113. Hoppen KT (1970). The Common Scientist in the Seventeenth Century. Routledge & Kegan Paul, London. Hughes JT (1991). Thomas Willis 1621–1675: His Life and Work. Royal Society of Medicine, London. Isler H (1965). Thomas Willis. Wissenschaftliche Verlagsgesellschaft, Stuttgart. Isler H (1968). Thomas Willis 1621–1675/Doctor and Scientist. Hafner, New York. Jones RF (1936). Ancients and Moderns: A study of the Background of the Battle of the Books. Washington University Studies NS: language and lit. VI, St. Louis. Kelly EC (1948). Encyclopedia of Medical Sources. Williams & Wilkins, Baltimore, MD.

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Keynes G (1961). The history of myasthenia gravis. Med Hist V: 313–326. Leibbrand W, Wettley A (1961). Der Wahnsinn. Orbis Academicus, Freiburg-Mu¨nchen. Locke J (1987). An Essay Concerning Human Understanding. Clarendon Press, Oxford (original edition 1700). Lower R (1665). Diatribae Thomae Willisii Doct. Med. & Profess. Oxon. de febribus vindicatio adversus Edmundum de Meara Ormoniensem Hibernum MD. apud Jo. Martyn & Ja. Allestry (cf. Dewhurst, 1983), Londini. Lower R (1670). Dissertatio de origine catarrhi in qua ostenditur illum non provenire a cerebro. In: R Lower, Tractatus de Corde. J. Redmayne, Londini, pp. 221–239. Major RH (1978). Classic Descriptions of Disease. Charles C. Thomas, Springfield, IL, pp. 474–477 (first ed. 1932). Malcolm N (1997). The Origins of English Nonsense. HarperCollins, London. Meyer A (1971). Historical Aspects of Cerebral Anatomy. Oxford University Press, London. Meyer A, Hierons R (1965). On Thomas Willis’s concepts of neurophysiology. Med Hist 9: 1–15. Morton LT (1970). A Medical Bibliography (Garrison and Morton). Andre´ Deutsch, London. Newman WR, Principe LM (2002). Alchemy Tried in the Fire. University of Chicago Press, Chicago, IL. Pagel W (1982). Joan Baptista Van Helmont. Reformer of Science and Medicine. Cambridge University Press, Cambridge. Partington JR (1961). A History of Chemistry, Volume 2. Macmillan, London. Piso C (1618). (Charles Lepois) Selectiorum observationum et consiliorum de praeteritis hactenus morbis, effectibusque praeter naturam ab aqua, seu serosa colluvie et diluvie, ortis liber singularis. Ponti ad monticulum (Pont-a`-Mousson). Piso C (1785). Von den Krankheiten, welche aus dem Blutwasser entstehen. Mit vorrede von Herm, Boerhaave. Leipzig. Ridley H (1695). The Anatomy of the Brain Containing its Mechanisms and Physiology: Together with Some New Discoveries and Corrections of Ancient and Modern Authors upon That Subject. Sam. Smith, London. Schneider CV (1660). Liber Primus de Catarrhis. T. Mewii & E. Schumacheri, Wittebergae. Soemerring STH (1778). De basi Encephali et orignibal nervorum cranio egre dientium  c VI Tab aeneis Goettingar, apud Abr. Vanderhoeck Vidaum. Spillane JD (1981). The Doctrine of the Nerves. Oxford University Press, Oxford. Stenonis N (1669). Discours de Monsieur Stenon, sur l’Anatomie du Cerveau. Robert de Ninville, Paris. Sylvius F de le Boe¨ (1663). Disputationes medicae. In: Opera Medica, 1679. Amstelodami, apud D. Elsevirium et A. Wolfgang. Tyson E (1699). Orang-Outang sive Homo Sylvestris, or the Anatomy of a Pygmie compared with that of a Monkey, an Ape, and a Man. London, Thomas Bennet and Daniel Brown. Facsimile: (1966), London, Dawsons of Pall Mall. Vieussens R (1685). Nevrographia universalis. J. Certe, Lugduni.

Vinchon J, Vie J (1928). Un maıˆtre de la neuropsychiatrie au XVIIe sie`cle, Thomas Willis. In: Annales Me´dicopsychologiques 86: 109–144. Wepfer JJ (1658). Observationes Anatomicae ex Cadaveribus eorum, quos Sustulit Apoplexia, cum Exercitatione de eius Loco Affecto. J.A. Ziegler, Schaffhusii (Schaffhausen). Wepfer JJ (1679). Cicutae aquaticae historia et noxae. J.R. Koenig, Basileae. Wepfer JJ (1727). Observationes Medico-Practicae de Affectinonis Capitis Internis & Externis. J.A. Ziegler, Scaphusii (Schaffhausen). Wepfer JJ (1787). Medizinisch-praktische Beobachtungen von den innern und a¨ussern Krankheiten des Kopfs. Aus dem Lateinischen mit den neuesten Erfahrungen bereichert und herausgegeben von D. Friedrich August Weiz, Leipzig, in der Weygandschen Buchhandlung. Willis T (1659). Diatribae duae Medico-philosophicae quarum prior Agit de Fermentatione sive de Motu Intestino Particularum in quovis Corpore, Altera de Febribus sive de Motu earundem in Sanguine Animalium; his accessit Diissertatio Epistolica de Urinis. J. Martyn, J. Allestry, & Th. Dicas, Londini. Willis T (1664). Cerebri Anatome: Cui Accessit Nervorum Descriptio et Usus. J. Martyn & J. Allestry, Londini. Willis T (1667). Pathologiae Cerebri, et Nervosi Generis Specimen, in quo Agitur de Morbis Convulsivis, et de Scorbuto. J. Allestry, Oxonii. Willis T (1670). De sanguinis accensione. In: T Willis, Affectionum quae Dicuntur, Hystericae et Hypochondriacae Pathologia Spasmodica Vindicata. Ad Virum Doctissimum Nathanael Highmorum, M. D. Cui accesserunt Exercitationes Medico-Physicae Duae. I. De Sanguinis Accensione. 2. De Motu Musculari, Londini. Willis T (1672). De Anima Brutorum, quae Hominis Vitalis ac Sensitiva est, Exercitationes duae. Prior Physiologica . . . altera Pathologica . . . Oxoniae, e Theatro Sheldoniano. Present quotations from the Lyons edition of 1676 (A. Huguetan, Lugundi). Quoted in present text translated by H. Isler. Willis T (1675). Pharmaceutice Rationalis sive Diatriba de Medicamentorum Operationibus in Humano Corpore. R. Scott/pars secunda, e theatro Sheldoniano (1675), Londini. Willis T (trans. Pordage S) (1681). W Feindel (Ed.) (1965). The Anatomy of the Brain and Nerves. McGill University Press, Montreal. Willis T (trans. Pordage S) (1683). Two Discourses Concerning the Soul of Brutes. A facsimile reproduction (1971). Scholars’ facsimiles & reprints. Gainesville, FL. Introduction by S Diamond. Willis T (trans. Pordage S) (1684). Dr. Willis’s Practice of Physick, Being the Whole Works of this Renowned and Famous Physician. T. Dring, C. Harper and J. Leigh, London. Wolff HG (1948). Headache and other headpain, Oxford University Press, New York. York G (1999). Hughlings Jacksons evolutionary neurophysiology. In: FC Rose (Ed.) A short history of neurology. Butterworth Heinemann, Oxford, pp. 159f (concomitance).

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 9

Understanding the nervous system in the 18th century CHRISTOPHER U.M. SMITH* Vision Sciences, Aston University; Universities of Aston and Birmingham, Birmingham, UK

INTRODUCTION The 18th century has often been called the age of “enlightenment” or, in German-speaking regions, Aufklärung. It is the age of Newton, Locke and Hume; of the Encylope´distes, of Voltaire, Lavoisier and Montesquieus’ Lettres Persanes; of Alexander Pope and Samuel Johnson, of Tom Paine and The Rights of Man and, at the end of the century, of Immanuel Kant and transcendental philosophy. It is the age of trade and discovery, of the European diaspora, the age of Bougainville and James Cook and the opening of the world of nature and natural history, an age of collections and above all classification. It is the age of secular history, of Gibbon’s Decline and Fall of the Roman Empire, of the birth pangs of archeology, of dictionaries, of the translation of ancient scripts, of the Rosetta Stone. It is also the age of revolutions – revolutions in the means of production and distribution and of political revolutions in America and later in France. It started as “the age of reason,” where the old systems of belief were subjected to searching scrutiny and ended in the Romantic reaction. It started with the Pope’s view of Nature as a mighty maze but not without a plan, a “great chain of being” where “whatever is, is right.” It ended with the first stirrings of evolutionary ideas, with Erasmus Darwin and Jean Baptiste de Lamarck; ideas which were to lead, in the next century, to the conclusion that whatever is, is far from “necessarily” right but may simply be due to happenstance. All could well have been other than it turned out to be and there is no reason to think, as Leibniz thought, that we live in the best of all possible worlds. It started with monarchy and ended with revolution and then Bonapartism. It is against this background that investigations of the brain and nervous system took place. Although

*

diseases of the nervous system had been recognized from the earliest times, it was not until the 18th century that the first glimmerings of a true understanding of the underlying neuroanatomy and neurophysiology became available. Much of this new understanding is associated with the growth of medical schools. The most important of these were located in Paris, London, Leyden, Edinburgh and Bologna. In Paris, Pourfour du Petit (1664–1741), after experience as a military surgeon in the Wars of Spanish Succession, continued his interest in head injuries with pioneering research on the structure and functions of the brain and spinal cord (Pourfour du Petit, 1710). In London, William Hunter (1718–1783), after studying medicine at Edinburgh, opened the famous Great Windmill Street School of Anatomy in 1768. Here he was joined by his younger brother John (1728–1793), and both carried forward extensive research into the nervous system, not only of humans but also of many infra-human animals, and, in so doing, as we shall see below, played important roles in the development of electrophysiological ideas. In Leyden, Hermann Boerhaave (1660–1738), who became known as “Europe’s Teacher,” numbered amongst his pupils some who would become the most prominent names in European neuroscience, Alexander Monro Secundus, John Pringle, William Cullen, Albrecht von Haller, Gerhard van Swieten, and many others, and was instrumental in getting Swammerdam’s Bibjel der Natur published (Boerhaave, 1737/1738). Many of Boerhaave’s pupils came from Scotland and returned to Edinburgh to develop one of Europe’s most prominent centers of teaching and research on the structure and function of the nervous system. Here the Monro dynasty (Primus, Secundus, and Tertius), William Cullen, Robert Whytt and many others not

Correspondence to: C.U.M. Smith, Vision Sciences, Aston University, Birmingham B4 7ET, UK. E-mail: [email protected], Tel: +44-121-454-1443, Fax: +44-121-204-4048.

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only developed scientific knowledge of the system but also taught generations of British and foreign students. Finally, the 18th century, especially toward its end, saw a great efflorescence of neuroscientific research in the ancient University of Bologna. Here Leopoldo Caldani (1725–1813), Felice Fontana (1730–1805) and, most famously of all, Luigi Galvani (1737–1798) and his nephew, Giovanni Aldini (1762–1834), laid the foundations of electrophysiology. It is clear that all of this work cannot be covered in a short chapter. Instead, I intend to focus on progress in understanding the fine structure of the nervous system and the manner in which messages are conducted by the nerves.

HOLLOW NERVES AND THEIR SPIRITS Earlier parts of this book have described the timehonored neurophysiology of the ancients, which was adopted and modified by later scholars, even during the Renaissance. These individuals believed that nerve fibers are tubular structures through which animal spirits travel from brain to periphery and vice versa. Although as long ago as 1543 Vesalius, in his great work on human anatomy, the Fabrica, had doubted the anatomical reality of this belief, the notion lived on well into the 18th century and can still be found in texts published in the middle of the 19th century. Alexander Monro Secundus, for example, devotes several pages to this time-honored, hollow-nerve neurophysiology in his 1783 Structure and Functions of the Nervous System, writing that “Most authors have supposed that the nerves are tubes or ducts carrying a fluid secreted in the brain, cerebellum and spinal marrow” (Monro, 1783, p. 74). Indeed, the old neurophysiology was so well-embedded in the common consciousness that it is often alluded to without comment in 18th-century literature. Tristram Shandy remarks, for instance, on that “very thin, subtle, and very fragrant juice . . . discovered in the cellulae of the occipital parts of the cerebellum” (Book 2, p. 19) and, in an earlier part of his hilarious autobiography, writes: “You have all, I dare say, heard of animal spirit, nine parts in ten of a man’s sense and nonsense . . . depend on its motions and activity” (Book 1, p. 1) (Sterne, 1760). It required both physiological and anatomical research to dislodge the old theories of the human constitution. Furthermore, it was not until the very end of the 18th century that a valid successor theory began to be pieced together. Let us first look at the microscopical evidence.

van Leeuwenhoek. Van Leeuwenhoek sent specimens of a transversely sectioned optic nerve to the Royal Society in 1674 and wrote that, to his great surprise, he could find no cavity: “I solicitously viewed three optic nerves of cows, but could find no hollowness in them” (van Leeuwenhoek, 1675). Van Leeuwenhoek continued his researches into the 1690s, but so strong was the prevailing neurophysiological theory that he speculated that nerves perhaps contained submicroscopic filaments or tubes along which animal spirits might travel: “diverse very small threads or vessels lying close by each other” (van Leeuwenhoek, 1677). The notion that nerve fibers were at some level hollow structures persisted throughout the 18th century, and Ford (2007) has traced it on well into the 19th century, where it is illustrated in a figure in Longet’s Anatomy and Physiology of the Nervous System (Longet, 1842). Microscopes and preparative techniques were just not good enough to prove that nerves did not contain cavities. Indeed, we now know that nerve fibers do contain a viscous fluid – axoplasm, which flows at different rates in both directions within the tubular axon. And, returning to the 18th century, it is not impossible that the great Italian anatomist, Felice Fontana (1730–1805), had observed this viscous fluid in the 1780s. In a letter written to a friend in 1782 he described how, after stripping the sheath from a nerve, he squeezed it between two lenses and observed “une matière glutineuse, élastique, transparente” to exude from the cut end (Fontana, 1784; quoted in Brazier, 1984, p. 146). The microscope, furthermore, sent an ambiguous message. Malpighi’s 1666 microscopy of the mammalian cerebral cortex seemed to show that it consisted of a mass of minute glands (Fig. 9.1) (Malpighi, 1666). This interpretation supported the traditional neurophysiology. The brain filtered an animating principle from the blood and pumped it out via the nerve tubes

THE MICROSCOPE The first practical microscopes were developed at the end of the 17th century by Robert Hooke and Anthony

Fig. 9.1. Malpighi, 1666, De Cerebri Cortice. Malpighi’s picture shows the cerebral “glands” and “fibers.”

UNDERSTANDING THE NERVOUS SYSTEM IN THE 18TH CENTURY to the periphery. William Cullen, Professor of Medicine at Edinburgh from 1747 to 1766, would not have balked at this interpretation: “The most common opinion,” he writes, “is that the brain is a secreting organ, which secretes a fluid necessary to the functions of the nervous system” (Cullen, 1827, vol. 1, p. 118).

SOME CLEVER EXPERIMENTS But if 18th-century microscopes and microscopical techniques were inadequate to settle the question of whether nerves had some element of hollowness, clever experimental techniques began to cast doubt on the idea that the brain secreted an animating principle into the nerves. Jan Swammerdam, in a series of brilliant experiments, had shown as early as 1633 that frog muscles (at least) could be caused to contract when the cut end of the sciatic nerve was stroked or pinched (Fig. 9.2). This seemed to rule out the ancient notion that muscular movement depended on a messenger of some sort sent by the brain down the hollow conduits of the nerves. “From these experiments,” he wrote, “it may, I think be fairly concluded, that a simple and natural motion or irritation of the nerve alone is necessary to produce muscular motion, whether it has its origin in the brain, or in the marrow, or elsewhere.” Although Swammerdam demonstrated his experiments widely to academic audiences and influential visitors (Nordstro¨m, 1954), their implications were so radical that, although widely known, traditional ideas were not dislodged. Swammerdam suggested that spirit or subtle matter flies in an instant through the nerves to the muscles [and] may with the greatest propriety be compared to that most swift motion, which, when one

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extremity of a long beam or board is struck with the finger, runs with such velocity along the wood, that it is perceived almost at the same instant at the other end. (Quoted in Cobb, 2002) But, as already noted, the old time-worn ideas held on tenaciously throughout much of the 18th century. This is an interesting case of a blocked paradigm-change. An anomalous finding, a crucial finding, is consciously overlooked because it cannot be accommodated within the prevailing paradigm. In this case, however, it must be noted that Swammerdam’s work was not published until Boerhaave brought out an edited version in his Bibjel der Natur (Biblia Naturae) over a century later (Boerhaave, 1737/1738; see also Cobb, 2002).

THE IRRITABLE AND SENSITIVE NERVOUS SYSTEM Swammerdam’s notion of irritability was renewed by Francis Glisson at the turn of the century, but it was left to Albrecht von Haller to establish the idea as central to physiological thought. Indeed, in Tissot’s 1755 preface to von Haller’s Dissertation on the Sensible and Irritable Parts of Animals, he lauds him as having made “the great discovery of the present age” (von Haller, 1755, p. iii). Von Haller carried through a vast number of experiments to discover which parts of an animal are “irritable.” He also used a wide variety of stimuli: air puffs, heat, lapis infinalis, oil of vitriol, butter of antimony, touching, squeezing, cutting, burning, etc. He concluded that irritability “does not depend on the nerves, but on the original fabrication of the parts which are susceptible of it” (p. 32). A little further on in the dissertation he homes in on muscle fibers, writing that “there is nothing irritable in the animal but the muscular fibres and the faculty of endeavouring to shorten itself when we touch it is proper to this fibre” (p. 37). Sensibility is, he insists, quite distinct from irritability. Von Haller writes that . . . the sensible parts of the body are the nerves themselves, and those to which they are distributed in the greatest abundance; for by intercepting the communication between a part and its nerve, either by compression, by tying, or cutting, it is thereby deprived of sensation . . . Wherefore the nerves alone are sensible of themselves . . . (von Haller, 1755, p. 31)

Fig. 9.2. Jan Swammerdam (c. 1663). That the drop of water in the capillary tube (e) does not move shows that the frog muscle (b) does not increase in volume when it contracts.

Far from all 18th-century physiologists agreed with von Haller. William Cullen, in particular, who co-founded the medical school in Glasgow and then moved to Edinburgh in 1755 as Professor of Chemistry and later, on the death of Robert Whytt in 1776, as Professor of

110 C.U.M. SMITH the Institutes of Medicine, held that the fine endings of has been remarked that this new preparedness to diagnerve fibers transformed into muscle fibers in a nose nervous debility allowed the growth of a fashionmuscle’s interior. Cullen, indeed, believed that the key able spa society and that tendency to “take the to all diseases lay in the nervous system. His students waters,” so well captured in the 18th-century writings came to call him “Old Spasm” in recognition of his of Samuel Richardson, Brinsley Sheridan, and Tobias teaching that illnesses were caused by a “spasm” or Smollett. disordered reaction of the nervous system. The slow retreat of ancient neurophysiology left a The resolution of the von Haller/Cullen disagreevacuum in medical theory that many sought to fill. If ment awaited, as did so much else in neurophysiology, the nervous system is not the carrier of animal spirit, the improved microscopy of the centuries succeeding and if it is not suitable for the concussive transmission the 18th century. Both agreed, however, that the web envisaged by Swammerdam and others, then how did of nerves was endowed with “feeling.” Robert Whytt, the human organism work? Cullen’s older colleague at Edinburgh, held the same VIBRATIONS AND INVISIBLE, opinion, writing that “we know certainly that the SUBTLE FLUIDS nerves are endowed with feeling” (Whytt, 1765). The notable 18th-century physician George Cheyne, also Many, like David Hartley, felt the influence exerted by educated at Edinburgh, agreed: the great achievements of Sir Isaac Newton (see Smith, 1987). Hartley conceived an associationist psychophysiolFeeling (physical sensibility) is nothing but ogy based on vibrations and vibratiuncles (residual vibraImpulse, Motion or Action of Bodies, gently or tions) in the nerve fibers and white matter of the brain violently impressing the Extremities or Sides of (Hartley, 1749). This notion, although derived from certhe Nerves . . . . (Cheyne, 1733, p. 49) tain speculations found in Newton’s Principia (Newton, 1713, vol. 2, p. 393) and Opticks (Newton, 1717, 2nd LIFE FORCES AND MEDICAL PRACTICES Query), did not find favor with some of the leading The recognition that the nerves are not just inanimate 18th-century physicians and anatomists. Both Boerhaave tubes for transmitting a vivifying spirit from the brain and Monro Secundus believed that the flaccidity of the to the muscles (as Cartesian neurophysiology had nervous system ruled vibrations, even of intraneuronal taught), but sensible in themselves, had an influence particles (as Hartley envisaged), out of court. Later, in on medical practice. Moreover this retreat from the his famous Traité sur le Venin de la Vipère (1781), Felice seeming aridities of Cartesian iatrophysics chimed well Fontana described how he examined nerve “cylinders” with other parts of 18th-century biological thought. In under the microscope and could detect no sign of any 1744, for example, Abraham Trembley had shown that vibration and, like Boerhaave and Monro Secundus, confresh water polyps, such as Hydra, could be subdivided cluded that Hartley’s theory did not accord with the facts. almost indefinitely, and that a new polyp would But if these vibrationist notions found no favor develop from each small fragment (Trembley, 1744). amongst the anatomists, Newton’s other hypothesis, that This was taken by many to imply that the living princiof an all-pervasive “aether” or “subtle fluid,” proved ple was not confined to one or a few organ systems, much more long-lasting. The 18th century was, indeed, but was widely diffused throughout the body. awash with “subtle fluids.” One of the most notorious The´ophile Bordeu (1722–1776) had developed this of these “aetherial” speculations was that initiated and interpretation in his insistence that life is essentially promulgated by Anton Mesmer (1734–1815). Mesmer “sensibilité” (Bordeu, 1774). Indeed he went so far as had qualified in medicine in 1766 with a dissertation to compare a living body to a beehive: a whole com(De Planetarum Influxu in Corporis humanum [The posed of living, sensitive units (see Haigh, 1976). Thus, Influence of the Planets on the Human Body]) on the returning to our subject, it is perhaps not surprising to influence of the heavenly bodies on human well-being. find that the distributed nervous system should have Just as Newton had shown that the planets are held in become far more significant in medical nosology. Thotheir orbits by a mysterious force called “gravity” so, mas Trotter, writing in 1807, observed that at the Mesmer believed, human bodies can be affected by a beginning of the 19th century we do not hesitate to similarly mysterious force, one which he dubbed “aniaffirm that nervous disorders have now taken the mal gravity.” Later, after he was introduced to a new place of fevers, and may justly be reckoned two thirds medical procedure involving the use of magnets by of the whole, with which civilised society is affected.” Father Maximillian Hell, Mesmer changed the name of (Trotter, 1807). Note the word “civilised”: Trotter is his mysterious force to “animal magnetism” (for a full thinking of the upper strata of European society. It account see Lanska and Lanska, 2007).

UNDERSTANDING THE NERVOUS SYSTEM IN THE 18TH CENTURY In essence Mesmer believed that good health depended on the free flow of life processes throughout the body’s innumerable channels. When, for one reason or another, these channels were blocked, this flow was impeded and illness resulted. In 1774, he successfully treated a patient by getting her to swallow a solution containing iron and then attaching magnets to various parts of her body. Later he dispensed with magnets and alleged the cures could be achieved by the physician directly controlling the mysterious magnetic effluvium. He was unable, however, to convince his fellow physicians, in particular Jan Ingenhousz, of the validity of his treatment and had to leave Vienna for Paris. Here he was successful in building up a substantial practice and even developed a special tub, the baquet, which he regarded as equivalent to the electrician’s Leyden jar, for concentrating the magnetic aether. Numerous patients could sit around Mesmer’s baquet and simultaneously experience the magnetic cure. However, nemesis awaited in the form of a Royal Commission set up by King Louis XVI in 1784, and headed by the American ambassador and natural philosopher, Benjamin Franklin. The Franklin commission comprehensively disproved Mesmer’s practice and showed that the undoubted effects, and sometimes cures, were due to the suggestibility of his, mostly female, patients (for further detail see Finger, 2006). This devastating report destroyed Mesmer’s credibility and he soon left Paris to die in obscurity in Switzerland in 1815.

ELECTRICITY, MEDICINE, AND THE NERVE FORCE Mesmer’s career shows, if nothing else, the confusion that reigned in the latter part of the 18th century concerning the nature of electricity and magnetism. Many attempts were made by physicians more orthodox than Mesmer to use electricity for medical purposes. In America, Benjamin Franklin tried the effect of Leyden jar discharges on patients suffering a wide variety of complaints (see Finger, 2006). In England, John Wesley, Erasmus Darwin and Joseph Priestley interested themselves in the application of electricity to medicine. Priestley reviews a large number of such attempts in his 1775 volume, The History and Present State of Electricity, but concludes that they have in general proved unsuccessful (p. 377) and remarks that “no other part of the whole compass of philosophy affords so fine a scene of ingenious speculation” (Priestley, 1775, p. 411). In France Abbe´ Jean-Antoine Nollet, and in England Stephen Gray, astounded lay audiences by safely electrifying boys and girls. Enlightenment was slow in coming, but come it did. In America perhaps the greatest electrician of them all,

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Benjamin Franklin, not only drew electricity from the storm clouds but also simplified theoretical understanding by proposing that there was only one type of electricity, where formerly it had been thought there were two: vitreous and resinous. Finally, and most importantly for us, significant lines of research on electric fish and then amphibia began to bear fruit. That electric fish generated painful shocks had been known since antiquity, and the electric catfish can be found on Egyptian tomb paintings. The Nile was fished in early Egypt. In the middle of the 18th century Michel Adanson suggested that their electric organs were analogs of the Leyden jar (Adanson, 1759). As the 18th century wore on, electric organs were closely studied by Walsh, Cavendish and John Hunter. Indeed Hunter’s dissection of the electric organ of Torpedo (Fig. 9.3) provided a model from which, in 1799, J.W. Nicholson designed an “artificial torpedo” and this, in turn, influenced Volta’s work in constructing the first battery (Pancaldi, 1990). Marco Piccolino quotes with approval Wu’s (1984) comment that modern electrophysiology was born at the moment when Walsh first drew a spark from the shock of an electric eel (Piccolino, 2007). But if electrophysiology were born with electric eels, its long and difficult gestation took place with amphibia in Bologna. Luigi Galvani (1737–1798) was far from the first to use frog gastrocnemius-sciatic preparations. We saw above that Jan Swammerdam had pioneered this preparation 150 years earlier and in 1752 Leopoldo Caldani (1725–1813), Professor of Medicine at Bologna, used an “electrified rod” to stimulate the crural (or sciatic) nerves of frogs (see Brazier, 1984, p. 138). But Galvani lived at a time when the major lineaments of electricity and, in particular, bioelectricity were becoming clear. Moreover, he followed up his observations and experiments relentlessly and his interpretations received widespread attention. Galvani’s first (serendipitous) observations had been made in the early 1780s while dissecting a frog with a

Fig. 9.3. John Hunter’s dissections of Torpedo. (i) Under surface of female, (ii) upper surface of female, (iii) under surface of male. From Phil Trans Roy Soc 63: 461–480.

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metal scalpel close to an electrical machine. But he later observed contractions of frogs exposed on the railings around his house during thunderstorms and connected this with Franklin’s work. Further, he also observed contractions when the sky was cloudless. He did not then recognise that the latter contractions were due to stimulation arising from the two dissimilar metals with which his preparations were in contact. Galvani firmly believed that he was observing the actions of an internal “animal electricity.” Indeed he believed he had proved this by showing that contractions occurred when the sciatic nerve of one preparation was laid over the cut muscle of another. What we nowadays call “injury currents” were then unknown. He concluded that frog convulsions were caused by the transport of an electrical fluid from the nerves to the muscles. He believed that this fluid, similar to, but not identical with, inorganic electricity, was present in animal neuromuscular systems and was discharged into the muscles. His model was the Leyden jar. Galvani’s experiments became very well known during the 1790s, and not only by the scientific community. Indeed Barnadino Ferrari, in a letter from Milan in 1792, writes that “Now here the experiments are also repeated in the salons of ladies, and they furnish a very good spectacle for all.” But the interpretation of these experiments sparked much controversy. Had Galvani discovered an animal electricity that, although confined to the neuromuscular system, was in other respects identical to the “inorganic” electricity investigated by electricians such as Priestley? On the other hand, was Galvani’s electrical fluid in some way different from that studied by the electricians? Or, finally, was Volta right when he concluded that the results obtained by Galvani were not the consequence of an electric fluid confined to the nervous system at all, but due to stimulation of the tissue by two dissimilar metals? In the early 1790s Richard Fowler, a pupil of Monro Secundus at Edinburgh, repeated Galvani’s experiments and concluded that Volta’s interpretation was correct (Fowler, 1793). The effect was caused by the application of two dissimilar metals, in his case zinc and silver. Fowler’s account makes fascinating reading. It details an immense number of experiments on frogs and shows how puzzling electricity and animal electricity was to an acute 18th-century mind. It also shows, once again, the tenacity of the old neurophysiology. He writes of his great surprise at finding that contractility persisted even when the heart had ceased beating. He could hardly credit his eyes, he writes, yet it is so, and he does not expect to be believed. The old idea of the brain filtering an animating principle from the blood and transmitting it along the nerves was once again disproved, for how could this happen if

the heart had ceased beating? This idea, lingering from a bygone age, can also be found in Galvani’s De Viribus, where he writes that the electric fluid is produced by the activity of the cerebrum where it is in all probability extracted from the blood . . . The brain was, for the most part, still largely seen as a gland. Erasmus Darwin, at the very end of the 18th century, still believed that the brain had this filtering function: an idea which was common at Edinburgh in his student days. William Cullen, Professor of Medicine at Edinburgh at this time, held this view and as late as 1835 we find Baillarger drawing attention to the stratification of the cerebral cortex and observing that the analogy between the structure of the cerebral surface and the appearance of a galvanic apparatus suggests that it secretes an “electric fluid” into the underlying white matter. (Baillarger, 1835) For Erasmus Darwin, as for many others, this electric fluid had a psychological as well as a physiological side. It was not identical to that which Franklin had coaxed out of the thunder cloud or that which Pieter van Musschenbroek and Edwald Kleist had extracted from their coated jars. But how this animal electricity could show both psychical and physical attributes is nowhere made clear. Darwin is, once more, at one with his mid-century Edinburgh teachers. Both William Cullen and Robert Whytt agreed that, while it was an indisputable fact that an animating spirit interacted with the physical body, how this happened remained, and was likely to continue remaining, a mystery (Whytt, 1763, pp. 147–148; Cullen, 1827, p. 18).

LOOKING BACK The 18th century was indeed an age of transition. The time-honored neuropsychology of classical and medieval times, mechanized in Descartes’ L’Homme (1664), was undermined by microscopical observations and careful experimentation. Yet, until the very end of the century, when work on electric fish and amphibians began to suggest an acceptable successor to “animal spirit,” the old understanding of Man’s constitution held firm. Nevertheless, and paradoxically for a century that emphasized careful measurement and mathematical reasoning, the mechanistic iatrophysics of the early part of the century was everywhere in retreat, replaced by more mysterious forces called variously élan vital, vis viva, vis insita, animation, etc. Erasmus Darwin was not the only one to pour scorn on Descartes’ hydraulically driven “earthen machines” (Descartes, 1664, p. 1). The Cartesians forgot, as he

UNDERSTANDING THE NERVOUS SYSTEM IN THE 18TH CENTURY says, that so far as a living organism is concerned, “animation [is] its essential characteristic” (Darwin, 1794, vol. 1, p. 1). Perhaps one can see this turning away from iatrophysics toward something “far more deeply interfused” as part and parcel of the Romantic reaction to the seeming superficialities of the Enlightenment rationalism with which the century began. However this may be, the increased emphasis on nerves as the substrata of sensitivity and sensibility worked through to influence medical practice. Thomas Trotter, writing at the very beginning of the 19th century, observed that the last century has been remarkable for the increase in a class of diseases which had but little engaged the study of physicians before that period . . . nervous disorders. (Trotter, 1807) Perhaps we can see in this refocusing of medical attention the first glimmerings of that interest in “mental health” which, in the next century, led to the development of psychiatry and psychotherapy (see Collie, 1988). But it was not until the structure and the functioning of the neuromuscular system was better understood, and this awaited the second half of the 19th century and even more the 20th, that physicians could hope to develop successful treatments. These centuries and these treatments form the subject of later chapters in this volume.

REFERENCES Adanson M (1759). A Voyage to Senegal, the Isle of Goree and the River Gambia. J. Nourse and W. Johnston, London. Baillarger JGF (1835). Me´moire historique et statistique sur la maison royale de Charenton. Ann Hyg Pub Med Leg 13: 5–192. Boerhaave H (1737/1738). Bybel der Natuure door Jan Swammerdam. Severinus, Vander and Vander, Leyden; English edn. (1758): Book of Nature, T. Filoyd, Trans. London; facsimile (1978) Arno Press, New York. Bordeu T (1774): Traite´ de medicine the´oretique et pratique. Rual, Paris. Brazier MAB (1984). A History of Neurophysiology in the 17th and 18th Centuries. Raven Press, New York. Cheyne G (1733). The English Malady. Strahan, London. Cobb M (2002). Exorcising the animal spirit: Jan Swammerdam on nerve function. Nat Rev Neurosci 3: 395–400. Collie M (1988). Henry Maudsley: Victorian Psychiatrist. St. Paul’s Biographies, Winchester. Cullen W (1827). In: J Thomson (Ed.), The Works of William Cullen. Vol. 1. Physiology. Blackwood, Edinburgh. Darwin E (1794). Zoonomia, or the Laws of Organic Life. J. Johnson, London. Descartes R (1664). L’Homme. Charles Agot, Paris. Finger S (2006). Dr Franklin’s Medicine. University of Philadelphia Press, Philadelphia, PA.

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Fontana FGF (1781). Traite´ sur le Venin de la Vipe`re. Nyon, Florence. Fontana FGF (1784). Lettre de M. l’Abbe´ Fontana a` M. Gibelin. J de Physique 24: 417–421. Ford BL (2007). Instrumentation and microscopy. In: H Whitaker, CUM Smith, S Finger (Eds.), Brain, Mind and Science: Essays in 18th-Century Neuroscience. Springer, New York. Fowler R (1793). Experiments and Observations Relative to the Influence Lately Discovered by M. Galvani and Commonly Called Animal Electricity. Duncan, Edinburgh. Galvani L (1791). De viribus electricitatus in motu muscularis. De Bononeinsi Scientiarum et Artium Instituto Atque academia commentarii. Tomus Septimus, Bologna. pp. 363–418. Haigh EL (1976). Vitalism, the soul, and sensibility: the physiology of The´ophile Bordeu. J Hist Med Allied Sci 31: 30–41. Hartley D (1749). Observations on Man, His Frame, His Duty, and His Expectations. Richardson, London. Hunter J (1773). Anatomical observations of the Torpedo. Phil Trans Roy Soc 63: 461–480. Lanska DJ, Lanska JT (2007). Franz Anton Mesmer and the rise and fall of animal magnetism: dramatic cures, politics, and ultimately a triumph for the scientific method. In: H Whitaker, CUM Smith, S Finger (Eds.), Brain, Mind and Medicine: Essays in Eighteenth-Century Neuroscience. Springer, New York. Longet FA (1842). Anatomie et Physiologie du Syste`me Nerveux de l’Homme et des Animaux Verte´bre´s. Fortin Masson, Paris. Malpighi M (1666). De cerebri cortice. In: De Viscerium Structura Exercitation Anatomica. Montius, Bologna. Mesmer FA (1766). Physical-medical treatise on the influence of the planets. In: G Bloch (Ed.), (1980), Mesmerism: A translation of the Original Scientific and Medical Writing of FA Mesmer. William Kauffman Inc., Los Altos, CA. pp. 1–22. Monro A (1783). Observations on the Structure and Functions of the Nervous System. Creech, Edinburgh. Newton I (1713). Principia Mathematica (2nd Edition). General Scholium. A. Motte Trans. (1729). S. Pepys, London. Newton I (1717). Opticks. Smith and Walford, London. Nordstro¨m J (1954). Swammerdamiana: excerpts from the travel journal of Olaus Borrichius and two letters from Swammerdam to The´venot. Lynchos 16: 21–65. Pancaldi G (1990). Electricity and life: Volta’s path to the battery. Hist Stud Phys Sci 21: 123–159. Piccolino M (2007). The taming of the electric ray: from a wonderful and dreadful “art” to animal electricity and electric battery. In: H Whittaker, CUM Smith, S Finger (Eds.), Brain, Mind and Medicine: Essays in EighteenthCentury Neuroscience. Springer, New York. Pourfour du Petit F (1710). Trois Lettres d’un Me´decin des Hoˆpitaux du Roy. Albert, Namur. Priestley J (1775). The History and Present State of Electricity with Original Experiments (4th edn.). Bathurst, London. Smith CUM (1987). David Hartley’s Newtonian Neuropsychology. J Hist Behav Sci 23: 87–101.

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Sterne L (1760). Tristram Shandy. Becket and Dehondt, London. Trembley A (1744). Me´moires pour Servir a l’Histoire d’un Genre de Polypes d’Eau Douce, a` Bras en Formes de Cornes. Verbeek, Leiden and Paris. Trotter T (1807). A View of the Nervous Temperament. Longman, Hurst, Rees and Orme, London. van Leeuwenhoek A (1675). A study of bovine optic nerve. Philos Trans R Soc 10: fig. 117. van Leeuwenhoek A (1677). Letter. Philos Trans R Soc 12: 899–905. Vesalius A (1543). De Humani Corporis Fabrica. Basileae. Facsimile impression culture et civilisation, Bruxelles, (1964).

Von Haller A (1755). A Dissertation on the Sensible and Irritable Parts of Animals. Nourse, London. Wu CH (1984). Electric fish and the discovery of animal electricity. Am Scientist 72: 598–607. Whytt R (1763). An essay on the vital and other involuntary motions of animals. In: The Works of Robert Whytt. Published by his Son. Balfour, Edinburgh. Whytt R (1765). Observations on the Nature, Causes Nervous, Hypochondriac or Hysteric, to Which are Prefixed Some Remarks on the Sympathy of the Nerves. Balfour, Edinburgh.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 10

The birth of localization theory STANLEY FINGER* Department of Psychology, Washington University, St. Louis, MO, USA

INTRODUCTION The idea that different parts of the brain, such as the cerebrum and the cerebellum, may serve different functions has a history that can be traced back to antiquity. In contrast, acceptance of the theory that the cerebral cortex can be divided into functional parts is largely a 19th-century development. The notion of cortical localization was first entertained, however, in the 18th century.

SWEDENBORG AND HIS PREMONITIONS The individual who is usually cited as the first person to write about cortical localization of function in a detailed way is Emanuel Swedenborg (Ramstro¨m, 1910; Toksvig, 1948; Schwedenberg, 1960; Akert and Hammond, 1962; Gibson, 1967; Norrsell, 2007). Born in Stockholm in 1688 and educated at Uppsala, Swedenborg modeled himself after Sir Isaac Newton. A true polymath, he established himself in mathematics, mining, and astronomy before he showed an earnest interest in anatomy and medicine during the 1730s. By this time there was increasing recognition of the fact that the cortical motor tracts cross en route to the muscles (Pourfour du Petit, 1710). Yet the idea that the cerebral cortex could be divided into distinct functional zones that could be described in some detail and even mapped seemed far from everyone’s mind. Swedenborg visited medical centers in France, Italy, and the Netherlands. He believed that by acquiring all the knowledge he could about the brain, he would be better able to understand the relationship between the body and the soul. But although he must have seen numerous cases of traumatic brain damage, he focused on synthesizing the observations of others rather than evaluating his own cases, because he wanted to be as objective as possible. His modus operandi was to place

*

his collected material in front of him and then to subject it to careful analysis and great reflection. Like others at the time, Swedenborg was convinced that the cerebrum had to be involved in higher functions, such as understanding, thinking, judging, and willing. But he belonged to the minority in two ways. First, he associated these functions with the cerebral cortex and not the internal white matter that had been drawing the attention of most prominent physicians, including Haller. And second, he did not believe that the cerebral cortex could be a unitary, indivisible structure. During the 1740s, Swedenborg wrote that different functions are probably represented in different cerebral loci (see Swedenborg, 1882–1887, 1938–1940, 1955). Such specialization could account for why damage to one part of the cerebrum might cause a paralysis, whereas damage to another cerebral site might not affect movement but result in a loss of critical thinking. It could also explain why different functions, such as hearing and vision, are not confused with one another. Swedenborg localized the motor centers in a large cortical region that encompassed the precentral gyrus and some postcentral gyrus, using today’s terminology, using today’s terminology. He even envisioned the inverted somatotropic arrangement of this functional region. In his treatises on the brain, he wrote that the muscles of the lower extremities are controlled by the upper convolutions, those of the middle part of the body by the middle convolutions, and the head and neck by the lower convolutions. Further, he theorized that the motor region is not responsible for all movements – its purpose is only to control willed or voluntary actions. He also commented on the intellectual functions of the cerebral regions anterior to the motor areas: If this portion of the cerebrum therefore is wounded, then the internal senses – imagination,

Correspondence to: Dr. Stanley Finger PhD, Department of Psychology, Washington University, St. Louis, MO 63130-4899, USA. E-mail: [email protected], Tel: +1-314-935-6513, Fax: +1-314-935-7588.

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S. FINGER memory, thought – suffer; the very will is During the 1790s, after he obtained his medical weakened, and the power of its determination degree and settled in Vienna, Gall began to present blunted . . . This is not the case if the injury is his new ideas to the public. The Catholic clergy and in the back part of the cerebrum. (Swedenborg, the conservative Hapsburg rulers of Austria, how1938 translation, p. 73) ever, looked upon his thinking as dangerously materialistic or soulless. By 1802, those in power had heard Although Swedenborg was well ahead of everyone else enough, and a general decree requiring approval for when it came to envisioning cerebral localization, his phypublic lectures followed (Capen, 1881; also see Gall, siological writings had no apparent impact on his contem1835, Vol. 1, p. 19). Knowing that it was really aimed poraries in science and medicine. This was in part because at him, and not willing to remain silent, Gall opted he never held a university post. It was also because he to move to France. He stopped along the way to give abandoned his cortical studies for theology after he began lectures and demonstrations in Germany, Denmark, to experience visions – some involving communicating Switzerland, and the Netherlands, convinced that he with the dead. As a result, influential scholars tended to was shedding new light on human behavior and the avoid or to look askance at him and his writings. Immaorganization of the nervous system, as well as revolunuel Kant, for one, used terms such as Wahnsinn (insantionizing medicine. ity) and Wahnwitze (foolishness) when referring to him During his travels and once settled in Paris, Gall con(Kant, 1983). But of greatest importance, Swedenborg tinued his studies, hoping to learn more about the funcnever published his best writings on the brain. These treations of the brain and their associated cortical structures. tises were published in the 1880s. This was after the disIn particular, he examined the crania of individuals who covery of the electrically excitable motor cortex in the constituted both the positive and negative extremes of dog and after the theory of cortical localization of funcsociety. These men and women included great writers, tion had become generally accepted (Swedenborg, 1882– scientists, and orators, as well as lunatics, criminals, 1887). Today, Emanuel Swedenborg is better remembered and those afflicted with congenital disabilities. When for his religious beliefs, as taught in the Swedenborgian he found a person with an exceptional talent or a person (New Jerusalem) Church, than for his theory of cortical very deficient in some ability, he examined the form of function. that person’s head for a cranial prominence or depression. And when he came across a person with unusual GALL’S ORGANOLOGY skull features, he tried to find out what traits distinBecause Swedenborg had no apparent impact on guished that individual from others. To help him with how people viewed the brain, Franz Joseph Gall is his correlations, and to build up his reference “library,” usually given the credit for putting the theory of cortihe collected hundreds of skulls, made casts of others, cal localization into play (Finger, 2000, pp. 119–136). and sketched (Fig. 10.1). Born in 1758, and unaware of what Swedenborg In addition to looking for unusual human skull feahad written decades earlier, Gall became equally tures, Gall was not averse to using other methods. One convinced that the cerebrum is composed of different was comparative anatomy, which for him involved functional regions, each associated with a different comparing the skulls of animals that differed behaviofaculty of mind. But unlike Swedenborg, he mainrally. He believed that nineteen of the twenty-seven tained that he could identify these different organs faculties he could identify in humans could also be by correlating bumps and depressions on the skull demonstrated in animals. Among the faculties humans with everyday behaviors, such as vanity, worshipping, supposedly share with animals are Reproductive and stealing. Instinct, Love of One’s Offspring, Affection, DestrucThe seeds for Gall’s Schädellehre or organology tiveness or Tendency to Murder, and Desire to Possess were planted early in his life, when he noticed that a Things. Some he classified as unique to humans are classmate with superior memory for verbal material Wisdom, Satire and Wit, Poetic Talent, Kindness and had bulging eyes. He subsequently recognized that Benevolence, Mimicry, and Religious Sentiment. Our some other students with bulging eyes were also excelhighest human faculties, Gall postulated, are housed lent in verbal memory. In contrast, his own eyes did in the frontal lobes, a part of the cerebrum not well not bulge, and he considered himself a poor verbal developed in animals. memorizer. From these casual observations, Gall Gall was also interested in people with tell-tale deduced that a highly developed brain area specifically symptoms after brain damage, such as a loss of devoted to verbal memory was the likely cause of the speech. Nevertheless, he made it clear that studying bulging eyes. He further reasoned that if one faculty brain-damaged people could at best only provide supof mind could be localized, so could others. porting data for his established localizations based on

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Fig. 10.1. A skull showing the centers of various faculties of mind. Plate XCIV from Gall’s atlas, a volume of his Anatomie et Physiologie du Système Nerveux (Gall and Spurzheim, 1810–1819).

bumps. He contended that most people with brain damage are not testable in a meaningful way, in part because they are prone to infections and complications, but also because their wounds are rarely confined to specific territories. For some of the same reasons, he had little interest in studying the effects of brain lesions on dogs, rabbits, and other animals. To appreciate how Gall drew his conclusions, one need only consider his faculty of Carnivorous Instinct or Tendency to Murder. The organ for this faculty was localized above the ears for several reasons. First, this area was found to be bigger in carnivorous than in herbivorous animals. Second, it was exceptionally large in a successful businessman who left his job to become a butcher. Third, a large prominence was found in this location in a student who was so fond of torturing animals that he became a surgeon. Fourth, this region was well developed in an apothecary who later became a public executioner. And fifth, it was also unusually large in sadistic and murderous tyrants, men who obviously delighted in seeing others die. Gall never contended that he knew the anatomical boundaries of each of his identified faculties. Nevertheless, he believed that the two hemispheres duplicated each other and that each half of the brain could serve as a complete organ of mind, just as each eye could serve as a complete organ for sight. This is why he typically showed and labeled just the left side of the brain in his publications. If unilateral lesions

cause symptoms, as often happens, it is because the balance between the two symmetrical sides of the brain is disrupted by the damage. Gall’s monumental publication was his five-volume Anatomie et Physiologie du Système Nerveux en général et du Cerveau en particulier (Anatomy and Physiology of the Nervous System in General and the Brain in Particular). The first two volumes and the atlas appeared in 1810, and the final two volumes were published in 1819 (Gall and Spurzheim, 1810–1819). Johann Spurzheim, who began to work with Gall in 1804, was given second authorship on the initial volumes. Nevetheless, Gall and his assistant did not always agree, and they parted company after 9 years. Once on his own, Spurzheim increased the number of organs of mind, reclassified the faculties, and showed how useful the new science could be for choosing a mate, educating children, selecting leaders, and the like (e.g., Spurzheim, 1825, 1832). It was Spurzheim who wrote numerous books about the doctrine and popularized the term “phrenology” – a word he did not introduce but preferred over Gall’s term “organology” (Young, 1970; Finger, 2000). Gall never made inroads with the French medical establishment. The Institut de France officially rejected his application for membership in 1808, even though the material he submitted with his application was not based on his controversial theory; it only described his anatomical work (see Barker, 1897).

120 S. FINGER In addition, Pierre Flourens was commissioned to test new experiments on laboratory animals with betterGall’s questionable theory experimentally in 1822. Floudeveloped cerebrums than amphibians and birds. rens subsequently stimulated the cerebral cortex and made large brain lesions in animals. Finding no eviBOUILLAUD AND AUBERTIN dence for cortical localization in any of his studies, The first cortical localization based on brain lesions to he repeatedly and vigorously attacked the theory of become widely accepted placed the center for fluent bumps and its supporters in his publications (Flourens, speech in the anterior lobes. Although Paul Broca is 1842, 1846, 1864). often cited for this clinical discovery, he was not the first The failure of Flourens to find differences followto make this association. Jean-Baptiste Bouillaud, a ing ablations of different parts of the cerebral cortex respected figure in French medicine, had previously was largely due to the fact that most of his experiments used clinical examinations and post-mortem findings were done on hens, ducks, pigeons, and frogs – animals to argue for an anterior localization of speech functions. obviously lacking highly developed forebrains. NeverIn 1825, after examining data from a fairly large theless, Flourens occasionally worked on cats and dogs, number of cases, Bouillaud wrote: which would suggest that his tests were too simplistic, that his animals were sick, or that he might have been In the brain there are several special organs. . . In blinded by his drive to show that the phrenologists had particular, the movements of speech are regulated it wrong. by a special cerebral centre, distinct and indepenAlthough Gall and his followers rightfully argued dent. Loss of speech depends sometimes on loss that their theory was not properly tested by lesion stuof memory for words, sometimes of want of the dies on sick hens and weak or dying frogs, serious muscular movements of which speech is composed damage was done (Hollander, 1901). Making matters . . . The nerves animating the muscles, which comworse, clinical observers, including John Harrison bine in the production of speech, arise from the (1825) and Thomas Sewall (1839), could not confirm anterior lobes or at any rate possess the necessary what the phrenologists were claiming about skull marcommunications with them. (Bouillaud, 1825; kers. As a result, established physicians who had earlier Trans. in Head, 1926, pp. 13–14) supported the theory now began to turn their backs on During the 1830s, 1840s, and 1850s, Bouillaud continit. Some even made it look as if they had never ued to bolster his position with more case studies embraced it (Freemon, 1992). As for aspiring new(e.g., Bouillaud, 1830, 1839, 1848). His list of cases comers to medicine, they increasingly avoided it, not eventually grew into the hundreds. Nevertheless, most wishing to jeopardize promising careers. of his contemporaries ignored or responded negatively After Gall died in 1828, Spurzheim and George to what he had to say about speech localization (e.g., Combe of Edinburgh tried to give new life to the falCruveilhier, 1839). One problem was that he had been tering theory. Both men even traveled to America, a founding member of the Socie´te´ Phre´nologique and where they gave lectures and demonstrations to both another was that he professed an admiration for Gall. professionals and the general public (Walsh, 1972; Although Bouillaud had abandoned Gall’s cranioscopy Freemon, 1992). Nevertheless, phrenology continued for the “clinical method,” the scientific establishment its slide among academics and medical professionals. preferred to distance itself as far as possible from anyIn contrast, it fared considerably better among the one and anything reminiscent of Gall or phrenology. uneducated laity. Yet another problem was that his descriptions were Lost in the battle that damaged many scientific brief and lacking in essential details. And making matreputations and helped make a few new ones was the ters worse, but perhaps most important of all, the litrealization that Gall had the right idea when he made erature was filled with reports showing that anterior the case for localization. It was not the theory of localilobe lesions did not always impair speech (Andral, zation but his reliance on cranioscopy and how he 1840). accepted or rejected new material that was faulty. As Bouillaud did not recognize that the left hemisphere for Flourens, by turning to brain lesions he had found a is dominant for speech in most people; i.e., that better way of assessing brain functions, but he strongly right-hemispheric lesions rarely produce major speech favored the wrong theory. Sadly, neither man had been disorders. Had he analyzed his data for left-versus-right willing to see any value in what the other was doing or differences, rather than just looking for anterior-posterior stating about the cerebral hemispheres. differences, he would have seen this, even in 1825 What was needed was a fresh approach to cortical (Benton, 1984). Consequently, he did not have what he localization, one starting with a closer look at needed to deal with some of his critics. humans with brain lesions. Also needed would be

THE BIRTH OF LOCALIZATION THEORY 121 Early in 1861, Pierre Gratiolet spoke before the Paris with comparative anatomy, another of his areas of Socie´te´ d’Anthropologie. At issue was the meaning of expertise, since comparisons across species suggested a very large skull of a Mexican Indian that had come a strong relationship between frontal lobe development to Paris. Could total skull size be a good correlate of and intelligence. intelligence, if such a skull belonged to a savage and Six days after Broca saw Leborgne for cellulitis and not an erudite Frenchman? The localizers did not mince gangrene of his paralyzed right leg, his sickly patient words. They argued that our highest functions, includdied. His brain was removed and presented to the ing speech, reside in the front of the brain. Hence, a Socie´te´ d’Anthropologie the next day. Broca (1861a) big skull would not necessarily indicate a higher intelliissued a brief statement at this time. He provided a gence, if the expansion were in the back. more detailed report at the meeting of the Socie´te´ The most vocal champion of the localizationist posid’Anatomie later in the year (Broca, 1861b). tion was Simon Alexandre Ernest Aubertin, who was Broca now openly sided with the localizationists, married to Bouillaud’s daughter Elise. Aubertin, Chef emphasizing that the faculty for articulate language de Clinique at the Charite´ Hospital, now cited case stuis, in fact, in the anterior lobes as had been contended dies to show that speech must be an anterior lobe funcby Bouillaud and Aubertin. In fact, he raised the possition. One such case involved a man who had shot bility that these lobes may also serve other executive himself in the head, shattering the bones in the front functions, including judgment, reflection, and abstracof his cranium and exposing his brain (Aubertin, tion. During Leborgne’s final years, when his lesion 1861). When his anterior cortex was lightly pressed, was spreading throughout his anterior lobes, he showed his speech suddenly and reliably stopped, although condefinite signs of losing his intellect. sciousness and other functions were not affected. As Broca called Leborgne’s inability to speak aphemie soon as the compression ceased, this man’s speech (“without speech”), but this word was soon replaced returned. by aphasie (“aphasia” in English). Armand Trousseau Aubertin’s case studies and arguments led others to (1864) suggested the change because he had been told take a harder look at the evidence. One such person by a Greek physician that aphemie had negative connowas Paul Broca, the founder of the Socie´te´ d’Anthrotations. As for Leborgne, because he often uttered a pologie. word that sounded like “tan,” he became known as “Tan” to some members of the medical community. Several reasons can be advanced for why Broca’s BROCA ON LOCALIZATION first case had so much impact (Finger, 2000, pp. Paul Broca openly championed cortical localization 142–145). First, unlike Bouillaud, Broca’s paper cononly after an enfeebled 51-year-old patient named tained essential details: details in the case history, Leborgne was transferred to his surgical service at details in its emphasis on articulate speech as opposed the Biceˆtre. Described as mean and vindictive by other to any defect in speech, and details in trying to find a patients, Leborgne had suffered from epilepsy since more circumscribed locus to account for the inability youth and was hospitalized at age 31 after losing his to speak at will. Second, Broca distanced himself from power to speak. He developed a paralysis on his right phrenologists by emphasizing that he had localized side with loss of sensitivity on the same side about speech more posteriorly than they did in the frontal 10 years after his speech was affected. lobes, and that he used a better method. Third, Broca had been born in 1824 in the same small town the passage of time and the hard ground tilling by (Sainte-Foy-la-Grande) as Gratiolet, and he obtained his Bouillaud and Aubertin had resulted in a greater willmedical degree in Paris in 1848. He took it upon himingness to consider evidence for localization. And self to examine Leborgne as a test of the contention fourth, it was Paul Broca, the fair-minded and highly that a loss of speech will always be associated with respected scientist, physician, and head of academic damage to the anterior lobes (Schiller, 1979). He even societies, who was now willing to back cortical localiinvited Aubertin to join him for the examination. zation of function. The more he had reviewed the evidence from differTo Broca’s delight (and relief!), additional cases supent perspectives, the more Broca had become positively porting his localization in the posterior part of the third biased toward the localizationist position. When he frontal convolution were soon forthcoming. Broca examined Leborgne, he knew the theory already had (1861c) described the case of Lelong later in 1861, and good clinical support. In addition, microscopic studies within 2 years he had eight cases (Broca, 1863). Neverthat he had carried out had revealed cellular differtheless, it took him some time to recognize that the ences in the cerebral cortex, also suggestive of specialesions affecting speech almost always damaged the left lized areas. Moreover, localization seemed consistent hemisphere. When this strange possibility first struck

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him in 1863, he was perplexed. Not knowing what to make of it, especially given Bichat’s widely accepted laws of symmetry, he issued only a weak, tentative statement. Late in 1864, Broca had more to say about hemispheric differences, and some of his thoughts on the subject were published in 1865 (Broca, 1865; see Berker et al., 1986, for an English translation). He now theorized that the two hemispheres are probably not very different from each other in innate capacity, even though the left may play the leading role for speech. He also emphasized that left-hemispheric leadership is not a hard and fast rule free from exceptions. In this context, he theorized that the third convolution of the right frontal lobe could become the dominant speech region following damage to the anterior left hemisphere, particularly if the damage occurs early in life.

THE DAXES ON CEREBRAL DOMINANCE Broca was not the first person to recognize what we now call cerebral dominance. In March 1863, while he was slowly warming to the possibility of hemispheric inequality, an obscure country physician by the name of Gustave Dax sent one copy of a manuscript to the Acade´mie de Me´decine and another to the Acade´mie de Sciences, Paris. Gustave Dax hoped to prove that his deceased father, Marc Dax, recognized the special importance of the left hemisphere for speech before anyone else. He claimed that his father had presented his ideas in 1836, at a cultural congress in Montpellier. In addition to including his father’s paper in his manuscript, he included his own clinical evidence to support his father’s discovery. The elder Dax based his insight on a large number of patients, some with sword wounds of the skull, others with strokes, and still others with brain cancers and abscesses. Forty cases came from the medical literature and an equal number were derived from his own clinical practice. He did not present autopsy material, but with such an abundance of clinical material he had every reason to question traditional thinking about the two sides of the brain being equal. Broca did not doubt what Marc Dax had written in 1836, but he and others wanted to know whether the paper had actually been made public then or for that matter at any other time. His own letters and inquiries proved negative, and there still is no evidence that Dax presented his findings in Montpellier in 1836. This resulted in an open dispute between Broca and his supporters and Gustave Dax in southern France (Dax, 1877; Roe and Finger, 1996; Finger and Roe, 1996). What is known with certainty is that the Dax manuscript arrived in Paris just days before Broca (1863)

made his first (tentative) public comments about the side of the lesion in his own cases. Although given to a committee for “secret” evaluation, the revealing title was immediately published and there were leaks. Late in 1864, after a lengthy delay, the Dax submission, which seemed to have been ignored by the Académie de Sciences, was rejected as nothing more than “phrenology” by Le´lut, who headed the committee at the Acade´mie de Me´decine. Infuriated, Gustave Dax separated his father’s original contribution from his own and published both papers in the Gazette Hebdomadaire de Médecine et de Chirurgie in 1865 (G. Dax, 1865; M. Dax, 1865). They appeared just before Broca’s own paper on cerebral dominance was published (Broca, 1865). With the passage of time, the Dax name slowly faded into oblivion, leading many people to conclude that Paul Broca was the first person to recognize cerebral dominance. The Daxes began to garner new attention in the 1960s, however, when several articles about their observations were published (Critchley, 1964, 1969; Joynt and Benton, 1964). More details have emerged about the Daxes since that time (Cubelli and Montagna, 1994; Finger and Roe, 1996, 1999; Roe and Finger, 1996).

JACKSON AND THE RIGHT HEMISPHERE John Hughlings Jackson’s first comments on cerebral dominance were made in 1864. After examining many patients with speech defects, he concluded that Broca made a valuable contribution to speech literature when he pointed to the third frontal convolution of the left hemisphere. In 1868, Jackson wrote that these patients usually performed reasonably well on perceptual tasks. He then astutely recognized that damage to the posterior part of the right hemisphere is more likely to impair spatial abilities than damage to any other part of either hemisphere. Some of Jackson’s most intriguing right hemisphere lesion cases were written up over the next few years. For example, in 1872 he described a man with paralysis of the left side who could not recognize people – not even his wife (Jackson, 1872). This man also had difficulty recognizing places and things, although his vision seemed to be more than adequate for the task. Another early case, Elisa P., lost her directional sense. She suffered from a large malignant tumor in the posterior part of her right temporal lobe (Jackson, 1876). Jackson (1874, 1876) coined the term “imperception” to describe the “loss or defect of memory for persons, objects, and places.” He associated imperception with lesions of the posterior part of the right hemisphere.

THE BIRTH OF LOCALIZATION THEORY In his mind, imperception was every bit as special as the language disturbances associated with lesions of the anterior part of the left hemisphere. The right hemisphere may not think in words, but the importance of its posterior region in getting from one place to another, in recognizing friends, and even in getting dressed was undeniable to Jackson.

THE MOTOR CORTEX If Broca’s 1861 report on “Tan” can be regarded as the most important clinical paper in the history of cortical localization, its laboratory counterpart has to be the discovery of the cortical motor area in the dog. The individuals who conducted the successful experiments in 1870 were two young Prussians, Eduard Hitzig and Gustav Fritsch. To understand the importance of what Fritsch and Hitzig (1870) accomplished, it must be recognized that, although many physicians had accepted what Broca had to say, others wanted more proof than isolated case studies to convince them of the reality of the new doctrine (Young, 1970; Finger, 2000). The experimentalists did not deny that Broca’s case studies cast suspicion on the time-honored concept of an indivisible cortical organ. But, they contended, clinical reports are notoriously unreliable and considerably less informative than data obtained from well-designed laboratory experiments. Gustav Fritsch became interested in motor functions during the Prusso-Danish War. When called upon to cleanse and dress a head wound, he noticed that accidentally irritating the exposed brain caused the opposite side of an injured soldier’s body to twitch (Kuntz, 1953; Walker, 1957). As for Hitzig, he became interested in cortical motor functions late in the 1860s, when he noticed that applying electrical currents to the back of the head or the ears caused eye movements in humans (Hitzig, 1867, 1869). He then turned to rabbits and, in a preliminary experiment, also obtained suggestive data with electrical stimulation. It was in this Zeitgeist that Hitzig invited Fritsch to join him on an electrical stimulation experiment with dogs. In fact, as Fritsch and Hitzig later pointed out, others with more experience had previously tried to elicit movements by stimulating the cerebral cortex. But their findings were negative, questionable, or just misinterpreted (e.g., Rolando, 1809; Todd, 1849). Not having animal facilities at work, the two investigators began their electrical stimulation experiments on a dressing room table in Hitzig’s house in Berlin. Systematically exploring the cortical surface, they found distinctive cortical sites that triggered muscular responses on the opposite side of the body. Because

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other cortical sites were silent, they felt they had discovered a distinct cortical motor region. As a further test, they used a scalpel handle to ablate the newly identified forepaw motor area on one side of the brain in two of their dogs. Although the lesion did not abolish movements from the contralateral forepaw, motor performance was impaired and abnormal postures were observed. Fritsch and Hitzig pondered the role of their newly discovered motor cortex. Because their brain-damaged dogs could still scamper about, the basic circuitry for skeletal muscle movements had to be situated below the cortical mantle. The excitable cortex, they surmised, must be involved with a decidedly higher function, one more closely related to conscious awareness and the willful control of the muscles. Unknown to them, Swedenborg had reached the same conclusion with human case material more than a century earlier. Fritsch and Hitzig ended their paper stating that it would now be worthwhile to explore the cerebral surface for areas concerned with sensation and even intelligence. As they expressed it, A part of the convexity of the hemisphere of the brain is motor, another part is not motor. The motor part, in general, is more in front, the non-motor part more behind. . .certainly some psychological functions, and perhaps all of them. . .need circumscribed centers of the cortex. (Bonin G von trans., 1960, p. 96)

DAVID FERRIER’S IMPACT The man who emerged as the leader of the “localizers” during the mid-1870s was David Ferrier, a Scottish physician who viewed John Hughlings Jackson as his intellectual mentor (Finger, 1994, 2000, pp. 155–175). Since 1861, Jackson had been interested in unilateral “epileptiform convulsions” without loss of consciousness – a disorder that would later be called Jacksonian epilepsy (Jackson, 1861, 1863a). At the time, almost everyone believed that these “partial” motor seizures originated in the corpus striatum or perhaps in the brainstem. Based on autopsy material, however, Jackson (1863b, c, d) increasingly felt that the cerebral cortex was often affected in these patients. Moreover, he was intrigued by how the seizures seemed to “march” across the body, spreading in some cases very reliably from the hand to the arm to the face. Jackson continued to develop his thoughts about a cortical motor area between 1865 and 1870, and his thinking was further influenced by his observations on patients with unilateral cortical damage – individuals

124 S. FINGER exhibiting paralyses that might be restricted to the oppoFerrier shed more light on his suspected sensory site hand or a foot. To Jackson, epilepsy was the “mobile areas by damaging them and observing how his moncounterpart of hemiplegia.” Together the two disorders keys behaved when various smells, sounds, and visual afford a “double method” for comparing the effects stimuli were presented. Would a brain-damaged monof discharging and destroying lesions. key still sniff an apple before tasting it? Would it turn Jackson recognized that somatotropic organization around when called? Could it now find a cup from was the only way to account for the progression of which it had just sipped some tea? the seizure across successive muscle groups in cases The conclusions Ferrier drew from his stimulation of spreading epilepsy, as well as for lesions just and lesion studies proved to be fairly accurate for affecting one part of the body. He believed that the some sensory systems, including hearing, which he hand, face, and foot, or the three “leading” parts localized in the superior temporal gyrus, and olfac(i.e., those capable of the greatest number of speciation, which he associated with the lower temporal lized voluntary movements), had to have the greatest lobe. Nevertheless, he did not do as well when it came representations at the cortical level. He also maintained to localizing the other senses, although his work that higher nervous centers had to be viewed as evoluserved as a stimulus for others to conduct their own tionary outgrowths of lower centers. informative experiments (e.g., Munk, 1878, 1881; When Ferrier began his electrical stimulation exBrown and Scha¨fer, 1888; Horsley and Scha¨fer, 1888; periments on the cerebral cortex during the 1870s, Scha¨fer, 1888). For example, he maintained that sight one of his goals was to test some of Jackson’s (1870) is controlled by the angular gyrus in the posterior part now fully developed ideas about a somatotropically of the parietal lobes (Ferrier, 1874, 1875a, b). The organized cortical motor region that could be affected experimentalist who first pointed to the primary role by epilepsy. Another was to confirm and extend the played by the occipital lobes was Hermann Munk experimental findings of Fritsch and Hitzig, who later (1878, 1881). claimed to be unaware of Jackson’s observations and Ferrier (1874, 1875b, 1876) also strove to understand insights when they conducted their landmark experithe functions of the “silent” cortex anterior to the ment in 1870. motor region. In one of his reports, he described three Ferrier’s first publication on cortical localization animals that were inattentive, apathetic, dull, and listappeared in 1873. It involved work conducted at the less, although they also tended to exhibit periods of West Riding Lunatic Asylum in Yorkshire, where he restlessness, characterized by moving back and forth had been invited to do localization research by its proand wandering aimlessly. He concluded that these gressive superintendent, James Crichton-Browne. He animals suffered from attention deficits. examined a large number of species, identified the Hitzig (1874a, b), who was also working on the antemotor cortex in his mammals, and then showed that rior frontal lobes of monkeys at this time, came to a animals higher on the evolutionary scale are more different conclusion. He thought the fundamental defimpaired by damage to the motor cortex than their icit associated with anterior frontal lobe damage was lower cousins (Ferrier, 1873). one of abstract thought. And before the century was By the end of 1874, Ferrier had turned his attention over, Leonardo Bianchi voiced a third opinion, after to monkeys, partly to distinguish his work from the having lived and socialized with his animals for some research previously conducted by Fritsch and Hitzig, time (Bianchi, 1895; see Finger, 1994, pp. 322–323; but also because of their greater significance to cliniTraykov and Boller, 1997). He found that bilateral cians. He found that electrical explorations well outdamage to the anterior frontal regions usually affected side the motor region sometimes elicited small a myriad of functions, including planning, critical movements. He also recognized that these movements thinking, decision making, emotionality, self-image, were not like those obtained with peripheral nerve stiperception of others, and social interactions. In short, mulation. Rather, they were similar to those normally they affected the very personalities of his animals, a shown by monkeys in response to sights, sounds, and finding he also applied to humans. other sensory stimuli. Perking the opposite ear and Ferrier, Hitzig, and Bianchi were all basically correct. turning the head to electrical stimulation suggested a Depending on the size and locus of the frontal cortex role in hearing, whereas certain eye and head movelesions, all of the changes they observed can be observed ments indicated that another cortical region was probnot only in monkeys, but in human patients as well. ably visual in nature (Ferrier, 1874). As Ferrier later Although Ferrier was criticized early on for not stated: “The mere fact of motion following stimulation keeping his animals alive for more than a few days, of a given area does not necessarily signify a motor he began to conduct long-term studies on healthy monregion” (1876, p. 163). keys during the 1880s (e.g., Ferrier and Yeo, 1885).

THE BIRTH OF LOCALIZATION THEORY 125 The needed change in protocol was made possible by belonged to the localizationists (for details of what Lister’s new aseptic surgical techniques, which reduced transpired, see Tyler and Malessa, 2000). the chances of post-operative infection. Throughout his career, Ferrier did everything in his Long-term studies with his animals convinced power to make his work appealing to physicians and Ferrier that an area’s function would remain lost if surgeons. Not only did he switch to monkeys early he completely destroyed that territory. Others, howon, he even included a functional map of the human ever, questioned the totality of the deficit and its supbrain based on his monkey data in The Functions of posed permanency. One disagreement erupted over the Brain, which came forth in 1876 (for more on Ferhis contention that there is total deafness after extenrier’s illustrations, see Millet, 1998) (Fig. 10.2). His secsive superior temporal lobe lesions, and another was ond book, Localization of Cerebral Disease, appeared over his insistence that absolute blindness would follow in 1878, and it was more clinical in nature (Ferrier, angular gyrus lesions. His major adversary on both 1878). The 1886 edition of The Functions of the Brain fronts was Edward Albert Scha¨fer, who could not included many more clinical studies and some greatly replicate his findings (Sparrow and Finger, 2001). expanded sections on the so-called executive functions, In 1881, Ferrier described some of his “new” monkeys such as ideation and problem solving, which were of at a session of the huge Seventh International Medical special interest to clinicians (Ferrier, 1886). Congress in London (see Finger, 2000, pp. 155–159). One animal, he said, had suffered extensive unilateral CONVERGING LINES OF EVIDENCE Rolandic area damage and was still hemiplegic 7 The theory of cortical localization of function continmonths after its surgery. The other had sustained bilatued to gain support during the closing decades of the eral superior temporal lobe lesions 6 weeks earlier and 19th century, and not just from the experimentalists was stone deaf, although it moved about and used its with their brain-damaged animals or the clinicians other senses normally. These two monkeys, he conwho were now looking at their patients in new ways. tended, proved that deficits following complete removal Surgeons who had read Broca and were following Ferof a specialized cortical area are, in fact, both total and rier’s detailed diagrams were also confirming the new permanent. doctrine, which would radically change operative pracLater that afternoon, Ferrier showed his monkeys to tices. Similarly, anatomists started to look more caresome of the attendees who had just heard him speak fully for differences in the cells comprising the about them. When his hemiplegic monkey limped into cerebral cortex, aided by better microscopes, preservathe demonstration room at King’s College Hospital, tives, and stains, and guided by the belief that differFrench neurologist Jean-Martin Charcot was taken a ences in structure imply differences in function. back by how much it resembled some of his patients. Thus, a major shift in how people viewed the funcA “decorticate” dog brought in by Friedrich tional organization of the brain took place during the Goltz was also exhibited at that time. Earlier in the second half of the 19th century, stimulated by clinical day and speaking in the same session as Ferrier, findings and supported by converging lines of evihe had described this dog’s sensory and motor funcdence. Yet even today, questions remain and much still tions as normal. And in opposition to Ferrier’s position, remains to be learned. Debates still flare about the prehe had argued that it would be a mistake to accept cise boundaries of certain functional areas, whether cortical localization of function. The dog behaved certain areas should be subdivided, and the degree to much as Goltz said it would, showing only a blunting which functional zones might overlap or shift after of intellect and raising questions among those present injury. Equally challenging has been trying to get as to who was right and who was wrong about cortical agreement on the basic deficits observed after damage localization. to specific parts of the cerebral cortex. After the demonstrations were over, the participants Localization theory today is much more complex agreed to sacrifice the dog and the hemiplegic monkey and dynamic than the localization of sharply demarto see if the ablations were, in fact, placed as cated centers envisioned by Broca, Fritsch and Hitzig, described. The lesion was found to encompass the and Ferrier. With advances in science and medicine, Rolandic region in the monkey, which was in accord the meaning of cortical localization in the future may with what Ferrier had contended. In contrast, signifideviate even more from the simple maps made by cant regions of the cerebral cortex were spared in these pioneers – the diagrams that changed the face Goltz’s “decorticated” dog, which could have of neurology and related disciplines during the second accounted for how well it moved about and responded half of the 19th century. to sensory stimuli (see Klein et al., 1883). The day

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Fig. 10.2. Ferrier’s 1886 diagram of a human brain showing the functional areas he derived from his experiments on monkeys.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 11

On the use of animal experimentation in the history of neurology FRANK W. STAHNISCH * Department of Community Health Sciences and Department of History, University of Calgary, Calgary, Canada

For a large number of problems there will be some animal of choice, or a few such animals on which it can be most conveniently studied. (August Krogh, 1929, p. 247)

INTRODUCTION It is generally assumed that animals always had a place in neurology and were seen to display similar maladies to those afflicting mankind. They were indeed objects of intensive study and close observation in various fields of medicine, so the topic of animal experimentation itself has become a widely discussed subject in recent historiographical literature (comprehensive studies are: Paton, 1984; Hardegg and Preiser, 1986; Guerrini, 2003). Close historical analysis of experimentation with animals, however, cannot support the belief that they had always been seen as “lab animals,” a notion so current in modern-day scientific jargon (e.g., Held, 1980, p. 214). Although this chapter gives an overview on the use of wild and laboratory animals in the history of neurology, it is far from conclusive and can only cover some landmark experiments. In so doing, it pays particular attention to the transfer of knowledge derived from animal experimentation to human physiology and clinical phenomena in neurology. In addition, various social backgrounds of the Western research endeavor in biomedicine (see Cunningham and Williams, 1992, p. 3), such as the influence of conflicting religious and cultural beliefs held by neuroscientists or the public, will be touched upon, to illustrate the complex efforts of different historical contexts (cf., Rheinberger and Hagner, 1993, p. 1). In tracing the history of the martyrs of neuroscience in different historical episodes and localities, only some *

instances of the history of animal experimentation can be covered, and the interested reader, who wants to learn more about the broader cultural contexts of this important issue in the generation of neurological knowledge, will be referred to more comprehensive descriptions in the historiographical literature (important accounts can be found in Brazier, 1988; Finger, 2000; Hagner, 2000).

ANIMAL EXPERIMENTS IN THE ANCIENT WORLD Aristotle’s (384–322 BC) biological works were not confined to purely theoretical considerations, like many contemporary natural philosophers. As Aristotle was an accomplished animal dissector, they were based on a multitude of comparative observations in shells, as well as in the eggs of snakes and chicken. In De partibus animalium and in Historia animalium, Aristotle reasoned from the anatomical organization of the body to its physiological actions, and he also described the central nervous system at various stages of its morphological development (Aristotle, 1855a, Book IV 11–12. 690 b 11–695 a 28; 1855b, Book V 16. 548 a 22–549 a 13). Aristotle looked upon the brain as an important organ for higher functions, although it was not his seat of soul, and he held the view that perception, imagination, and the capacity to move had to be essential features of both animal and human life (van der Eijk, 2000, pp. 64f.). In Greek medical culture, the unifying concepts of form and function in living animals merged with broader ideas on the nerves as the seat of bodily formae or, in Aristotle’s specific view, of “hylomorphism,” i.e., the coordinated functioning and essential integration of the physical body through the dynamic

Correspondence to: Frank W. Stahnisch, Community Health Sciences, Heritage Medical Research Building, Room G30, University of Calgary, 3330 Hospital Drive N.W, Calgary, AB, Canada T2N 4N1. E-mail: [email protected], Tel: ++1-403-210-6290, Fax: ++1-403-270-7307.

130 F.W. STAHNISCH structure of the soul. Animals, which displayed certain Along these lines, Galen conducted the paradiganatomical resemblances to humans, were likewise matic experiment on a nerve in ancient medicine and seen to possess the same formae and suffer from simisummarized it in his inquiries of De usu partium. His lar diseases to man (Wittern, 1987, pp. 69–79; von target was the voice-related nerve, and his experiment Staden, 1989, pp. 249–259). clearly had neurophysiologic interest, as it could be In the same way as Aristotle presented the brain as seen as an explanation for the loss of voice following an exceptional organ, because of its influence on the injuries of the recurrent laryngeal nerve. Galen had psyché as the highest forma, he still adhered to a carinitially set out to find the nerves working the lungs, diocentric physiological model. This model ascribed in order to study breathing. He came to realize, howthe brain’s role basically as tempering “the heat and ever, that a pig on which he was operating immediately seething” of the heart, and its massive extension made stopped squeaking, but continued to breathe, after he it perfectly able to cool the vapors of the heart through had severed one specific pair of the nerves in its throat its impact on the many ascending blood vessels that (Nutton, 1995a, pp. 33–38). lead to this central bodily organ (Clarke, 1963, pp. 1–6). When Galen confirmed his experiment in other aniGalen of Pergamon (129–c. 200/216 AD), personal mals such as dogs and goats, he became increasingly physician to the Roman Emperor Marcus Aurelius (121– convinced that he had found the “nerves of voice.” 180 AD), developed Aristotle’s early biological observaAnd this pair of nerves tions into a decisive comparative anatomy, closely investi– the recurrent laryngeal nerves – is at times gating a myriad of animals, some of which displayed still called after the eponym of “Galen’s similar traits to humans. Galen had a well-developed sense nerves.” He also related these findings to the of the value of his experimental studies, and investigated clinical observation that a surgeon, who had virtually every beast he could retrieve from the Roman operated on a boy to extirpate some deep glandmarkets, such as Barbary apes, parrots, and pigs. Like ular swellings, rendered his patient voiceless, as Aristotle, he granted only limited consciousness to ania result of severing these nerves. In another boy, mals. Assuming animals would suffer less pain, he a similar procedure had left the patient with a accordingly advanced and broadened his experimental markedly reduced voice, after one of the recurprotocols. He even studied a war elephant from the rent nerves was affected. Galen, as might be Circus Maximus, at a time when anatomy was a form expected, explained these findings in the context of public entertainment, with dissection shows on the of his physiological theories. (Galen quote after crowded streets and market places of Ancient Rome translation of Pendergast, 1930, p. 60) (cf., Guerrini, 2003, pp. 13–18). All his animals were closely observed, studied physiologically, and then inspected In different experiments, Galen cut the spinal cord at post mortem. And because Galen – together with Hippovarious levels to observe which parts of the body would crates (c. 460–c. 377 BC) – was one of the most influential be affected and paralyzed. The outcome of such an physicians in antiquity, his ideas dominated Western medexperiment in a monkey, for example, was a paralysis ical thinking into the Renaissance. of the respective extremity, from which he concluded In De usu partium, Galen introduced an early methothat an undamaged connection of the brain and spinal dology of dissection and animal experimentation to cord was a prerequisite for the instigation of muscle a new generation of anatomists and naturalists (Galen, contractions (see Canguilhem, 1992, pp. 18f.; Finger, 1821, Book I, Chapter 6; Book VIII, Chapter 8); 2000, pp. 41–47). When cutting only halfway through he saw anatomy and physiology as the only legitimate the cord, he observed that paralysis occurred on the approaches to obtain basic medical knowledge. But even same side as the cut. And, in a related set of experiwhen Galen used the works of his predecessors – espements, he noticed that an injury of the spinal cord just cially the Alexandrian school of human anatomists (e.g., below the occiput would lead to the sudden cessation Herophilos of Chalkedon, c. 330/320–c. 260/250 BC; Eraof breathing. These experimental observations in anisistratos of Kos, c. 330–255/250 BC) – he grounded most mals added new light to human neurology, because of his observations and hypotheses on animal dissection they explained, for example, why a gladiator from and vivisection (von Staden, 1989, pp. 249–259). The phythe Circus Maximus would die shortly after neck siology presented in De usu partium further supported injury, whereas another continued to live and breathe, Galen’s view that animal experiments could be used when being severed by a sword wound to the spinal effectively to advance knowledge about human illness column at a lower level (Woollam, 1958, pp. 5–18). and therapy, above all in neurology, as the nervous system The tradition that followed from Aristotle and Galen strongly fascinated him. For example, he closely observed conceived of the living body as a hierarchical system, the effects of ligaturing or cutting individual nerves. one in which the primitive formae of physiological

ANIMAL EXPERIMENTATION IN action – the facultates naturales, such as digestion, metabolism, and creation of humors – acted as the basis for higher faculties, known as the facultates vitales, such as cooling or distribution of the humors in the body, and the facultates animales, i.e., sensibility, appetite, and movement. The psyché was seen as the ultimate cause of living actions operating through the facultates. Despite the striking contemporary effect exerted by Galen’s paradigmatic ligature experiment, and its conceptual integration into earlier neurophysiologic accounts, it was only received in Northern European countries at the beginning of the 16th century, following Jean Fernel’s (1497–1558) Latin translations (Rothschuh, 1973, pp. 41–43). Throughout medieval times, ancient observations on animal behavior, anatomy, and physiology were preserved in Mid-Eastern medical writings. Their crowning achievements, such as the compilation in Ibn-Sina’s (also known as Avicenna; 980–1037) Canon Medicinae (O’Sullivan, 1996), were rediscovered in the West only during the late-medieval period, and they were subsequently melded with Christian views on the genesis of living things. In the case of Galen’s work, the ancient experiments and observations were accepted as virtually unquestionable sources of medical knowledge. Yet, challenges to those findings and to medical authority were raised throughout the Renaissance (Tansey, 1993, pp. 121f.).

A REDISCOVERY OF ANIMAL EXPERIMENTATION IN RENAISSANCE NERVE RESEARCH The human psyché had played a double role in relation to the body from ancient times into the Renaissance. It was believed that the psyche was integrally linked to the human body as a cause of physiological actions, and that it acted as a vital “tool,” only separable from the human body on death. The Renaissance thus played an important role in the wide-ranging transition from medieval to more modern accounts of the mind–body relation (Michael, 2000, pp. 147–158). Mainly through further advances in comparative morphology, especially the dissection practices of Taddeo Alderotti (c. 1215/23–c. 1295/1303), Mondino dei Luzzi (c. 1275–1327), and the North-Italian anatomists (see Nutton, 1995b, pp. 139–206), additional inquiries into the structure and function of the nervous system began to emerge. Since the 12th century, the dissection of pigs had been a sporadic part of medical teaching. In Italy, for example, Frederick II (1194–1250) realized the necessity of anatomical dissections for new advancements in medical training. Hence, he decreed that no medical student should enter practice without having studied anatomy at least for 1 year. Moreover, Frederick II

THE HISTORY OF NEUROLOGY 131 supported the establishment of the first medical faculty at Velia, near Salerno. It was strongly influenced conceptually by Constantin the African (c. 1010/1015–c. 1087), who had brought Greek medicine back to the Western World (Nutton, 1971, p. 1). Due to the emphasis of early humanist studies upon older Greek medical traditions – with their programmatic maxim ad fontes – everything pointed toward a more empirical approach to medicine. As such, in the studium of the arts and medicine, anatomy began to be practiced as an auxiliary subject – an additional training in surgical skills alongside internal medicine. The classical heritage of Salerno hence consisted of more than a new conceptual approach, because it basically re-connected with a tradition of medical doctrine and learning going back to Roman and Greek times (Kristeller, 1945, pp. 138–142). Just as Galen had performed his dissections and vivisections on pigs – for their morphological resemblance to man – the medical school of Salerno, and later dei Luzzi in Bologna, relied heavily on pigs for anatomical and physiological purposes, specifically in relating these findings to theoretical knowledge of the human body and to surgical applications. Human anatomy itself, mainly performed on executed malefactors, gave rise to dei Luzzi’s Anatomia Corporis Humani (posthumous, 1494), which became a standard work for 200 years. In the Anatomia, he also made extensive use of anatomical considerations to outline the medical causes of death in legal cases; for example, when considering the lethality of wounds, poisoning, abortion, and other conditions. Nevertheless, dei Luzzi retained some old Galenic doctrines, including that of the rete mirabile as a “nervous network” to be found at the base of the human brain (Siraisi, 1981, pp. 118–135). Throughout the Renaissance, vivisection experiments were re-introduced into the medical field, such as when the rational and learned Mondinian anatomists thrived for improvements in general anatomy and applied knowledge for surgical applications. These men were eager to show that the human body and even its brain were thoroughly intelligible, with regard to form and function. Yet although the Mondinian anatomists had advanced anatomical knowledge through comparably systematic dissections, human bodies were still in short supply due to Christian morality and the power of the church. The few cadavers available for dissection purposes were those of criminals, and they were often only reluctantly handed over by the public authorities (French, 1993, pp. 86–90). Because of the shortage of human bodies and their putrefaction in lengthy anatomical dissections, many anatomists, including Andreas Vesalius (1514–1564), continued to dissect and vivisect animals for research and

132 F.W. STAHNISCH educational demonstrations (French, 1993, pp. 81–83). of many animals, which he deemed convenient for This road had been preconceived in a way, when the the study of particular aspects of the nervous influence young Vesalius was already dissecting neighborhood cats on blood vessel function and the governing of the and other animals. He was soon to become professor of heartbeat, in his De motu cordis (Harvey, 1628). anatomy at Padua at the age of 23, where he dissected In his second major work, Anatomical Exercises on and vivisected not only for research purposes, but also the Generation of Animals (1651), Harvey conducted for classroom instruction (Wittern, 2004, pp. 167–171). various ligation experiments on the nerves and blood Vesalius relied strongly upon animals as stand-ins vessels of dogs, pigs, frogs, snakes, and fish. At the for the dissection of human bodies. And despite his basis of his approach lay a deep conviction that all anifervent criticisms of Galen, due to the latter’s reliance mals display similar physiological principles, despite on animals as objects of study, he did not altogether distheir striking differences in size, configuration, and credit claims about a correspondence between animal physical activity (Keller, 2000, pp. 330–334). Harvey’s and human anatomy. De motu cordis was also instrumental in that it brought Vesalius therefore accepted much of what Galen about the downfall of earlier humoral theories of phyhad written about the nervous system, including the siological action, by replacing them with a clear physiveracity of the plexus reticularis in humans, when he cal mode of bodily functions: just like the heart was to himself relied on a sheep’s head to lay bare its vascular pump the blood through their vessels, the nerve structure (O’Malley, 1964, pp. 73–76). Vesalius was humors were to be pumped through the network of furthermore to derive many physiological claims about the individual nerve tubes (Frank, 1980, pp. 93–97). the brain’s function by inference from dissections of But a growing number of anatomico-pathological living animals. This particularly regards Galen’s perobservations now suggested the material properties of ception of networks of the nerve tubes to bring sensory the organs to be more important than their ancient phyperceptions to the brain and how this central organ siological facultates. This view is specifically apparent controlled locomotion, a property that ceased to exist in the Italian works of the circle of Marcello Malpighi when the nerves descending from the brain were cut (1628–1694) and Giovanni Battista Morgagni (1682– (Singer, 1952, pp. 4–7). And even the naturalistic illus1771), who both had a high impact on the development trations of Vesalius’ famous De Humani Corporis of neuromorphology and physiology. Malpighi, for Fabrica of 1543 often presented the human body in a instance, was among the first scientists to study various style such as any other animal of study. animal organs and histological structures with magnifyAt the turn of the 17th century, the British Lord ing lenses, after he had injected the blood vessels of Chancellor and influential philosopher Francis Bacon individual organs with colored water (Meyer, 1930, (1561–1626) laid a new programmatic emphasis on the pp. 237f.). improvement of science by promoting systematic aniHe also performed studies on the peripheral nerves mal experimentation and vivisection “in regard of the and the autonomic nervous system in sheep, in search great use of this observation” in medicine (Bacon, of their microstructure and their connections to respec1605, p. 374). In this manner, Bacon sided with members tive organs, which he published in his Exercitationes de of the Cambridge school of natural philosophers in Structura Viscerum (1678). Malpighi furthermore conpromoting animal vivisection (Losee, 1993, pp. 63–73), ducted individual vivisectional experiments, when cutbecause he thought that animal experimentation might ting the nerves in living animals, such as guinea pigs, have been “well diverted upon the dissection of beasts cats, frogs, and birds, to assess their functions – with alive [the practice of vivisection], which, not withstanda special view to the lungs’ breathing action through ing the dissimilitude of their parts, may sufficiently the control of the vagus nerve. And regarding satisfy this inquiry” (Bacon, 1605, p. 374). comparative anatomy, Malpighi also contrasted his The presumed utility of animal experimentation experimental observations – using colored substance soon became reality: when William Harvey (1578– to determine the structure of the nerves in the body – 1657), for example, traveled to Pavia in 1599, the chair with his investigations on the spongious structure of for anatomy had just transferred from Vesalius to man’s cerebral cortex, for example. He emphasized Hieronymus Fabricius ab Aquapendente (1537–1619). that the cerebral cortex is made up of “a mass of very Yet the latter still clung to Vesalius’ use of animal disminute glands” with their nerve fibers attached, after section and through him Harvey acquired an interest in he had dried little pieces of the brain and spinal cord the pursuit of anatomical research and the vivisectional by exposing them to the air (Guerrini, 2003, pp. 42f.). approach (Guerrini, 2003, pp. 27–29). After his return Malpighi’s contemporary, Thomas Willis (1621–1675), to London in 1602, the influential British anatomist the anatomist and professor of natural philosophy at and physiologist made wide and highly creative use Christ Church College, Oxford, wrote a lasting monograph

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on brain anatomy and physiology, Cerebri Anatome (1664), in which he also made great use of animal experiments for comparative purposes. He was firmly convinced that

in such, distinct cells, and parted one from another, are wanting, in which the divers Species and Ideas of things are kept apart. (Willis, 1664, p. 76)

by the frequent dissection of all sorts of living Creatures [. . .] I shall shew [!] the communities and differences which the subjected parts obtain in various Animals, compared among themselves, and with man; certainly from such a compared Anatomy, not only the faculties and uses of every Organ, but the impressions, influences, and secret ways of working of the sensitive Soul it self will be discovered. [. . .] A compared Anatomy may yield us a more full and exact Physiology of the Use of Parts. (Willis, 1664, p. 61)

Willis’ research program displayed a tight interplay of religious convictions, clerical patronage, and anatomical curiosity, in which the anatomy and physiology of the brain was central. He worked around the problem that the morphological construction of the human brain seemed so much more complicated than that of any animal he had dissected, an observation that Willis interpreted as direct proof that God had distinguished man as an animale rationale et spirituale. But because the nervous systems of man and the quadrupeds were so similar, Willis felt himself compelled to assume an auxiliary and immaterial principle, which had to account for the considerable differences in consciousness and the human use of language (Rousseau, 1973, pp. 141–150). The decisive aspect in Willis is the assumption of a distinct human soul, which demarcated man from the souls of the brutes. And this basic anthropological constant implied that neurophysiology could only be explained through the specific set-up of the morphology of the brain (Bynum, 1973, pp. 453–458). What in Willis’ case held for anatomical research purposes pertained also in clinical neurology. The French surgeon Franc¸ois Pourfour du Petit (1664– 1741), perhaps better known for his numerous contributions to ophthalmology, performed lesion experiments in animals and specifically destroyed the “intercostal nerves” (Zehnder, 1969, pp. 10–17). In 1727, Pourfour du Petit had described the clinical signs of the sympathectomy syndrome, which in the 19th century came to be associated with the Swiss ophthalmologist Johann Friedrich Horner (1831–1886). During the European Wars of the Grand Alliance, Pourfour du Petit closely observed soldiers with head wounds and described the respective contralateral motor loss in his Lettres d’un Médecin des Hôpitaux du Roi à un Autre Médecin de ses Amis (1710). In the first essay, he mentions having made lesions in the brains of some dogs, and how this resembled the observations in brain-damaged humans, bringing experimental physiology and clinical neurology closer together (French, 1999, pp. 181–201). The perception that animal experiments were critically important to the advancement of medical and biological knowledge, however, was not limited to just the medical doctors and the naturalists in Europe. It inspired many hommes de lettres too. Learned individuals were often invited to attend experiments and discussions about natural philosophy in early-modern learned societies. At this time, research was still a

Twenty years after the publication of his magnum opus, Willis commented in The Soul of Brutes (1684) on the putative functions of the corpus striatum: As to the Offices and Uses of the streaked Bodies, though we can discern nothing with our eyes, or handle with our hands, of these things that are done within the secret Conclave or Closet of the Brain: yet, by the effects, and by comparing rationally the Faculties, and Acts, with the Workmanship of the Machine, we may at least conjecture, what sort of works of the Animal Function, are performed in these or those, or within some other part of the Head. (Willis, 1684, p. 27) In Willis’ neurophysiology, the cerebral cortex had a double function: it acted upon the animal spirits and was at the same time the seat of the faculty of memory, because man, whose memory was so highly developed, was also the creature that displayed the biggest cerebral cortex at autopsy. Willis further believed that sensory and motor functions were integrated in the striatum, where he was to locate the sensorium commune. In the course of his investigations he found, nevertheless, that those Gyrations or Tunings about in fourfooted beasts are fewer, and in some, as in a Cat, they are found to be in a certain figure and order: wherefore this brute thinks in, or remembers scarce any thing but what the instincts [. . .] so that this beast considers or recalls scarcely anything except what the instincts and needs of nature suggest. In the lesser four-footed beasts, also in Fowls and Fishes, the superficies of the brain being plain and even, wants all cranklings and turnings about: wherefore these sort of Animals comprehend or learn by imitation fewer things, and those almost only of one kind; for that

134 F.W. STAHNISCH public affair and scientists not only showed their latest its animal spirits to the water which drives research results, experiments, and apparatus among them, of which the heart is the source and the themselves, but also to an interested (often aristobrain’s cavities the water main. (Descartes, cratic) public (Troehler, 2000, pp. 165–170). 1664, p. 22) For example, Rene´ Descartes (1596–1650) had But the French philosopher was not naı¨ve in addressing witnessed some experiments and observations by such issues from medicine and biology, as he himself Giovanni Alfonso Borelli (1608–1679) from Pisa, and had a profound interest in anatomy and physiology. regarded them as confirming his earlier views about Soon after his travels to Holland in 1619, for example, the structure and function of living organisms. Descartes visited local slaughterhouses to procure aniNevertheless, those experiments were of a seemingly mal heads for his own dissecting purposes (Finger, “hit-and-miss nature” in that when one method failed, 2000, pp. 73–75). And it is even likely that he himself Borelli tried another – for example when he sought to performed vivisectional experiments, because he so identify the nerve–nerve and nerve–artery anastomoses valued natural knowledge over book knowledge. It in various animal species (Borelli, 1680/1681, has further been stated that when a visitor came to pp. 140–147). Where Malpighi had most often used a his home and asked to see his library, Descartes suppomultitude of frogs for his experiments, Borelli used sedly pointed to some sheep parts he just had dissected other pet animals, as described in his De Motu and remarked that those were his dearest books Animalium (1680/1681). This specifically regards his (Vrooman, 1970, p. xi). With regard to animal physiolinvestigations of the anatomical topography of the ogy, Descartes was particularly interested in nervous nerves and his assumptions about their primary funcreflex action, because he perceived those quasi-autotion as channels for the succus nerveus spirituosus to matic actions – such as pulling a limb away from a mechanically inflate the muscles into action. But his flame – as easily to be explained by basic mechanical crucial experiment remained inconclusive in this occurrences. He even perceived such mechanisms as respect. When Borelli decided to test the hydromechathe main process of animal life per se, so that in the nical theory of nerve action, by plunging the limb of Cartesian model this mindless behavior was all there an animal in a tub of water and cutting into its muscould be to the life of brutes. cles, to his astonishment no sparkling spirit entered During the 17th century, the Dutch microscopist Jan the nerve tubes (Cobb, 2002, pp. 395f.). Swammerdam (1637–1680) carried out vivisection In his mechanical explanation of sensory transducexperiments that were to overturn Descartes’ mechanition, Descartes had assumed the existence of a subtle cal nerve-conduction theory. He showed, for example, fluid that moved through the nerves into the muscles, that muscles did not change volume during contraccausing them to expand in width and shorten in tion, and hence are not contracted by an influx of length, and leading to movement (cf., Fuchs, 2001, corpuscles. Swammerdam performed his experiments pp. 67–72). Within the Cartesian tradition, both “chiefly on the frog; for the nerves are very conspicuous animal and human bodies were viewed as mechanical in these animals, and may be easily discovered and laid machines, and nervous action was understood in bare.” And the “motions of the muscles are not so conhydraulic terms of water transmission in the nerve siderable in animals which have warm blood, or rather tubes – like the automata and pumping machines they do not last long” (Swammerdam, 1757, pp. 122f.). in the grottos of the royal gardens at St. Germain He pursued his most striking experiments on the largest in Paris. It therefore seemed quite reasonable that muscles, which he “separated from the thigh of a frog, Descartes, who witnessed this cultural development and together with its adherent nerve, prepared in such a of a thorough physicalization of life, thought that natmanner as to remain unhurt.” Swammerdam then stiural bodies were inhabited by clocklike mechanisms mulated the muscle by poking a needle into the adjacent that mediated sensation and motion through the nerve, and thus could observe the thigh muscle to conpropulsion of physical pressures (Rousseau, 1976, tract, even if the whole preparation had been isolated pp. 147–150). And in his posthumously published masfrom the frog’s body. This observation seemed to prove terwork De l’Homme (1664), he makes this analogy to him that “any matter of sensible [. . .] bulk flows even more explicit: through the nerves into the muscles” (Swammerdam, And truly one may very well compare the nerves 1757, pp. 123f.). of the machine which I am describing to the In a different but similarly elegant experiment, he tubes of the mechanisms of these fountains, its took the same frog muscle preparation with its adhermuscles and tendons to diverse other engines and ent nerve to introduce a fine silver wire exactly into springs which serve to move these mechanisms, the position, which he had formerly interrupted by

ANIMAL EXPERIMENTATION IN cutting the nerve with a knife. This procedure should prevent the conduction of the anticipated “nervous fluid,” but this time – and to his full surprise – he could not observe the slightest muscle contractions. He had demonstrated that no nerve transmission was possible through a mere mechanical nerve-prosthesis in his preparation (Cobb, 2002, pp. 397f.). Although he did not primarily intend to disprove the contemporary theory of nerve fluid action, Swammerdam’s experimental outcomes nevertheless posed a huge obstacle for further mechanical theorizing about the physiological action of the nerves (Holmes, 1993, pp. 316f.). His experimental results were only possible because of the use of an adequate animal model. The proper size of the leg muscles in frogs, the fact that the muscle could be cut out in combination with the nerve, and the extraordinary survival time of the explanted organ preparation under laboratory conditions all played crucial roles in performing this difficult experiment. Swammerdam also thought that this outcome could be generalized, as most findings in animal physiology were also applicable to knowledge about human nerve functioning: Experiments on the particular motion of the muscles in the frog, which may be also, in general, applied to all the motions of the muscles in man and brutes. (Swammerdam, 1757, p. 122)

NEUROPHYSIOLOGICAL EXPERIMENTATION DURING THE ENLIGHTENMENT An alternative approach to the mechanistic tendency prevalent in Cartesianism was the vitalist position on “irritability.” It was chiefly formulated by the famous exponent of Harveian physiology and Cambridge physics professor, Francis Glisson (1597–1677), who wanted to rebut the concepts of a propulsion of particles, fluids, or vibrations in the nerve tubes, which he saw as intrinsically incapable of explaining living phenomena (Frank, 1980, pp. 22f.). In 1677, as published in the Tractatus de Ventriculo et Intestinis, he hypothesized that, due to the mechanical theory of nerve action, a larger quantity of water in a closed glass tube must be transferred through the inflow of nervous spirits into his arm, when sticking his extremity into the only open end of the tube and flexing the muscles. When he conducted this experiment, however, he found neither a decrease nor an augmentation of the water volume. And in his 1677 stimulation experiments on frogs, Glisson noted a ubiquitous capacity for what he called irritability – the specific property of living tissue either to transfer a stimulus to extended parts of

THE HISTORY OF NEUROLOGY 135 the body or to contract in response to mechanical and electrical stimulation (Clarke, 1968, pp. 123–126). On the whole, Glisson saw the Cartesian position as incapable of explaining the lively physiological reactions that generated muscle contraction and glandular excretion. Instead, he defended the idea of the fiber as the main constitutive element of the solid body parts – including the nervous system. However, no proper fibril theory of physiological action had been established before Glisson. According to his model, the fiber was the morphological unit for most of the bodily parts and irritability was its physiological property. Without the influence of these qualities, the bodily fibers would be in constant rest (as in sleep) or in unchanging movement (such as in fits or cramps) (Brown, 1968, pp. 50–57; Duchesneau, 1982, pp. 141–170). With the help of elaborate animal experiments conducted by the Swiss-German naturalist Albrecht von Haller (1708–1777), the observable actions at the physiological workbench, such as those described by Glisson, were referred back to the morphological organization of living bodies. In fact, von Haller carried out an enormous amount of experimental studies on animals at his university laboratory in Goettingen, especially in the years 1740–1750. He had already started these in the 1730s, but only as incidental or isolated trials before he moved to more elaborate studies, especially of lower animals. And while doing all kinds of investigations in a wide range of animal species, von Haller published a methodological account of experimenting with animals in his four-volume edition, the Mémoires sur la Nature Sensible et Irritable des Parties du Corps Animal (1756–1760). Here, he formally established the methodological rules that were to guide the experimental practice of his pupils. Von Haller was firm as to the value of animal experimentation for the advancement of knowledge in neurophysiology (Steinke, 2005, p. 141). With a view to his observational practice in clinical patients, he played down the invasiveness and artificiality of the animal experiment: The experiments, which I have the honour to present to you, have almost only required the effort of looking. Nature has offered herself to the physician, she has not made him to buy her favors. (von Haller, 1756, Vol. 1, p. i, transl. F.S.) With regard to the anatomical findings in the human brain and spinal cord, von Haller did not deny great structural differences between humans and beasts. But he emphasized instead the many physiological and finer morphological similarities. In the animal experiments, brutes felt lesions of their nerves as much as humans, and intoxicated animals stumbled just as do

136 F.W. STAHNISCH drunken men. So it was highly likely that their nervous siology of the living body, von Haller was convinced systems displayed a similar structure: that nature was determined by fixed universal laws. The basic notion which was in harmony with von Haller’s Whatever is of a more subtle kind, is wholly of physico-theological view held that the complex structhe same structure [fabrica] in various quadruture of the world was created by God. Research, includpeds. But the larger and rougher parts vary ing animal experimentation, thus had a theological accordingly to the duties [munera] that the element and was further approved by God, insofar as creator has assigned to each species of aniit served the betterment of mankind (Steinke, 2005, mals. (von Haller, 1757, Vol. 1, p. ix, transl. F.S.) pp. 189–192). In the mid-18th century, von Haller was drawn into a In this context, William Paley (1743–1805) sought prolonged debate with the Scottish anatomist Robert to popularize neurophysiology in his 1802 treatise on Whytt (1714–1766) on the nature of irritability, sensiNatural Theology, where he related differences bility, and the possible seat of the conscious soul – between man and beast to the material organization whether the latter was to reside in the brain or was of sensibility and irritability in the living body to be seen as dispersed over the whole body. In (Nuovo, 1992, pp. 14–16). Paley argued that if his conone of the first handbooks devoted exclusively to temporaries were to contemplate a pocket watch, they the area of clinical neurology – the Observation on would be forced to accept the idea that its designed the Nature, Causes, and Cure of those Disorders complexity enabled it to function. In fact, in his NatWhich Have Been Commonly Called Nervous, ural Theology, Paley gives various accounts of the Hypochondriac, or Hysteric (1765) – Whytt gave morphological structure of animal species, but then his opinion that some involuntary but coordinated attributes these to the generative power of a Deity. motions could exist in the animal body. Vis-à-vis For him, no animal could have contrived its own limbs his experiments in the decapitated frog, Whytt saw and senses, nor could it have been the author of the the body preserving design itself to which it was constructed. Thus, one of Paley’s central assumptions that he shared with the power of motion for above an hour; when its Haller was that physiological functions proved the hind feet or toes are cut, or otherwise hurt, the presence of a designing intelligence. Paley found the muscles of its thighs, legs, and trunk are strongly proof for the unity of the Deity in “the uniformity contracted, by which it raises its body from the of plan observable in the universe,” when he considtable, and sometimes moves from one place to ered the resemblance of “all large terrestrial animals” another. (Whytt, 1766, p. 159) in the morphological structure of their bodies (Paley, He further extended these experiments to snakes and 1802, pp. 470–472). Hence, similar considerations tortoises, which seemed likewise to withstand decapihad to be taken into account for all living beings, tation and display normal physiological functioning in prompting more debates over the relationship between their trunks. In contrast, von Haller argued that it was natural philosophy and religious doctrines (Eddy and the fundamental property of muscle to be irritable, Knight, 2005, pp. 231–248). and that nerves could only be regarded as sensible At the same time, while debate raged furiously over to stimulation, yet that they would not display a disthe general scientific frustration with existing theories position of irritability. Von Haller himself favored of nerve action, another natural element came into the ascription of physiological properties to various the focus of natural philosophers, including brain types of anatomical structures in the living body, researchers. During the latter half of the 18th century, without taking refuge in the traditional extended they asked whether the nervous system might work corporeal soul, or to Whytt’s doctrine of intrinsic by electricity. The outstanding researcher, who took “sympathy” between such nerves that lay in anatomiup the fluido elettrico of the nervous system in the cal proximity or pertained to comparable systems in 1770s as his main object for investigation, was the anathe human and the animal body (cf., Wright, 1990, tomist and physiologist Luigi Galvani (1737–1798) of pp. 261–273). Bologna. Between 1772 and 1774, he set out to give Von Haller’s views on the irritability of muscles and numerous presentations in Italy and abroad addressing the sensibility of nerves set the tone for further conmuscle action in frogs and the calming effect of ceptual developments in neurophysiology, and his opiates on the “irritability” of the nervous system sophisticated investigation of frogs developed into the (Brazier, 1984, pp. 191–194). His frog work indeed gold standard of animal experimentation for more than followed notable scientific studies by other physiolohalf a century. By concluding that animal experiments are gists (e.g., John Walsh, 1725–1795, and John Hunter, a valid method to gain innovative knowledge of the phy1728–1793).

ANIMAL EXPERIMENTATION IN Most of Galvani’s basic experiments were conducted in the 1780s, and they provided a foundation for his most important writings in neurophysiology. They were subsequently published with important new observations and theories on animal physiology in his De Viribus Electricitatis in Motu Musculari, (1791a). Special machines for the generation and storage of electricity, such as the Leyden Jar, were used in these experiments. They had become available since the middle of the 18th century, and had been introduced into many clinical and laboratory contexts (Dorsman and Crommelin, 1957, pp. 275–280). Much of Galvani’s animal experimentation – as was quite paradigmatic for this period – took place at his home, where he stored the majority of his electrical instruments. While his assistants were once amusing themselves with one of his electrical devices, he noticed for the first time that the apparatus had thrown a spark precisely at the time when touching the frog’s leg muscle with a piece of metal made it twitch. When he later tried to reproduce the experiment by tapping the nerve with a scalpel, excluding any involvement with the electrical machines, Galvani could not evoke any contractions in the muscle. He therefore concluded that electricity had been conveyed through the human body and that the spark was responsible for triggering intrinsic animal electricity in the nerves (Finger, 2000, pp. 109–111). His experiments led to the well-known debate with the Pavian physics professor Alessandro Volta (1745– 1827), who heavily questioned Galvani’s assumption of intrinsic “animal electricity” in living bodies. Instead, Volta contended that his findings could be explained by the use of dissimilar metals as a source for elettricità metallica in the foregoing experiments (Bresadola and Piccolino, 2003, pp. 381–391). By the time of this debate, the frog had entered the stage of animal research as the most common object for research in neurophysiology. Of all the animals available for the study of specific problems in electric nerve conduction, the frog appeared especially suited as a simplified, more accessible version of larger animals – in particular mammals – and was also the favorite research animal for Galvani, who later went on to diversify in experimenting with sheep and also with patients in his medical practice. Out of this debate, there resulted new experiments by Galvani with his nephew Giovanni Aldini (1762– 1834), who had already assisted him for some time. They showed that muscle contractions could be produced if nerve-muscle preparations were touched with merely one piece of metal, and they went on to apply their basic findings to various areas of clinical neurology, such as paralyses, epilepsy, and muscle cramps.

THE HISTORY OF NEUROLOGY 137 After Galvani’s death in 1798, Aldini became professor of physics at Bologna, and ventured further into human neurophysiology. To this end, Aldini procured the cadavers of recently executed criminals to see whether, with the help of Volta’s bimetallic pile, he could evoke the same phenomena in dismembered human bodies, as he had previously found in the frog experiments when applying electric currents (Aldini, 1803, p. 83). These spectacular experiments made a strong and enduring impression on his scientific contemporaries, who understood them in terms of a reanimation approach with the help of galvanic currents. Aldini also hoped to improve knowledge of neurological disorders, such as epilepsy, by better understanding human electrophysiology, following the program of Galvani (1791b, pp. 9–41). Aldini correspondingly treated some of his patients who had nervous and mental disorders, and in some cases reported a complete rehabilitation of their problems following the transcranial administration of electric currents. In so doing, he helped popularize electrotherapy, which had roots back in the 1740s and would further continue into the 19th century (Parrent, 2004, p. 576). As noted, in addition to neurophysiologic observations on Ranus ranae, from which an array of conceptual advances could be established throughout the 18th century, electric fish had helped to set the tone for much innovative neuroscientific research. In fact, Galvani had himself experimented with electric fish, and Volta used them as a biological model for his battery. Since the 1770s, the electric eel, Gymnotus electricus, and the torpedo, Torpedo marmorata, had been intensively studied in England, France, Italy, and in other parts of Europe (Dierig, 2000, pp. 6f.). Notably, John Walsh and the anatomist John Hunter had investigated their electric organs and their muscular systems by physiological experiments and anatomical dissections, respectively (Hunter, 1773; Walsh, 1773). There was little doubt by the start of the 19th century that fish could produce electricity. However, it was one thing to say that certain unusual fish produced electricity, and quite another to argue that frogs, farm animals, or even humans possessed the same characteristics. Nevertheless, the experimental attraction of electric fish developed into an enduring obsession with the phenomena of electricity and electrical forces during the Enlightenment, which expanded from natural philosophy well into a more modern neurophysiology. At the same time as others were developing electric fluid theories, Viennese physician Franz Anton Mesmer (1734–1815) presented an arcane theory in which he postulated the existence of an invisible fluid, calling it “animal gravity” and later “animal magnetism” in his Mémoire

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sur la Découverte du Magnétisme Animal (1779). He maintained that it acted upon all living organisms. Mesmer related these forces to electricity and used his theory to produce medical cures. He claimed, for example, that he could redirect the force to remove obstructions in the nerves and the body, and after he left Austria he became famous for his curative séances in the bourgeois circles of Paris (Schott, 1982, pp. 198–207). Even after Mesmer’s death, the preoccupation with invisible forces and the phenomena of electrical transduction continued to be widely discussed in learned societies all over Europe. Alexander von Humboldt (1769–1859) and Emil Du Bois-Reymond (1818–1896), for instance, kept on seeking to clarify electrical phenomena in living organisms in the early period of industrialization (Dierig, 2000, pp. 7f.).

ANIMAL EXPERIMENTATION THROUGHOUT THE 19TH CENTURY During the first half of the 19th century, the study of bioelectricity was revived by an innovative school of experimental physiologists, still committed to using frogs as their pet subjects (Holmes, 1993, pp. 319–323). Carlo Matteucci’s (1811–1868) “rheoscope,” which relied on isolated frog nerve-muscle preparations, was considered as the most sensitive measuring device for galvanic currents. With it, the central figure of German “physical physiologists,” Emil Du Bois-Reymond, showed that nerves possess a potential across their membranes that gives rise to transient electrical changes (Lenoir, 1982, pp. 27–35). He particularly appreciated the frog’s “enormous ability to survive” under laboratory conditions (Du Bois-Reymond, 1851, p. 37). At this time, the electrical potential between the surface of a nerve tract and a muscle section became quite literally known as the Froschstrom (Trumpler, 1992, p. 98). Du Bois-Reymond, a Berlin physiology professor, was privileged, but also in some ways prototypical for an experimental investigator in the 19th century (Coleman and Holmes, 1988, pp. 8f.): He began his experiments in his parents’ home and then continued in a small one-room laboratory at the university institute for philosophy, before being able to open his first provisional institute for experimental physiology. All these workshops lacked space, so frogs were given priority over domestic animals, as they could easily be transported in sackfuls to the physiological laboratory and stored in small terrariums (Dierig, 2000, pp. 9f.). Animals had now begun to be used in large numbers for investigations of brain and spinal cord localization. This area of study was stimulated by Pierre Flourens (1794–1867), who did stimulation and lesion studies on animals; the latter damaging the cerebral and cerebellar

cortexes of pigeons, cats, and other animals and observing their behaviors (Neuburger, 1981, pp. 295–299). Flourens’ experimental findings in his Recherches Expérimentales sur les Propriétés et les Fonctions du Système Nerveux dans les Animaux Vertébrés (1824) opposed the observational studies of the organologists/ phrenologists, namely Franz Joseph Gall (1758–1728) and Caspar Spurzheim (1776–1832), who did not place great faith in the evidence provided by cerebral lesions in humans or animals. They cited problems with survival, infection, and testability – all of which seemed to make lesion data suspect (cf., Gall and Spurzheim, 1809). Yet Flourens, like many other early experimental physiologists (such as Julien Legallois, 1770–1840, and Henry Dutrochet, 1776–1847), recognized the power of experiments and generalized freely from his animal studies to humans (Hagner, 2000, pp. 114–117). Ultimately he concluded that the functional strength of the human cortex was expressed by its bulk and many ascending and descending fibers, in contrast to the localization of specific cortical faculties claimed by the phrenologists. An increasing pragmatism to solve the problems of vital function in neurophysiology led to further changes and developments in 19th-century surgery and medicine (Elliott, 1987, pp. 48–50): Franc¸ois Magendie (1783–1855), who became the first physiology professor at the College  de France, and Claude Bernard (1813–1878), both compared patho-anatomical changes to observable clinical traits, emphasizing the functional and dynamic phenomena of health and disease (Cranefield, 1972, pp. 46–51). By 1822, Magendie had made the striking observation that the anterior and posterior roots of the nerves that arise in the spinal cord have different functions, that the posterior appear particularly intended for sensibility, whereas the anterior appear more particularly connected with movement. (Magendie, 1822, pp. 276–279, transl. F.S.) He had arrived at this conclusion by performing operations on six-week-old puppies (Stahnisch, 2003, pp. 11f.), which helped to establish one of the basic laws of modern neuroscience, one still bearing his name along with that of the famous British anatomist and surgeon Charles Bell (1774–1842). The clinical orientation of Magendie’s animal experiments was already apparent in his early investigations on the neurophysiology of vomiting (Magendie, 1813, pp. 244–248) and of heat regulation and absorption (Magendie, 1821, pp. 18–23), which he conducted on army horses in close collaboration with the veterinary professors at the E´cole Ve´te´rinaire d’Alfort. And apart from his well-known experiments on nerve

ANIMAL EXPERIMENTATION IN reflex action and descriptions of plant and animal poisoning on the nervous system, Magendie, in his Recherches sur le Liquide Céphalo-Rachidien (1842), also engaged in the analysis of cerebrospinal fluid in the brains and spinal cords of cats and young hares. His goal was to try to simulate, using animals, the disease conditions observed in hydrocephaly, in rabies, and in various psychiatric disorders (Stahnisch, 2008, pp. 175–179). Together with his close collaborator Claude Bernard (Bernard, 1850–1860, pp. 1–35), Magendie managed to carry out abundant animal experiments sheltered in a cramped room under the staircase of the College de France, relying chiefly on domestic animals, such as puppies, rabbits, cats, and pigeons from the Parisian street markets (Stahnisch, 2003, pp. 148–150, 161–172). Magendie’s reputation was, however, harmed after the French writer Honore´ de Balzac (1799–1850) ascribed “sardonic laughter” to the main figure, Dr. Maugredie, in his novel, La Peau de Chagrin (1831). He presented the Parisian experimental physiologist as a distinguished intellect, but also as very skeptical and only believing in the action of the scalpel (de Balzac, 1831, pp. 157–161). Balzac saw Magendie and his peers as a group of heartless scientists with no respect for the suffering of their animal subjects. The impact of the broad anti-vivisectionist movement in France was likewise felt by Bernard (Westacott, 1949, pp. 167–169). Also a highly successful experimenter – with numerous contributions to nerve reflex action (Bernard, 1847, pp. 79–81), to brainderived diabetes (Bernard, 1849, pp. 49–51), and to the functioning of the abdominal nervous system (Bernard, 1852, pp. 472–475) – Bernard was repeatedly attacked by the anti-vivisectionists. For example, he was assailed by an American Quaker who eventually entered his college laboratory and tried to discourage Bernard from what he viewed as a thoroughly cruel attitude toward animals. The Quaker was not convinced that animal experiments were necessary for future progress in medicine, and this episode, apart from its parallel rhetorical function in the disciplinary narrative of experimental medicine, reflected a growing cultural gulf between scientific and public sentiments. This was a time when vivisection experiments resulted in massive bleedings and anesthetics were just being discovered, still being uncommon in laboratory experimentation (Sechzer, 1983, pp. 5–12). The use of animals by physiologists faced many drawbacks and unforeseen reactions, above and beyond convincing their clinical peers of the utility of the approach. Vivisection thus had varying meanings in different historical contexts; as, for instance, the British circumstances were socially determined by

THE HISTORY OF NEUROLOGY 139 upper-class Victorian sentiments regarding living beings, as well as philanthropic sensitivities (Westacott, 1949, pp. 130–136). This attitude was not as pervasive in other European countries and it led to the unique British inspection system on animal experimentation at the time, a development that was strongly supported by the Cruelty to Animals Act of 1876 (Troehler and Maehle, 1988, p. 169). There were, however, a number of vocal medical protagonists, who entered the scene arguing for the use of animals in experimentation, by explaining their objectives and denying any cruelty. This is evident in the mutual article of the London surgeon and pathologist James Paget (1814–1899), the anatomist and natural historian Richard Owen (1804–1892), and the president of the British Neurological Society Samuel Wilks (1824–1911) in Vivisection: its Pains and its Uses (1881). It can also be seen in the work of the pathologist and first medical health officer to the City of London, John Simon (1816–1904), author of Experiments on Life, as Fundamental to the Science of Preventive Medicine (1882). The French context, in contrast, proved to be more influenced by the high importance and the breath-taking advances in clinical medicine and in the practice of pathology. Experimental physiology thus had to prove its thrust as a new medical discipline with regard to those other well-established and highly developed fields of scientific medicine (Rupke, 1987, pp. 5f.). Dissatisfaction was also palpable within the discipline of experimental physiology, fostered by growing national rivalries between the most scientifically advanced nations. This is particularly apparent in the works of the great Berlin anatomist and physiologist Johannes Mueller (1801–1858), who was disquieted by the “completely doubtful and uncertain results” of Magendie’s investigations (Mueller, 1824, pp. 114f., transl. F.S.). In 1824, Mueller began to reproduce the experiments on the spinal nerves using young rabbits, but at first his experiments delivered inconclusive results, and he was uncomfortable with the use of mammals, such as rabbits, for these investigations. Later, Mueller “came upon the happy thought to apply frogs to the controversial experiments, animals whose life is so tenacious that they long survived the opening of the spinal cord” (Mueller, 1824, p. 115, transl. F.S.). Mueller shied away from experiments on mammals after this (Holmes, 1993, pp. 321f.). When laboratories and experimental paradigms further improved, other factors became more important, such as standards, the application of new vivisectional techniques, and the deliberate manipulation of natural processes. These developments are not only apparent in the works of the later French physiologists, such as Charles-E´duard Brown-Se´quard (1817–1894),

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but marked a new tradition within the German “physical school” of Carl Ludwig (1816–1895) and Hermann von Helmholtz (1821–1894) (for further reading into their neurophysiology see: Finger and Wade, 2002, esp. pp. 234f. and 250f.), the British experimenters Michael Foster (1836–1907) and William Richard Gowers (1845–1915), and the young American neurophysiologists Henry Newell Martin (1848–1893) and Henry P. Bowditch (1840–1911). It was, of course, debated whether the approach to morbid anatomy championed since Marie Franc¸ois Xavier Bichat (1771–1802) in his Anatomie Générale of 1801 and Jean-Baptiste Bouillaud (1796–1881) from the Recherches expérimentales sur les fonctions du cerveau (1830) was less productive than the new tradition of experimental physiology. Most American and British doctors migrating to Paris evidently regarded pathological observations and animal experimentation on roughly equal grounds (Maulitz, 1987, 9f.). And it is probably only with regard to specific neurological questions that priority was given to one type of experimentation, for example as is apparent in Bichat’s pathophysiological experiments on the role of carotid blood supply for brain function in cats and in dogs (cf., Albury, 1977, pp. 50–58), or the post-mortem observations of Paul Pierre Broca (1824–1880) – as in Du siège de la faculté du langage (1865). The Paris school(s) of scientific medicine thus gave birth to an interrelated methodology, in which clinicopathologic observations were further subjected to the proofs of the animal laboratory. In this regard, Claude Bernard’s words are notable: that the hospital [is] the antechamber of medicine, it is the first place where the physician makes his observations. But the laboratory is the temple of the science of medicine. (Bernard, 1856, p. 209, transl. F.S.) This development is also apparent in the mutual electrophysiologic observations of Jean-Martin Charcot (1825–1893) and Guillaume Benjamin Duchenne de Boulogne (1806–1875), as reflected in the Paralysie pseudo-hypertrophique (Charcot, 1871), or De l’Électrisation Localisée et son Application à la Pathologie et à la Thérapeutique (Duchenne de Boulogne, 1872), as well as in Brown-Se´quard’s neural ablation experiments on amphibians and tortoises (Brown-Se´quard, 1851, pp. 476f.). When working with different animals, such as pigeons, guinea pigs, and dogs, BrownSe´quard found that well-defined lesions of the cortical layer often held no consistent neurological outcome. In his experiments, he observed a wide range of different behaviors, including ipsilateral and contralateral motor responses from poking, and abnormalities after

destroying various brain areas. Brown-Se´quard’s neurophysiologic assumptions distinguished closely between paralyses and so-called pseudoparalyses (Goetz, 2000, pp. 1841f.), which he saw as not always in line with the data from other species or from earlier experiments. In principle, Brown-Se´quard believed that the great variety of these findings would refute cortical localization theory, so while giving a lecture in 1874 in Boston, titled “On Localization of Functions of the Brain” he boldly proclaimed: The character of symptoms in brain diseases is not in the least dependent on the seat of the lesions, so that a lesion of the same point may produce a great variety of symptoms, while on the other hand, the same symptoms may be due to the most various of lesions, various not only as regards the kind, but also the location of organic change. (Brown-Se´quard, 1875, p. 123)

OF FROGS, MICE, AND RATS By the end of the 19th century, a growing need was felt for the use of higher mammals for laboratory purposes, largely because they would serve as better models for the understanding of human physiology, pathology, and behavior (Holmes, 1993, p. 327). Most famously, in the 1890s, the Russian physiologist Ivan Petrovitsch Pavlov (1849–1936) used dogs and rabbits in his psychophysiologic conditioning experiments, when he investigated their reflex-like behavior to changes in external circumstances and when his associates performed brain lesion experiments in his factory style laboratory (Todes, 1997, pp. 220–228). Similarly, the German psychiatrist Hans Berger (1873– 1941) started off his basic encephalographic experiments in Jena around 1900 with rats and in dogs. As a “conservative psychiatrist,” he only attempted to apply his new brain-recording device 20 years later to the patients on his psychiatric wards. He did not aim at recording just the continuous changes in the electrical activity of the brain (Borck, 2005, pp. 43–58), but understood the EEG-trials with the string galvanometer during the summer of 1924 as the late realization of a “plan, which I have cherished over 20 years that the device would develop into some kind of cerebroscope [Hirnspiegel]: the creation of the electroencephalogram!” (Berger, 1924, p. 164). This undertaking could only be realized when Berger eschewed his moral sentiments with regard to clinical trials and transferred the measuring device to the psychiatric patients on his wards. With hindsight, Flourens’ work had previously marked the beginning of systematic animal experimentation

ANIMAL EXPERIMENTATION IN THE HISTORY OF NEUROLOGY in neurophysiology (see the experimental approaches in Flourens, 1824). This program later diversified its approaches in the laboratory animals used and in the application to human neurology (Neuburger, 1981, pp. 295–299). The tradition led to Gustav Theodor Fritsch’s (1838–1927) and Eduard Hitzig’s (1838–1907) cortical electrophysiological stimulation work in dogs and eels Ueber die elektrische Erregbarkeit des Grosshirns (Fritsch and Hitzig, 1870), Hermann Munk’s (1839–1912) and Friedrich Goltz’s (1834–1902) ablation experiments on the dog’s cerebral cortex (Munk, 1878, pp. 162–178; Goltz, 1882, pp. 579f.), David Ferrier’s (1843–1928) cortical mappings in monkeys (Ferrier, 1875, pp. 409–421), Charles Sherrington’s (1857–1952) famous stimulation studies on the cortex of monkeys and apes (Sherrington and Gruenbaum, 1903/1904, pp. 152–155), and Karl S. Lashley’s (1890–1958) lesion experiments on rats for the localization of mechanisms of vision (Lashley, 1931, pp. 419–432). It is evident that some investigators conducted their work explicitly in opposition to cerebral localization, some accepted the doctrine, and still others believed in a watered-down version of this neurological theory. From the sheer number of animal experiments and the growing need to conduct vivisectional studies in higher apes and monkeys, it is evident that a major change had occurred in the laboratories of contemporary neurophysiologists. With the advent of asepsis and antiseptics in general surgery, it was now possible to keep the laboratory animals alive for ever longer periods of time (Guerrini, 2003, pp. 117f.). Especially in the case of Ferrier and his surgical colleague Gerald Yeo (1845–1909), this had become crucial, as they were able to study even healthy monkeys – operated on a month earlier – without the animals developing meningoencephalitis from that surgery. In fact, London anti-vivisectionists were outraged by what they saw as Ferrier’s vicious operational procedures. After the British Medical Journal had published a report on 20 August 1881 of the International Medical Congress of the same year, writing that the members had demonstrated two monkeys which had been operated upon by Ferrier and Yeo, the anti-vivisectionist Victoria Street Society started a fierce campaign against the neurophysiologists (Westacott, 1949, pp. 135f.). Their trial took place on 17 November 1881: Leading members of the International Medical Congress made use of this platform and emphatically stressed the essential need for animal research in the advancement of modern medicine and neurology, and argued that animal research saved lives (Finger, 2000, p. 169). These protagonists of experimental physiology had come to understand that the anti-vivisectionists clearly sought to put an end to experimental medicine.

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The anti-vivisectionist Victoria Street Society, led by Ms. Frances Power Cobbe (1822–1904), had kept on pushing the government to pass ever stronger animalprotection laws (Cobbe, 1894, p. 98). Indeed, Cobbe was steadfast in her actions for the total abolition of animal research and tried to win over Parliament. Her efforts eventually led to the British Cruelty to Animals Act, under which laboratory experimenters had to be licensed each year by the government. While showing that their work was directed to the saving or prolonging of human life, it had also to be clear that it strictly observed basic rules to minimize pain. There would be severe penalties if laboratory animals were abused. These lines of debate had already been present in the Ferrier lawsuit, when the supporters presented the cases of several patients, who as they claimed had been explicitly saved by neurosurgery due to the cortical mappings developed by Ferrier and his co-workers. With this new knowledge derived from animal experimentation, surgeons could now feel more comfortable when they conducted brain surgery, because they were no longer constrained to merely rely on clinical signs and symptoms. A further letter of public support in favor of Ferrier – probably written by his friend, the Victorian psychiatrist James Crichton Brown (1840–1938) – appeared in The Times three years after the Ferrier trial on 16 December 1884, clearly stating the impact of animal neurophysiology on the practice of brain surgery: Sir, While the Bishop of Oxford and professor Ruskin were [. . .] denouncing vivisection at Oxford last Tuesday afternoon there sat at one of the windows of the Hospital for Epilepsy and Paralysis [. . .] a man who could have spoken a really pertinent word upon the subject, and told the right rev. prelate and great art critic that he owed his life . . . to some of these experiments on living animals [. . .], for it is of an unique description, and inaugurates a new era in cerebral surgery. (cit. after Finger, 2000, p. 173) These sentiments persisted and are evident in the case of the Edinburgh neurophysiologist Edward Albert Sharpey-Schaefer (1850–1935) on cerebral localization and neurotransmission – e.g., in his Experiments on the paths taken by volitional impulses passing from the cerebral cortex (1910). Schaefer was especially attacked by anti-vivisectionists for the fact that some of his life-saving experimental results were derived from dog experiments, in which some animals had been drowned to study the effects of resuscitation (Sparrow and Finger, 2001, p. 44). Yet fears ran high in the emotional and political atmosphere of these days, especially among members of the working class, who were scared that Schaefer would want to use

142 F.W. STAHNISCH human subjects to refine his research. At the Royal Fridtjof Nansen (1861–1930) and the German-American Commission on Vivisection, which was instituted after neurobiologist Jacques Loeb (1859–1924) (see Jahn, the so-called “Brown Dog Riots,” Schaefer justified his 2000, p. 230). research at the University College of London by claimWhat became possible through the creation of simiing that only with the help of fatal animal experiments lar marine laboratories was paralleled by a growing had he been able to discover “a more fruitful method number and expansion of metropolitan zoos. Among of resuscitating the drowned” (Schaefer cit. after the most notable were those in Paris, London, and Landsbury, 1985, p. 61). Berlin. As envisaged by naturalists, such as Alfred This whole research tradition, which shed so much Brehm (1829–1884) with regard to the zoological park light on clinical neurology, effectively began with in Hamburg, they held an important tradition of close motoric studies, evolved to include sensory functions, collaboration between naturalists and applied researchand slowly focused more and more on executive funcers, evident since the days of Georges Cuvier (1769– tions, such as memory, attention, and personality. With 1832) and Xavier Bichat (Rothfels, 2002, pp. 23–47). the further elaboration of comparative anatomy and However, particularly beginning with Karl Lashley’s the introduction of evolutionary concepts into the experimental program on the cerebral cortex (Lashley, fields of neuromorphology and neurophysiology in 1931, pp. 419–432) – one that focused on vision, learnthe late-19th century, experimental neurophysiologists ing, and memory – rodents seemingly replaced frogs oriented themselves ever closer to humans as their cenas animal models of choice in many laboratories. tral reference point (Paton, 1984, pp. 17f.). Yet for Progress in behavioral testing, other experimental some lines of research, the frog still continued to be techniques, biostatistical approaches and the preservathe animal of choice, or as Bernard had emphasized: tion and evaluation of healthy and damaged brains “No other animal has been used for greater or more also led to new discoveries (e.g., Witkowski, 1986, numerous discoveries, at all points in science; and pp. 149–159). One landmark was Clarence Cook Little’s even today, physiology without frogs would be impos(1888–1971) creation of the first inbred mouse strain sible” (Bernard, 1865, p. 115). It is startling to see with “dba” in 1909 (Castle and Little, 1909, pp. 313). hindsight that the mouse and the rat were still little Before the availability of genetically “identical” used at the end of the 19th century. mice, scientists could not tell whether their results Around 1900, however, a new paradigm developed were brought about by random genetic shift or by in animal experimentation, which paralleled further deliberate experimental manipulation. The introducspecialization in experimental physiology. It was the tion of the Little mouse presented geneticists with a sudden advancement of experimental biology, comkind of “living test tube” for laboratory work, and mencing with Anton Dohrn’s (1840–1909) newly for the early neurogeneticists, such as William Ernest built Stazione Zoologica in Naples (Heuss, 1991, Castle (1867–1962), who investigated movement disorpp. 153–158). It created a huge supply of all kinds of ders in the mouse model (Castle, 1944, pp. 226–230), different laboratory animals and fostered knowledge and Ernest Edward Tyzzer (1875–1965), who studied about the differences in comparative anatomy of the brain tumors in inbred mice (Little and Tyzzer, 1916, various species with regard to their possible uses in p. 393), these developments seemed to make mice experimentation. The Stazione Zoologica soon began ideal for the investigation of hereditary neurological to serve as a central knot in a huge network of experidiseases, as well as the study of cancer (Little, 1960, mental investigators as well as research institutions pp. 1469–1471). from all over Europe and America. The Naples station In fact, cancer and mice became inseparable for even served as a model for “big science” in experimenLittle and his co-workers in the ensuing decades. The tal biology, and was adopted on the other side of the study of cancer genetics in mice and the hope for betAtlantic, for example, in the creation of Cold Spring ter treatment options preoccupied not only this particuHarbor Marine Station (Fangerau and Mueller, 2005, lar group, but soon became a national priority, when pp. 211–215). US President Richard Nixon (1913–1994) formally Dohrn’s research center provided the basis for established his program for a “War on Cancer” in numerous comparative studies of the nervous system, 1971–1972. It dramatically increased research funding either from morphological or physiological perspectives: to the National Cancer Institute and the biomedical “an aquarium supplemented by a physiological laboraresearch community (Rowan, 1984, p. 170). Together tory,” as Du Bois-Reymond wrote about it in a letter with this political development, mice were reinforced to Dohrn in 1870 (see Groeben and Hierholzer, 1985, as the standard model for the conduct of biomedical p. 5). And the Naples station also attracted hundreds research in the middle of the 20th century (Rader, of scientists, including the Norwegian neuroanatomist 2004, pp. 1f.).

ANIMAL EXPERIMENTATION IN THE HISTORY OF NEUROLOGY 143 maturity, and to compare these findings with humans A VIEW BACK INTO THE 20TH CENTURY and other species (Tocher Clause, 1993, p. 335). The breeding of genetically homogeneous rats and Donaldson’s and others’ programs now included their use in neuroscientific laboratories coalesced with studies on the size and number of neurons and denresearch agendas of various early-20th-century sciendrites, and on chemical changes in the myelin sheaths tists, who viewed the rat as a perfect subject for their of developing and aging nerves. At the same time, needs. At the American Wistar Institute, for example, Donaldson was able to look at behavioral development a group of three scientists had been responsible for and at neurological disorders in specific rat strains. the breeding and distribution of an early prototype of Hence, he addressed clinical issues pertaining to neurogenetically engineered animals (cf., Dallenbach, 1938, degenerative diseases, as well as problems of aging pp. 434–435). The work of the neuroanatomist Henry (Donaldson, 1916, pp. 350–352). Herbert Donaldson (1857–1938) in the United States, As artificial constructs of voluntary human manipulawho had trained with the Italian Nobel Prize winner tion and as biotechnological hybrids, Wistar rats required Camillo Golgi (1844–1926), aimed at establishing a vast more engineering, experimental tinkering, and technoloset of data on mammalian growth and development. gical refinements than earlier subjects used in neurophyMilton J. Greenman (1866–1937), an ambitious siologic investigations (Rader, 2004, pp. 23–27). The scientific administrator who sought an occupational changes occurring in animal experimentation are ever niche in a small research institution, and embryologist more obvious under the circumstances of the “World as Helen Dean King (1869–1955), perceived rats as an ideal Laboratory” today, especially when it comes to newer means to study mammalian genetics. For these researchexperimentation in the neurosciences: the biochemical ers, rodents served various research endeavors, and the manipulation of damaged fiber tracts in rats’ spinal cords Wistar Institute created a new identity for late-19th-cenwith “miracle molecules,” such as the growth factor tury research convictions as well as for a new biotechnoNoGo, is to initiate repair processes in severe spinal logical tradition of the 20th century (Tocher Clause, cord injuries (SCI), otherwise leading to a devastating loss 1993, pp. 335–341). As put by Donaldson: of neurological function below the level of injury or adverse effects in multiple body systems. These new The choice was a fortunate one, as the albino rat is repair strategies are primarily targeted toward acute easy to keep, breeds freely, bears young that are neuroprotection, enhanced axonal regeneration, or the both numerous and immature, and is also respontreatment of demyelization (Blight, 2002, pp. 1051–1053). sive to changes in its environment as well as being Another promising development involves placing easily trained. It would be hard to find another anispinal marrow implants into so-called Robo rats, as a mal that combined so many virtues in so compact means for brain-controlled prosthesis interfaces. Rat– and pleasing a form. (Donaldson, 1909, p. 8) computer hybrids may have positive applications to conThis statement reflects a decisive and ground-breaking ditions of paralyses, severe motor-neuron-diseases, and transition in neuroscientific animal experimentation, other neurodegenerative and traumatic disorders. At from the use of static materials, such as pathological this time, Robo rats provide a relatively inexpensive specimens and cadavers, to the enduring and active and simple means of replacement for large and very manipulation of living organisms. expensive systems currently being used in monkey and Accompanying the move from hypotheses-driven human research (Francis and Chapin, 2006, pp. 172f.). experimentation to distinctly technology-driven tendenThe development of “miracle molecules” and Robo cies in the life sciences (Lenoir, 1998, p. 27), voluntary rats marks an ongoing and sophisticated research variations of traits and phenotypes were studied in the tradition in animal hybridization leading to neurololaboratory through controlled breeding experiments. gical treatment and functional “enhancement” (Lemov, Wistar rats, like “Little mice” previously, enabled neu2005, pp. 197–201). From the start, when rats were roscientific experiments on embryological brain develintroduced to laboratories, the degree to which this speopment, neurogenetics, and neuronal regeneration. cies has been controllable in laboratory experiments is Donaldson, for example, saw himself as a clinical truly astonishing. Subsequent neuroscientists proposed and a basic neurologist, and primarily focused on the that, if they knew the right conditions to administer development and growth of the brain. Although his animal-derived knowledge to humans, they could undertaking, at least at first glance, had looked like a “explain the full range of human behavior and make simple attempt to correlate brain size and weight with it predictable and therefore controllable” (Lemov, intelligence, he became aware that, with the help of 2005, p. 3). the Wistar rats, he was able to deliver specific data Yet, as in the mid-19th century, changed cultural on the growth of the nervous system from birth to values have led to a revival of anti-vivisectionism and a

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new rise of animal rights movements, especially in the US and Great Britain. Similar trends are discernible in the rest of the Western societies, i.e., in laws against cruelty (Troehler and Maehle, 1988, p. 167). In retrospect, various regulations of animal experiments were also introduced in the German states in the 1880s, following anti-vivisectionist agitation. But the level of the former British Cruelty to Animals Act – enforcing the need of licensing and documentation – was again only realized by the German Reichstierschutzgesetz of 1933, being itself subject to major sociopolitical transitions: the celebration of the German woods and animals was a frequent cliche´ in the “blood and soil” literature, which predated many themes of the Nazi movement and established itself in the minds of many party leaders to protect animals from unnecessary cruelty – regardless of the needs and aims of medical science (Sax, 2000, pp. 110–123). As has been pointed out by Franklin (1999), such sentimentalist and political counter-movements to modern culture and scientific medicine can be regarded as social turning points, which have not only brought the issue of animal protection back into ethical and cultural focus, but have paralleled the development of juridical control of biomedical experimentation. Accordingly, it was also the widespread view of a new animal protection movement that led to the passing of the US Congress Animal Welfare Act in 1966. Under the terms of these regulations, the American Department of Agriculture was charged with safeguarding domestic animals from experimental abuse. And since that time, more laws have been passed and animal research has become more and more difficult, restrictive, and, in many instances, prohibitively expensive. The American Foundation for Biomedical Research, which promotes “public understanding and support for humane and responsible animal research,” states that such “research has played a vital role in virtually every major medical advance of the last century and many major developments leading to Nobel Prizes in physiology or medicine involved animal research” (FBR, 2007, pp. 1f.). Still, social and ethical questions about animal research continue to be raised by animal rights groups (Troehler, 2000, pp. 170–174; Guerrini, 2003, pp. 146– 152). And history suggests that these tensions, closely intertwined with specific social and cultural contexts, can have profound effects on neurological as well as basic neuroscience research, and will not abate soon.

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Whytt R (1766). Physiological Essays. 3rd edn. I. Balfour, Edinburgh. Willis T (1664). The Anatomy of the Brain and Nerves (transl. W Feindel, 1964). McGill University Press, Montreal. Willis T (1684). Two Discourses Concerning the Soul of Brutes (transl. S Pordage). Dring, Harper, and Leight, London. Witkowski JA (1986). Ross Harrison and the experimental analysis of nerve growth: the origins of tissue culture. In: British Society for Developmental Biology (Ed.), Symposium (8th): 1983: A History of Embryology. British Society for Developmental Biology, Nottingham, Nottinghamshire, Cambridge, pp. 149–177. Wittern R (1987). Diagnostics in Classical Greek Medicine. In: Y Kawakita (Ed.), History of Diagnostics. Proceedings of the 9th International Symposium on the Comparative History of Medicine – East and West, 23–29 September 1984, in Japan. Taniguchi Foundation, Osaka, pp. 69–89. Wittern R (2004). Die Gegner Andreas Vesals. Ein Beitrag zur Streitkultur des 16. Jahrhunderts. In: F Steger, KP Jankrift (Eds.), Gesundheit – Krankheit. Kulturtransfer medizinischen Wissens von der Spaetantike bis in die Fruehe Neuzeit. Boehlau, Cologne, Vienna, pp. 167–199. Woollam DHM (1958). Concepts of the brain and its functions in classical antiquity. In: MW Perrin (Ed.), The Brain and Its Functions. Blackwell, Oxford, pp. 5–18. Wright JP (1990). Metaphysics and physiology: mind, body and the animal economy in eighteenth-century Scotland. In: MA Stewart (Ed.), Studies in the Philosophy of Scottish Enlightenment. Clarendon Press, Oxford, pp. 251–302. Zehnder E (1969). Franc¸ois Pourfour du Petit (1664–1741) und seine experimentelle Forschung u¨ber das Nervensystem (Zuercher medizingeschichtliche Abhandlungen. New Series). Vol. 60. Juris Press, Zurich.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 12

The anatomical foundations of clinical neurology MARINA BENTIVOGLIO 1 * AND PAOLO MAZZARELLO 2,3 Department of Morphological and Biomedical Sciences, Faculty of Medicine, University of Verona, Verona, Italy 2 Department of Experimental Medicine, University of Pavia, Pavia, Italy 3 Museum for the History of the University of Pavia, Pavia, Italy

1

INTRODUCTION Knowledge of the anatomy of the nervous system is one of the pillars of clinical neurology and a fundamental prerequisite for discoveries of pathogenesis, diagnosis, and therapy of neurological diseases. The long itinerary of this knowledge dates back to antiquity and to the foundations of human anatomy in Ancient Greece, progressing through the evolution of concepts of brain (cerebrum, encephalon) and mind in Aristotle’s, Plato’s, Hippocrates’, and Galen’s doctrines (Finger, 1994, 2000; Swanson, 2000). The first steps of this itinerary, which lasted for a remarkable number of centuries, are dealt with in other chapters of this book. The “encephalocentric” view, deriving from Hippocratic-Galenic doctrines, favored a localization within the brain for cognitive abilities and loci for the origins of movements and sensations. According to the contrasting Aristotelian “cardiocentric” view, psychic functions were instead localized in the heart. The traditional opposition between these doctrines spanned antiquity and the Middle Ages, persisting through the Renaissance and even later. This debate stimulated the anatomical study of the brain. We shall start this journey from the Renaissance explosion in the approach to the human body, its functions, and its diseases. For the interpretation of anatomical studies of the brain, it is worth recalling here the doctrine of “psychic pneuma,” of which Aristotle was considered the founder and which was developed by Galen (Manzoni, 2001). According to this doctrine, inhaled external air becomes a vital spirit in the heart, transported with the blood to a vascular network at the base of the brain, the rete mirabile, a network of very thin blood vessels observed by Galen in ungulates. Vital pneuma becomes psychic

*

pneuma in the rete mirabile, with a final transformation in the brain cavities, the cerebral ventricles, and animal spirits pass then to the nerves, considered as hollow tubes (Finger, 1994, 2000; Manzoni, 1998, 2001). This doctrine had major consequences for neuroanatomy and for the interpretation of neurological illness: attention was focused on brain cavities rather than on the surrounding brain matter and mental and nervous disorders were related to alterations of the psychic pneuma.

ART AND ANATOMY The anatomical revolution of the 16th century, deeply connected to the renewal of visual arts, is at the origin of the modern view of the human body. Anatomical representation per se became a new tool of investigation, a strategy to gain a conceptual order in the chaos of body structures revealed by the increasingly applied direct anatomical dissection. Due to this approach, the boundaries between art and anatomy were ill-defined during the Renaissance, as shown by the fact that painters and sculptors, including Leonardo da Vinci and Michelangelo, attended the dissection rooms frequently, as well as by the “artistic” representation of human body structures in medical texts. The renovation of anatomy in the 16th century was largely due to physicians staying at universities and in the Renaissance Italian courts, where they were infected by the spirit of cultural freedom.

Leonardo da Vinci Leonardo (1452–1519) was especially sensitive to the Renaissance new cultural opening in his approaches to the world and nature. His engagement in the anatomical

Correspondence to: Marina Bentivoglio, Department of Morphological and Biomedical Sciences, Faculty of Medicine, Strada Le Grazie 8, 37134, University of Verona, Verona, Italy. E-mail: [email protected], Tel: +39-045-8027-158, Fax: +39-045-8027-163.

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study of the brain and spinal cord derived from his interest in the nervous origin of muscle movements (Keele, 1963; Gross, 1999). His drawings depicted nervous structures accurately, distancing themselves from traditional

anatomical representations. Stimulated by his experimental attitude, Leonardo injected molten wax into a hole at the base of the skull before removing its vault to preserve the shape of the brain. He

Fig. 12.1. Leonardo’s drawing of the optic nerves and chiasm and of cranial nerves. Weimar, Schloss Museum.

THE ANATOMICAL FOUNDATIONS OF CLINICAL NEUROLOGY 151 could thus obtain a cast of brain cavities, in sharp conseizures, or of weak movements of the head or limbs trast with their classical spherical representations in of paralytic patients. He considered these movements older texts, and showed the existence of two paired latindependent from voluntary control, and therefore eral ventricles. Furthermore, Leonardo studied the crafrom the soul (Keele, 1963). nial nerves (Fig. 12.1), depicting some branches of the trigeminal nerve and noting that they converged into Vesalius and Renaissance neuroanatomy the “median ventricle.” He also investigated the brachial Jacopo Berengario from Carpi (c. 1460–c. 1530), a surplexus, which he related to the origin of shoulder and geon in Bologna and an anatomist who timidly arm movements, and depicted for the first time the viscopposed Galen’s theories, expressed doubts on the exiseral sympathetic chain, as well as the vagal and phrenic tence of the rete mirabile at the cranial base. nerves. Of great relevance are Leonardo’s studies of Berengario did not avert too far from Galenic ideas, the visual pathway (Fig. 12.1): following the nerve from and placed the formation of psychic pneuma into the the eye, he discovered the optic chiasm and could trace small blood vessels of the pia mater. He was probably the optic fibers up to the middle part of the basal brain the first to detect the presence of a fluid in the cerebral surface. In his drawings of the skull, Leonardo depicted ventricles and he considered it a kind of “excrement,” the anterior, middle, and posterior fossae, and the frona residual of the processes used for forming the animal tal sinus, as well as the anterior and middle meningeal spirits. In contrast, physician and surgeon Nicolo` arteries. Massa (1504–1569) claimed to have observed the rete Further, by performing what has been defined as the mirabile, which proved so difficult to visualize that a first neurophysiological experiment after Galen, Leolens in candlelight was needed for this purpose. In nardo observed that frogs survive decapitation for a Massa’s opinion, however, cerebral arteries and the few hours, whereas they die immediately after spinal choroid plexus of the lateral ventricles play more cord transection. He thus formulated the hypothesis that important roles than the rete mirabile in the production the source of life and movement is located in the spinal of animal spirits. cord. Leonardo frequently drew functional hypotheses De Humani Corporis Fabrica Libri Septem (1543) on the basis of morphological observations. Thus, the by Andreas Vesalius (1514–1564), the pioneer of a study of limb muscles gave him the idea of the recipronew “human” neuroanatomy (Finger, 2000), is a main cal and opposite action of agonist and antagonist musturning point in studies on the architecture of the cles, finalized to a coordinated motor action. human body. Written mostly during the seven years Leonardo did not reject the doctrine that had placed of Vesalius’ professorship at the University of Padua, psychic functions in the cerebral ventricles. But he and illustrated with more than 300 plates, mostly commoved the sensorium commune (the collecting site of missioned to professional painters (probably from different sensory modalities, which was also capable Titian’s School), this opus proposed a substantial reviof integrating them in global perception) to the “medsion of the anatomy of the classical texts used in the ian ventricle,” where he had identified the convergence European centers of learning (O’Malley, 1964; Carlino, of cranial nerves. 1999). In particular, Vesalius’ Fabrica included new Leonardo’s studies on sensations and movements knowledge acquired via the direct and systematic dissecled him to conceive the nervous system as an organized tion of the body, which allowed him to correct several ensemble of parts, distinct but integrated in a sensoryof Galen’s mistakes and revealed a novel potential for motor arc, the function of which is far more articuteaching and for scientific research. lated and complex than in Galen’s doctrine. Leonardo Vesalius dedicated two of the seven books composdevised a hierarchical schema, where bone and joints ing the Fabrica to the nervous system: the fourth, dealobey tendons, tendons obey muscles, muscles obey ing with the spinal cord and peripheral nervous system, nerves, and nerves obey the sensorium commune (the and the seventh, which contains magnificent representasite of the soul), which is also a recipient of sensations. tions of the brain and sensory organs. Following a His view of the nervous system as a well-organized scheme of horizontally arranged images, from the vault society led Leonardo to develop some theories on nerto the base of the skull, he was able to differentiate the vous alterations during disease. For example, he prowhite matter from the gray matter and to identify, with posed that the soul is incapable of conceiving the great realism, numerous anatomical structures, such as function of a sensory modality, if this modality were the septum pellucidum, fornix, corpus callosum, cauabsent since birth, as in the case of congenital blinddate nucleus, thalamus (optic thalami), and venous ness. Leonardo also hypothesized that movements can sinuses. In a plate that depicts the basal brain surface be autonomous in certain conditions, as in the case of for the first time, Vesalius illustrated seven pairs of uncontrolled movements of epileptic patients during

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cranial nerves, still following Galen’s classification. In his illustration of the sixth nerve, he represented the sympathetic nerve trunk as a branch emerging from the vagal nerve. This error may be due to the fact that he investigated cadavers of hanged individuals, which were not ideally suited for anatomical details. In his 1538 opus, Tabulae Anatomicae Sex, Vesalius had admitted the existence of the rete mirabile in humans, but he acknowledged his mistake and denied its existence in humans in his later Fabrica. In agreement with Massa, Vesalius pointed to the cerebral arteries and the choroid plexus of the lateral ventricles as important for the production of animal spirits. He mentioned that these structures were thought to play a role in the “refinement” of the animal spirits, but he admitted that he had some doubts about the existence of such entities. In addition, Vesalius denied, in opposition to Galen’s followers, that the cerebral ventricles function as sites for the localization of mental faculties. Parisian anatomist Charles Estienne (1505–1564) also criticized Galen’s theories. In 1545, he published an illustrated volume in which he described the central canal of the spinal cord and the cerebrospinal fluid. Additionally, he differentiated the sympathetic nerve trunk from the pneumogastric nerve. After Vesalius, the main protagonist of the new anatomy during the Renaissance was the physician Gabriele Falloppia (1523–1562), born in Modena and professor at the Universities of Ferrara, Pisa and, from 1551, Padua. In his Observationes Anatomicae, published in 1561, Falloppia identified the innervation of the heart and provided a classification of the cranial nerves, delineating with remarkable precision the courses of the trigeminal, glossopharyngeal and acoustic nerves. He also described the cervical and lumbar enlargements of the spinal cord and traced the origin of the optic nerves close to the colliculi. Falloppia delineated the trajectory of the arteries at the cranial base, including part of the anastomoses belonging to the structure that was later identified as the “polygon of Willis” (see below). Additionally, Costanzo Varolio (Varolius, 1543– 1575), professor of anatomy and surgery at the Universities of Bologna and Rome, concentrated on the anatomical study of the nervous system. He renovated the approach to the examination of the brain by cutting it into slabs, starting from the overturned base instead of its dorsal surface. He could thus appreciate that the brain stem is not an intracranial portion of the spinal cord, but instead is an independent structure. He delineated the brainstem portion rostral to the medulla oblongata that seems to form a “bridge” and called it the “pons” (hence the eponym pons of Varolius), noting its connections with the cerebellum. Furthermore, counter to the dominating opinion at that time, Varolio was able to demonstrate that the optic nerves do not originate from the

anterior extremity of the brain. He also showed that the optic nerves terminate on each side in the thalamus. As for the choroid plexus, Varolio concluded that it is composed of structures that drain excess humidity from the brain and discharge it into the ventricles. He was also probably the first to use the term “cortex,” with which he nevertheless designated the entire thickness of the brain matter surrounding the ventricles. Other important representatives of the Roman anatomical school were: Arcangelo Piccolomini (1525– 1586), who investigated the origin of nerves and the distribution of cortical matter versus “medullary” (myelinated) matter; Bartolomeo Eustachi (1510–1574), a classical scholar of great erudition who studied the fine structure of the nerves; and Realdo Colombo (1510–1559), Vesalius’ student in Padua and professor of anatomy in Pisa and Rome, who criticized the rete mirabile. Mention must also be made of Giulio Cesare Aranzio (c. 1530–1589), who described the canal that connects the third and fourth ventricles (later called aqueduct of Sylvius) and delineated the “hippocampus,” a term that he introduced. Substantial progress in the anatomy of sensory organs was achieved by two anatomists of the University of Padua, Girolamo Fabrizi d’Acquapendente (Fabricius; c. 1533–1619), student of Falloppia, and Giulio Casseri (Casserius, 1552–1616), who was Fabrici’s successor in the chair of surgery. In his Pentaesthesion, Casseri provided in 1609 the first description and illustration of the mammillary bodies, and in his Tabulae Anatomicae, published in 1627, he provided remarkable illustrations of the corpus callosum, thalamus and arteries at the cranial base (Riva et al., 2001). The contributions of Fabricius and Casserius to the neurological sciences were rediscovered in the early-20th century by Giuseppe Sterzi (1876–1919), a professor at the University of Cagliari (Sardinia) and a pioneer in comparative neuroanatomy (Riva et al., 2000).

THOMAS WILLIS AND NEUROANATOMY IN THE 17TH CENTURY During the 17th century, the anatomy of the nervous system gained in importance as a support for physiological studies. Significant neuroanatomical contributions were provided by Franz de Le Boe¨ (Franciscus Sylvius, 1614–1672), the author of studies on the cerebral cortex, whose name remains attached to the “lateral fissure of Sylvius” and the “aqueduct of Sylvius” which, as mentioned above, had already been described by Aranzio. Rene´ Descartes (1596–1650) showed a great interest in the nervous system, and, although not formally trained in anatomy, conducted animal dissections and attended human autopsies, hoping to learn more about the organ of mind (Finger, 1995, 2000, p. 79) in neuroanatomy,

THE ANATOMICAL FOUNDATIONS OF CLINICAL NEUROLOGY 153 which, at that time, was considered largely known. Desas “striatal bodies.” Willis associated motor actions, cartes’ philosophical thinking focused, however, on one but also the senses, with these striped structures. He anatomical structure, the pineal gland (or conarium), that further described various fiber tracts (medial lemnishe believed was capable of tilting, thus influencing the cus, thalamostriatal fibers, thalamocortical projections, dispersion of animal spirits into specific nerves conpathways descending from the cortex and from the nected with the ventricles. In humans, but not animals, striatal bodies) and provided very clear descriptions he designated the pineal body as the seat of the “unitary of the claustrum, internal capsule and cerebral cortex, soul” (res cogitans), an entity that could not be broken identifying for the first time the anterior commissure. down into distinct faculties that might be localized in difWith a remarkable intuition, Willis related the richferent parts of the brain. According to Descartes, the ness and depth of cortical convolutions of the human “unitary soul” has to interact with the physical soma brain with the superiority of human mental faculties (res extensa) in a single, central location; hence, sensory, versus those of animals. Further, he accurately described motor and cognitive functions were tied to the pineal the cranial nerves, from the first to the tenth, on the gland. basis of their foramina of exit from the skull, and he Neuroanatomical and neurophysiological studies defined the ophthalmic branch of the trigeminal nerve, led to further criticisms of Galen’s doctrines. The although he confounded the glossopharyngeal nerve two works of Konrad Viktor Schneider (1614–1680), with the hypoglossal nerve. Willis also added the eleDe Catarrhis (1660–1664) and De Osse Cribriformi venth or spinal accessory nerve and recognized the rela(1655), confuted the theory of phlegm as cerebral tionships of the vagal nerve with the lungs and heart. secretion. In his 1658 Observationes Anatomicae, Willis studied the peripheral nerves using a microJohann Jakob Wepfer (1620–1695) described the cerescope, and reached the conclusion that they are not holbral arteries in detail, identifying the structure later low tubes. His studies on blood vessels also led him to known as the circle of Willis, and further objecting to deny at last the existence of a rete mirabile in humans. the Galenic notion of a rete mirabile in humans. Via injections of alcohol and ink into the internal caroThe protagonist of 17th-century neuroanatomy (see tid artery, he and Lower succeeded in accurately traCh. 8) was Thomas Willis (1621–1675), physician in cing the arterial polygon from which cerebral arteries London and professor of natural philosophy at the Unioriginate, which a century later would be called the versity of Oxford, to whom (in translation) we owe the “circle of Willis” by physician Albrecht von Haller term “neurology.” He was the author of the opus Cer(see below). Willis also investigated the pineal gland, ebri Anatome, cui Accessit Nervorum Descriptio et discarding Descartes’ idea that it is the seat of the soul. Usus (1664), a work entirely dedicated to the central The neuroanatomical opus of Niels Steensen (Stenon, nervous system and peripheral nerves. The first 20 Stensen, or Steno, 1638–1686), Discours sur l’Anatomie, chapters describe the brain and nervous system in gendu Cerveau, published in 1669, focused on methodologieral, whereas the other chapters are dedicated to the cal problems and premature conclusions. Stenon disanatomy and physiology of nerves (Dewhurst, 1982; cussed the difficulties of anatomy, a discipline which Hughes, 1991; O’Connor, 2003). Willis’ work marks a needed, in his opinion, total dedication, and which instead milestone in the progress of neuroanatomy and its faced limitations not only on the part of physicians (who contribution to neurology. had too little time for anatomical studies), but also of proWillis conferred to neuroanatomy the dignity of an fessors of anatomy, who were obliged to follow fixed independent field of investigation, limiting and circumprocedures when performing dissections. On the conscribing for the first time its field of application and trary, anatomical studies needed to be free and not tied deeply revising its nomenclature. Willis made original to pre-established constrictions. and novel anatomical observations on the entire nervous In four plates, Stenon illustrated the brain strucsystem, and his book offered the most complete overtures, painstakingly depicting the relationships of the view of his times on human and comparative brain anatcorpus callosum to the cerebral hemispheres and the omy. These studies were approached even more from a vault of the third ventricle. He pointed out the dorsal neuropathological orientation in his opus Pathologiae position of the pineal gland, describing its shape and Cerebri, published in 1667, and from the point of view showing that it is not mobile, as suggested by Desof physiological psychology in De Anima Brutorum, cartes’ theory of animal spirits – subtle entities about which appeared in 1672. which he was also skeptical. Willis, who collaborated with Richard Lower (1631– Stenon also investigated the relationships between 1691) as a dissector and Christopher Wren (1632–1723) the infundibulum and the hypophysis, discovered the as an illustrator, distinguished the white from the gray so-called interthalamic mass (Grmek and Bernabeo, matter and provided the first precise description of the 1996), and criticized several of the representations of group of nuclei at the base of the brain that he defined cerebral anatomy depicted by Willis. Additionally, he

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made important studies on the muscles, which he described in 1667 as groups of fibers made up of fibrils, differentiating the muscles into “white” and “red” types. These observations took him far from Galen, who had considered muscles as amorphous masses, and anticipated the famous studies of Giovanni Alfonso Borelli (1608–1679) on muscle physiology (De Motu Animalium, 1680–1681). One of the first investigators who successfully applied microscopy to the anatomical investigation of tissues was Marcello Malpighi (1628–1694). In 1665 and 1666 he published four neuroanatomical contributions: De Lingua, De Externo Tactus Organo, De Cerebro and De Cerebri Cortice. In the first, by means of cooking his preparations, Malpighi identified tongue papillae, which he considered as sensory endings of peripheral nervous fibers, reaching thereupon analogous conclusions concerning skin papillae. In De Cerebro, he used the microscope to study the white matter in higher neural centers and singled out numerous fibers and tried to trace their courses. He hypothesized that they originate from the gray matter and believed that they continue within the spinal cord to peripheral

receptors. In De Cerebri Cortice, Malpighi viewed the cerebral cortex as a “porous gland structure” similar to that of the liver, spleen and kidney. The first important study dedicated to the anatomy of the spinal cord was made by Gerard Blasius (1625–1692), who published his Anatome Medullae Spinalis Nervorum in 1666. This author clearly differentiated the spinal gray and white matter, demonstrated the origin of the anterior and posterior spinal roots and depicted for the first time the “H” shape of the gray matter in a transverse section of spinal cord (Naderi et al., 2004). Shortly after Malpighi, Antony van Leeuwenhoek (1632–1723), a Dutchman, applied microscopy to the study of the nervous system, using one-lens optical systems. He aimed at verifying whether nerves, in analogy with blood vessels, are tubular structures suited for the transport of animal spirits, as believed since antiquity. His observations on the dissection of optic nerves from cows and sheep did not reveal canals; the nerves seemed to be composed of filamentous particles interconnected in long chains (Fig. 12.2). The studies of Raymond Vieussens (c. 1641–1715) of Montpellier were of great relevance for understanding

Fig. 12.2. Pioneering findings on the composition of the nerve and on axons. Left: Leeuwenhoek’s drawing of a “small nerve (BCEF),” composed of many “vessels” in which “the lines or strokes denote the cavities or orifices of those vessels. This nerve is surrounded, in part, by five other nerves (GGGGG)” in which only “external coats” are represented (reproduced from van der Loos, 1967). Right: Nerve fibers drawn by Fontana as “primitive nervous cylinders” covered by an “external membrane.” Reproduced from Zanobio (1959).

THE ANATOMICAL FOUNDATIONS OF CLINICAL NEUROLOGY 155 the nervous system. In Neurographia Universalis, which systolic and diastolic) that could compress and release appeared in 1684 and was based on 500 autopsies, Vieusthe brain, so as to push the “nervous fluid” along persens described many structures (e.g., the dura mater, ipheral nerves. These ideas were similar to those elabocentrum ovale, striatal bodies, dentate nucleus of the rated by his contemporary, Giorgio Baglivi (1668– cerebellum, celiac ganglia) and provided descriptions 1707), professor of anatomy at the University of of other structures that had been observed in lesser Rome, and replaced Galen’s theory on active contracdetail. Humphrey Ridley (1653–1708), an Englishman, tion and relaxation of the brain (Manzoni, 1998). Brain was also active at the end of the 17th century. In his book, movements were finally ascribed to arterial pulsations The Anatomy of the Brain, published in 1695, he and to breathing in the early 18th century. described the inferior cerebellar peduncles, the circular In 1739, Swiss anatomist Johann Jacob Huber (1707– sinus or Ridley sinus (the venous ring that encircles the 1778) provided the first accurate representation of the hypophysis), and the dura mater. spinal cord with its roots and subdivisions into columns. Huber’s observations were implemented in 1786 in Paris, by Fe´lix Vicq d’Azir (1748–1794), who THE 18TH CENTURY considered the spinal cord as a cylindrical structure Despite the pioneering neuroanatomical investigations formed by four columnar partitions separated by sulci, of Malpighi and Leeuwenhoek, during the 18th century which contain the white and gray matter, thus accountefforts concentrated on the gross anatomy of the nering for the “H” shape of cross-sections. vous system of humans and animals, due to the very Several other anatomical contributions to the devellow power of resolution of the microscopes and the opment of neurological sciences bloomed in the 18th difficulties in handling and processing the nervous tiscentury. Samuel Thomas Soemmering (1755–1830) classue for microscopic observations. In some instances, sified the cranial nerves in 12 pairs, and described the the results stimulated theoretical speculations, leading substantia nigra and the macula lutea (which he called to the elaboration of ideas that influenced the developlimbus luteus), observing a small oval depression, the ment of neurological sciences. fovea centralis, within the latter structure. In his Opticks, published in 1704, Sir Isaac Newton Antonio Scarpa (1752–1832), professor at the Univer(1642–1727) correctly surmised that the fibers of the sity of Pavia, was the author of Tabulae Nevrologicae, optic nerve arising from each nasal half cross in the which illustrated the course of the glossopharyngeal, chiasm, whereas those of temporal origin extend into vagal, and hypoglossal nerves, and the innervation of the brain on the same side. Newton’s idea helped the heart in humans. Scarpa also provided detailed explain the singleness of binocular vision, as well as descriptions of the peripheral and central nervous sysclinical findings. It was adopted by British oculist John tem. For example, he described the olfactory bulb, the Taylor (1703–1772) and confirmed with the anatomical rootlets of the olfactory nerve and the striae that form studies of Johann Gottfried Zinn (1727–1759) in 1755 the olfactory tract. He also discovered the nasopalatine (Finger, 1994). nerve, demonstrated that spinal ganglia are exclusively The visual pathways were investigated farther by connected with the posterior roots, and showed that Giovanni Santorini (1681–1737), who in 1724 described the thoraco-lumbar sympathetic ganglia establish relathe lateral geniculate body, which he correctly interpreted tionships with the anterior roots. The vestibular ganglion as the site of central termination of the optic nerve. In was named after him (Franceschini, 1963). 1776, Francesco Gennari (1750–1797) identified a stripe Other relevant anatomical contributions to neurolin the occipital cortex, to which his name was then ogy were made by Domenico Mistichelli (1675–1715), attached (Glickstein and Rizzolatti, 1984; Finger, 1994). who described the decussation of fiber tracts in the Progresses in the anatomical foundations of neurolspinal cord and in the pyramids in 1709; by Franc¸ois ogy were achieved in Rome by Antonio Pacchioni Pourfour du Petit (1664–1741), who related the cervical (1665–1726), who described in detail the dura mater sympathetic chain with pupillary motility in 1727; by and provided the first detailed account of the “glanduDomenico Cotugno (1736–1822), who provided seminal lae conglobatae durae meningis humanae” (globous contributions on the cerebrospinal fluid in 1764; and by glands of the human dura mater), the arachnoid granVincenzo Malacarne (1744–1816), who devoted an ulations or villi known as Pacchionian granulations, entire book to the cerebellum, introducing anatomical which he considered as lymph-producing glands terms, such as cerebellar tonsilla, uvula and lingula. (Clarke and O’Malley, 1996). Pacchioni viewed the Emanuel Swedenborg (1688–1772) showed a great meninges as some kind of muscular envelope forming interest in brain anatomy early in his life, although he a contractile apparatus, endowed with the function to practiced dissection only to a limited extent. Inspired generate “oscillating-trembling” movements (almost especially by Willis, Malpighi and Vieussens, he

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reached the conclusion that the nervous system is a hierarchical ensemble, and attributed great functional importance to the cerebral cortex as an organ critical for thought, as well as the site for perceptual and motor functions (Norrving and Sourander, 1989; Gross, 1997, 1999). Swedenborg also anticipated cortical localization, more or less correctly localizing the motor cortex and associating the region anterior to it with “executive” functions. He theorized that the brain is composed of numerous functional units interconnected by fibers. His views, however, only became known at the end of the 19th century, when his seminal works on the brain were found, translated and published. The hypothesis that the brain is composed of different “organs” was also forwarded on purely speculative grounds by Charles Bonnet in his Palingénésie Philosophique, published in 1769. Franz Joseph Gall (1758– 1828) would do the most to promote this concept (see below). In opposition to such thinking, Albrecht von Haller (1708–1777) proposed that all portions of the roof brain share the same organization, a structural unity that was viewed as consistent with the unity of the soul. Between the end of the 18th century and the beginning of the 19th century, some scientists, and in particular the Scotsman John Hunter (1728–1793) and the Frenchmen Georges Cuvier (1769–1832) and Fe´lix Vicq d’Azir, tried to integrate increasingly detailed comparative anatomical and physiological investigations with practical medicine (Clarke and Jacyna, 1987). One of the most important consequences of the new data-driven thrust was that, instead of progressing from the top down, anatomists started to adopt the opposite strategy, approaching the brain from the spinal cord. This also brought about a revolution in anatomical practice, to the extent that, during dissection, the lower elements (spinal cord and medulla oblongata) began to be visualized foremost, thereupon followed by the more “elaborate” elements, the cerebrum and cerebellum. Most responsible for this new methodological approach was Gall, who proposed the theory of “organology,” later termed “phrenology” by his fellowresearcher Johann Caspar Spurzheim (1776–1832), which implied that the cerebrum is a federation of different functional organs. The doctrine of phrenology, inspired by physiognomy and based on faulty methods like craniometry, was ill-fated, though it played an important role in brain function localization (Finger, 1994, 2000; Zola-Morgan, 1995). It is, however, important to recall that, as a result of his anatomical dissections, Gall made important anatomical discoveries, eliminating the commonly held view that the spinal cord is a tail of the brain and providing a clear description of the commissures. Gall and

Spurzheim also established the basic division between gray and white matter. Importantly, Gall’s investigations drew attention to the role of the cerebral cortex as the site of intellectual functions, pioneering the idea that different cortical regions perform different functions. The impact of this approach on integrative and clinical neuroscience is still discussed today in relation to efforts in mapping brain areas implicated in different functions, for example with in vivo neuroimaging techniques (see, for example, Kosik, 2003). One of the most important anatomical contributions to neurology in the second half of the 18th century was made by Abbot Felice Gaspar Ferdinand Fontana (1730–1805). By means of precise “microdissections” (“with a very sharp needle”) of the peripheral nerves, this Italian scholar immersed the nerve threads in water and could thus identify minute “more or less transparent” cylinders, which could not be dissected farther. He called them cylindres nerveux primitives, “the simple and first organic elements of nerves.” Fontana thus discovered the organization of peripheral nerves and the existence of the nerve fiber, probably distinguishing the axis cylinder (called “axon” later on) and the myelin sheath (“a cover in the form of an outer sheath”) (Brazier, 1963; Bentivoglio, 1996) (Fig. 12.2).

FROM GROSS ANATOMY TO THE MICROSCOPIC ORGANIZATION OF THE NERVOUS SYSTEM At the beginning of the 19th century, the Italian anatomist and physiologist Luigi Rolando (1773–1831) described the cerebral convolutions and sulci in detail (Lambiase, 1992). Then, in 1829 and 1830, he described the central fissure, observing the gyri (precentral and postcentral) on either side of this fissure, which was called the “fissure of Rolando” by Franc¸ois Leuret (1797–1851) in 1839 (Clarke and O’Malley, 1996). Rolando also described other structures, including the substantia gelatinosa at the periphery of the spinal dorsal horn (Castellani, 1972). In the footsteps of Malacarne, Johann Christian Reil (1759–1813) investigated the structure of the cerebellum and described the cerebral insula in 1809. In the same year, he also introduced the use of alcohol as a fixative for tissue specimens. Also significant were the contributions of Franc¸ois Magendie (1783–1855) to knowledge about the cerebrospinal fluid, which he had baptized céphalo-spinal or céphalo-rachidien, because it could be “found in the head and in the spinal cavity” (Clarke and O’Malley, 1996). Magendie also described the midline foramen that connects the cerebral ventricles and the subarachnoid space, which now bears his name.

THE ANATOMICAL FOUNDATIONS OF CLINICAL NEUROLOGY 157 Hubert von Luschka (1820–1875) further elucidated use of thionin or toluidine blue (with affinity for the anatomical foundations of cerebrospinal fluid cirbasophilic elements) is still used today, including for culation in 1859. He described the two lateral recesses routine neuropathological examinations. through which the cerebrospinal fluid is drained from The technological advancements in microscopy durthe fourth ventricle into the subarachnoid space. The ing the 1820s led to the widest possible general theory membranes and cavities of the brain were subsequently on the organization of living organisms. “Cell theory” described in greater detail by the Swede, Gustav Magheld that all plants and animals are composed of indinus Retzius (1842–1919), who wrote the Biologische vidual cellular elements. Proposed by botanist Matthias Untersuchungen. This opus contains numerous original Jacob Schleiden (1804–1881) and zoologist Theodor anatomical observations of several animal species Schwann (1810–1882) in 1838–1839, this theory was (including the amygdala and the convolution of developed by Robert Remak (1815–1865) and by Retzius in the rhinencephalon, which he named in Rudolf Virchow (1821–1902), who stated in 1858 that honor of his father). every cell derives from a cell (“omnis cellula e celThus, a great deal of anatomical knowledge had lula”) (Harris, 1999; Mazzarello, 1999). been acquired during the first half of the 19th century, The cell theory represented a milestone in the develalthough the microscopic organization of the nervous opment of theoretical concepts in biology, providing a system remained mysterious. The microscopes in use coherent explanation of the microscopic organization at the beginning of the 19th century had poor resoluof living organisms on the basis of a unitary elementary tion and frequently provided distorted images with an principle. However, this code of structural interpretation abundance of “globular structures.” A technological did not seem applicable to neural tissue. This was larturning point occurred in the 1820s, thanks to the gely due to technical reasons, since nervous tissue was invention of an achromatic objective in 1818 by not only difficult to process for microscopic observaGiovanni Battista Amici (1784–1863), which would later tions, but was also unrevealing after staining with tradibe improved by Joseph Jackson Lister (1786–1869). tional techniques. Even more importantly, the The methods for tissue hardening and fixation also histological images derived from microscopic observaimproved during the 1830s and 1840s with the use of tions of the nervous tissue were difficult to interpret solutions of chromates and chromic acid, as recomwithin the context of the reductionist framework of mended by Adolph Hannover (1814–1894). In 1842, elementary units formulated by the cell theory. Benedikt Stilling (1810–1879) wrote about freezing to Some pioneering findings had, however, already obtain serial histological sections, after having frozen been obtained. In 1824, Rene´ Joachim-Henri Dutrochet a block of spinal cord by accident (the tissue block (1776–1847) had described rounded bodies in the spinal was left overnight out of the window). Tissue hardenganglia of invertebrates, and in 1833 Christian Gotting by freezing became more widespread after 1871, fried Ehrenberg (1795–1876) had demonstrated, also with some technical expedients that facilitated its use in vertebrates, similar spherules, which he defined as (Bracegirdle, 1978). Ganglienkugeln (ganglion globes). This was the eleImportant advancements were also due to the introment destined to become the nerve cell body or soma, duction of the microtome, which allowed the cutting which was then investigated microscopically by Gabriel of thin sections at a consistent thickness. Jan EvangeGustav Valentin (1810–1883) and by Purkinje. lista Purkinje (1787–1869) built a rudimentary microThe fiber, another constituent of the nervous mattome, but in the second half of the 19th century this ter, also attracted neurohistologists. One of Purkinje’s technology became increasingly sophisticated. In 1866, students, Joseph F. Rosenthal (1817–1887), introduced Wilhelm His (1831–1904) was able to investigate the the term Achsencylinder (axis cylinder) to designate sequence of brain development in embryos with his the fiber, although the term “axon” was not introduced microtome (Rasmussen, 1953). Better microtomes suiuntil 1896 by Rudolf Albert Ko¨lliker (Shepherd, 1991; ted for cutting thin serial frozen sections were introBentivoglio, 1996). duced in the 1870s, and they permitted investigators to In 1837, during a congress of German doctors and study the elements of the nervous system in more detail naturalists held in Prague, Purkinje described the soma (Rasmussen, 1953). of the large nervous cells of the cerebellum that bear The introduction of techniques for staining histolohis name (Fig. 12.3), as well as the emergence of progical sections with natural stains, such as carmine, or cesses (subsequently called “dendrites”), but whose with chemical stains produced in Germany, was also existence had already been guessed the year before important, as this allowed investigators to differentiate by Valentin. Purkinje observed processes of different tissue components. In 1884, Franz Nissl (1860–1919) kinds, but could not demonstrate a direct relationship provided a new way of staining nervous tissue. His between these extensions and the nerve fiber. The pro-

158 M. BENTIVOGLIO AND P. MAZZARELLO cesses that emerged from the soma extended toward A summary of these views also gives an overview of a a terra incognita, a poorly defined intercellular space difficult itinerary of knowledge that gave birth to the in which some authors later observed a punctate and modern neurological sciences. finely “granular” or “reticular” or amorphous substance, according to the methods and species used KARL DEITERS for investigation. The main fundamental questions The book written by German histologist Karl Deiters remained open: what are the relationships between the (1834–1863) was published 2 years after he had died of soma, the processes emerging from it, and the nervous typhus (Deiters, 1865). Under the mentorship of Virchow fibers? And how are these relationships established and Maximilian Schultze (1825–1874), Deiters had within different regions of the nervous system and embarked on histological and anatomical studies of the with the enigmatic extracellular substance? nervous system, using chromic acid and potassium A partial answer to these questions, which is of funbichromate as a tissue fixative and carmine staining damental importance for the interpretation of neurolofor his sections. Deiters also succeeded in the microdisgical lesions, derived from initial findings on the section, under the microscope, of motoneurons of the relationship between cell body and nerve fibers (van ox spinal cord, isolating them from the surrounding tisder Loos, 1967; Clarke and Jacyna, 1987; Shepherd, sue (Fig. 12.3). Schultze published the manuscript that 1991; Breidbach, 1996), but the observations of Robert Deiters could not finish, in which he had described glial Remak were a turning point. Remak had distinguished cells and several brain structures, including the myelinated and non-myelinated fibers in the sympalateral vestibular nucleus, named “Deiters, nucleus” thetic nervous system and, in his doctoral thesis of after him. The book also described the nervous cell or 1838, had clearly stated that the cell bodies located in “ganglion cell” that Deiters magnificently illustrated the ganglia of the autonomic nervous system are con(Fig. 12.3). As in other tissues, this element was described nected with the fibers that emerge from nerve cells. as composed of a protoplasmic substance containing a The experimental efforts of other histologists sucvesicular roundish nucleus with a nucleolus. ceeded in unraveling what became a general principle Two types of processes, he wrote, extend from the cell of the neurological sciences, i.e., the continuity body. One of these is represented by “protoplasmic probetween the soma, its processes, and the fibers. cesses” (the term “dendrite” would be introduced by WilAn important contribution was also provided by helm His in 1889), in which the cell body protoplasm, Adolph Hannover, who, stimulated by Remak’s work, granular or pigmented, extends. The protoplasmic proinvestigated the cerebral cortex using chromic acid as cesses ramify, usually with a dichotomy, into very fine fixative. In 1840, he explicitly stated that the fiber branches, which are lost in the intercellular (“porose”) continuity with the soma was “more than likely.” This fundamental substance. The second type of process is a concept soon received confirmations in studies on “nervous prolongation” or axis cylinder, emerging with invertebrates by Hermann Helmholtz (1821–1894) and a cone (Fig. 12.3). In Deiters’ opinion, this process does other histologists. Soon after, Ko¨lliker (1844, 1849) rennot give off branches. On the contrary, other histologists, dered the continuity between cell somata and fibers a such as Reinhold Buchholz (1863), who had investigated postulate shared by the community of histologists. molluscs, had observed that the axis cylinder emits In 1846 and 1853, Rudolf Virchow described “a connumerous fine branches before forming the peripheral nective substance formed in the brain and spinal cord in fiber, and such branches were supposed to cross profuwhich the nervous elements are embedded” (Nervenkitt, sely in the nervous centers of invertebrates. neuroglia). Views on the fine structure of the nervous sysAccording to Deiters, the initial segment of the nertem were thus becoming even more complicated and, vous fiber, which in some instances detaches from the although the tissue components had been sketched, no stem of dendrites, contains, at its origin, a granular clues were yet available on the three-dimensional organiprotoplasm similar to that of the soma, appearing as zation of the various structural components and, overall, a hyaline, rigid, “glassy” matter, light-refrangible, with on the microscopic anatomy of the nervous system. low sensitivity to histological reagents. Its width is proportional to the size of the parent cell body and the Reticular theories first segment is approximately equivalent to the soma The “reticularist” theories of the organization of the diameter. The fiber becomes thinner and expands again nervous system, nowadays neglected in view of the victo enter a medullary sheath (the myelin), thus forming tory of “neuronism,” offered interesting perspectives, the axis cylinder. which are highly relevant for interpretations of brain Deiters also described a second system of the axis activity and integrative functions in health and disease. cylinder, represented by numerous fibrils originating

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A

B

C

D

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Fig. 12.3. The plate illustrates the progress in the visualization of the neuron summarized in the text: motor neuron of the spinal ventral horn dissected out and drawn by Karl Deiters (A). The other three drawings represent the Purkinje cells of the cerebellum, as first drawn by Jan Evangelista Purkinje (B) and, after the introduction of the Golgi impregnation, by Camillo Golgi himself (C) and Santiago Ramo´n y Cajal (D).

160 M. BENTIVOGLIO AND P. MAZZARELLO from the protoplasmic prolongations with a triangular of the nerve cell are its fibrillary nature and its prolonemergence. These fibers are hyalin and refrangible as gations. Through repeated branching, these prolongawell, i.e., similar to the thinnest nervous fibers emerging tions become continuous with small terminal directly from the soma of some ganglion cells, but ramibranches, representing a direct continuation of the fied. Prior to 1865, other histologists had supposed that fibrils. The interconnections between such thin terminal the nervous cells are interconnected, thus constituting branches would produce an irregularly distributed fine a structural substrate for reflex and automatic phenomreticulum. Schultze and Butzke proposed, therefore, ena. Deiters did not observe anastomoses between nergeneral views that anticipated the subsequent neurofivous elements and cautiously suggested that some brillary neo-reticularist theories of Albrecht Bethe kind of interconnection could occur through the second (1872–1954), Istva´n Apa´thy (1863–1922), Franz Nissl axis cylinder system he had described, which, through its (1860–1919) and Hans Held (1866–1942), which were ramifications, could ensure sufficient interconnections elaborated on at the end of the 19th century and at the between different ganglion cells. In Deiters’ opinion, beginning of the 20th. however, this does not occur in protoplasmic prolongaIn the meantime, the concept that prolongations of tions (whose more distal branches do not reach nervous nervous cells establish reciprocal relationships formcenters) or in the axis cylinder originating directly from ing a complicated network was gaining credit. The the soma as a single and unramified element. Although existence of an anatomical structure subserving neural Deiters proposed his preliminary functional hypothesis transmission from one center to the other was cautiously, it is currently believed that his second system thus suggested, providing a hypothesized physical basis reflects axon terminals (boutons terminaux) on denfor the integration of nervous activities ranging from drites, and not processes emerging from the dendrites the simple (automatic and reflex) to the complex. How(Shepherd, 1991). ever, the space in which neural processes might interDeiters’ observations became well known. Camillo connect was difficult to observe and, as a Golgi (1843–1926) judged them “the finest possible findconsequence, ideas on intercellular relationships were ings with the means available at his times” (Golgi, 1885). very confusing. In the early 1850s, Franz Leydig (1821–1908) studied the cell groups that form the nervous system of inverTHE FIRST RETICULAR THEORIES tebrates. He observed a “dotted” or weakly fibrillary In his preface to Deiters’ book and in two subsequent matter in the central part of such nervous ganglia, publications, Schultze (1868, 1871) elaborated on a difand noted that nervous prolongations seem to get lost ferent theory on the structure of the nervous matter. in this matter, defined by Leydig as Punktsubstanz On the basis of his observations of an intercellular fibril(punctate fundamental substance). Its fibrillary aspect lary structure, Schultze, following up other studies (such suggested that the most distal branches of the prolonas those of Remak and Ko¨lliker), opposed the idea that gations (dendrites) interconnect in a network giving the fundamental substance of nervous cells is granular. origin to nervous fibers (axons). In contrast, a finely granular substance, containing a The problem of the relationships between these difyellow or yellow-brown pigment, could be observed ferent elements was debated in the following years interspersed between fibrils, the main constituents of and was complicated by the presence of glial cells ganglion cells. In Schultze’s opinion, fibrils course and their processes, by the variability of the preparathrough the dendrites to reach the cell body, where they tions obtained with different reagents and conditions undergo some kind of “evolution” that enables them to of the tissue samples, and by the species under study. form the stroma of the axis cylinder. Coursing through Every histologist applied his own procedure and the latter, the fibrils can then penetrate into other protoreached his own conclusions on the organization of plasmic prolongations of adjacent cells, thereby forming the nervous system. Thus, in 1863 Wilhelm Waldeyer a “net” that interconnects different nervous regions. (1836–1921) proclaimed the existence of a dense netThus, in Schultze’s interpretation, fibrils are not work formed by the extensions of “large” and “small” assigned a well-defined origin and termination, but nervous cells (possibly confusing neurons and glia) course directly from the periphery to the center, and and argued that the axis cylinder does not originate then again to the periphery of the ganglion cell, to then directly from the cell soma. An irony of fate would enter an adjacent cell. Ganglion cells are, therefore, make this German anatomist an official proponent “transit relays” in neural pathways (Fig. 12.3). of the nervous cell as unitary element formed by Along the same lines, Victor Butzke (1872), an invessoma, dendrites and axon (Waldeyer, 1891), for which tigator from Moscow who worked in the Pathology he coined the term “neuron,” becoming one of the Institute in Bonn, believed that the main characteristics first “neuronists.”

THE ANATOMICAL FOUNDATIONS OF CLINICAL NEUROLOGY In the fifth edition of his textbook of histology, published in 1867, Ko¨lliker proposed that the nerve cells of the spinal cord are interconnected through anastomoses, i.e., fusion of their protoplasmic prolongations (dendrites), and that the nervous fibers interconnecting cell groups in the two halves of the spinal cord originate from this network (Ko¨lliker, 1867). A different interpretation of the relationships between the various nervous elements of the cerebral cortex was developed by Georg Eduard Rindfleisch (1836–1908), who revived the old idea of a diffuse nervous central substance in vertebrates, defined as “interstitial granulo-fibrous substance” (Golgi, 1875). Protoplasmic prolongations and part of the axis cylinder would dissolve in this substance, after thinning out due to repeated branching and decomposing into a brush of fibers that pierce a row of minute dots. The interstitial granulo-fibrous substance is thus considered the fundamental element of the nervous system, whereas ganglion cells have the task of collecting and transmitting neural excitation. Rindfleisch theorized that the axis cylinder could establish a direct continuity with the nervous fiber in some instances. In the same period, another German investigator, Joseph von Gerlach (1820–1896), further developed Ko¨lliker’s theory of ganglion cell interconnections. In 1872 Gerlach proposed that nerve cells are anastomized via a network formed by protoplasmatic prolongations (the “protoplasmic network”; see Adhami, 1974; Shepherd, 1991). This gigantic fine reticulum would have realized a system of anatomical (and therefore functional) connectivity between nervous elements through an intercellular continuum. “Medullary” (myelinated) nervous fibers could originate from this fine interdendritic reticulum or directly from the axis cylinder emerging from the cell body, forming a second coarser network. This model was, therefore, in sharp contrast to the cell theory – the nervous system does not result from a mosaic of elementary “bricks,” but was viewed instead as a gigantic loom of threads inglobating the cell bodies. This led to the supposition that nervous functions are subserved by a network of telegraph-like wiring, as explicitly mentioned by Hermann von Helmholtz, Emil du Bois-Reymond (1818–1896) and other explorers of the borderland between physics and biology (De Palma and Pareti, 2006). Gerlach summarized his theory in the chapter on the spinal cord in a textbook of histology edited by Salomon Stricker (1834–1898) in 1869–1872. Gerlach’s view, which actually referred to previous models and especially to Ko¨lliker’s schematic representation, remained associated with the theory of a protoplasmic (dendritic) reticulum (Shepherd, 1991). Gerlach’s model was supported in 1873 by Franz Boll (1849–1879).

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DEVELOPMENT OF RETICULARISM

The turning point in microscopic studies of the nervous system took place in 1873, when Camillo Golgi (1843– 1926) introduced the black reaction. This histological technique consisted of the fixation of nervous tissue in potassium bichromate for a variable period of time (one to 45 days or even longer), followed by immersion in a solution of silver nitrate. The result is the selective precipitation of a salt, silver chromate, which fills the whole extent of neurons and glia, including their processes. The peculiar (and still unexplained) property of this intracellular reaction is that it impregnates only a few cells (approximately 1–5% in every microscopic field at most), which thus stand out against the background. This selectivity is the main reason for the revealing power of the black reaction, which became the main tool for the study of the structure of the nervous system. Due to the deposition of an insoluble compound within and around thin elements that could not be visualized otherwise, the Golgi method provided some kind of “morphological amplification” of neural structures. Thus, the Golgi impregnation represents both a discovery of a chemical-biological phenomenon and a method of investigation. A few months after the publication of the first results obtained with the black reaction, in an article titled “On the structure of the gray matter of the brain,” Golgi published his observations on the structure of the cerebellum (in which he also described the cells named after him), the olfactory bulb and the hippocampus (see Golgi, 2001, for the English translation), as well as on neuropathological alterations in a case of chorea (Mazzarello, 2006, 2009). Golgi (1885) collected his neuroanatomical studies in the book On the Fine Anatomy of the Central Organs of the Nervous System, reprinted in the following year. Golgi’s neurocytological discoveries overturned Gerlach’s dominating theories. Golgi demonstrated that dendrites do not fuse in a network and discovered that the axis cylinder (axon) is an obligatory component of nerve cells (Fig. 12.3). Importantly, Golgi stated that axons give off ramifications, undermining Gerlach’s reticularism. According to Golgi, the axon, and not the dendrite, is the element conveying the nervous impulse over distances, whereas he tentatively ascribed a trophic function to the dendrites. Golgi did not, however, abandon the reticularist paradigm. The “holistic” or “global” neurophysiological theory, supported in the first half of the century by the French experimental physiologist Jean Pierre Flourens (1794–1867), still exerted a remarkable influence at the beginning of the 1870s. According to this

162 M. BENTIVOGLIO AND P. MAZZARELLO view, the cerebral cortex functions as a single, equipoprocesses of each nerve cell represent one independent tential unit, a hypothesis fully compatible with a model unit (His, 1886; Shepherd, 1991). of cells as communicating vessels, in which every eleAugust Forel (1848–1931), another Swiss investigament establishes a relationship with all the others via tor, reached similar conclusions (Forel, 1887). He had a syncytium. been a student of Johann Bernhard Aloys von Gudden Observing his preparations impregnated by the (1824–1886) in Munich and in 1879 had been appointed black reaction, Golgi believed that the network interdirector of the Burgho¨lzli psychiatric hospital and proconnects the axonal branches that he observed. This fessor of psychiatry at the University of Zurich. Workwas the “diffuse neural network,” through which ing with material impregnated with the black reaction, neural transmission occurs by continuity. In the reticuForel did not observe any confluence of axonal larist model proposed by Golgi, the axons represent the branches in a network, and also wondered whether substrate of communication within the nervous system, the nervous tissue, as with all other tissues of the body, and the network has a functional correlate, representcould be considered “discontinuous.” This view was ing a “physiological organ” that accounts for the also supported by Gudden’s findings on experimental complexity of brain functions. degeneration, showing that the damage to nerve cell The concept of network was thus, for the first time, groups did not involve distant cells (see below). Forel’s explicitly related to complex integrated functions, protheory on the connectivity of nervous elements viding also an explanation for recovery of function after appeared in January 1887. Because the journal to which brain damage. According to Golgi, only the “communihe had submitted his paper was slow in publishing cating vessel system” ensured by the network can its submissions, Forel missed the priority of a theory explain the transfer of functions from damaged brain destined to become the neuron doctrine. areas to narrowly linked other ones. Despite the breakThe paladin of the neuronal theory as fundamental through provided by this view, Golgi’s interpretation principle of organization of the nervous system was was incorrect and destined to be overthrown. Yet, durSantiago Ramo´n y Cajal (1852–1934). During a scientific ing the ensuing debate, Golgi had already abandoned visit in 1887 to psychiatrist Luis Simarro Lacabra (1851– his studies on the nervous system to concentrate on 1921) in Madrid, Cajal observed histological sections malaria (Mazzarello, 2006, 2009). impregnated by the black reaction. At that time, Cajal As shown by the findings mentioned above (also see had realized how inadequate the ordinary methods were Pannese, 2007), it was widely believed in Golgi’s time to study the nervous tissue. The observation of preparathat nerve cells must be embedded in an amorphous tions impregnated by the Golgi stain was a flash of substance occupying most of the volume of the gray lightning: “a look was enough” and Cajal was enrapmatter. The systematic use of the black reaction tured. Nerve cells appeared “colored brownish black revealed instead that the central nervous system coneven to their finest branchlets, standing out with unsursists mainly of cells. passable clarity upon a transparent yellow background. All was sharp as a sketch with Chinese ink,” Cajal (1996) wrote in his autobiography. As “new facts THE NEURON DOCTRINE appeared in my preparations, ideas boiled up and jostled In 1886, three investigators, Nansen, His and Forel, each other in my mind . . . A fever for publication proposed that the nervous system is formed of indedevoured me,” added Cajal, as he worked on the retina, pendent units. The Norwegian Fridtjof Nansen (1861– cerebellum and spinal cord, applying modifications he 1930), a young zoologist destined to become a famous had made to the Golgi staining procedure. polar explorer, international diplomat, and a Nobel At the beginning of 1888, Cajal founded the journal Peace Prize winner (Huntford, 1997), was preparing Revista Trimestral de Histología Normal y Patológica his dissertation and visited Golgi’s laboratory in the to publish his own findings, in which he denied the exisspring of 1886. Trained by Golgi and his student tence of the diffuse neural network and stated that “nerRomeo Fusari, Nansen applied the black reaction vous impulses are transmitted through contacts.” The and rejected reticularism, stating that there are no anaphysiologist Sir Charles Scott Sherrington (1857–1952) stomoses between axons and their finest ramifications christened these contacts as “synapses” in 1897. The (Aarli, 1989; Mazzarello, 2006). reduced speed of conduction through a reflex arc, as Investigating the free endings in the neuromuscular opposed to a continuous cable, would now be explained junction and those of sensory fibers in peripheral senas being due to the gap between sensory and motor fibers. sory receptors (such as Pacini corpuscles), the Swiss Cajal defined “the law of the dynamic polarization,” anatomist Wilhelm His also hypothesized that the stating that nerve cells are polarized. They receive inforcentral processes end freely, stating that the body and mation on their cell bodies and dendrites and convey

THE ANATOMICAL FOUNDATIONS OF CLINICAL NEUROLOGY 163 information to distant locations through axons. This Studying the chick embryo, in 1672 Malpighi discov“unidirectional” view of the transmission of the nervous ered the fundamental transverse organization of the impulse turned out to be a basic principle of the funcneural tube and thus the classical model of the organitioning of neural connections. The same concept was zation of the central nervous system (Swanson, 2000). also developed at the same time by Arthur van GehuchLater on, Karl Ernst von Baer (1792–1876) and Robert ten (1861–1914) and William James (Shepherd, 1991; Remak pioneered neuroembryological studies (Papez, Mazzarello, 2009). 1953b; Schmiedebach, 1995). Ko¨lliker (1879) characterCajal’s studies on the structure of the nervous system ized the developmental stages of the neuraxis. Wilhelm were collected in his Textura del Sistema Nervioso del His demonstrated the ectodermic origin of neural Hombre y los Vertebrados (1894–1904), which had a structures and the mesodermic origin of blood vessels French translation (Cajal, 1911). Cajal’s opus, one of the in the nervous system. With remarkable terminological masterpieces in the history of science, is a milestone in talent, His introduced, besides the term “dendrite,” the anatomical contributions to neurology and in the also the terms “neuroblast,” “neurite” and “neuropil.” foundation of modern neuroanatomy, providing a Of considerable relevance are His’ studies on the detailed description of the entire organization of the nerdevelopment of the nervous system and especially vous system of different species – one illustrated by of the cerebral cortex. He clearly pointed out that Cajal’s renowned drawings (Fig. 12.3). Especially remarkgerminal cells divide rapidly in the ventricular epitheable and modern are Cajal’s contributions on the structure lium; the neuroblasts then migrate from the inner to of the cerebral cortex (DeFelipe and Jones, 1988). the outer zones, whereas cells of a third type (spongioGolgi and Cajal, who shared the Nobel Prize in 1906 blasts) form a syncytium through which the neurofor their studies on the nervous system, met only in blasts migrate (Bentivoglio and Mazzarello, 1999). Stockholm, when they received the award. Golgi gave Influenced by Carl Weigert, Ludwig Edinger (1855– his Nobel lecture first, and he tied it to his belief in 1918), who provided seminal contributions to neuroem“reticular” neural networks. It was firmly but politely bryology, was also one of the founders of comparative contradicted by Cajal’s Nobel Lecture. neuroanatomy, a field then mastered by Cornelius Cajal also elaborated on the anatomical mechanisms Ubbo Arie¨ns Kappers (1877–1946). Edinger was also a underlying psychic phenomena such as attention, ideapioneer in the study of clinical applications of neurotion and associations. He proposed that these processes anatomy (Lewey, 1953). The Edinger–Westphal nucleus depend on the state of “contraction” of glial cells of was identified by Edinger in human fetuses in 1885, the gray matter, which influence the degree of isolation and in adults by Carl Friedrich Otto Westphal (1833– and transmission of the currents in nervous centers, 1890) in 1887. Developmental studies then became a and proposed that increased connections between neumodel for the study of nervous system organization, rons could increase brain capacity and mental skills thanks to Cajal’s investigatons, which contributed (Mazzarello, 1999; DeFelipe, 2006). A similar hypothremarkable knowledge on axonal and dendritic develesis was also forwarded in 1893 by Eugenio Tanzi opment and growth; Cajal also discovered and named (1856–1934; see Chapter 44). the axonal growth cone (Cajal, 1991; DeFelipe, 2006). Cajal also made fundamental observations on the The concept of neuronal migration is very impordevelopment of the nervous system and its reaction to tant today for developmental malformations, including injuries. His studies on the degeneration and regeneraneuronal migration disorders that are a frequent cause tion of the nervous system are of special interest to clinof drug-resistant epilepsy. This concept had a difficult, ical neurologists. He deals with the regrowth of long gestation. With his technique, Golgi detected the peripheral axons (but not of central ones) after damage, radial arrangement of fibers emerging from the neufunctional recovery (e.g., after lesion of different cortiroepithelium lining the central canal. The first Golgi cal areas), dendritic “plasticity,” and severed axons givimpregnation of the cerebral cortex of mammalian ing off collaterals (Cajal, 1991; DeFelipe, 2006). fetuses was performed by Giuseppe Magini (1851– 1916), who detected radial fibers extending from the ventricular neuroepithelium and observed cells intercaNOTES ON THE CONTRIBUTIONS lated along these processes (Bentivoglio and MazzaOF DEVELOPMENTAL NEUROANATOMY rello, 1999). Magini proposed that the cells along the TO NEUROLOGY radial fibers are neurons. Radial fibers were then The study of nervous system development represented observed in the developing spinal cord and cerebral one of the most productive and stimulating aspects of cortex by several other investigators. Cajal was the the anatomical contributions to neurology, and it is still first to suggest that radial fibers are represented by at the forefront of neurological sciences. modified astrocytic processes functioning as a support

164 M. BENTIVOGLIO AND P. MAZZARELLO during cortical histogenesis, but he criticized Magini’s Della Sala, 1993; Hippius and Steinberg, 2006). Gudden observations on the existence of neurons along radial extensively utilized the method of “secondary atrophy” fibers. Only with the advent of electron microscopy of central structures after removal of sensory organs was the existence of radially arranged glial processes or cranial nerves in young animals. With this approach, along which young neurons migrate finally ascertained he could demonstrate not only the course of direct and (in the early 1970s by Pasko Rakic). With a new burst crossed retinal fibers in the visual pathway, but also of technical advancement and knowledge at the dawn several other fiber tracts, including the supraoptic comof the 21st century, radial glial cells are now regarded missure that was named after him (the interpeduncular as progenitor stem cells (Rakic, 2006). nucleus and the deep tegmental nucleus that Gudden described in the brain stem also bear his name). In 1870, Gudden discovered that the damage of TRACING NEURAL PATHWAYS some cortical areas resulted in retrograde degeneration Knowledge of the origin and termination of neural of distinct thalamic nuclei. His finding that cortical pathways is intertwined historically with clinical neulesions do not result in the atrophy of peripheral nerves rology. It has exerted a profound influence on neurolbecame known as “Gudden’s law.” In 1875, he ogy, not only in terms of basic science, but also designed a microtome suited for cutting the entire because it has shed light on localization of function human brain, which was then used by Forel (who and the emergence of symptoms in diseases. described the zona incerta and the fields of Forel in Studies of central neural pathways developed in the the subthalamic region). second half of the 19th century and, until the second Dutchman Cornelis Winkler (1855–1941), who prohalf of the 20th century, they were mainly based on vided information on the central auditory pathways the alterations elicited in the nervous tissue by damage. and prepared neuroanatomical atlases of the rabbit Ludwig Tu¨rck (1810–1868) was one of the first to utilize and cat brain, was deeply influenced by Gudden. In degenerative features induced by pathological processes 1879, Constantin von Monakow (1853–1930), also influor experimental lesions to define the course of fiber enced by Gudden, performed an ablation of the occipital tracts, and in particular the corticospinal tract. The bunlobe and detected retrograde degeneration of the lateral dle of Tu¨rck (the eponym of the temporopontine tract) geniculate bodies a year later. Monakow also investiwas, however, described by other anatomists and not by gated the auditory pathways, the thalamus and the cerethis Austrian investigator (Schmahmann et al., 1992). bral cortex, with the primary aim to elucidate functional Anterograde degeneration after axon transection, systems (Finger, 1994; Wiesendanger, 2006). described by Augustus Volney Waller (1816–1870), and In 1876, Fleschig introduced a “myelogenetic termed “Wallerian degeneration” after him (Dennymethod” for the study of fiber tracts with myelin Brown, 1953), was to become an important tool in tract staining in the developing nervous system. It was based tracing studies, which were developed in the 20th century. on the fact that myelinizating neural pathways Experimental tract tracing based on degeneration reach maturity at different times. Fleschig’s method techniques also benefited from the “atrophic degenhad a limited use in tract tracing, but helped define diferation” method of Bartolomeo Panizza (1785–1867). ferent cortical areas on the basis of the sequence of After damaging the retinal fibers from the eye in maturation. young animals, Panizza searched for the degeneration An innovative technique for anterograde tract tracaused by these lesions when the animals were older. cing based on degenerative features was introduced In 1855, he was able to identify the visual pathway by Vittorio Marchi (1851–1908) and Giovanni Algeri. and its cortical center, a lesion of which rendered the These authors observed that the myelin sheath of animal blind (Berlucchi and Taraschi, 1963; Mazzarello degenerating axons could be stained by bichromate foland Della Sala, 1993; Finger, 1994; Gross, 1999; lowed by osmic acid (the Marchi technique), thus Colombo et al., 2002). His cortical localization was visualizing degenerating fibers that “would totally be demonstrated 6 years before the seminal publication missed by carmine staining” (Marchi and Algeri, of Paul Broca (1824–1880) on the cortical area for lan1885). Marchi, who developed the technique after his guage. Unfortunately, Panizza’s discoveries were stay in Golgi’s laboratory, provided important contrineglected and the discovery of the cortical center for butions on the organization of cortical descending vision was subsequently ascribed to Hermann Munk pathways and in particular the corticospinal tract. (1839–1912). After decades, anterograde tract tracing through The degeneration technique used by Panizza was selective silver impregnation of degenerating axons and proposed again by Gudden, to whom the technique terminals was introduced by Walle Nauta (1916–1994) was later attributed (Papez, 1953a; Mazzarello and and subsequently modified by Lennart Heimer

THE ANATOMICAL FOUNDATIONS OF CLINICAL NEUROLOGY 165 (1930–2007). The introduction of tract tracing with selecdata and diffusion spectrum imaging in the study of tive silver impregnation of degenerating fibers (Nauta long association cortical pathways in non-human priand Gygax, 1951; Fink and Heimer, 1967) marks the birth mates has recently revealed the potential of this latter of the modern era for the experimental study of neural imaging technique, casting new light on the study of connections and has also been applied to the human brain the human brain and clinical disorders (Schmahmann after circumscribed lesions (Mesulam, 1979). et al., 2007). Imaging connectivity in the human brain With an acceleration of knowledge and techniques has thus been defined as the next frontier in neuroathat is still ongoing, this field was soon revolutionized natomy and clinical neurology (Mesulam, 2005). by the application of bidirectional axonal transport to the study of brain connectivity (see Bentivoglio, CORTICAL LAMINATION AND 1999). The axonal transport of anterograde tracers, ARCHITECTURE initially based on the use of tritiated amino acids and The cerebral cortex, the investigation of which is still a autoradiography (Cowan et al., 1972), allowed investimain chapter of neuroscience and neurology, has kept gators to study the course and termination of intact its mysteries for a long time. Jules Gabriel Franc¸ois Bailfiber pathways. The discovery of retrograde axonal larger (1809–1890) proposed that the cerebral cortex is transport (Kristensson and Olsson, 1971) and the introsubdivided in six layers in which gray and white matter duction of retrograde tracers permitted the precise alternate. Cerebral architectonics, i.e., the study of regioidentification of the neurons of origin of certain pronal differences in cortical structure, can be traced back to jections. These approaches rapidly brought about a Gennari (Glickstein and Rizzolatti, 1984; see above). wealth of knowledge on the organization of neural Remarkable contributions were then provided by several circuits in health and disease. The introduction of the investigators, including the seminal contributions of lypophilic dyes carbocyanines, which diffuse along Theodor Meynert (1833–1892), a pioneer of cortical lamineuronal membranes, has allowed tract tracing post nar organization, cellular composition and regional funcmortem, including in the human brain (see, for examtions (Papez, 1953c; Seitelberger, 1997), whose name has ple, Sparks et al., 2000). remained attached to many brain structures (e.g., the Multiple labeling techniques, mastered especially by basal nucleus of Meynert mentioned above). Henricus G.J.M. Kuypers (1925–1989), helped give rise As mentioned previously, Cajal contributed to modto the modern field of “chemical neuroanatomy,” in ern knowledge of the cerebral cortex and its cell types. which neurotransmitters and other neuroactive moleCortical cell types were also identified by other investicules are identified within neuronal circuits, providing gators, including Carlo Martinotti (1859–1918; the key information to clinical neurologists. The list of Martinotti cells giving off an ascending axon), Vladithese contributions would be very long. Examples of mir Aleksandrovic Betz (1834–1894; the giant Betz cells such findings are the dopaminergic nature of the of the motor cortex), and Gustaf Retzius (the Cajal– nigrostriatal system that paved the way for modern Retzius cells with horizontal dendrites in layer I). studies on Parkinson’s disease, and the definition of Cerebral architectonics was mastered by the eminent cholinergic projections to the cerebral cortex deriving German neuropsychiatrist, neuropathologist and neurofrom forebrain neurons located in the basal nucleus anatomist Oskar Vogt (1870–1959), who introduced the of Meynert, which has guided research on the role of term “architectonics” in 1903, and his wife Ce´cile acetylcholine in cognitive functions and their decline Mugnier Vogt (1875–1962). The Vogts achieved a minin Alzheimer’s disease. ute parcellation of the cerebral cortex, recognizing a Transcription factors and protein gene products are multiplicity of cortical areas (more than 200), whose currently been mapped in the brain in health and disease, interplay could subserve intellectual and behavioral phecombining new knowledge in the post-genomic era with nomena. Among other students and coworkers, the that acquired by means of tract tracing in the last decVogts inspired Korbinian Brodmann (1868–1918), who ades. Furthermore, the development of brain imaging worked from 1901 to 1910 in their laboratory in Berlin, techniques provides novel approaches to the study of where he conducted his fundamental studies on the neural pathways in the living brain. For example, by comparative cytoarchitecture of the mammalian cortex. means of diffusion magnetic resonance imaging tractoThese investigations culminated in a monograph in graphy, fiber bundles are now mapped in vivo in laborawhich Brodmann (1909; available in English translation) tory animals and in the human brain, permitting differentiated 52 cortical areas. Brodmann’s cytoarchiinvestigators to study the cerebral white matter and fiber tectonic parcellation and numbering of cortical areas tracts during diseases and following recovery, and guidhas remained as a reference classification for modern ing interventions (Johansen-Berg and Behrens, 2006). neuroscience and neurology, including neuroimaging. Comparisons between autoradiographic tract-tracing

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Constantin von Economo (1876–1931) and Georg N. Koskinas (1885–1975) published their celebrated atlas of the human cerebral cortex in 1925 (Triarhou, 2005, 2006a; English edition now available, von Economo and Koskinas, 2008). As a final example of the close theoretical and practical interactions between neuroanatomy and clinical neurology, and with specific reference to von Economo’s contributions, a tribute should be paid to his observations in patients affected by encephalitis lethargica, which paved the way for modern studies on the anatomy of brain circuits that regulate sleep and wakefulness. In his studies on lethargic encephalitis, von Economo (1930) concluded that, although sleep, like life, “is a much too complex condition to be localized,” neuronal cell groups located at the junction between thalamus and midbrain supervise sleep. He observed that lesions in the rostral part of this region were associated with insomnia and caudal lesions with somnolence. These observations pioneered modern studies on activating and sleep-promoting systems (Saper et al., 2005; Triarhou, 2006b).

CONCLUSIONS The material presented in this chapter summarizes the anatomical contributions that have helped to put neurology on a solid scientific footing. Over the last four centuries, the shift of attention from cerebral cavities to the surrounding brain matter and its cortical surface has led to a remarkable progress of knowledge of the nervous system in health and disease. This knowledge is now increasing very rapidly, with new horizons based on molecules and genes, on computational approaches to neural networks, and with research on complex mental functions, including their impairments in neurological and psychiatric disorders. The anatomical foundations of clinical neurology are tightly linked with the development of neurophysiology, neuropharmacology and, more in general, with the entire field of basic and clinical neuroscience. Anatomical knowledge has guided and still guides drug-based therapeutical strategies, as well as neurosurgical interventions, including, for example, novel approaches based on deep brain stimulation. The anatomy of the living brain in health and disease is the protagonist of the rapidly developing neuroimaging technology. The never-ending story of the anatomical foundations of clinical neurology continues to evolve at the dawn of the 21st century and a new millennium. As stated by Cajal (1996) at the end of his autobiography, the nervous system remains populated by “millions of palpitating cells which, for the surrender of their secret . . . demand only a clear and persistent intelligence to contemplate, admire, and understand them.”

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 13

The contributions of neurophysiology to clinical neurology: an exercise in contemporary history GIOVANNI BERLUCCHI * Department of Neurological and Visual Sciences and National Neuroscience Institute, University of Verona, Verona, Italy

INTRODUCTION The emergence of a unified field of neuroscience in the last three decades of the 20th century has blurred, if not erased, the boundaries between the traditional disciplines dealing with the nervous system. Yet, well before the advent of neuroscience, two main reasons warranted the existence of a privileged connection between neurophysiology and clinical neurology. First, granted that the task of the neurophysiologist is that of understanding the normal working of the nervous system, it is a historical fact that normal nervous functions have often been inferred from disorderly functions. If in this vein neurophysiologists have undoubtedly learned much from experimental lesions in animals, it has been the clinical neurologists who have obtained first-hand information on the effects of pathology on the functioning of the most complex and interesting of all nervous systems, that of man. As a fortunate consequence of this division of labor, convergent evidence from lesion studies in animals by neurophysiologists and in humans by clinical neurologists has set our current knowledge about nervous functions on a firm comparative foundation. The special relations between physiological and clinical investigations on the nervous system have been aptly captured by the neurologist Gordon Holmes. In commenting on his own investigations of the visual cortex in man, he has written: This has required the collection of a large number of observations, for while the physiologist can rely on experiments which he can select and control, and can obtain from them more precise, sometimes critical and often measurable data, the clinician must depend on the analysis of observations which are rarely so simple or *

clear cut, and he is often unable to correlate them with the causal lesions responsible for them. The physiologist may be compared with the builder in ashlar or hewn stones which can easily be fitted together; the physician resembles the mason who has to use irregular rubble and therefore requires more time and labor to attain his end. But in some branches the “rubble” collected and put together by the clinician is essential, or can at least be complementary to the conclusions of the experimentalist. This is particularly so in the investigation of those functions of the brain which require the co-operation of a conscious subject who is able to communicate his experiences, as in the examination of sensory functions. (Holmes, 1944) The second reason for the existence of a special link between neurophysiology and clinical neurology is that their joint endeavors in the first half of the past century have given birth to clinical neurophysiology. This hybrid field of basic and clinical research has become independent from the parent disciplines and has developed in its own right. Clinical neurophysiology was recognized as an autonomous specialty with the foundation of the International Federation of Electroencephalography and Clinical Neurophysiology in 1947, and the launching in 1949 of its official publication organ, the journal Electroencephalography and Clinical Neurophysiology, known in short as the EEG Journal (Brazier and Cobb, 1979) and currently published with the title Clinical Neurophysiology. Herbert Jasper, the founder and first chief editor of the EEG Journal, was a pioneer of the application of neurophysiological methods to the study of neurological diseases (Andermann, 2000).

Correspondence to: Giovanni Berlucchi, Dipartimento di Scienze Neurologiche, e della Visione, Universita` di Verona, Strada Le Grazie 8, 37134 Verona, Italy. E-mail: [email protected], Tel: +39-045-8027141, Fax: +39-045-8027279.

170 G. BERLUCCHI For many years he collaborated with neurosurgeon Wilder unit, a choice which has been at the root of the concepPenfield at the Montreal Neurological Institute in studies tual and experimental advances of neuroscience up to combining electrical stimulations and recordings from this day. He conferred a physical reality to Marshall the brain of unanesthetized patients able to report their Hall’s concept of the reflex diastaltic arc in terms of subjective experiences (Penfield and Jasper, 1954). neuronal components and the synapses causing the uniThe present chapter reviews a number of historical directional march of impulses along reflex pathways contributions of neurophysiology to clinical neurology (Sherrington, 1897). He distinguished dedicated neuroin the 100 years that have elapsed since the publication nal pathways, such as those carrying exclusive inforof Sherrington’s The Integrative Action of the Nervous mation from a particular sensory receptor, from the System (1906), a book generally considered the neurofinal common path of the motoneurons, which allows physiologist’s bible. Most of those who made the coneach muscle potentially to be controlled by all sensory tributions called themselves physiologists rather than inputs, as well as by the will. With relatively simple neurophysiologists, because the latter term became behavioral observations following accurate peripheral popular only after Dusser de Barenne, Fulton, and Gerand central nervous lesions, he categorized many types ard founded the Journal of Neurophysiology in 1938 of reflex activities and inferred from the effects of (Jung, 1974). The term “neurology” is much older convergent allied and antagonistic reflex pathways that because it was introduced into the medical literature the output mechanisms of the nervous system are in the 17th century by Thomas Willis (Eadle, 2003). aimed at serving the singleness of action of the organThe phrase “clinical neurology” seems to have a more ism. He was the first to have a clear idea of the imporrecent origin, since it appears to have been first used tance of neuronal inhibition as a crucial component of in the United States in a textbook by Wechsler (1927) the normal working of the central nervous system and the title of an edited American translation (Sherrington, 1932). Sherrington’s investigation of the (Strecker and Meyers, 1924) of a German book by phenomenon and mechanisms of spinal shock after Curschmann (1924; see Steinberg, 2002). In Europe separation of the cord from the brain, and of decerethe term became popular after the publication of the brate rigidity after brainstem transections, did for many book Introduction to Clinical Neurology by Holmes years inspire clinical interpretations of disorders of mus(1946). cle tone and posture in man. For some neurophysiological contributions reviewed In 1875, in a major breakthrough in clinical neurolohere, the attribute “historical” is justified by their gengical testing, Erb and Westphal had independently diseral recognition as such by the scientific community, covered the knee extension response to percussion of while the choice of others has been dictated by their the patellar tendon, and had described its modifications actual or predictable impact on the advancement of neuin conditions such as tabes dorsalis and limb palsy roscience, as seen from the present author’s viewpoint. (Erb, 1875; Westphal, 1875; see Bonduelle, 2000; Louis, 2002). Initially this muscle response, christened knee THE FOUNDING FATHERS OF jerk by Gowers (1886), was wrongly attributed to a NEUROPHYSIOLOGY AND THE direct muscle reaction to percussion because of its very DEFINITIVE ESTABLISHMENT OF THE short latency. It was Sherrington who identified the NEURON THEORY knee jerk as a phasic enhancement of a tonic reflex maintaining the muscle tonus, because “severance of After Golgi and Cajal created neurohistology in the the afferent nerves of these muscles destroys their 19th century, Charles Scott Sherrington and Edgar tonus, and renders at the same time the knee jerk ineliDouglas Adrian acted as fathers to modern neurophycitable, just as also does the severance of their motor siology in the 20th century. They were jointly awarded nerves” (Sherrington, 1906). the Nobel prize in 1932 for their discoveries regarding Sherrington also showed that decerebrate rigidity in the functions of neurons. animals is a caricature of the normal muscle tonus. This provided an important clue to the understanding Sherrington and nervous integration of human spasticity as an abnormal reflex, though it Sherrington’s The Integrative Action of the Nervous now appears that an increased input from muscle spinSystem (1906) presented an elaboration of the concept dles is not as crucial for spasticity in primates as it is of reflex action, which was defined as the greatest sinfor decerebrate rigidity in cats and dogs. gle contribution of the physiologist to clinical neurolSherrington himself did not appear to take much interogy (Fulton, 1953). According to Granit (1966), est in clinical neurology. He hardly cited the ideas of his Sherrington’s fundamental merit was the choice of great contemporary neurologist Hughlings Jackson, and the neuron and its interconnections as his analytical apparently did not fully understand the work of his good

THE CONTRIBUTIONS OF NEUROPHYSIOLOGY TO CLINICAL NEUROLOGY neurologist friend Henry Head (Denny-Brown, 1957). Yet many of his neurophysiological discoveries were of major clinical relevance. The physiologist Angelo Mosso from the University of Turin was the first to see changes in brain blood flow through skull cracks in patients responding to sensory stimuli, doing mental arithmetic, and undergoing emotional experiences (Mosso, 1880). Shortly thereafter, Roy and Sherrington (1890) (Fig. 13.1) saw in animal experiments that the products of brain metabolism can cause variations of the caliber of cerebral arterioles. From this they inferred the existence of an intrinsic mechanism by which the blood supply to the brain can be varied locally in correspondence with local variations of functional activity. Many decades later the essential truth of this prescient intuition was fully acknowledged by physiological studies using radioactive measures based on inert gases, as developed by Sokoloff and Kety (1960) in the Physiology Department of the University of Pennsylvania, and first applied to the human cortex by Lassen and Ingvar (1961). These ground-breaking studies of the relations between cerebral blood flow and metabolism paved the way for the development of the modern brain imaging techniques, now a major tool for diagnosis in clinical neurology, as well as for

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research in all branches of neuroscience (Frackowiak, 1998; Raichle and Mintun, 2006). Further, following the localization of the motor cortex in the frontal lobes by Fritsch and Hitzig in dogs and by Ferrier in macaques (see Finger, 1994), Sherrington used more refined electrical stimulation techniques under asepsis to map the motor cortex in anthropoid primates (a gorilla, an orangutan, and two chimpanzees) whose brains are evolutionarily closer to that of man (Leyton and Sherrington, 1917). One of his former students, the famous neurosurgeon Penfield of the Montreal Neurological Institute, improved neurosurgical procedures by exploiting Sherrington’s precise cortical maps for constructing corresponding maps in the human brain (Penfield and Rasmussen, 1950). Finally, all fields of neuroscience benefited enormously from Sherrington’s ideas, which were transmitted and elaborated by many outstanding pupils who went on to pursue a career in physiology, including Magnus, Eccles, Bremer, Granit, Forbes, Fulton, and Camis (see Denny-Brown, 1957). Among other pupils of Sherrington who became clinicians, the most distinguished along with Penfield was the neurologist Denny-Brown, who trained with Sherrington as a PhD student and then worked in neurology at the National Hospital in London. He was then called to chair Harvard University’s Neurology Unit of Boston City Hospital in 1941, whereby he played a major role in the development of neurology in the United States (Vilensky et al., 2004).

Adrian and the single-neuron code

Fig. 13.1. Charles Roy and Charles Sherrington in front of the Department of Pathology of Cambridge University in 1893, 3 years after the publication of their joint paper on cerebral blood flow (from Granit, 1966).

Ivan Pavlov, the first neurophysiologist to be awarded a Nobel prize (in 1904, though for his work on the digestive system), is rightly regarded as a giant of physiology belonging in the same class as Sherrington. Yet his influence on neuroscience was not as great as that of Sherrington because he did not attempt to reduce his hypothetical mechanisms of the conditioned reflexes, such as, for example, cortical inhibition, to the neuronal level (Granit, 1982). Unlike Pavlov, Edgar Douglas Adrian also chose the neuron as his analytical unit, though with a different means from Sherrington’s (Adrian, 1935). As detailed in a following section, Adrian’s work has furnished the most important roots to the development of electroencephalography and electromyography, two major tools for investigation in both neurophysiology and clinical neurology, which eventually became the springboard for the take-off of clinical neurophysiology. By recording the electrical activity of single nerve fibers, he proved that the messages conveyed to the brain in each fiber from all sensory organs are trains of electrical impulses varying in frequency, but not in amplitude,

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with the intensity of the stimulus. Whether a sensation is tactile, auditory, visual, or other, depends on the sensory organ and the cortical area receiving the signals, not on the nature of the single signals, which are by themselves unvarying across sensory systems (Adrian, 1947a). Similarly, the commands sent by each motoneuron to the muscle fibers under its control, as well as the signaling between one group of neurons and another, are based on all-or-none action potentials coursing along individual nerve fibers (Adrian, 1947b). The work of Adrian and Moruzzi (1939; Fig. 13.2) extended to the cortex the notion that the rate and the temporal spacing of action potentials emitted by a single nerve fiber form a unitary code for neuronal communication, which presumably underlies all aspects of brain functioning, from sensation and movement to thought and action planning. Adrian’s conviction that impulses in nerve fibers represent the main language by which one neuron speaks to another continues to be the basic credo of neuroscientific thought, even if other secondary means of interneuronal communication, such as paracrine chemical signals, are also known to exist. For decades up to the present, action potentials have been recorded from countless single neurons and other excitable cells in most animal species including man, and a vast amount of current wisdom in all fields of neuroscience comes from the use of the technique originally championed by Adrian.

Adrian’s legacy and the contribution of single-neuron studies to the understanding of the brain One of the most profound empirical and conceptual contributions of neurophysiology to the notion of functional specialization in the brain is the demonstration that even single neurons are functionally specialized (e.g., Barlow, 1995). The search for single

Fig. 13.2. Edgar Adrian (left) and Giuseppe Moruzzi in 1953 during a visit to Tuscan villas.

neuron specialization in anesthetized and especially in freely behaving animals is based on Adrian’s concept that sequences of action potentials convey information about the evoking stimulus. Entirely new vistas on the general organization of the cerebral cortex have been furnished by Mountcastle’s (1957) discoveries on the receptive fields of single neurons in the somatosensory cortex; by those of Kuffler (1953) on the receptive fields of single neurons in the retina, and those of Hubel and Wiesel (2005) on the receptive fields of single visual cortical neurons; and by those of Evarts (1966) on the relations between single motor cortex neurons and specific muscles and movements. Hubel and Wiesel’s demonstration of how visual cortical neurons handle different attributes of the visual input, such as form, motion, and color, was especially fruitful for subsequent developments (Hubel and Wiesel, 2005). They found that a single cortical neuron can extract specific features of the visual stimulus, such as the orientation of a simple line segment of an object contour. This occurs because a subset of presynaptic neurons converging onto that neuron responds to adjacent light points along the line segment, and their responses are combined postsynaptically. If such convergence on single neurons in the early stages of the visual system can reconstruct a line from single light points, a further convergence from lower to higher stages of the cortical hierarchy might arguably turn relatively raw information into a meaningful picture; that is, to confer onto single neurons the capacity to respond selectively to whole entities of the natural visual environment. That such sophisticated neurons do indeed exist was first shown by the discovery of neurons selectively responsive to human and simian hands and faces in the inferior temporal cortex of macaques (Gross et al., 1972), later confirmed by Perrett et al., (1982). Evidence for the existence of similarly sophisticated neurons was then obtained in other sensory modalities as well as in motor regions of the brain, where neurons have been shown to fire in selective association with various aspects of movement production and control. A few selected examples indicate that, in the brains of experimental animals, there are neurons whose activity matches specific aspects of cognition and behavioral control of the entire animal. Single neuron activities can index how the animal pays attention to items or locations in its environment (e.g., Wurtz et al., 1982; Chelazzi et al., 1993), and how it memorizes information for later action control (Fuster and Jervey, 1982). The response threshold of sensory cortical neurons often coincides with the whole animal’s threshold for the behavioral detection of those stimuli (Shadlen and

THE CONTRIBUTIONS OF NEUROPHYSIOLOGY TO CLINICAL NEUROLOGY Newsome, 2001). Some hippocampus neurons in rats, called place units, fire when the animal is in specific locations of its familiar environment, so as to construct a neuronal hippocampal map of the outside space (O’Keefe and Nadel, 1978). Detailed features of behavioral associative learning become manifest in the activity of single neurons of the monkey cortex as the animal learns the task (Miyashita, 2004). Associative cortical areas of macaques contain neurons whose activity encodes the goals of viewed biological movements (Puce and Perrett, 2003), as well as other neurons which index precisely the animal’s intention to move the eyes or a limb (Andersen and Buneo, 2002). In the monkey premotor cortex, the so-called mirror neurons become active either during the performance of a specific movement or during the observation of the same movement made by another individual. This discovery has provided a strong argument for the use of single-neuron data for understanding the biological bases of imitation, action understanding and simulation, empathy, and even language evolution and development (Rizzolatti and Craighero, 2004). Finally, current explorations of human brain mechanisms underlying risky evaluations and decisions build on findings from single neuron studies in monkeys making choices based on previous experiences and future expectations (Glimcher, 2005). The lesson for clinical neurology from single neuron studies in behaving animals is that sensory, motor, and integrative functions of all degrees of complexity are potentially reflected at the single neuron level. Further, neurons linked to particular functions make up systems that are distributed in the brain, rather than being concentrated in circumscribed centers. Nevertheless, discrete lesions crucially placed within these distributed systems can impair functioning in selective ways, giving rise to specific patterns of impairment with preservation of other functions. This is particularly true in clinical neuropsychology, where modular theories of cognitive functioning can be tested against the putative removal of a “mental module” by a cerebral lesion. At present, functional localization in the nervous system appears to be alive and well in neurophysiology and clinical neurology alike (Mountcastle, 1998; Albright et al., 2000).

THE UPS AND DOWNS OF FUNCTIONAL LOCALIZATION IN THE NERVOUS SYSTEM IN THE 20TH CENTURY At the transition between the 19th and the 20th centuries, Flourens’ (1858) view of the cerebral cortex as a unitary substrate of a unitary intelligence was overturned by localizationist and connectionist conceptions.

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The cortex had come to be regarded as a mosaic of functionally specialized centers linked by discrete fiber connections, so that selective functional losses could occur upon direct damage to the centers or to their connections. Clinical neurologists including Broca, Wernicke, Liepmann, Lichtheim, Bianchi, Dejerine, and others, had been able to ascribe various specific psychological functions to specific regions and interconnections of cerebral cortex, particularly in the domains of language and voluntary motor control. Physiologists, such as Hitzig, Ferrier, Munk, SharpeySchafer, and others had supported the regional specialization of the cortex by describing selective effects of circumscribed lesions and electrical stimulation in experimental animals, although such effects were largely restricted to basic sensory and motor functions (see Finger, 1994).

Antilocalizationist tendencies in neurology and psychology This localizationist and connectionist view of the cortex came under severe attack when World War I furnished clinical neurologists with study material in the persons of young soldiers with missile wounds of the brain. Influential neurologists like Monakow, Head, Marie, Holmes, and Goldstein were already dissatisfied with the rather crude anatomical and behavioral analyses of the so-called brain cartographers and diagram-makers of the previous era. The new evidence convinced them that only elementary motor and sensory defects could be precisely related to specific sites of brain damage, as in the case of discrete, topographically-organized visual field losses resulting from different bullet trajectories within the occipital lobes (Holmes, 1944). Any attempt to localize language and other higher nervous functions in the brain came to be regarded as a futile exercise, and it was generally believed that disorders of such functions had better be imputed to diffuse alterations of brain organization (Boring, 1950; Finger, 1994). The neurologists’ aversion to localization of psychological functions in the brain was shared by holisticallyoriented physiological psychologists led by Lashley (1930), whose concepts of mass action and functional equipotentiality virtually resurrected Flourens’ notion of global cortical functioning. At the same time, selectivity of neural connections and specificity of functional representation were also questioned, if not completely dismissed, by radical functionalists who liked to depict the developing nervous system as a random, unstructured, and essentially equipotential network, to be molded and shaped into a functionally adaptive system by use, practice, and conditioning

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(Weiss, 1950). In a different vein, but again in sharp contrast with localization and connectionism, the Gestalt doctrine of psychoneural isomorphism equated brain activities underlying psychological functions with diffuse electrical fields spreading throughout the cortex as volume conductors, rather than with distinct patterns of nerve impulses in orthodox neuronal circuits (Kohler and Held, 1949). Finally, interest in brain–behavior relationships was discouraged by extreme behaviorists, who advocated the restriction of behavior analysis to directly observable input–output relationships of the whole organism, with total disregard for any independent neurophysiological evidence (Skinner, 1938).

Neurophysiology re-establishes the reality of functional localization However, a definite movement toward a return of brain localization and connectionism began to take place some time before the middle of the century, and neurophysiology was a protagonist in promoting it. It is then that the bases were laid for the presentday conviction that anatomical and physiological specificity and selectivity are the hallmarks of a cerebral organization in which there is no room for either mass action or functional equipotentiality (Mountcastle, 1998; Albright et al., 2000). As detailed below, combined neuroembryological and neurophysiological experiments showed that, well before birth, genes and developmental processes determine highly specific neural connections, which are then maintained and perfected by environmental influences. Cytoarchitectural and myeloarchitectural subdivisions of the cortex, as described by the early neuroanatomists, were given specific functional meaning by the neurophysiological demonstration that most of them contain orderly maps of the sensory or motor peripheries, as well as populations of neurons with quite distinctive physiological properties. An important neurophysiological distinction surfaced between neuronal systems conveying specific sensory or motor information, and deep brain systems with diffuse projections to the thalamus and cortex, which can modulate the activity of the entire nervous system in the sleep–wake cycle, as well as in attentional and motivational regulations. There are several of these diffusely projecting systems, each marked by a single transmitter specific for that system, and for its action on its cortical and subcortical targets. Better controlled lesion experiments in animals and more accurate analyses of neurological patients made it clear that, depending on its locus, focal brain damage can bring about unique combinations of impairments and spared psychological capabilities. Such patterns of

deficits allow reasonable inferences about the cerebral localization and organization of normal psychological processes. Brain stimulation in experimental animals, and particularly deep brain stimulation, proved suitable for evoking complex integrated behaviors. Species-specific behaviors evoked by deep brain stimulation in cats were documented in particular by the physiologist Walter Hess, who received the 1949 Nobel Prize for his discovery of the functional organization of the diencephalon in the coordination of the activities of the internal organs (Hess, 1964). The discovery by Berger of EEG effects over the entire cortex from sensory stimulation and changes in alertness (Berger 1929) prompted a search for regulatory systems that could cause such a diffuse reaction. Attention was focused on subcortical structures, and particularly on the hypothalamus and the brainstem. Lesion and stimulation experiments in animals had already pointed to a capacity of these structures to modulate total brain activity and to play a major role in instinctive and adaptive forms of general behavioral integration. The notion of the hypothalamus as a neuroendocrine center controlling the hypophysis and various hormonal activities (Ranson and Magoun, 1939) was emerging, along with the concept of specialized neurons secreting hormones rather than neurotransmitters (Scharrer, 1952, 1974). The finding of impaired vigilance and coma after hypothalamic lesions in experimental animals (Ranson and Magoun, 1939), and the lesion-EEG studies of Bremer (1936, 1974; Fig. 13.3), had suggested that waking requires an adequate cortical tone sustained by a continuous arrival of ascending facilitatory inputs at the cortex. Accordingly, the neurosurgeon Penfield had hypothesized that the involvement of functional areas of the cerebral cortex in common integrated action needs the coordinating action of a centrencephalic system, including those parts of the diencephalon and

Fig. 13.3. Horace Magoun (left) and Fre´de´ric Bremer at the first meeting of the International Brain Research Organization in Pisa (1961).

THE CONTRIBUTIONS OF NEUROPHYSIOLOGY TO CLINICAL NEUROLOGY brainstem which send symmetrical projections to the cortex of both hemispheres (Penfield, 1958). In a landmark neurophysiological discovery, Moruzzi and Magoun (1949) showed that electrical stimulation of the brainstem reticular formation produces an EEG reaction identical to the arousal reaction caused by natural sensory stimuli over the entire cerebral cortex and the thalamus. Initially a unitary arousal system lying in the brainstem reticular formation was thought to modulate the activity of the entire nervous system in the sleep–wake cycle, as well as in subtler modifications associated with different motivational states and levels of attentional control. Subsequently the notion of a brainstem arousal system as a functional unit was challenged on several grounds. Moruzzi (1972) showed that ascending brainstem influences can also induce sleep in an active way, and his midpontine pretrigeminal preparation in the cat provided a neurophysiopathological basis for understanding the preservation of consciousness in the so-called locked-in syndrome (Laureys et al., 2004). Chemical neuroanatomy (Dahlstrom and Fuxe, 1999) allowed the differentiation of multiple ascending systems (at least six) within the brainstem reticular core (Steriade and McCarley, 1990; Robbins and Everitt, 1996; Berlucchi, 1997; Steriade, 2001). Each of these systems is made up of relatively few neurons, all characterized by the same neurotransmitter (a biogenic amine or acetylcholine) specific to that system. The enormous branching of the axons of these few neurons ensures a widespread distribution of their projections in most of the diencephalon and telencephalon, and especially in the cerebral cortex, thus offering a structural counterpart to their putative regulatory and modulatory functions. An ascending modulation of cortical activities by diffusely projecting subcortical systems has been and continues to be a very influential concept in neurology for interpreting data from behavioral and clinical analyses, as well as from EEG, event-related potentials, and brain imaging studies. All current neuropsychological theories about attentional mechanisms, either intensive or extensive, or voluntary or reflexive, and their derangements in clinical neuropsychological syndromes, such as unilateral neglect, assign a major role to arousal systems and bottom-up subcortical influences upon the cortex. The chemically tagged ascending brainstem systems are also thought to be heavily involved in various memory and emotional mechanisms, including dependence on substances of abuse, as well as in normal and disturbed consciousness, and in the organic underpinnings of the major psychoses (Cools and Robbins, 2004). Selective activation of the dopaminergic system is thought to underlie the rewarding effects of brain stimulation,

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leading to self-stimulation in experimental animals, as serendipitously discovered by Olds and Milner (1954; see Olds, 1974; Milner, 1991). Currently, deep brain stimulation is utilized in clinical neurology mostly for the treatment of motor disorders and pain control, and in psychiatry for cases of obsessive compulsive disorder (Wichmann and DeLong, 2006).

NATURE AND NURTURE IN NEURONAL CONNECTIONS, THE REALITY OF DISCONNECTION SYNDROMES IN CLINICAL NEUROLOGY, THE CONCEPTUAL SHIFT FROM HEMISPHERIC DOMINANCE TO HEMISPHERIC SPECIALIZATION, AND THE EMERGENCE OF A NEUROSCIENCE OF CONSCIOUSNESS Many neurological diseases are caused at least partly by inherited or acquired genetic mutations, which alter the normal pattern of structural and functional organization of the brain. Examples include common diseases, such as Alzheimer’s disease, the major psychoses, and less common conditions, such as Huntington’s disease and other neurological conditions involving the degeneration of long connection tracts. Understanding of these disorders requires an understanding of how the neuronal organization of the system is put together during embryogenesis, and how the connections between neurons are maintained or modified during the life span. A further issue concerns the cogency and the clinical usefulness of the distinction between acquired neurological deficits that depend primarily on a loss of neuronal populations, and those that depend primarily on disconnections between otherwise functioning neuronal populations. These questions were addressed most effectively in the work of Roger Wolcott Sperry (Fig. 13.4).

Fig. 13.4. Torsten Wiesel, Roger Sperry, and David Hubel in Stockholm receiving the Nobel prize for Physiology or Medicine in 1981.

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Sperry, Hubel, and Wiesel and inborn neural connections and organizations Sperry considered himself a psychologist-cum-biologist rather than a neurophysiologist, possibly because he did not use the electrophysiological methods that characterized the neurophysiology of his time. Yet to the extent that his work re-established the reality of innate Sherringtonian circuits and solved the mystery of the functions of the corpus callosum, he should be recognized as an outstanding honorary neurophysiologist. His scientific career had begun in the 1930s, at a time when the work of two of his teachers, Paul Weiss and Karl Lashley, had built up an apparently substantial and convincing case against the classical Sherringtonian model of central nervous integration. In that frame of mind, Cajal’s neurotropic hypothesis, whereby central nervous organization was thought to come about by an orderly growth of selective neuronal interconnections during embryonic life (Cajal, 1909), had also been questioned, if not denied outright. Preference was accorded to the alternative notion that the developing nervous system starts out as an essentially random network, to be shaped into a functionally adaptive system by use and practice, and by elimination of inappropriate connections (Sperry, 1974). Undeterred by the fact that in the eyes of his teachers the connectionism of Sherrington and Cajal had become an example of simplistic and outmoded naı¨vete´, Sperry single-handedly proceeded to demolish the “blank slate” hypothesis of the developing nervous system. His ingenious and deceivingly simple experiments led him to conclude that the developing nervous system possesses a high degree of internal self-organization, prior to and independent of any environmental influences. His most eloquent results showed that in replicating original embryogenesis, central nerve regeneration in adult cold-blooded vertebrates rebuilds a preordained pattern of connections that persists even when forced by experimental manipulations to subserve completely maladaptive forms of behavior. Like Cajal’s chemotropic hypothesis, Sperry’s chemoaffinity hypothesis maintains that, early in development, the populations of nerve cells acquire and retain individual chemical identification tags, by which they can be recognized and distinguished from one another, such that lasting functional synaptic connections are established only between neurons that are selectively matched by inherent chemical affinities (Sperry, 1951, 1974; see Hunt and Cowan, 1990; Meyer, 1998). Although we now know that the formation of neuronal circuits may be more variable and functiondependent than Sperry was prepared to admit (Cline, 2003), the existence of a high degree of prenatal

organization of neuronal connections in the mammalian brain is best illustrated by the prenatal organization of the visual cortex (Hubel and Wiesel, 2005). In 1981, Sperry was awarded half the Nobel Prize for his discoveries concerning the functional specialization of the cerebral hemispheres, and Hubel and Wiesel received the other half for their discoveries concerning information processing in the visual system. The two different motivations fail to expose a strong conceptual link between the work of Hubel and Wiesel and that of Sperry (Berlucchi, 2006). In keeping with Sperry’s ideas, Hubel and Wiesel (2005) found that the complex wiring underlying the receptive field organization of visual cortical neurons is present in immature cats and monkeys before any exercise of visual function, and therefore must be innately determined. However, the innately determined functioning of the visual system is disrupted by lack, reduction, or distortion of normal visual experience during critical postnatal periods. Similar limitations or manipulations of visual experience occurring after the critical periods have little or no damaging effects on visual behavior, attesting the essential participation of early visual experience in the maintenance of the selective connections laid down by developmental factors alone. Moreover, Hubel and Wiesel provided definitive evidence that the damaging absence of early visual experience can operate, as expected, because of disuse, but also, and even more effectively, because of a competition between deprived and non-deprived portions of the visual system (Hubel and Wiesel, 2005). Their discovery of the respective roles of development and experience in the organization of the visual cortex lay to rest the old philosophical nature-versus-nurture controversy, forcing extremely strict nativists and empiricists alike to concede that neither the genes plus development alone, nor experience alone, can give rise to and maintain functioning neural structures.

Sperry and the corpus callosum Sperry’s second great contribution to neurophysiology and clinical neurology was the discovery of the functions of the corpus callosum. One of the cornerstones of Lashley’s anti-connectionist stance had been his inability to find any demonstrable function for the corpus callosum, which he was inclined to regard as a mere “skeletal structure.” Lashley (1951) was impressed by findings suggesting that surgical callosal sections did not appear to cause clear-cut behavioral signs of interhemispheric disconnection in experimental animals, as well as in human patients submitted to callosotomy for controlling drug-refractory epileptic seizures. Thanks to better planned tests, Sperry’s

THE CONTRIBUTIONS OF NEUROPHYSIOLOGY TO CLINICAL NEUROLOGY (1961) split brain studies in cats and monkeys showed instead that the corpus callosum, far from being a mere mechanical link between the two hemispheres, is the essential route for the exchange of sensory, motor, and higher-order information between the two hemispheres. When new callosotomized epileptic patients became available for experimental studies, Sperry et al., (1969) found that sensory inputs restricted to and perceived by a single hemisphere became inaccessible to the conscious experience of the other hemisphere. From a neurophysiological standpoint, this was compelling proof that information acting on the mind is transmitted in the brain primarily, if not exclusively, via orthodox neuronal connections. This is true also of high frequency pathological discharges in epilepsy, whereby the corpus callosum is a major avenue for the interhemispheric spread of seizures (Moruzzi, 1939; Berlucchi, 1990). Electrical fields propagating through the brain as a volume conductor or chemical volume transmission may play some part in normal or pathological information processing, but such mechanisms are clearly insufficient by themselves to sustain interhemispheric communication in the absence of direct fiber connections between the two sides. The real existence of disconnection syndromes not only between the hemispheres, but also within a hemisphere, was also supported, in confirmation and rehabilitation of the so-called diagram-makers, by Geschwind (1965a, b; see Absher and Benson, 1993).

Hemispheric specialization as opposed to cerebral dominance Another bonus from the research on the effects of corpus callosum section in humans was the discovery of parallel and largely independent conscious processes in the two hemispheres, with language mainly or exclusively on the left and non-verbal abilities mainly on the right (Sperry, 1982). However, the initial claim that there are two separate conscious minds and free wills under the cranial vault of a split-brain patient was undoubtedly an exaggeration. Yet split-brain research rekindled the interest of clinical neurologists and neuropsychologists in the different cognitive abilities of the two hemispheres, previously based on the effects of unilateral lesions. The research of Henry He´caen and Oliver Zangwill on patients with unilateral brain lesions in the late 1940s and early 1950s had ushered in the modern era of investigation of hemispheric cerebral dominance (see Benton, 1991). As a partial consequence of split-brain research, the 1960s saw an explosive increase of studies on differential deficits following right and left hemispheric lesions. Congruent evidence from unilateral lesions

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and split-brain patients led to a definitive rejection of the classical overall left cerebral dominance in favor of a complementary functional specialization of the two hemispheres. The unique specialization of the left hemisphere for all language functions was confirmed not only in right-handers but also in most left-handers, but the right hemisphere was in turn found to be predominant in various cognitive tasks that cannot be aided by verbal mediation, like the exploration and cognition of space, the discrimination and recognition of unfamiliar and familiar faces, and the perception and memory of colors, and complex visual shapes. Lesions of the right hemisphere were attributed a special role in the unilateral hemineglect syndrome, as well as in emotional and affective disorders such as anosognosia, e.g., the denial of illness, and the flattening of affect (Geschwind and Galaburda, 1987). As a match to hemispheric asymmetries of functions in brain-injured patients, a multitude of tests with different sensory inputs channeled into single hemispheres of normal observers provided complementary evidence on various aspects of interhemispheric transfer and cognitive differences based on simple or choice reaction times (Milner, 1971). The time-honored methodology of mental chronometry was also applied to the analysis of attentional modulation of cognitive processes, allowing important distinctions between automatic and voluntary orienting mechanisms, as well as between the allocation of attention to spatial locations and that to objects (Posner, 2005). In turn, results in normal observers prompted similar studies in brain damaged patients, and in clear opposition to behavioristic tendencies, it became again acceptable for neurophysiology and clinical neurology to study the brain correlates of consciousness and mental processes in general.

Plausibility of a neuroscience of consciousness and memory For much of its history, neurophysiology has shied away from difficult psychological problems, such as the neural bases of memory and consciousness. A prudent separation between neurophysiology and all psychological sciences was constantly advocated in the past by famous neurophysiologists, including Pavlov and Adrian. Pavlov managed to avoid psychological terms in describing his conditioned reflexes, because he thought that the physiologist is lost when he uses the psychologist’s lexicon. For his part, Adrian always maintained that, although sensory signals could be traced by his techniques in the intact brain, their effect on the mind was scarcely one for the physiologist to settle (Adrian, 1947a).

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On the psychology side, radical behaviorists have traditionally prided themselves on an intentional policy of eschewing any attempt to correlate the pattern of behavioral effects under examination with causative changes in cerebral organization (Skinner, 1938). Such an attitude is shared by present-day ultracognitive neuropsychologists, who declare themselves to be interested in how the mind works but not in how the brain works (Coltheart, 2002). A few years ago the term consciousness was conspicuously absent in the analytical index of the first edition of a popular neuroscience textbook (Kandel and Schwartz, 1981), yet the same term appears 32 times in the analytical index of the 4th edition of that same handbook (Kandel et al., 2000). Fresh views emerging in the years separating the two editions must have turned cognition into a proper subject matter for neurophysiology and the neurosciences in general, including clinical neurology. Indeed the neurological problem of consciousness can now be tackled with the enormous technological achievements of the last decades. The changing patterns of brain activities and states in awake, mentally active humans can be imaged in a noninvasive way with a variety of methods, based on the recording of spontaneous or evoked electrical activities, as well as on the monitoring of changes in local blood flow related to metabolic and electrical activities of neurons and glia (Frackowiak, 1998; Raichle and Mintun, 2006). However, even the old method of searching for associations between brain lesions and cognitive deficits is still viable, since a new life has accrued to it by the possibility of an in vivo localization of brain lesions linkable with cognitive deficits. As examples, a few lines of investigations can be singled out as especially effective in providing some glimpses of the neural bases of consciousness and memory. As regards the neurology of memory, the field was revolutionized by the work of Brenda Milner on the famous patient H.M., who had been submitted to a bilateral medial temporal removal for epilepsy control. The resulting extremely severe anterograde amnesia was associated with normal short-term memory and fair-to-good long-term memory for preoperatory facts and events. The demonstration that this patient could learn at a nomal rate and retain skills of which he was totally unaware made a definitive case for a fractionation of memory into components, which had been postulated mainly on theoretical grounds but never revealed with such compelling evidence (Milner, 1962; Milner et al., 1968). The subdivision of long-term memory into the declarative and non-declarative categories, in their turn subdivided into different subcategories, has been given a solid neurological basis by the evidence that forms of memory distinguishable at the cognitive level are also associated with distinct neural

substrates at cortical and subcortical sites (Milner et al., 1998; Squire, 2004). Further, that different knowledge categories are represented in different regions of the cortex has been made clear by the existence of strikingly selective agnostic disorders that affect information processing of some categories of objects or living beings but not of other categories (Warrington and Shallice, 1984; Damasio, 1990). Finally, possible approaches to the neurology of consciousness have been furnished by the discovery of dissociations between conscious and unconscious forms of vision, as occur in blindsight and other special conditions in both brain-damaged patients and normal observers, and by the proposed distinction between an occipito-temporal brain system for conscious visual perception and an occipito-parietal brain system for visually-guided action, unaccompanied by awareness (Goodale and Milner, 2004). The term blindsight was originally coined to denote appropriate motor or verbal reactions of patients with primary visual cortex lesions to visual inputs from the supposedly blind contralesional part of their visual field (Stoerig and Cowey, 1997; Weiskrantz, 2004). Such appropriate reactions associated with the patients’ self-proclaimed unawareness of those inputs conflict with responses to visual inputs from the normal field, accompanied by full conscious awareness of the stimuli. This dramatic dissociation between those forms of visually guided behavior which are accompanied by consciousness and those which are not can be found in other pathological conditions as well as in normal observers in special testing conditions (Marzi et al., 2004). The blindsight phenomenon has therefore offered the opportunity to study the brain during conscious and unconscious information processing, where conscious and unconscious can be defined operatively (Stoerig and Cowey, 1997; Weiskrantz, 2004).

IONS, RECEPTORS, CHANNELS, AND SYNAPSES: DISCOVERIES IN NEUROPHYSIOLOGY AND APPLICATIONS IN CLINICAL NEUROLOGY If the year 1953 marked the triumphal birth of molecular biology with the discovery of DNA, 1952 was a similarly successful, if less clamorous, year for neurophysiology, with its spectacular advances in the understanding of neuronal excitability and synaptic transmission at a subcellular level.

Ionic bases of excitability and chemical nature of central synaptic transmission A series of papers by Hodgkin, Huxley, and Katz published in 1952 (Hodgkin and Huxley, 1952a, b, c, d; Hodgkin et al., 1952) presented a masterly quantitative

THE CONTRIBUTIONS OF NEUROPHYSIOLOGY TO CLINICAL NEUROLOGY description of the selective changes in the permeability of the membrane of the squid giant axon, which account for the generation and propagation of the action potential. The resulting “ionic hypothesis” of the action potential argued indirectly, though very convincingly, for the existence of separate pores or transporters. These would respond to decreases in the resting membrane potential by allowing sodium and potassium to flow across the membrane with different kinetics along their respective electrochemical gradients. Another epochal paper published in the same year announced the conversion of Eccles, perhaps the most distinguished pupil of Sherrington, to the acceptance of the chemical nature of the synaptic transmission between central neurons (Brock et al., 1952). For years Eccles had headed the so-called sparks faction, supporting the notion that impulses are transmitted between neurons by electrical induction, in the battle against the so-called soups faction, led by Sir Henry Dale, who instead believed in chemical synaptic transmission (Valenstein, 2005). In their 1952 paper, Eccles and coworkers reported that intracellular recordings from the cat spinal cord had falsified Eccles’ own hypothesis of an electrical synaptic inhibition of motoneurons, and therefore that the inhibitory synaptic action had to be mediated by a specific inhibitory transmitter released from the terminals of the inhibitory terminals.* Since the experimental evidence had left the chemical transmitter hypothesis as the only likely explanation for inhibition, it seemed reasonable to attribute synaptic excitation to a chemical transmitter as well. Subsequent experiments in Eccles’ own laboratory and in other laboratories established that synapses between central neurons did indeed work according to the general principles of chemical transmission previously discovered by Loewi and Dale in the automatic nervous system and the neuromuscular junction (Katz, 1966; Eccles, 1974). Put simply, presynaptic active fibers release a transmitter which binds to receptors on the postsynaptic membrane, and such binding changes the electrical state of the postsynaptic cell. In the same year, Fatt and Katz (1952) described the phenomenon of quantal release of acetylcholine at the neuromuscu*

[Note: The use of the verb “to falsify” in the paper by Brock et al., (1952) reflects the influence exerted on Eccles by the philosopher Karl Popper, who had befriended Eccles in the 1930s (Eccles, 1974). Popper had convinced Eccles that the best scientists must always endeavor to disprove (falsify) their own favorite scientific hypotheses by means of experiments. The long-standing association between the two culminated in their joint publication of the controversial book The Self and Its Brain (Popper and Eccles, 1977).]

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lar junction, which eventually led to another general principle of synaptic transmission, namely the vesicular release of synaptic transmitters as an electrically controlled form of neurosecretion, invariably requiring the entrance of calcium ions into the presynaptic terminal (Katz, 1966).

Voltage- and ligand-gated channels The ionic hypothesis of the action potential and the generality of chemical synaptic transmission in the peripheral and central nervous system started a massive search for the identification of molecules acting as ionic channels, receptors, and transmitters up to this day (Numa, 1987-88; Hille et al., 1999). Voltage-gated ionic channels were identified as integral proteins whose molecular configuration is sensitive to changes in the electrical field across the membrane, so as to allow appropriate opening and closing of channels. In contrast with voltage-gated channels, ligand-gated channels are also integral membrane proteins, but open in response to the binding of a chemical messenger (usually a synaptic transmitter) to a specific site of their molecule. The prototypic ligand-gated ion channel is the channel linked to a nicotinic receptor in the muscle plate, which opens upon the binding of acetylcholine to the molecular receptor site, allowing sodium and potassium to flow simultaneously through it along their electrochemical gradients (Colquhoun and Sakman, 1998). Families of voltage-gated and ligandgated ionic channels selective not only for sodium and potassium, but also for calcium, chloride, and for other small ions have now been identified. Many developments were generated by the discovery of glutamate as a central neurotransmitter, as well as by the identification of a third general type of ionic channel sensitive both to the electrical potential across the membrane and to the binding of glutamate to the receptor associated with the channel. The so-called NMDA receptor (Dingledine, 1986) opens when both conditions are present, but not when only one or the other of them is present alone (Collingridge et al., 1988). Before Eccles and the neurophysiologists accepted the concept of central chemical synaptic transmission, the list of ascertained or suspected synaptic transmitters was limited to those identified in the peripheral nervous system, i.e., acetylcholine and the catecholamines adrenaline and noradrenaline. Subsequently several molecules have gained recognition as synaptic transmitters in the central nervous system, for each of which there exist specific postsynaptic receptors linked to ionic channels. Ascertained central synaptic transmitters include acetylcholine, the aminoacid group (glutamate, glycine, and gamma-aminobutyric acid or

180 G. BERLUCCHI GABA), the amine group (adrenaline, noradrenaline, voltage-gated calcium channels in presynaptic termdopamine, serotonin, histamine), and ATP. There are inals and cerebellar neurons are in turn held responsiin addition many neuroactive peptides whose status ble for familial hemiplegic migraine and different as synaptic transmitters is as yet incompletely demonforms of episodic and spinocerebellar ataxia. Other strated. Glutamate, the most common excitatory forms of epilepsy and benign familial neonatal contransmitter in the brain, acts on various types of vulsions have been associated with mutations and receptors. malfunctioning of ligand-gated channels linked to glycine, GABA, and nicotinic cholinergic receptors Pharmacological revolutions in neurology (Kullmann, 2002).

and psychiatry The identification of molecules acting as ionic channels, receptors, and transmitters, and the clarification of their physiological roles in the working of the nervous system have been of enormous importance for clinical neurology. A number of neurological or psychiatric disorders can now be ascribed to damage, malfunctioning, or absence of a specific class of molecules in one or the other of the three categories. Typical examples include myasthenia gravis, due to loss of acetylcholine receptors of the muscle plate (Fambrough et al., 1973), and Parkinson’s disease, due to loss of the dopamine transmitter in the nigro-striatal pathway (Carlsson, 2000; Hornykiewicz, 2002). The serendipitous discovery in the magic year, 1952, of the calming effect of chlorpromazine on agitated schizophrenics (Delay et al., 1952) has revolutionized neuropsychiatry by suggesting that the major psychoses may be caused by abnormalities in one or more transmitter–receptor aminergic brainstem systems projecting to diencephalon and cortex. Transmitter– receptor malfunctioning in the cholinergic system may be involved in Alzheimer’s dementia. Knowledge of the molecular physiopathological bases of some of the above conditions has led to at least partially successful therapeutic interventions, such as the administration of l-dopa to Parkinsonian patients (Carlsson, 2000; Hornykiewicz, 2002) and the use of psychotropic drugs acting on the brainstem aminergic systems in the major psychoses. Grafts of embryonic dopaminergic neurons into the striatum of Parkinsonian patients have also been tried, so far with mixed results (Bjo¨rklund et al., 2003; Olanow, 2004). More recently, the concept of neuronal channelopathies (Kullmann, 2002) has been introduced to refer to neural dysfunctions amenable to inherited or acquired mutations of both voltage-gated and ligand-gated ionic channels, with consequent alterations of channel function. Neuronal channelopathies associated with mutations affecting different voltage-gated sodium and potassium channels are now held responsible for various forms of infantile and adult epilepsy, previously regarded as idiopathic, as well as for episodic ataxia and neuromyotonia. Further, mutations of

Developments in the understanding of neural plasticity William James (1890) was the first to use the word plasticity with regard to the hypothetical changes in nervous activity that underlie the formation of habits, and the psychiatrist Tanzi (1893) was the first to postulate that plastic neural changes involved in learning and memory are likely to occur as physical modifications of the interneuronal articulations subsequently called synapses by Sherrington. Many decades later, still from a theoretical point of view, Hebb’s (1949) book The Organization of Behavior made a strong impact on neurological thinking by suggesting that learning and memory could be based on changes in effectiveness of transmission at given synapses in orthodox “Sherringtonian” circuits. Only in the second half of the 20th century did it become possible to test the synaptic hypothesis of memory experimentally, thanks to reductionistic approaches combining electrophysiological and molecular analyses of cellular and synaptic changes induced in the simple nervous systems of invertebrates. Eric Kandel, one of the pioneers of the field (Kandel and Spencer, 1968; Kandel, 2000) with his studies of synaptic plasticity mediating simple forms of learning and memory in the mollusk Aplysia californica, was awarded the Nobel Prize in Physiology or Medicine in 2000, along with Carlsson and Greengard for their discoveries concerning signal transduction in the nervous system. A relatively simple model of synaptic plasticity in the nervous system of mammals was provided by the discovery of the electrical phenomenon called long-term potentiation (LTP) and the role played in it by the NMDA receptors. LTP is a long-lasting change in the efficacy of synaptic transmission due to repeated stimulation of the same or different synaptic inputs to a neuron. It was discovered by Terje Lmo in 1968 (see Lmo, 2003) and subsequently analyzed in detail by Timothy Bliss and Lmo himself (Bliss and Lmo, 1973) at the Institute of Neurophysiology, Oslo University. LTP and the converse phenomenon of long-term depression (LTD) of synaptic transmission activity are thought to be basic forms of neural plasticity heavily implicated

THE CONTRIBUTIONS OF NEUROPHYSIOLOGY TO CLINICAL NEUROLOGY not only in normal learning and memory, but also in functional recovery following brain lesions, as well as in abnormal neural reactions leading to diseases. NMDA-mediated pathological changes in synaptic transmission may indeed occur in a variety of neurologic diseases, which include epilepsy and ischemic brain damage, and perhaps also neurodegenerative disorders such as Parkinson’s, Alzheimer’s, and Huntington’s diseases, and amyotrophic lateral sclerosis. Some less severe disorders of human cognition can be ascribed to LTP-related dysfunctions in brain regions known to be critical for memory. Employment of repetitive transcranial magnetic stimulation is now being proposed for restoring LTP to normal levels in amnesic patients, as well as for obtaining beneficial results from appropriately induced LTP effects in brain regions of patients with Parkinson’s disease, epilepsy, or chronic neuropathic pain. Putative LTP effects have also proven to be effective in some cases of depression, where repetitive transcranial magnetic stimulation has been used as a substitute for electroconvulsive therapy. There is also considerable interest in the development of pharmacological agents active at NMDA receptors as new therapeutic agents in various neurological disorders (Cooke and Bliss, 2006).

THE CONTRIBUTIONS OF CLASSICAL NEUROPHYSIOLOGY TO ELECTROENCEPHALOGRAPHY, ELECTROMYOGRAPHY, NEUROGRAPHY, AND OTHER INSTRUMENTAL APPROACHES IN CLINICAL NEUROPHYSIOLOGY The initial developments of clinical neurophysiology centered on the techniques of electroencephalography (EEG) and evoked potentials, electromyography (EMG), and nerve conduction studies.

Berger, Adrian, and the birth of electroencephalography The introduction of electroencephalography and electrocorticography into basic and clinical research is usually associated with the name of a psychiatrist, Hans Berger, from Jena. Berger carried out a long series of competent investigations on brain electrical potentials in animals and humans, but published his results only partially and in some cases several years after obtaining them. He must be credited for correctly describing and naming the fundamental electrical phenomena that can be recorded from the scalp in various physiological and pathological conditions, from the alpha waves at rest to their blockade upon sensory stimulation (Berger, 1929; Berger, 1932; Berger, 1933–1934; Berger, 1935). It

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is therefore indisputable that a position of primary importance in the history of electroencephalography must be assigned to a psychiatrist, yet there is no doubt that some neurophysiologists made timely and crucial contributions to the field of EEG. Indeed Berger was preceded by Richard Caton, lecturer and then Professor of Physiology in Liverpool, who briefly reported in 1875 that electrical activities can be generated at the brain surface of animals, both spontaneously and in response to sensory stimuli. In a sense he may thus be considered the discoverer of both EEG and sensory-evoked brain potentials (Caton, 1875; see Brazier, 1959). However, even more crucial contributions from neurophysiology to electroencephalography were due to Adrian. He very effectively defended the validity of Berger’s interpretation of the EEG waves against those who did not believe that the tiny electrical currents of the brain could cross the skull and the scalp. Adrian dispelled all doubts about the actual neuronal genesis of the EEG waves in experiments on animals (Adrian and Matthews, 1934), which along with the cerveau and encephale isolé EEG studies by Bremer (1936, 1974) is considered by some (e.g., Cobb, 1969) the marker of the real beginning of the electroencephalography and clinical neurophysiology era. In addition, Adrian showed that the alpha waves of man originate mainly in the occipital cortex, and duly recognized Berger’s fundamental work by naming those waves “Berger’s rhythm” (Adrian and Yamagiwa, 1935). Adrian thought that the EEG waves were due to a summation of the activities of individual neurons, and in collaboration with Moruzzi he showed that the EEG waves from the motor cortex are indeed associated with discharges of action potentials along single fibers of the pyramidal tract (Adrian and Moruzzi, 1939). The proposal that the EEG waves are envelopes of action potentials from groups of neighboring cortical neurons is now known to be at least partially incorrect, but Adrian’s concepts of synchronization and desynchronization are still in current use for relating the EEG waves to electrical events at the neuronal level.

The EEG as a means of clinical investigation As regards the clinical use of the EEG, there is evidence that Berger had already seen abnormal EEG discharges in petit-mal epilepsy by recording with intracortical needles in the early 1930s. Yet his overcautious attitude kept him from publishing the results, because he was afraid of a contamination of the EEG recordings by muscle artifacts from the myoclonic twitches accompanying the attack (Jung, 1974). The first EEG study of epilepsy and impaired consciousness was thus published by Gibbs, Davis, and Lennox

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in 1935. One of the authors, Hallowell Davis, was a neurophysiologist working under Forbes, a pupil of Sherrington, in the Department of Physiology of Harvard University headed by Cannon. Davis’ students had read Berger’s papers and, after some skepticism, Davis had confirmed the presence of the alpha waves on his own scalp with a home-made “brain wave” apparatus. The neurologists William Lennox and Fred and Erna Gibbs, working at the Boston City Hospital, asked Davis to organize a brain-wave recording session on one of their patients with petit-mal epilepsy. The spike-and-wave EEG pattern, which is now known to be an electrical hallmark of that condition, was discovered in a single recording session in the Physiology Department in December 1934, during an attack with loss of consciousness (Gibbs et al., 1935). With this historical event, clinical electroencephalography was born in a Physiology Department with the midwifery help of a neurophysiologist (Davis, 1974). Shortly thereafter the clinical usefulness of the EEG for the localization of brain tumors was established by Grey Walter (1936), a former member of the Physiology Department of Cambridge University, and, in brief, EEG became a lasting indispensable diagnostic tool for clinical neurology, as well as for research on normal brain mechanisms.

The use of evoked and event-related potentials in neurophysiology and clinical neurology Since the 1930s, neurophysiologists have investigated in depth the various discrete electrical EEG changes that can be produced by natural activation of the sense organs, or by electrical stimulation at various locations along the afferent pathways to the cortex. The method has proved useful for establishing correlations between structure and function, such as the general localization of a sensory modality in the cortex, the topographic representation of the peripheral sensory periphery on the specialized cortical areas, the relative importance of each portion of the peripheral field in the cortical representation, and the possible existence of multiple cortical representations of the same sensory modality. Among the pioneering neurophysiological contributions one can mention: (1) Kornmu¨ller’s (1933) finding that visual cortex mapped with evoked potentials coincides with the citoarchitectonically defined area striata; (2) Bishop and O’Leary’s (1938) study of the different waves produced in the visual cortex by electrical stimulation of the optic pathway; and (3) Adrian’s demonstration that areas of skin preferentially used in the exploration of the outside space, such as the snout in pigs, the nostrils in horses, and the hands in monkeys,

have a proportionally greater representation in the somatosensory cortex compared to less-used peripheral parts (Adrian, 1947a). Other early neurophysiological contributions using evoked potentials include Talbot and Marshall’s (1941) demonstration of the retinotopic organization of the visual cortex, Woolsey’s (1952) exhaustive mapping of sensory areas of the cerebral cortex from a comparative point of view, and the socalled strychnine neuronography used by Dusser de Barenne and McCulloch (1939) for tracing connections between cortical areas. After the first neurophysiological studies in normal humans (Brazier, 1984), the evoked potential method has found applications in clinical neurology, especially for the early diagnosis of neurological disorders and for their localization in the nervous system. As an example, the pattern-reversed stimulation of the visual system was developed and is still useful for the early diagnosis of optic neuritis in multiple sclerosis, based on an increased latency of the evoked response (Halliday et al., 1973). Abnormalities of auditory evoked potentials (Robinson and Rudge, 1977) and somatosensory potentials evoked in the spinal cord and somatosensory cortex on stimulation of the median and posterior tibial nerves (Small et al., 1978) are also useful to detect demyelinating lesions in the brainstem and cord. Abnormality of the latency and amplitude of the evoked response are also seen in a variety of conditions including compression and degeneration. Event-related potentials originally discovered in normal observers by physiologists or neurologists with physiological training include the contingent negative variation (CNV) or expectancy wave (Walter et al., 1964), the Bereitschaftspotential or readiness potential (Kornhuber and Deecke, 1965), the P300 wave (Sutton et al., 1965), the mismatch negativity (Na¨a¨ta¨nen et al., 1978), and other brain electrical phenomena. These have subsequently been variously employed in investigations in normal observers for basic research (Rugg and Coles, 1995), as well as in neurological patients for assessing disorders of attention, arousal, motor preparation, and other sensory and cognitive functions (Regan, 1989).

Neurophysiological and clinical uses of electromyography Like the EEG, electromyography (EMG) is currently an essential diagnostic tool in clinical neurology for investigating the severity, the pathophysiology, and the distribution of neuromuscular disorders (Sta˚lberg and Falck, 1997). Neurophysiologists rank prominently among those who established the theoretical and empirical bases for the development of the EMG technique. The possibility of recording muscle electrical

THE CONTRIBUTIONS OF NEUROPHYSIOLOGY TO CLINICAL NEUROLOGY potentials with surface electrodes positioned on the skin overlying the muscles was already known in the 19th century, but the groundwork for a full exploitation of the EMG in experimental and clinical tests was done in 1929 by Adrian and Bronk. They were able to record from single motor units by means of a concentric electrode that they had developed for the purpose and that is still of much use in present-day EMG tests. Based on the Sherringtonian concept of the motor unit, they could indirectly measure for the first time the discharge of single motoneurons as muscle unit potentials during a voluntary contraction of their own arm muscles. By this approach they established the two basic principles of muscle force regulation: as contractions become more powerful, the discharge frequency within a single unit rises, and so does the number of units coming into play (Adrian and Bronk, 1929). Neurophysiologists were also strongly involved in the first clinical applications of the EMG technique with single muscle unit recording. In 1938, Derek Denny-Brown, a former pupil of Sherrington who worked at the National Hospital in London (see above), reported the first EMG characteristics of fasciculation and fibrillation in skeletal muscles (Denny-Brown and Pennybacker, 1938), and in 1941 Buchthal and Clemmesen described characteristic EMG indexes of neuropathy and muscle atrophy in poliomyelitis. Fritz Buchthal, founder and director of the Institute of Neurophysiology in Copenhagen, contributed in many ways to the understanding of the physiological and pathological EMG bases by promoting important technical advances such as quantitative EMG (e.g., Buchthal and Pinelli, 1953; Buchthal et al., 1955). Another neurophysiologist who made pioneering contributions to clinical EMG was Eric Kugelberg, who described the EMG alterations in muscular dystrophy for the first time (Kugelberg, 1949). Kugelberg had started his scientific career at the Karolinska Institute in Stockholm in the neurophysiological laboratory of Ragnar Granit, who was awarded the Nobel Prize in Physiology or Medicine in 1967, along with Haldan Hartline and George Wald for their discoveries concerning the primary physiological and chemical processes in the eye. Kugelberg then went on to found one of the first clinical neurophysiology laboratories at the Karolinska Institute.

Combined use of EEG and EMG in polisomnography Polysomnography is the combined recording of EEG and other physiological parameters (such as ocular movements, EMG activities, blood pressure, respiration, and so forth) during sleep in humans. Recordings of the EEG during sleep in humans were first obtained by Berger (1929) followed by neurophysiologists

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including Blake and Gerard (1937) and Hallowell Davis, his wife Pauline and their collaborators (Davis et al., 1938). Nathaniel Kleitman, a professor of physiology at the University of Chicago, was responsible for starting systematic investigations on the phenomenology of sleep in humans. With Aserinsky (Aserinsky and Kleitman, 1953) and Dement (Dement and Kleitman, 1957a, b) he identified various stages of sleep and particularly the stage associated with dreaming and rapid eye movements. These findings in humans were linked with those of experiments in animals (Jouvet, 1967; Moruzzi, 1972; see also above, page 175), engendering one of the most lively developments of neurophysiology in the 20th century. The clinical applications of polysomnography resulted in the foundation of a specialty called sleep medicine, dealing not only with sleep disorders, but also with sleep as an activator of pathological expressions such as epilepsy and circulatory and respiratory dysfunctions (Dement, 2005; also see sleep chapter in this volume).

Neuron conduction studies Two physiologists from Berlin, Piper and Hoffmann, pioneered the method of electrical stimulation of peripheral nerves in man, in order to record direct and reflex motor responses with skin electrodes overlying the contracting muscles. By using this method, Piper (1907) made the first assessment of conduction speed in myelinated motor fibers. His assistant, Hoffmann (1910), who later taught physiology in Freiburg im Breisgau, was able to demonstrate (mostly on himself) two kinds of muscle responses in the calf to electrical stimulation of the tibial nerve in the posterior popliteal fossa: a fast one due to direct stimulation of motor fibers, and a delayed one due to stimulation of afferent fibers. The delayed response is now known as the H-reflex, a near electrical equivalent of the myotatic reflex. The technique inaugurated by Hoffmann is still widely used in clinical neurology for bypassing the receptors in tests of various reflex centers and pathways in normal and pathological conditions (see Pierrot-Deseilligny and Mazevet, 2000). A later major contribution of neurophysiology to clinical neurography was the classification of single fibers of peripheral sensory and motor nerves into categories with different conduction velocities and specific functions. This classification was made possible by the first employment of the cathode-ray oscillograph in nerve recording studies by the American physiologists Erlanger and Gasser (1937), who shared the 1944 Nobel Prize in Physiology or Medicine for their discoveries relating to the highly differentiated functions of single nerve fibers. Nerve conduction studies are currently employed in clinical neurology for the

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diagnosis of focal neuropathies and polyneuropathies, allowing the distinction between demyelinations, axonal degenerations, and conduction blocks. A relatively recent development in electrical studies on peripheral nerves is microneurography, a technique initiated in Uppsala by clinical neurophysiologists Hagbarth, Vallbo, and their coworkers, who had trained in neurophysiology at the Karolinska Institute in Stockholm with Granit. They were able to record from and stimulate single fibers in human peripheral nerves with percutaneously inserted needle electrodes, and to correlate their activities with perception and other functions (Hagbarth and Vallbo, 1968; Vallbo and Hagbarth, 1968; Vallbo, 1981). In clinical neurology, the microneurographic method has allowed and allows one to obtain evidence on spindle function and more generally on proprioceptive, tactile, nociceptive, and autonomic mechanisms in normal observers and in patients with spasticity or rigidity and other neurological disorders (Vallbo et al., 2003).

Newer instrumental technologies The new technologies presently applied in basic neuroscience and in clinical neurology include magnetoencephalography, positron emission tomography, magnetic resonance imaging, and transcranial magnetic stimulation. These techniques have evolved in fields different from classical neurophysiology, such as radiology, medical physics, and engineering, and highly specialized clinical neurophysiology, although in a few cases certain basic premises for their development were foreseen by traditional neurophysiologists. For example, the coupling between brain work and blood flow, which is the foundation of modern brain imaging with functional magnetic resonance, was already predicted in the afore mentioned studies of Mosso (1880) and Roy and Sherrington (1890) and later elaborated by Sokoloff and Kety (1960) and Lassen and Ingvar (1961). However, on the whole it seems fair to say that neurophysiological inquiry has benefited from the new instrumental techniques far more than neurophysiology has contributed to their development.

ACKNOWLEDGMENTS The preparation of this chapter has been aided by grants FIRB and PRIN from the Ministero dell’Universit a e della Ricerca of Italy. Thanks are due to Mr. Marco Veronese for preparing the figures and to Prof. Paolo Moruzzi for supplying Fig. 13.2.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 14

Landmarks of surgical neurology and the interplay of disciplines STANLEY FINGER 1 * AND JAMES L. STONE 2 Department of Psychology, Washington University, St. Louis, MO, USA 2 Departments of Neurological Surgery and Neurology, University of Illinois at Chicago, Chicago, IL, USA 1

INTRODUCTION The discovery of cortical localization of function, with its origins in neurology and important support from the experimental physiologists, had scientific, philosophical, and practical ramifications. On the one hand, scientists and philosophers now had a new way of thinking about the faculties of mind, the cerebral hemispheres, and the functional organization of the brain. And on the other, it was instrumental in giving clinicians the help they sorely needed for diagnosing the sources of previously “hidden” brain disorders. In these pivotal ways, cortical localization of function was well positioned to change the possibilities for brain surgery. But significant obstacles still had to be overcome. Brain surgery was rarely performed in European hospitals before the closing decades of the 19th century, in part because location of the “mischief” could not be ascertained easily in patients who did not exhibit external signs, such as depressed fractures, focal changes in skull coloration, or abnormal bulges on the cranium (Wilkins, 1997). Hence, when brain surgery was performed, the cases were likely to have severe, traumatic head injuries and/or surface outgrowths, not necessarily tumors of the brain itself. In this context, in 1835 Professor Zanobi Pecchioli of the University of Siena removed a “cancerous fungus of the dura mater,” which had also eroded the skull and formed a large extracranial mass (Pecchioli, 1838; Giuffre`, 1984). A second major factor steering general surgeons away from operating on the brain was that such interventions were often associated with serious complications, such as meningitis and abscesses, which could result in death. This was especially so in large, crowded European hospitals. Further, opening the dura mater was frequently

*

associated with post-operative cerebrospinal fluid leakage and herniation of the brain, also contributing to mortality. Without question, those who dared to practice this very dangerous art required not only better guides and indications for operating, but improved surgical techniques with more control over such factors as infection and changes in intracranial pressure. This chapter looks at the development of brain surgery primarily in the second half of the 19th century, when the theory of cortical localization was leading to new ways of thinking about disorders of the nervous system. The emphasis will be on a few prominent surgeons and landmark events that markedly changed perceptions about surgical neurology. We shall begin with Paul Broca, whose case studies and insightful publications during the 1860s played a major role in starting the localization revolution, and who was the first surgeon to perform a craniotomy based on principles of cerebral localization. Other individuals who will figure prominently in the development of what Harvey Cushing would later call “neurosurgery” are William Macewen, Rickman Godlee, and Victor Horsley. Their seminal contributions will be described after first showing how the surgical environment was dramatically altered by the availability of general anesthetics and antiseptic chemicals. We shall conclude with brief mention of some of the other notable events in the pre-Cushing era, and some remarks about what Cushing did for the field in the opening decades of the new century. Throughout this chapter it will become clear that the advent of “modern” brain surgery was highly dependent on developments in other disciplines, specifically

Correspondence to: Dr. Stanley Finger, Department of Psychology, Washington University, St. Louis, MO 63130-4899, USA. E-mail: [email protected], Tel: +1-314-935-6513, Fax: +1-314-935-7588.

190 S. FINGER AND J.L. STONE neurology, experimental neurophysiology, and general right extremities. Further, before the developsurgery. It will also be seen that clinical neurology ment of this paralysis, there was a short period owes a debt of gratitude to the few surgeons of this where the patient demonstrated an alteration in period who had successes when operating on the brain, his language faculty with coincidental normal since they contributed to the guiding theory of cortical intelligence (comprehension) . . . I thus believe localization of function, answered questions about surthat the beginning of this abscess process began vival and recovery of function, and improved the qualat the level of language articulation of the brain. ity of life for many neurological patients. That is to say, it started at the posterior aspect of the third left frontal gyrus. (Broca, 1876; trans. in Stone, 1991, p. 155)

BROCA’S CASE OF 1871

In 1861, Paul Broca published his case studies of Messieurs Leborgne (“Tan”) and LeLong, two individuals who lost fluent speech after damage to the posterior frontal lobe (Broca, 1861a, b, c; Finger, 2000, pp. 137– 154). Two years later, Broca (1863) had accumulated eight such cases, and the number continued to rise over the next 2 years. By 1865, the famous Paris surgeon was not only able to associate loss of fluent speech with damage to the third frontal convolution, but to proclaim that the causal lesion for such a loss will likely be found in this part of the left hemisphere (Broca, 1865). The opportunity for Broca to put his new information about the localization of fluent speech to practical advantage presented itself in 1871. Approximately 3 years after he had been appointed Professor of Clinical Surgery, a laborer aged 38 was sent to his service at l’Hoˆpital Pitie´. He had been kicked by a horse above the left frontal-parietal region. Pierre Baron did not have a fracture, excessive bleeding, sensorimotor problems, fever, or loss of consciousness when first examined. But his condition changed for the worse several weeks later, following an epidemic of hospital erysipelas, and he experienced headaches, vomiting, a drop in pulse, and fever. These non-localizing signs and symptoms improved somewhat, but by 1 month after injury Broca noted that his speech was becoming affected. Sometimes he did not respond and at other times he repeated a phrase in French for “It is not going badly,” even when this answer had nothing to do with the question. Shortly thereafter, Pierre Baron had great difficulty articulating his words. In addition to his aphemia, he exhibited a paralysis and a loss of sensation of his right hand, although he could move his tongue and his other extremities to verbal commands. He was deteriorating rapidly and days later he was in light coma. Broca explained: These late symptoms . . . in a patient who did not sustain any appreciably serious accident, revealed the existence of an intracranial abscess . . . Location of this abscess was evidently on the left, as the patient demonstrated paralysis of the

On the basis of what he knew about the localization of the faculty for articulate language, Broca now opened the left side of Baron’s skull and searched for the suspected abscess. Although his patient had a nearby scalp laceration, Broca stated he was primarily guided by his knowledge of the cerebral center for articulate language and by his research on cranio-cerebral topography (Seguin, 1878). Using cadavers, he had inserted pegs through holes in crania at selected points and then determined the brain parts touched by the pegs (Seguin, 1878). His creative investigations had enabled him to know where to open Pierre Baron’s skull to get right to the region that now bears his name. The instant Broca elevated the bone above the speech area, a large amount of “creamy white pus” spilled forth. He decided not to probe below the dura at the time. His patient regained consciousness that afternoon, but could still not talk, even though he tried to speak and had reasonable language comprehension. Later in the day, after he relapsed into coma, Broca operated a second time, certain his patient would die if nothing more were done. Consequently, the dura was punctured with a syringe, which was then used to search (suction) for additional pus. The next afternoon Pierre Baron was dead. The autopsy revealed pus between the dural and pial membranes. In addition to this infiltration, which “resembled an abscess,” there was “superficial encephalitis” and necrosis centered in the third frontal gyrus of the left hemisphere. The organ of fluent language appeared “red, inflamed, and soft,” in accordance with what Broca had predicted. Broca concluded his short report on Pierre Baron by writing that clinicians will recognize the significance of the case, even though his patient did not survive. For the first time, the diagnosis and treatment of a brain disorder was based on cortical localization of function. Additionally, Broca had demonstrated how newlydetermined skull–brain relationships, namely craniocerebral topography, could be useful to surgeons. Given the landmark nature of the Baron case, it seems surprising that Broca opted to wait 5 years, until 1876, to publish his study. One possibility for this is that he might have felt unsuccessful, since his patient

LANDMARKS OF SURGICAL NEUROLOGY AND THE INTERPLAY OF DISCIPLINES died. Another is that many of his colleagues might have disagreed with his decision to operate. Trephination, even for head injuries, had fallen out of favor. Broca (1866) and his notable contemporary, C.E. Sedillot (1870), were in the distinct minority when they were recommending surgical elevation of depressed skull fractures to avert seizures and other complications. The case of Pierre Baron might not have been published at all were it not for Just Lucas-Championnie`re, Broca’s talented student and a man who had also studied surgery under Joseph Lister in Glasgow (Stone, 1991). Lucas-Championnie`re is often cited for writing the first detailed monograph on antiseptic surgery (1876) and introducing Lister’s antiseptic principles to France (Keith, 1919). He used Lister’s methods for various surgeries, including treating fractures of the cranium (Lucas-Championnie`re, 1875, 1878b), and he wrote two reviews on brain surgery, advocating aggressive antiseptic trephination for trauma and suspected brain abscess based upon cerebral localization (LucasChampionnie`re, 1876, 1878a). A similar message was soon to be promoted by other surgeons, including von Bergmann in Germany (1880), Roberts in Philadelphia (1883), and Wiesmann and Kronlein in Zurich (1884). Broca did not mention using general anesthesia in his report. He stated that Monsieur Baron moved somewhat during surgery, yet “never cried or gave any sign of consciousness.” Broca also made no mention of antiseptic procedures, which by 1871 were known though used by few French surgeons. Antiseptic principles became more generally accepted in France after Broca died in 1880. These developments merit further comment, as they significantly altered the future of brain surgery.

GENERAL ANESTHETICS Agents that could diminish pain and even affect consciousness, such as wine and opium, had been used in surgery since classical antiquity (for histories, see Keys, 1963; Bingham, 1973; Cottrell, 1980; Atkinson and Bolton, 1989; Tracy and Hanigan, 1997). In 1772, Joseph Priestley discovered nitrous oxide, and 3 years later Sir Humphry Davy noted that it might be useful for surgery because it has anesthetic properties. Nevertheless, there is no evidence to show that it was used for surgery at this time. Nitrous oxide became better known in the opening decades of the 19th century, when it was distributed at “laughing gas parties.” Another newfound source of amusement in the new century was the so-called ether frolic. It was from these social events that several American dentists in the 1840s thought to use these anesthetics to extract teeth. The American surgeon Crawford W. Long of Georgia is usually cited as the first person to use

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ether in other surgeries, and in 1842 he used it for three minor procedures, including the removal of a small tumor from the neck of James Venable, one of his patients. Long, however, did not publicize what he had done for several years, by which time others had published their experiences with general anesthetics. One such person was Horace Wells, a Connecticut dentist who had a tooth of his own removed under ether late in 1844. Wells then demonstrated the anesthetic to John Warren and medical students at Harvard University, but the students considered the 1845 demonstration a failure when the patient, who had received insufficient ether, suddenly cried out. Wells then worked with another dentist, William Morton, to perfect the use of sulfuric ether, and in 1846 Morton and Warren used it successfully to remove a tumor from the jaw of a patient at the Massachusetts General Hospital. By mid-century, ether, nitrous oxide, and chloroform were being used in surgery. Chloroform, discovered in 1831, was probably first used in human surgery in 1847 (Simpson, 1990). It became the agent of choice in Great Britain and throughout much of Western Europe after Queen Victoria used it in childbirth, whereas ether was the preferred general anesthetic in North America. General anesthetics meant that patients no longer had to endure the pain long associated with most operations. Surgeons could now take more time to perform delicate or lengthy operations that might not even have been attempted previously. Nevertheless, not all surgeons were quick to turn to the new anesthetics: some surgeons still looked upon these agents as experimental; there was still the belief that pain is beneficial to the healing process; and they were costly and difficult to obtain in some places. In addition all had risks, such as hypotension, shock, and unpredictable idiosyncratic reactions. Only after learning more about these anesthetics, and with the advent of better monitoring procedures, would surgeons become less hesitant about using these agents for brain and spinal cord cases (see below).

LISTER’S CRUCIAL ROLE It can be argued that, even with the establishment of localization principles and general anesthetics, surgical outcomes might have changed little were it not for Joseph Lister (Fig. 14.1; for biographies, see Godlee, 1917; Thompson, 1934). It was Lister who demonstrated that often deadly post-operative infections, including hospital gangrene, could be minimized or even eliminated by chemical means from a frightful 40–50% mortality level in major European city hospitals.

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Fig. 14.1. Joseph Lister (1827–1912), whose chemical procedures minimized post-surgical infections. (With permission of the University of Illinois, Department of Neurology, Center for the History of Neuroscience.)

Survival rates were actually higher, and infections lower, in rural areas than they were in the city hospitals. The miners treated for head injuries in Cornwall (Hudson, 1877), and the settlers suffering from epilepsy of traumatic origin in the Mississippi Valley (Dudley, 1828), for example, had better chances of surviving craniotomies than industrial workers in Edinburgh, London, and other large cities prior to Lister. Surgeons who did not wash their hands or clean their instruments as they went from patient to patient were a major source of the difficulty. Nevertheless, the better results in the countryside were more likely to be attributed to cleaner air (Dudley, 1828; Jensen and Stone, 1997; Stone, 2002). Joseph Lister graduated from medical school at University College Hospital, London, in 1852. He then moved to Edinburgh, where he served as a house surgeon. In 1859, he was appointed Regius Professor of Surgery at Glasgow University, and a year later he took the post of surgeon at the Glasgow Royal Infirmary, where he initiated the principles that made him famous. Some physicians and surgeons had recognized that infections could be reduced by washing hands, instruments, and wounds with alcohol, chlorinated soda,

and other chemicals, before Lister appeared on the scene (Thompson, 1934; Bowman, 1942; Alexander, 1955; Lawrence and Dixey, 1992; Wilkins, 1997). Certain agents, including pitch, tar, wine, and turpentine, have long histories. In the parable of the Good Samaritan, for example, there is a description of a wound treated with wine. Still, most city hospitals continued to have poor sanitation, wounds were not carefully cleaned, and only a few mid-19th-century surgeons actually employed disinfecting agents. Moreover, although some medical attention had been drawn to the hidden dangers of the “invisible world” by Benjamin Marten, Cotton Mather, Benjamin Franklin, and others in the 1700s (Finger, 2006, pp. 151–164), cleanliness and the use of such agents lacked a well-accepted theoretical foundation before Louis Pasteur popularized germ theory. During the 1860s, Pasteur showed that microscopic germs, which cause fermentation and probably putrefaction in animal tissue, could be filtered from the air and killed by heat. Thomas Anderson, a professor of chemistry at Glasgow University, informed Lister about Pasteur’s work. Additionally, Lister probably read an article by Wells in the British Medical Journal of 1864 on germ theory. Lister had seen many patients die in filthy city hospitals from infections after undergoing surgery. When it came to survival and health statistics, his Glasgow Royal Infirmary ranked poorly. Hence, he was ready to recognize the importance of the new chemistry for surgery. He would meet with Pasteur in 1878, 1881, and 1892, and would praise Pasteur throughout his professional life for furnishing him with the theory he needed for revolutionizing surgery, post-operative treatment, and hospital hygiene in general. Starting in 1865, Lister began to use Pasteur’s theories of putrefaction, brought about by living airborne particles, to account for infections after surgical wounds. His sacred mission was, first, “the destruction of any septic organisms which may have been introduced into the wound,” and, second, to prevent new germs from even getting to the wound (Lister, 1867a, p. 353). After trying several agents, he settled on carbolic acid (phenol, phenic acid), a dark, smelly liquid that is the active ingredient of creosote. At the time it was being used to disinfect garbage dumps. Lister began by treating large, open wounds of the arms and legs that were associated with bone fractures. He cleaned the skin and muscle wounds and spread carbolic acid putty on them. They were then covered with a thin sheet of tin (to minimize evaporation and

LANDMARKS OF SURGICAL NEUROLOGY AND THE INTERPLAY OF DISCIPLINES 193 prevent airborne germs from entering), and the putty Cerebral localisation . . . has been as a lamp to was changed regularly. The results were so good that lighten the path of the clinicist through a darkness he soon extended his work to abscesses, although not almost chaotic; it has sharpened clinical vision, so abscesses of the brain, and published his results and that now many things are clearly seen which were thoughts in 1867 (Lister, 1867a, b, c). formerly supposed not to exist; it has given a deciLister accepted the chair of clinical surgery in Edinsion to clinical and pathological descriptions burgh 2 years later. Convinced that “minute organwhich will be searched for in vain in the older isms” (“putrid exhalations”) in the atmosphere must records; it has cleared our conception as to the sigplay a significant role in spreading infections, he intronificance of numerous symptoms, and rationaduced a carbolic acid spray for saturating operating lised many purely empirical generalisations, and rooms with antiseptic on New Year’s Eve, 1870. His is every day bringing us nearer that which Virchow new spray made the surgical theatre pungent and irrihas termed the goal of modern medicine, namely, tating for both patient and surgeon, but it made it localisation of disease . . . There are already signs much safer. Lister also treated the instruments, the surthat we are within measurable distance of the rounding skin, and his own hands, as he broadened his successful treatment by surgery of some of the use of the effective agent. Further, he experimented most distressing and otherwise hopeless forms of with other chemicals, including boric acid, zinc, merintracranial disease . . . cury, and ammonium chlorides, always looking for He added that improvement. Lister’s system of surgery changed as he learned after what I have seen of the unfailing safety . . . more. In fact, soon after he started, pure carbolic acid with which the most formidable and repeated gave way to a weaker solution and his putty was operations can be performed on the brain and replaced by a different dressing. The new approach to its covering, under stringent antiseptic precausurgery was not, however, accepted right away, not tions, and these on animals of the most delicate, even in Lister’s native Scotland (Granshaw, 1992; almost human organisation, I cannot but believe Lawrence and Dixey, 1992). The most serious problem – that similar results are capable of being stemming mainly from practitioners who did not achieved on man himself. follow all of his recommendations – was that it did Ferrier was referring to his own monkeys with cortical not always seem to work. Two others were the increased ablations. Since adopting Listerian procedures a few time needed and the expenses involved. Yet another years earlier, he and his surgical colleague Gerald limiting factor was the competing idea that greater Yeo had been able to keep their brain-damaged moncleanliness could be just as effective as chemical keys healthy for months and even years after their surantisepsis. geries, allowing them to study the long-term effects of Over time, more and more surgeons would accept large cerebral ablations, a subject of great interest to what Lister was saying. Of great importance in this neurologists (Finger, 2000, pp. 155–175). regard was Lister’s move to London in 1877, where Neurologically oriented physicians in other counhe was appointed Professor of Clinical Surgery at tries, including the United States, now agreed that surKing’s College Hospital. His move was met by articles geons should consider operating more upon the human in the Lancet opposing him and his new appointment, brain, since they could be guided by cerebral localizaand faculty and students heckled him (Granshaw, tion and could use antiseptic procedures. In New York 1992; Gaw, 1999). Within a few years, however, many City, for example, Edward C. Seguin and his associate surgeons in London’s largest hospitals were turning to R.W. Amidon published several papers on cerebral his antiseptic methods (together with improved cleanlocalization, cranio-cerebral relations, and indications liness) and he was recognized as a hero. for neurosurgical intervention (Seguin, 1878; Amidon, 1884, 1885). More comprehensive reviews and appeals THE INTERPLAY WITH NEUROLOGY for brain surgery were published by neurologists P.C. AND OTHER DISCIPLINES Knapp of Harvard University in 1891 and Moses Allen Eminent English and French neurologists, including Starr in 1893 – the latter succeeding Seguin at ColumJackson, Ferrier, Gowers, and Charcot, saw merit in bia University (Greenblatt, 1997). the doctrine of cerebral localization, and were anxious Neurologists and general physicians, including Silas to see the new doctrine applied to, and confirmed by, Weir Mitchell, Charles K. Mills, and William Osler, all brain surgery. In his Marshall Hall Oration of 1883, then in Philadelphia, and Seguin and his associates in David Ferrier (1883, p. 807) stated: New York City, collaborated with willing surgeons

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and, in 1887, began to operate on brain tumors in the United States. These men were stimulated by news from across the Atlantic, especially the recent success of British surgeons William Macewen, Rickman Godlee, and Victor Horsley, who based their surgeries on the latest developments in clinical and experimental neurology.

WILLIAM MACEWEN William Macewen (Fig. 14.2), Lister’s most ardent disciple in Scotland, was born on the Island of Bute west of Glasgow in 1848, but moved with his large family to Glasgow in 1860 (Bowman, 1942; Macmillan, 2004). He enrolled as a medical student at the University of Glasgow 5 years later, determined to become a surgeon. When he attended Lister’s lectures on surgery, he was immediately taken by his vision, his theory, and, importantly, his results. Macewen graduated from medical school and accepted positions at the Glasgow Royal Infirmary clinic and the nearby Hospital for Sick Children. After working on other body parts for several years, he began to think more about the brain. During the 1870s, to use his own words, “the brain was a dark continent,” and operating on it was considered so futile and harmful that “the trephine was regarded as an almost obsolete

Fig. 14.2. Sir William Macewen (1848–1924), disciple of Lister and pioneer of brain surgery, late in life.

instrument” (Macewen, 1888, p. 302). But he had read some of Broca’s publications and was impressed by Fritsch and Hitzig’s, Jackson’s, and Ferrier’s new clinical and experimental findings, realizing their implications for brain surgery (Jefferson, 1960; Walker, 1967; Macmillan, 2004, 2005). Macewen’s desire to operate directly on the brain did not have an encouraging start. In 1876, the year in which Broca’s craniotomy case was published, he had good reasons to operate on an 11-year-old boy admitted to the Royal Infirmary. He suspected he was suffering from a brain abscess after enduring a head injury 2 weeks earlier. The motor signs and aphasia gave Macewen the information he needed in order to know where to open the skull, and it was not where the boy’s forehead exhibited a scar from the injury: Had this cicatrix been taken as a guide to the localization of the abscess, and an operation performed there, no abscess would have been found. But other phenomena were exhibited which enabled its seat to be definitely recognized. A convulsion, accompanied by loss of consciousness, commenced on the right side, and gradually involved the whole body. On its cessation absolute hemiplegia of the right side was present, and remained for two hours, during which the patient was aphasic . . . From these symptoms an abscess was diagnosed to be situated in the immediate vicinity of Broca’s lobe. (Macewen, 1888, p. 303) Macewen advised antiseptic surgery with Broca’s region as his target, but the boy’s parents rejected his advice after hearing what other medical people and some relatives thought. In the end, an operation was not performed – and the boy died. Macewen was now given permission to perform his intended operation on the dead boy’s brain, much as if he were still alive. It revealed an operable brain abscess about the size of a pigeon egg in Broca’s area, precisely where Macewen had said it would be. This case served to strengthen Macewen’s belief in the importance of timely surgical interventions based on functional maps of the brain. Indeed, Macewen was a man of very strong beliefs, especially when it came to his patients. Sarcastic, rude, and even hostile at times, students and staff would refer to Macewen as “the Great I Am” and “the Lord God Almighty” (Walker, 1967, p. 179). The year 1879 proved a landmark for Macewen. First he examined pus under a microscope and found it teeming with microorganisms, confirming Lister’s germ theory (Bowman, 1942, p. 65). And second, he began a series of successful operations on the brain.

LANDMARKS OF SURGICAL NEUROLOGY AND THE INTERPLAY OF DISCIPLINES These surgeries utilized Lister’s principles and were based on descriptions and new functional maps of the cortex. Most important in the latter domain were Broca’s work and David Ferrier’s 1876 book, The Functions of the Brain, which included both animal experiments and brain-damaged human cases. One of Macewen’s first cases was a teenage girl with swelling over her left eye. She had previously had a tumor of the left orbit removed, but it now seemed to have grown back. Moreover, she developed seizures of the right arm and face that were increasing in frequency and intensity, and she was suffering from headaches. Macewen hypothesized that a potentially lethal tumor, in some way related to the tumor of the orbit, was growing and exerting pressure on the left motor cortex. The girl was sedated and, under antiseptic conditions, her skull was opened over the left frontal lobe. A continuation of the tumor that adhered to the top and undersurface of the dura was discovered and successfully removed. The girl, who probably had a meningioma, was described in print in 1879, and she was listed as “Case in which the Symptoms Exhibited pointed to Lesion in Frontal Lobe” in Macewen’s more comprehensive 1888 paper. A second early case involved a 9-year-old boy who fell out of a window 15 feet above the ground and landed on his head. He developed Jacksonian seizures beginning on the left side of his face within a few days of his fall. The convulsions then worsened and he lost consciousness. In 1881 Macewen wrote that the symptoms suggested right hemispheric damage involving the brachio-facial centers, and that his hypothesis was consistent with some skull discoloration in the region of the coronal suture. Nevertheless, he described the boy under “Case in which Motor Phenomena were the Sole Guides to the Cerebral Lesion” in 1888. This boy was anesthetized and a skull fracture was found. Because it did not press on the brain, and therefore could not account for the symptoms, a disk of bone was subsequently removed. Nevertheless, no blood came forth from the extradural space. A cut was next made through the dura near the Rolandic fissure. This time two ounces of “clotted blood” gushed out. The boy recovered rapidly after his subdural hematoma was drained. In his comments on advances in brain surgery, David Ferrier (1892) singled out the aforementioned case from 1879 as one to be remembered. With reference to cortical localization, he wrote: No more triumphant vindication than this could be given of the surgical value of cerebral localization; for a reliance merely on external indications would in all probability have sacrificed the life of the patient, or resulted in incurable infirmity. (Ferrier, 1892, p. 890)

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Macewen performed many other successful brain operations (Macmillan, 2005). His patients suffered from a variety of ailments, including subdural hematomas, tuberculomas, syphilitic lesions, splinters of bone that pressed on the brain, and brain abscesses secondary to ear diseases (Macewen, 1893). He also republished summaries of some of his original case reports and added newer findings to his publications of 1881 and 1888, which were illustrated (Fig. 14.3). Although many of his patients showed scalp or skull abnormalities that were helpful in guiding the surgery, Macewen maintained that his hands were guided by the localizing symptoms alone in several instances. As far as he was concerned, his case headings pretty much said it all. Typical were three case headings for patients seen in 1883 and described in 1888: “Intracranial Effusion of Blood diagnosed from Motor Symptoms alone”; “Syphilitic Tumour in Paracentral Lobule Diagnosed from Motor Symptoms alone”; “Focal Lesion in Ascending Convolution Recognized by Motor Symptoms alone.”

Fig. 14.3. Three of William Macewen’s cases with “hidden” cerebral lesions. In each case, the locus of the pathology was diagnosed by cortical localization of function and the surgery was performed according to Lister’s antiseptic procedures. (From Macewen, 1888.)

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Macewen’s record using Listerian principles was truly exceptional, especially given earlier statistics. In Macewen’s practice, brain surgery was clearly not a death sentence. The dura was not, as many were led to believe, a thin membrane between the cranium and eternity.

THE GLIOMA CASE OF RICKMAN GODLEE After describing his first seven cases in his 1888 paper, Macewen referred to an operation performed in London in December 1884 by Dr. Bennett and Mr. Godlee, assisted by Dr. Ferrier. Unlike the earlier cases in his own practice, this operation involved the removal of a glioma, a deadly hidden tumor of the brain substance itself. The Bennett–Godlee case was another landmark case in the new era of brain surgery (Trotter, 1934; Kirkpatrick, 1984). And it drew more attention than Macewen’s earlier cases for many reasons. Not only did the surgeon Rickman J. Godlee (Fig. 14.4) operate at the Hospital for Epilepsy and Paralysis, Regents Park, London, but the

Fig. 14.4. Rickman Godlee (1849–1925), the first surgeon to find and remove a glioma based on the doctrine of cortical localization of function.

diagnosis was made by “Physician to the Hospital,” Alexander Hughes Bennett, whose well-known physician-father had died from a brain tumor. Moreover, providing helpful opinions on this case were a star-studded group of London physicians associated with the nascent field of neurology, including David Ferrier and John Hughlings Jackson. Additionally, although Macewen had applied Lister’s antiseptic principles to brain surgery before Godlee, many people found it easier to associate Godlee with Lister, because he was Lister’s nephew and later biographer. Yet another reason for the case becoming so famous was that it was carefully followed in widely read medical and lay publications, such as the British Medical Journal and the Times of London, as well as publications elsewhere. Macewen’s first papers did not have this kind of publicity; they appeared in the considerably less widely circulated Glasgow Medical Journal, although an 1881 report did appear in the Lancet. The Godlee case was, in fact, used as ammunition by the medical establishment in their battle against the anti-vivisectionists (Finger, 2000, pp. 155–175). Many British citizens who were opposed to experiments on live animals previously could not see how animal research on the brain, such as the experiments conducted by David Ferrier, could save human lives. Now, they were informed, the information provided by the experimentalists was actually being applied to relieve human suffering, and one could point to the work of a surgeon at a London hospital. Lastly, as previously noted, the Bennett–Godlee case had to do with a tumor within the brain without any skull involvement or cranial signs to support its location. Most of Macewen’s cases had scalp or skull markings that could have helped support the diagnosis. Further, none of his early surgeries seemed quite as spectacular as correctly localizing and actually removing a dreaded glioma. The Bennett–Godlee case became known on 16 December 1884, as the result of a published letter criticizing the anti-vivisectionists and the laws limiting animal experimentation in the UK. This letter, titled “Brain Surgery,” appeared in the Times of London 3 years after Ferrier’s trial, in which he was wrongly accused by the anti-vivisectionists of working on animals without a license. Signed “FRS” (Fellow of the Royal Society), it was actually written by Ferrier supporter and asylum director, James Crichton-Browne, who had also seen the patient. His letter began: Sir, . . .While the Bishop of Oxford and Professor Ruskin were, on somewhat intangible grounds, denouncing vivisection at Oxford last Tuesday afternoon there sat at one of the windows of the

LANDMARKS OF SURGICAL NEUROLOGY AND THE INTERPLAY OF DISCIPLINES 197 Hospital for Epilepsy and Paralysis, in Regents With Henderson under chloroform, Godlee opened Park, in an invalid chair, propped up with pillows, the skull and searched for the suspected tumor. There pale and careworn, but with a hopeful smile on his was initially great disappointment when nothing was face, a man who could have spoken a really pertiobserved on the surface of his pulsating brain. He then nent word upon the subject, and told the right rev. probed deeper and found exactly what had been preprelate and great art critic that he owed his life, dicted – a growth “about the size of a walnut,” hidden and his wife and children their rescue from just below the surface in the motor region. After the bereavement and penury, to some of these experiembedded tumor was removed by hand and the blood ments on living animals which they so roundly convessels in the cavity cauterized, Henderson began his demned. The case of this man has been watched recovery. with intense interest by the medical profession, Henderson showed signs of improvement as soon as for it is of an unique description, and inaugurates he overcame the effects of the anesthetic. He stopped a new era in cerebral surgery. (FRS, 1884, p. 5) having seizures, his vomiting and headaches ceased, and he began moving his left leg freely. The clearest remnant Crichton-Browne ended his 1884 letter stating that this of what he had endured was his still paralyzed arm, most surgical case “will be a living monument of the value likely due to irreversible destruction of the cortical arm of vivisection,” and that the patient “owes his life to area by the tumor. Nevertheless, infection was detected Ferrier’s experiments, without which it would have a few days later and Henderson developed a cerebral herbeen impossible to localize his malady or attempt its nia, facial swelling, and then seizures. He died at the removal” (FRS, 1884, p. 5). National Hospital about a month after his surgery (Anon, Within a matter of days, the Lancet published a 1885). An autopsy revealed meningitis and brain softensummary of the case (Anon, 1884). The patient was a ing, but no remaining tumor. It was later suggested the young Scottish farmer named Henderson. He suffered scalp cleansing with carbolic acid had not been adequately from motor epilepsy for 3 years and had been treated performed, but this is uncertain. with bromide and iodide of potassium with minimal Neurosurgical interventions based on functional effect. He now had a useless left arm, weakness in maps of the cortex began to be performed fairly reguhis left leg, and visual problems. larly after Bennett and Godlee described their case at a Henderson’s neurological signs and symptoms, London meeting of the Medical and Surgical Society in which included severe headaches and vomiting, led BenMay 1885, and especially after their report was pubnett, who was on the staff at the Regents Park Hospital, lished that year (Bennett and Godlee, 1885). Among to suspect a cerebral tumor. He deduced that it was not those attending the 1885 London meeting were Ferrier very large and was probably situated in or near the hand and Jackson, who looked upon the operation as a milearea of the motor cortex, as then defined by London stone in surgical neurology, and William Macewen, physiologists. Having watched his own father die a who spoke about his own cases. few years earlier from an intracranial tumor that could Macewen’s talk did not receive the warmest of have been removed, Bennett appreciated the need for receptions by the Londoners. Most had thought that immediate surgery, but knew nothing about Macewen’s Godlee had performed the first modern brain operasuccesses. tion. But, after hearing him speak, Bennett called the Although Henderson agreed to the surgery, Bennett Glasgow surgeon’s earlier findings “encouraging,” was not a surgeon. Thus, he and perhaps others in his although he still emphasized that the earlier cases circle asked Rickman Godlee to operate. Godlee was described by Macewen were not suffering from deadly a capable junior surgeon at University College Hospigliomas. As for Godlee, ever the gentleman, he persontal, a skilled anatomical demonstrator, and a dedicated ally congratulated Macewen for what he had accomprofessional committed to Lister’s teachings. After plished. some hesitancy, Godlee consented to operate. David Ferrier’s words a few years later are particuOn 25 November 1884 Henderson was prepared for larly memorable. When he received the 1892 Cameron surgery in quarters quickly modified for the event (the Prize for research in therapeutics, he stated: “The honhospital lacked a proper operating room). Instruments our of having actually led the way in human [brain] were brought over from King’s College Hospital and surgery belongs to our countryman Macewen of Glasa carbolic acid spraying machine was used to disinfect gow” (Ferrier, 1892, p. 892). American surgeon Harvey the room during the 2-hour operation. Among those Cushing seconded Ferrier’s high praise of the Scottish watching, and agreeing with the diagnosis and chosen surgeon: “To Macewen belongs the distinction of havcourse of action, were Alexander Hughes Bennett, ing been the chief pioneer in craniocerebal surgery,” David Ferrier, and John Hughlings Jackson. wrote Cushing (1927, p. 14) several decades later.

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VICTOR HORSLEY Any early history of neurosurgery would be incomplete without mentioning Victor Horsley (Fig. 14.5), who conducted numerous brain lesion and electrical stimulation experiments on animals, and was the first surgeon to devote most of his clinical practice to neurological disorders. Interestingly, Horsley was also one of the first Englishmen to lecture and write about ancient trepanned skulls, believing craniotomies began as treatments for fractures causing seizure disorders (Paget, 1919; Lyons, 1966, 1967; Finger and Clower, 2001; See Ch. 1). Bright, energetic, daring, and optimistic, Horsley entered University College in 1875 and fell under the spell of Burdon Sanderson and Edward Scha¨fer, who promoted experiments on animals as the best way to advance modern medicine (Sparrow and Finger, 2001). He studied the cerebral effects of various anesthetic agents on himself and fellow students (Bingham, 1973). He also accepted Lister’s antiseptic principles. Horsley was especially drawn to “the so-called motor cortex,” a term he preferred, because he believed this area also mediated some somatosensory

Fig. 14.5. Victor Horsley (1857–1916), the London surgeon who applied what he had learned from brain research on animals to humans with epilepsy and other diseases.

functions. He published a series of important papers on this region in the 1880s, the most important of which were with Scha¨fer (Beevor and Horsley, 1887, 1888; Horsley, 1887; Horsley and Scha¨fer, 1885, 1888; Sparrow and Finger, 2001). He then applied the delicate surgical techniques he had gleaned from his research on primates to sick and injured humans. Horsley is often recognized for the first successful removal of a spinal cord tumor (with Charles A. Ballance), surgical treatments for trigeminal neuralgia, operations for craniostenosis, attempts to surgically alleviate involuntary movement disorders, intracranial surgeries for subcortical and pituitary tumors, and the development of a stereotactic frame for deep brain operations (with R.H. Clarke). Sir William Osler (1920), the neurologically-oriented clinician who closely followed the early development of neurological surgery, considered Horsley’s 1887 removal of a spinal cord tumor a triumph of monumental proportions. Additionally, he is frequently cited for the treatment of epilepsy by cortical excision, which was the earliest and perhaps most heralded of his surgical accomplishments. Prior to Horsley, craniotomies were occasionally performed for epilepsy of traumatic origin. The purpose of these operations, however, was usually to remove pieces of broken, depressed bone or a buildup of blood or putrid fluid under an observable injury (Temkin, 1971). Surgeons did not set forth to remove diseased cerebral cortex, and only rarely did they intentionally open the dura (for an exception, see Dudley, 1828; Jensen and Stone, 1997). In fact, before John Hughlings Jackson’s (1870, 1873) insightful neurological papers from the early 1870s, few men of medicine even thought of epilepsy as a cortical disorder. Horsley began to operate on three patients with cortical epilepsy during the spring of 1886. His intent now was to find and remove the damage causing the seizures, a bold new approach recommended by Hughlings Jackson, who advised Horsley on his earlier surgical cases. Horsley’s first patient was a man from Scotland under the care of Jackson and Ferrier. He had sustained a depressed skull fracture at age 7, having been hit by a cab on Princes Street in Edinburgh. He developed Jacksonian seizures, starting in his right leg, 8 years after his accident. Because his life was now threatened by status epilepticus (3000 fits in one fortnight), surgery was recommended. Based on what he had learned from his own research on localization of functions using monkeys, and a careful study of cranio-cerebral relations in the human, Horsley opened the skull superiorly over the left motor cortex and cut through the meninges. He examined the exposed brain and found a vascularized scar, which he then removed

LANDMARKS OF SURGICAL NEUROLOGY AND THE INTERPLAY OF DISCIPLINES along with some surrounding cortex. The result was a resolution of his seizure disorder. Horsley’s second case was somewhat more notable because this man suffered from a tuberculoma under the dura that could only be localized on the basis of signs and symptoms. He was another of Jackson’s patients and he had been exhibiting “fits” that started in his left thumb and forefinger, which led Jackson to suspect a brain tumor. Thanks to his own research on monkeys, Horsley again knew precisely where to apply his trephine. The tuberculoma was found and ablated, and this man was also cured of his epilepsy. Horsley presented these two cases and another successful case of surgery for epilepsy at a meeting of the British Medical Association in 1886. He was enthusiastically congratulated by those in the audience and praised by others after his talk was published (Horsley, 1886). Another significant landmark had been achieved.

OTHER PIONEERS OF SURGICAL NEUROLOGY IN THE LATE-19TH CENTURY In London, Charles A. Ballance, Horsley’s classmate and surgical associate at Queen Square, was an innovative neurological surgeon whose experience included at least 400 brain operations. He is usually credited with the first successful complete extirpation of an acoustic tumor (in 1894; see Ballance, 1907; Stone, 1999). He was also a pioneer in nerve grafting, became the first president of the Society of British Neurological Surgeons, and wrote notable books on brain surgery (Ballance, 1907, 1922). Another important surgeon during these years was William W. Keen. Keen was America’s foremost neurological surgeon of the era and was affiliated with Jefferson Medical College and several other Philadelphia institutions. He was a close associate of neurologist Silas Weir Mitchell, with whom he had worked on gunshot wounds, phantom limbs, and other neurological problems during the American Civil War. Keen was the first American surgeon to remove a meningeal tumor successfully (in 1887), and to stimulate the brain before a cortical resection (in 1888). Some successful surgical cases, and the first instance of cortical leg area stimulation, were presented by Keen at the “Symposium on Cerebral Localization” of the First Congress of American Physicians and Surgeons in 1888, with Ferrier and Horsley in attendance. To improve dissemination of neurosurgical knowledge, Keen visited Great Britain, and in return Macewen, Horsley, and Ballance came to America to spend time with Keen (Stone, 1985). Robert F. Weir of Columbia University’s College of Physicians and Surgeons, and Roswell Park of Buffalo, New York, also performed neurosurgical opera-

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tions in the closing decades of the 19th century, and also participated at the First Congress of American Physicians and Surgeons (Stone, 1985). In Paris, Antony Chipault published the most comprehensive review of neurosurgical procedures (1894– 1895) of the period (Baduel and Bucy, 1981; Chipault, 1894–1895; Wilkins, 1997). Additionally, Auguste Broca, Paul Broca’s son, introduced ventricular drainage for hydrocephalus and also published a comprehensive practical manual on cerebral surgery (Broca and Maubrac, 1896). Significant contributions to neurological surgery also came forth from Germany. Ernst von Bergmann, who was affiliated with the University of Berlin, was active in experimental brain physiology, and was a strong proponent for aggressive neurosurgical treatment, published his widely read text on brain surgery in 1888. His Die Chirurgische Behandlung der Hirnkrankheiten was translated into English as The Surgical Treatment of Brain Disorders two years later (Bergmann, 1890), and is considered a classic in the field. At about the same time, Fedor Krause came into neurosurgical prominence in Berlin with innovative approaches to neurological surgery, including skull base operations (Walker, 1967). Turning to Italy, Francesco Durante broke new ground in 1885, when he removed an olfactory groove meningioma from a woman whose symptoms included proptosis, loss of smell, and memory impairment. Eleven years later, following a reoccurrence of the cranial-based tumor, he performed a second surgery. The woman was still living in 1905 (Guidetti, 1983). Durante served as Chairman of Clinical Surgery at the Royal University of Rome for 45 years and was made a Senator of the Kingdom of Italy for his surgical successes.

NEUROSURGERY COMES OF AGE Although numerous landmarks in brain surgery date from the late-19th century, operating on the complex and fragile organ of mind was not for every general surgeon. Indeed, most who tried their hands at it were abruptly discouraged, and the wave of initial enthusiasm was already starting to dissipate as the new century began. Ironically, statistics show that the number of surgeons reporting brain operations was much lower by the onset of the World War I (1914) than it had been during the 1890s (Scarff, 1955). Harvey Cushing is often cited for reversing the trend and making neurosurgery an attractive medical specialty, one with its own rules and requirements (Bliss, 2005). Cushing trained at Johns Hopkins University under William S. Halsted, who was perhaps the first prominent general surgeon to emphasize slow and meticulous operating techniques, with strict control of blood

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loss, and gentle handling of all tissues to promote quicker operative recovery and healing. Cushing was also influenced by his brilliant neighbor and Johns Hopkins medical colleague, William Osler, and by trips to Europe, where he studied cerebral localization with Charles Scott Sherrington and was able to observe many of the brain surgeons cited in this chapter. While a medical student at Harvard, Cushing introduced the first anesthesia chart, and in Baltimore he plotted blood pressure changes during surgery – two innovations that have saved many lives (Tracy and Hanigan, 1997). His promotion of subtemporal decompression in deteriorated tumor cases was also of great importance. It lowered intracranial pressure and often improved his patients enough to allow him to do localizing neurological examinations, which in turn permitted more precise surgeries. In 1912, Cushing accepted a professorship at Harvard University and an appointment at the new Peter Bent Brigham Hospital. At the Brigham, he continued what he had already started, further enhancing his fame as the leading brain surgeon of the era with his surgical treatments of trigeminal neuralgia and work on brain tumors. Remarkably, surgical mortality with brain tumors diminished from about 50% to 5% under his direction. Cushing was by all accounts a difficult, intense, hard-driving perfectionist, who welcomed challenges, cared deeply about his patients, and worked to the point of exhaustion to break new ground. He also felt a need to be in full control of all aspects of the care of his patients, teaching that a neurosurgeon must also be a good neurologist. His innovations are too numerous to review in this chapter, but it should be noted that he also pioneered the use of X-rays to detect foreign objects in the brain, performed pituitary surgeries, and developed new operative techniques. Cushing also trained many of the next generation’s prominent neurosurgeons, both in North America and abroad (Greenblatt and Smith, 1997; Bliss, 2005). Walter Dandy, Gilbert Horrax, Hugh Cairns, John Fulton, Percival Bailey, Kenneth McKenzie, and Wilder Penfield are among those who trained with Cushing.

INTERDISCIPLINARY CROSS-FERTILIZATION In retrospect, what Cushing and other neurosurgeons in the early 20th-century accomplished could not have happened were it not for some farsighted men, including Broca, Macewen, Godlee, and Horsley in the last three decades of the 19th century. Each of Cushing’s predecessors was a general surgeon, and each recognized the intrinsic value of the theory of cortical localization of function and used it as a point of depar-

ture. In this regard, these surgeons owed much to Ferrier, Scha¨fer, and other dedicated researchers who had been exploring the brains of live animals in their laboratories. The pioneers of neurosurgery also benefited from new insights about fighting infections and the use of anesthetics, as well as advances in medical instrumentation, such as monitoring devices. Major advances in surgical neurology, pathology, experimental physiology, and other fields of medicine stemmed from fertile interactions with one another. The earlier pioneers of neurological surgery appreciated that medical specialization was unlikely to advance very far in a vacuum. They learned from neurology and borrowed from other disciplines and, in turn, they contributed to other disciplines. Successes in the operating room stimulated additional anatomical and physiological explorations with laboratory animals. Such studies shed additional light on such things as the functional organization of the brain. The cross-fertilization of disciplines has not diminished. One need only look at the topic of functional recovery after brain damage to appreciate the ways in which neurosurgery, neurology, experimental physiology, and a myriad of other disciplines can converge to deal with important issues. Without question, cross-fertilization will remain an important feature of both neurosurgery and neurology.

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LANDMARKS OF SURGICAL NEUROLOGY AND THE INTERPLAY OF DISCIPLINES Bennett AH, Godlee RJ (1885). Case of cerebral tumour. BMJ 1: 988–989. Bergmann E von (1890). Surgical Treatment of Diseases of the Brain. Wood’s Medical and Surgical Monographs. Vol. VI. William Wood, New York. Bingham WF (1973). The early history of neurosurgical anesthesia. J Neurosurg 39: 568–584. Bliss M (2005). Harvey Cushing: A Life in Surgery. Oxford University Press, New York. Bowman AK (1942). The Life and Teaching of Sir William Macewen: A Chapter in the History of Surgery. William Hodge and Co., London. Broca P (1861a). Perte de la parole, ramollissement chronique et destruction partielle du lobe ante´rieur gauche du cerveau. Bull Soc Anthropol 2: 235–238. Broca P (1861b). Remarques sur le sie`ge de la faculte´ du langage articule´; suivies d’une observation d’aphe´mie (perte de la parole). Bull Soc Anat 6: 330–357, 398–407. Broca P (1861c). Nouvelle observation d’aphe´mie produite par un le´sion de la moite´ poste´rieure des deuxie`me et troisie`me circonvolutions frontales. Bull Soc Anat 6: 398–407. Broca P (1863). Localisation des fonctions ce´re´brales. Sie`ge du langage articule´. Bull Soc Anthropol 4: 200–203. Broca P (1865). Sur le sie`ge de la faculte´ du langage articule´. Bull Soc Anthropol 6: 337–393. Broca P (1866). Tre´panation du craˆne practique´e succe`s dans un cas de fracture avec enfoncement et enclavement. Bull Soc Chir Paris 7: 508. Broca P (1876). Diagnostic d’un abce`s situe´ au niveau de la re´gion du langage; tre´panation de cet abce`s. Rev Anthropol 5: 244–248. Broca A, Maubrac P (1896). Traite´ de Chirurgie Cerebrale. Masson et Cie, Paris. Chipault A (1894–1895). Chirurgie Ope´ratoire du Syste`me Nerveux. 2 Vols. Rueff et Cie, Paris. Cottrell JE (1980). Anesthesia and Neurosurgery. Mosby, St. Louis, MO. Cushing H (1927). The Meningiomas. Jackson, Wylie & Co., Glasgow. Dudley BW (1828). Observations on injuries of the head. Transyl J Med 1: 9–40. Ferrier D (1876). The Functions of the Brain. Smith, Elder and Co., London. Ferrier D (1883). The progress of knowledge in the physiology and pathology of the nervous system. BMJ 2: 805–808. Ferrier D (1892). Cerebral localisation in relation to Therapeutics (Cameron Lecture). Edinburgh Med J 37: 881– 897. Finger S (2000). Minds Behind the Brain. Oxford University Press, New York. Finger S (2006). Doctor Franklin’s Medicine. University of Pennsylvania Press, Philadelphia, PA. Finger S, Clower WT (2001). Victor Horsley on “trephining in pre-historic times.” Neurosurg 48: 911–918. FRS (1884). Brain Surgery. The Times (London), December 16: 5 (author believed to be James Crichton-Browne). Gaw JL (1999). “A Time to Heal”: the Diffusion of Listerism in Victorian Britain. American Philosophical Society, Philadelphia.

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Giuffre` R (1984). Successful radical removal of an intracranial meningioma in 1835 by Professor Pecchioli of Siena. J Neurosurg 60: 47–51. Godlee RJ (1917). Lord Lister. Macmillan and Co., London. Granshaw L (1992). “Upon this principle I have based a practice”: The development and reception of antisepsis in Britain, 1867–1890. In: JV Pickstone (Ed.), Medical Innovations in Historical Perspective. St. Martin’s Press, New York, pp. 17–42. Greenblatt SH (1997). Cerebral localization: from theory to practice. In: SH Greenblatt (Ed.), A History of Neurosurgery. American Association of Neurological Surgeons, Park Ridge, pp. 137–152. Greenblatt SH, Smith DC (1997). The emergence of Cushing’s leadership: 1901–1920. In: SH Greenblatt (Ed.), A History of Neurosurgery. American Association of Neurological Surgeons, Park Ridge, pp. 167–190. Guidetti B (1983). Francesco Durante (1844–1934). Surg Neurol 20: 1–3. Horsley V (1886). Brain surgery. BMJ 2: 670–675. Horsley V (1887). A note on the means of topographical diagnosis of focal disease affecting the so-called motor region of the cerebral cortex. Am J Med Sci 96: 342–369. Horsley V, Scha¨fer AE (1885). Experimental researches in cerebral physiology: on the muscular contractions which are evoked by excitation of the motor tract. Proc R Soc Lond 39: 404–409. Horsley V, Scha¨fer AE (1888). A record of experiments upon the functions of the cerebral cortex. Philos Trans R Soc Lond B Biol Sci 179: 1–45. Hudson RS (1877). On the use of the trephine in depressed fractures of the skull. BMJ 2: 75–76. Jackson JH (1870). A study of convulsions. Trans St. Andrews Med Grad Assoc 3: 162–204. Jackson JH (1873). On the anatomical, physiological, and pathological investigation of the epilepsies. West Riding Lunatic Asylum Med Rep 3: 315–319. Jefferson G (1960). Sir William Macewen’s contribution to neurosurgery and its sequels. In: Selected Papers of Sir Geoffrey Jefferson. Charles C. Thomas, Springfield, pp. 132–149. Jensen RL, Stone JL (1997). Benjamin Winslow Dudley and early American trephination for posttraumatic epilepsy. Neurosurg 41: 263–268. Keith A (1919). Just Lucas-Championnie`re – movement as a means of treatment. In: Menders of the Maimed. Lippincott, Philadelphia, pp. 188–201. Keys TE (1963). The History of Surgical Anesthesia. Dover Publications, New York. Kirkpatrick DB (1984). The first primary brain tumor operation. J Neurosurg 61: 809–813. Knapp PC (1891). The Pathology, Diagnosis and Treatment of Intra-cranial Growths. Rockwell and Churchill, Boston, MA. Lawrence C, Dixey R (1992). Practicing on principle: Joseph Lister and the germ theories of disease. In: C Lawrence (Ed.), Medical Theory, Surgical Practice: Studies in the History of Surgery. Routledge, London, pp. 153–215. Lister J (1867a). On the antiseptic principle in the practice of surgery. Lancet 2: 353–356.

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Lister J (1867b). On a new method of treating compound fractures, abscesses, etc., with observations on the conditions of suppuration. Lancet 1: 326–329, 357–359, 387– 389, 507–509; 2: 95–96. Lister J (1867c). Illustrations of the antiseptic system of treatment in surgery. Lancet 2: 668–669. Lucas-Championnie`re J (1875). Tre´panation du craˆne faite pour une fracture de la vouˆte sans plaie communicante; gue´rison comple`te. Bull Mem Soc Chir Paris 1: 226–231. Lucas-Championnie`re J (1876). Chirurgie Antiseptique. J.B. Baillie`re et Fils, Paris. Lucas-Championnie`re J (1878a). La Tre´panation Guide´e par les Localisations Ce´re´brales. Masson, Paris. Lucas-Championnie`re J (1878b). Discussion sur le tre´pan. Bull Mem Soc Chir Paris 4: 66–74. Lyons JB (1966). The Citizen Surgeon: A Biography of Sir Victor Horsley. Peter Dawnay, London. Lyons JB (1967). Sir Victor Horsley. BMJ 2: 361–373. Macewen W (1879). Tumour of the dura mater – convulsions – removal of tumour by trephining – recovery. Glasgow Med J 12: 210–213. Macewen W (1881). Intra-cranial lesions, illustrating some points in connexion with the localisation of cerebral affections and the advantages of antiseptic trephining. Lancet 2: 541–543, 581–583. Macewen W (1888). An address on the surgery of the brain and spinal cord (delivered at the annual meeting of the British Medical Association, held in Glasgow, 9 August 1888). BMJ 2: 302–309. Macewen W (1893). Pyogenic Diseases of the Brain and Spinal Cord. Maclehose and Sons, Glasgow. Macmillan MB (2004). Localization and William Macewen’s early brain surgery. Part 1. The controversy. J Hist Neurosci 13: 297–325. Macmillan MB (2005). Localization and William Macewen’s early brain surgery. Part 2. The cases. J Hist Neurosci 14: 24–56. Osler W (1920). Eulogy of Sir Victor Horsley. Oxford Mag 38: 175. Paget S (1919). Sir Victor Horsley: A Study of his Life and his Work. Constable and Co., London. Pecchioli Z (1838). Storia di un fungo della dura madre, operato coll’estirpazione dal Professor Zanobi Pecchioli. N Gion Lett Sci 36: 39–44. Roberts JB (1883). Surgical encephalitis and cerebral localization. Med Bull (Phila) 5: 53–57.

Scarff JE (1955). Fifty years of neurosurgery, 1905–1955. Int Abstr Surg 101: 417–513. Sedillot CE (1870). Plaie de teˆte avec fracture: tre´panation. Bull Soc Chir 11: 140–143, 149–151. Seguin EC (1878). Lectures on the localization of spinal and cerebral diseases. Lecture VIII. Med Rec 14: 361–362. Simpson D (1990). Simpson and “the discovery of chloroform.” Scott Med J 35: 149–153. Sparrow EP, Finger S (2001). Edward Albert Scha¨fer (SharpeySchafer) and his contributions to neuroscience. J Hist Neurosci 10: 41–57. Starr MA (1893). Brain Surgery. William Wood, New York. Stone JL (1985). W.W. Keen: America’s pioneer neurological surgeon. Neurosurg 17: 997–1010. Stone JL (1991). Paul Broca and the first craniotomy based on cerebral localization. J Neurosurg 75: 154–159. Stone JL (1999). Sir Charles Balance: pioneer British neurological surgeon. Neurosurg 44: 610–632. Stone JL (2002). Percivall Pott and the miners of Cornwall. Br J Neurosurg 16: 501–506. Temkin O (1971). The Falling Sickness. 2nd edn. Johns Hopkins University Press, Baltimore, MD. Thompson CJS (1934). Lord Lister: The Discoverer of Antiseptic Surgery. John Bale, Sons and Danielsson, Ltd., London. Tracy PT, Hanigan WC (1997). History of neuroanesthesia. In: SH Greenblatt (Ed.), A History of Neurosurgery. American Association of Neurological Surgeons, Park Ridge, IL, pp. 213–221. Trotter W (1934). A landmark in modern neurology. Lancet 2: 1207–1210. von Bergmann E (1880). Die Lehre von den Kopfverletzungen. Verlag von Ferdinand Enke, Stuttgart. Walker AE (1967). Sir William Macewen. Fedor Krause. In: AE Walker (Ed.), A History of Neurological Surgery. Hafner, New York, pp. 178–179, 248–249. Wiesmann P, Kronlein RU (1884). Modernen Indicationen Zur Trepanation. Druck von J.B. Hirschfeld, Leipzig. Wells S (1864). Some causes of excessive mortality after surgical operations. BMJ 2: 384–388. Wilkins RH (1997). Treatment of craniocerebral infection and other common neurosurgical operations at the time of Lister and Macewen. In: SH Greenblatt (Ed.), A History of Neurosurgery. American Association of Neurological Surgeons, Park Ridge, IL, pp. 83–96.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 15

Jean-Martin Charcot and the anatomo-clinical method of neurology CHRISTOPHER G. GOETZ * Department of Neurological Sciences and Pharmacology, Rush University Medical Center, Chicago, IL, USA

JEAN-MARTIN CHARCOT Jean-Martin Charcot (1825–1893) was the most renowned clinical neurologist of his era, and his writings have been translated and disseminated widely (Goetz et al., 1995) (Fig. 15.1). The facts of his life are briefly summarized: born in Paris in 1825, the son of a carriage maker, he studied medicine after wavering between careers in art and science; he received his medical degree in 1853 and spent part of his internship at the Salpeˆtrie`re Hospital where he would return as a faculty member in 1862 and remain throughout the rest of his career (Fig. 15.2). In 1872, he received the post of Professor of Pathologic Anatomy and, in 1882, a new chair was specifically created for him, Professor of Diseases of the Nervous System, the first neurological professorship in Europe; he died unexpectedly during his summer vacation in 1893 while on a trip to rural France with his students. He left behind him the first school of neurology, a younger generation of international students devoted to neuroscience, and a framework for thinking about the nervous system both clinically and anatomically. This heritage persists in the practice of contemporary neurology. At the height of Charcot’s career, his classroom drew students and colleagues from around the world, and these lectures and patient demonstrations brought international attention to disorders that had been previously considered obscure or poorly understood: Parkinson’s disease, Huntington’s disease, Gilles de la Tourette syndrome, a variety of stroke syndromes, and numerous neuromuscular disorders. Charcot’s severe, imperial demeanor and his succinct clarity of

*

expression were key elements to his stature, and young foreigners or French provincials who studied with him gained sufficient credibility to return to their homelands with the credentials to be considered neurological experts. Charcot’s own team of investigators at the Salpeˆtrie`re included students, interns, and residents in training, but also medical artists, photographers, electrotherapists, psychologists, and the staff of his pathology laboratory. This integrated program defined the Salpeˆtrie`re as the Mecca of neurological study in the closing years of the 19th century, and became a model for other programs that would develop internationally during the 20th century (Gelfand, 1994). The unifying theme of the Charcot program was the linking between clinical neurological signs and structural neuroanatomical lesions. This strategy, called the méthode anatomo-clinique or anatomo-clinical method, was anchored in a two-part discipline of careful clinical examination and longitudinal follow-up during life and then, at the time of death, a detailed anatomical analysis of the brain and spinal cord. The success of Charcot’s anatomo-clinical methodology led to the modern neurological nosology. Even with major advances in neuroscience over the last decades, the classification of neurological diagnoses has remained firmly anchored in Charcot’s tradition (Goetz, 1987). Subsequent generations of neurological researchers have adapted and expanded methodologies to continue the Charcot legacy that defines neurological disease by the correlation between clinical signs and focal lesions, whether structural, biochemical or molecular.

Correspondence to: Christopher G. Goetz MD, Professor of Neurological Sciences, Professor of Pharmacology, Rush University Medical Center, Suite 755: 1725 W. Harrison Street, Chicago, IL 60612, USA. E-mail: [email protected], Tel: +1-312-942-8016, Fax: +1-312-563-2024.

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C.G. GOETZ ambitious physicians would vie for a better assignment in a more respected hospital, closer to the medical school itself in central Paris (Michale, 1985). Further, in the first years of Charcot’s tenure at the Salpeˆtrie`re, a new administrative movement reorganized the public hospitals in order to develop specialty units, funneling all patients from within the system to units located in individual hospitals. This reshuffling of patients to create dermatology, hepatic, pulmonary and cardiac specialty units at the prestigious hospitals left Charcot with two large groups of elderly charges that, at first glance, would be considered “left-overs”: chronic rheumatological and neurological cases (Lellouch, 1992). At a time when both terms were vaguely applied, the mixture of cases on the Charcot unit still required much more specific focus and categorization, which became the first of Charcot’s early missions (Charcot, 1872–1873). To the modern physician, rheumatology and neurology may appear remarkably different, but in the 19th century they were considered closely intertwined in that they affected primarily elderly patients, represented chronic conditions, and were largely untreatable. Clinical examples of rheumatological and neurological interdigitation included joint deformities that occurred in Parkinson’s disease and tabes dorsalis, and involuntary movements like chorea associated with rheumatic heart disease (Sydenham’s chorea). Charcot commented on this overlap:

Fig. 15.1. Jean-Martin Charcot (1825–1893) in his academic robes painted by E. Tofano in 1881. This portrait was commissioned and executed before Charcot was named to the newly created Chair of Diseases of the Nervous System in 1882.

EMERGENCE OF CHARCOT’S NEUROLOGICAL INTERESTS The celebrated stature of Charcot, the international designation of neurology as a medical specialty, and the luminous prestige of the Salpeˆtrie`re in the late-19th century all emerged from relatively humble beginnings. Charcot himself did not come from a well-attached medical or bourgeois family and was the only child among his siblings to attend university. When he received a hospital appointment in the public health system in 1862, his assignment to the medical unit of the Salpeˆtrie`re was not a prestigious post. Considered a hospice, not a hospital, the Salpeˆtrie`re was a sprawling walled-in institution primarily organized to house destitute and old women who, once institutionalized, lived there until death. Located beyond the Botanical Gardens and very much at the outskirts of central Paris, the Salpeˆtrie`re was generally considered a poor place for building an academic career. At best, assignment to this staff would be a stepping stone. In most instances after a temporary post at the Salpeˆtrie`re,

We should think of arthritis as a tree whose main branches are gout, rheumatism, certain migraines, skin rashes, etc. On the other hand, the neurological tree has for its branches, neurasthenia, hysteria, epilepsy, all the types of mental conditions, progressive paralysis, gait ataxia, etc. The two trees live side by side; they communicate through their roots and they interrelate so closely that one may wonder if the two are not the same tree. If you understand this concept, you will appreciate what occurs in most neurological conditions; without this understanding, you will be lost. (Charcot, 1887–1888, 6 December 1887, p. 74) Working with these two large groups of otherwise medically rejected patients, Charcot considered anatomical overlaps and, in the case of joint deformities, hypothesized that the spinal cord could be the anatomic site of shared involvement. To test this premise, Charcot examined and documented the physical findings of his patients and, when they died, he had ready access to their bodies for anatomical study because they were charges of the state. Early comparative studies of clinical signs and autopsy findings became the core of the research strategy to be known as the anatomo-clinical method. Applied across diseases and across the neuraxis, the method became emblematic of Charcot and

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Fig. 15.2. Drawing of the Hoˆspice de la Salpeˆtrie`re with crippled patients ambulating through the gardens. Charcot spent almost his entire career at this institution, elevating its stature from a hospice for elderly women to the premier neurological service in the world.

the Salpeˆtrie`re, serving as the guiding principle of early neurological research and becoming the pillar underlying modern neurological diagnostic classifications.

THE ANATOMO-CLINICAL METHOD AND ITS MEDICAL ORIGINS Charcot’s major advances with the anatomo-clinical method occupied the early years of his academic career, primarily between 1862 and 1875. The concept of correlating clinical signs to anatomical lesions is not a concept that can be credited to Charcot, for this tradition was initiated by the premier early representative of the Paris Medical School, Laennec, and several other predecessors of Charcot (Weisz, 1987). Laennec developed and applied correlative methods, using the term méthode anatomopathologique. Focusing primarily on pulmonary and cardiac diseases, he gathered clinical data primarily on acutely ill patients. After they died, he applied very primitive anatomical studies, focusing on the examination of the external surfaces of involved organs. Visual and tactile examination revealed congestion, inflammation, pus, blood and other fluids. In this way, Laennec and his followers ascribed jaundice to hepatic disease, and bloody sputum to pulmonary disease; with further application, the key signs of renal, gastrointestinal and other organspecific disorders became delineated (Laennec, 1819). Such efforts led to an international appreciation of French

medicine, and the Paris hospitals became the key medical institutions of the early- and mid-19th century (Ackerknecht, 1967). Charcot himself received his medical training in this tradition, and logically applied this discipline to the nervous system. Charcot began the first phase, clinical documentation, with detailed notes describing the history and physical examination findings of the patients in his unit. Many of these observations or clinical case histories were accompanied by drawn sketches of the patient’s deformities, postures or clinical signs. Later in the development of the Salpeˆtrie`re program, when Charcot would attract students and assistants, additional supportive documentation was included. Gait and tremor recordings, photographs of the patient taken at different angles to capture neurological deficits in 3 dimensions, handwriting samples and other documents were catalogued with the updated notes. These folios were of varying sizes depending on the duration of follow-up and, likely, on the interest of the research team. In some cases, published articles or correspondence from other colleagues regarding similar cases were inserted into the files to provide a comprehensive record (Fig. 15.3). Charcot placed a high value on clear and complete clinical documentation and lauded the example of his colleague, Duchenne de Boulogne: “The description of locomotor ataxia given by Duchenne de Boulogne is among the most vivid and remarkable. It is rightfully considered a masterpiece” (Charcot, 1887, p. 11F, p. 9E).

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Fig. 15.3. The anatomo-clinical method of Charcot. In this photograph, numerous medical documents concerning a patient are assembled. Charcot first collected hand-written notes on the patient and monitored the clinical disease progression over time. Photographs, drawings, and footprints of the patient helped to characterize the clinical features of the illness. After death, autopsy material was collected in the same patient file. Clinical-anatomic correlations were suggested based on these combined data. In addition, Charcot, who read several languages, kept pertinent articles from the medical literature in the folder to complement his own material (Bibliothe`que Charcot, M VIII, No. 6).

Several types of innovative strategies were utilized in addition to written notes. Sphygmographs, tools originally developed to measure pulse amplitude and rhythm, were adapted to record tremors; medical photography allowed objective documentation of physical signs, and multiple cameras or rotating lenses captured disorders of movement; sculptors, professional artists, and specialists in wax casting assisted in the clinical documentation of neurological disorders (Goetz, 1991) (Fig. 15.4). The second part of the anatomo-clinical method occurred in the autopsy room and in the anatomical and histological laboratories of the Salpeˆtrie`re. In the 1860s these facilities were very modest, but as Charcot’s fame increased and more public funding was directed to his unit, his laboratories gained a very high level of sophistication. After death, the brain and spinal cord were examined, and anatomical drawings, depictions of findings viewed under the microscope, and detailed written descriptions were added to the clinical file. The anatomical lesions were charted against the clinical signs and tabulated against other cases with similar signs or similar anatomical lesions. In this way, the first correla-

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tions could be effected between a given clinical presentation and its anatomical basis. Continuing his discussion in reference to Duchenne de Boulogne’s clinical contributions, Charcot emphasized the importance of the second part of the anatomo-clinical method: However, hesitation reigned indefinitely until the day when the spinal lesion described long ago by Cruveilhier could be brought together with the clinical description . . . When the circumstances are favorable, this furnishes the basis of a physiological interpretation of normal or abnormal clinical signs and as a natural consequence provides more depth and exactitude to our diagnosis. (Charcot, 1887, p. 12F, pp. 10–11E)* Just as Charcot had introduced new clinical tools to the first phase of the anatomo-clinical method, he was innovative in his approach to the anatomical axis. He was responsible for bringing into French medical science the use of the microscope as developed by the German school, specifically Virchow, with a direct application to neurology. In his view, histological study permitted the clinician:

Note: For quotations that have both an original French and English published translation, F refers to the page number of the original French and E to the English translation.

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Fig. 15.4. Composite of several techniques developed by Charcot to document clinical signs: a sphygmograph for recording tremor frequency, medical drawings, photography, and medical sculpture. In his later years, the Salpeˆtrie`re service had electrodiagnostic, psychology, and ophthalmology divisions as well.

To penetrate into the organ of interest down to the primary anatomic elements . . . Histological study relates so closely to the pathogenesis or cause of diseases that the two become merged. (Charcot, 1874, pp. xxii–xxiii F, pp. 14–15E) Charcot’s evolution of methodological terminology from anatomo-pathologique to anatomo-clinique underscores an important historical distinction. Charcot’s methodological approach was first and foremost a clinical one, and the clinician was the pivotal scientist to perform the work. Grammatically, anatomo serves a modifying attribute of clinique and establishes the clinical prioritization that must be at the core of all studies. Although other scientists could contribute, Charcot was unwavering in his stand, that the clinical observation was always the essential starting point that “constitutes the first steps of every scientific premise in studying diseases” (Charcot, 1874, p. xxiii F, p. 15E).

FRUITS OF CHARCOT’S ANATOMOCLINICAL METHODOLOGY: AMYOTROPHIC LATERAL SCLEROSIS To exemplify the fruition of Charcot’s anatomo-clinical method, several neurological conditions could be chosen, ranging from stroke syndromes based on cortical localization to the differentiation between Parkinson’s disease and multiple sclerosis. The most archetypal example, however, is amyotrophic lateral

sclerosis, also known as Charcot’s disease. Because the method led to the discovery of a disease that had previously been unrecognized and its components confused, the history of Charcot’s research efforts and application of his methodology is particularly revealing (Goetz, 2000a). At the centenary celebration of Charcot’s birth in 1925, Pierre Marie cited the words of one of Charcot’s students (possibly Marie himself, who had said of amyotrophic lateral sclerosis, “like a certain goddess of antiquity, it sprang fully armed from the head of its creator” (Marie, 1925, p. 738). Indeed, Charcot’s famed presentation in 1874 was and remains compelling in its style of concise delivery and its anatomoclinical exactitude. Marie’s allusion, however, conjures the image of a single and explosive discovery, whereas, in fact, Charcot’s description of amyotrophic lateral sclerosis did not evolve in this dramatic way. Rather, this work represented the synthesis of a large series of previous studies, each a small contribution to the “fully armed” creation. Substantial clinical material for studies of weakness and muscle wasting existed among the thousands of patients who lived at the Salpeˆtrie`re over Charcot’s career. As chronic inhabitants of the hospital, these patients provided clinical information and later autopsy material for Charcot’s eventual analyses. Using the anatomo-clinical method, Charcot separated cases of acute onset weakness from those with slowly

208 C.G. GOETZ progressive courses and chronic disability (Charcot, weakness linked the two, each clinical division must 1877). Being in charge of a chronic care hospital, he have a different anatomical lesion. concentrated primarily on chronic and progressive Charcot was attentive to select only the most archeforms of weakness. Charcot did not limit his consideratypical cases with motor problems in order to assure tions to diagnostic categories established by others and that he could “extract a specific pathological state reviewed cases independently. In this context, he made from the chaos of imprecision” (Charcot, 1887–1888, his first major discovery of anatomo-clinical signifi20 March 1888). In some cases, he noted that clinical cance to amyotrophic lateral sclerosis in 1865. He preand pathologic features resembled the 1865 case, and sented a case report to a local meeting at the Socie´te´ in others the findings were those of his 1869 observaMe´dicale des Hoˆpitaux de Paris of a young woman tions. These corroborative findings strengthened his diagnosed as hysteric, who had developed profound concept of the two-part motor system organization. weakness, and showed increased muscle tone, with More perplexing and exciting, however, he found that, contractures of all extremities during life (Charcot, even with careful selection, some prototypic cases had 1865). Her intellect was preserved, she had no sensory both atrophy and spasticity with contractures. At abnormalities, and her urinary control was normal. At autopsy, he found both the anterior horn cell lesion death, Charcot found specific and isolated lateral coltypical of acute amyotrophy, and also the distinctive umn degeneration in the spinal cord: bilateral and symmetric sclerosis of the lateral spinal cord columns. These cases became the third essential On careful examination of the surface of the element to support his thesis and represented the first spinal cord, on both sides in the lateral areas, diagnosed cases of amyotrophic lateral sclerosis as a there are two brownish-gray streak marks prospecific clinical disorder with a specific pathologic corduced by sclerotic changes. These grayish bands relate (Charcot, 1877). Writing on the clinical constellabegin outside the line of insertion of the postertion of features, he noted: ior roots and their anterior border approaches, but does not include the entrance area of the a) progressive atrophy invading the muscles; b) anterior roots. They are visible throughout the fibrillary contractions which are especially seen thoracic region and continue, though greatly in the active period of the atrophy; c) the preserthinning out, up to the widening point of the cervation of faradic contractility that the wasted vical cord. Below, they are barely visible in the muscles exhibit to the last moment . . . Other thoraco-lumbar region. Transverse sections symptoms are quite foreign to protopathic spinal taken at different levels allow one to see that amyotrophy; first, motor weakness that occurs the lateral columns have in their most superficial early and which, if it does not precede atrophy, and posterior regions, a gray, semitransparent at least is strikingly evident when the latter is appearance, rather gelatinous . . . At no point not yet well-developed . . . The extremities, more does the diseased tissue penetrate the gray mator less deprived of their natural movements, are ter which remains unaffected. (Charcot, 1865, usually in lateral sclerosis affected by rigidity at pp. 30–31) rest, resulting from what is called continual spasmodic contractures. This phenomenon is An early second observation concerned weakness in absolutely foreign to primary atrophy. (Charcot, patients without contractures. In 1869, while working 1877, p. 280F, p. 186E) with his colleague Joffroy, Charcot encountered pediatric cases of infantile paralysis and noted that, in these cases, the spinal lesions were systematically limited to the anterior horns of the gray matter (Charcot and Joffroy, 1869). The two seemingly unrelated observations from 1865 and 1869 – lateral column degeneration in the patient with chronic progressive paralysis, and contractures without atrophy of muscles and anterior horn degeneration in patients with infantile paralysis with atrophy of muscles – became the reference points for Charcot’s motor system analyses. He returned to the Salpeˆtrie`re wards to find additional patients to test his hypothesis that the motor system in the spinal cord was organized into this two-part division, and whereas

He noted spinal cord changes to correlate with these clinical signs. In regards to white matter alterations, he commented: The region invaded by sclerosis extends forward to a level with the outer angle of the anterior horn and even beyond it. Behind it is nearly bounded by the posterior gray substance. (Charcot, 1877, p. 281F, p. 186E) With regard to the gray matter changes, he continued: They differ in nothing essential from those which we studied in connection with protopathic spinal muscular atrophy. This means that here, too,

JEAN-MARTIN CHARCOT AND THE ANATOMO-CLINICAL METHOD OF NEUROLOGY lesions are systematically localized in the anterior gray horn. In that region, just as in with spinal muscular atrophy, lesions affect both the neuroglia and the motor nerve cells themselves which are more or less diffusely degenerated, atrophied, or even completely destroyed. (Charcot, 1877, p. 283F, p. 187E) As a result of these tenacious studies, Charcot suggested with conviction that specific clinical signs predictably occurred when certain spinal cord lesions were present and predictably did not occur when the signs were absent. He established for the first time a medical paradigm for a direct relationship between a neurological lesion and a patient’s clinical problem. In opening the horizons for the study of direct relationships between clinical and anatomically pathologic states, Charcot presented the revolutionary concept that a precise anatomic diagnosis could be made before death. Charcot recounted: In the beginning, it was a matter of studying a series of cases primarily from an anatomic perspective. Nonetheless, the clinical characteristics of the patients had always been recorded carefully. Eventually among these different cases, it became possible to delineate a certain number of fundamental features, characteristics that permitted us later to recognize the condition clinically during life. (Charcot, 1877, p. 245F, p. 200E) With the success of the spinal cord research, Charcot and his student team expanded this work to confirm that comparable lesions in the brain stem were associated with weakness of the muscles controlling the face, mouth and tongue. In 1871–1872, Charcot’s student, Gombault, published a pivotal analysis, titled “Symmetrical sclerosis of the lateral spinal columns and the anterior pyramids of the lower brain stem: progressive muscular atrophy: glosso-laryngeal paralysis” (Gombault, 1871–1872). As with much of Charcot’s work, the clinical description of bulbar signs in amyotrophic lateral sclerosis actually dated back to research by Duchenne de Boulogne from over a decade before. Charcot commented that many investigators had previously tried without success to correlate a primary lesion of the gray matter of the medulla with the clinical signs known as glosso-labial-laryngeal paralysis. Now, with his anatomic study, and his appreciation of the anatomic parallels between the anterior horn of the spinal cord and the nuclear regions of the brain stem, he definitively confirmed this early hypothesis that previously had been only suggested (Charcot, 1877). His

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conclusions became anatomo-clinical pillars of modern neurology – when gray matter motor nuclei are damaged, weakness is associated with muscular atrophy in the body areas supplied by those cells; when white lateral column damage occurs, weakness is associated with progressive contractures and spasticity. Whereas all the essential descriptions of the motor neuron diseases were developed in early works, the term, amyotrophic lateral sclerosis, was not offered by Charcot until 1874, in his two lectures (12 and 13) gathered in Volume 2 of his Complete Works (Charcot, 1877). These lectures synthesized the prior studies and were enormously successful in their succinct and compelling logic. They drew major attention nationally and internationally to the condition, and simultaneously to Charcot and the Salpeˆtrie`re. The discovery isolated the anatomic areas of concern for spinal cord motor control and permitted medical anatomists to establish proof of the parallels between the motor control organization of the brain stem and the spinal cord. The name, amyotrophic lateral sclerosis, incorporated the two aspects of gray matter involvement (amyotrophy) and white matter damage (lateral sclerosis) (Fig. 15.5). The designation was anatomic and steered away from clinical terminology of the earlier eras. His own later description of the importance of the work is not overinflated: I do not think that elsewhere in medicine, in pulmonary or cardiac pathology, greater precision can be achieved. The diagnosis as well as the anatomy and physiology of the condition “amyotrophic lateral sclerosis” is one of the most completely understood conditions in the realm of clinical neurology. (Charcot, 1887–1888, lesson of 28 February 1888; Goetz, 1987, p. 179)

OTHER CONTRIBUTIONS BASED ON THE ANATOMO-CLINICAL METHOD In addition to Charcot’s studies of amyotrophic lateral sclerosis, several other contributions evolved from the same type of methodology. He described several clinical-pathological correlations that occurred in stroke syndromes and was a strong advocate of cerebral localization theory (Goetz and Bonduelle, 1996). He led the pivotal debate against his colleague Brown-Se´quard on the foundations of cerebral localization, defending the concept that cortical and subcortical regions controlled specific faculties, and that specific clinical presentation could confidently be ascribed to predictable anatomical lesions (Goetz, 2000b). Charcot’s emphasis was restricted primarily to motor and sensory systems,

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Fig. 15.5. Cross-section of the spinal cord in the superior cervical region in a patient with amyotrophic lateral sclerosis. From Charcot and Joffroy’s 1869 report in the Archives de Physiologie Normale et Pathologique: a represents cells or debris in the anterior horn; b represents sclerosis of the lateral columns.

and he did not extensively study higher cortical functions, like aphasia or apraxia (Goetz and Bonduelle, 1996). Charcot provided the first clinical differentiation between multiple sclerosis and Parkinson’s disease, two entities that had previously been coalesced clinically because they both had tremor as a predominant symptom (Charcot, 1872–1873). Though Charcot failed to identify a structural basis for Parkinson’s disease, the clear-cut demylinating lesions of multiple sclerosis that he correlated with isolated symptoms and signs helped him to separate the two diagnoses during life. Building on the clinical work of his colleague Duchenne de Boulogne, he investigated the gamut of symptoms in locomotor ataxia, and, based on his autopsy studies, favored the anatomical terminology tabes dorsalis to place emphasis on the distinctive lesions affecting posterior columns of the spinal cord (Charcot, 1877). His studies helped define the pathological correlates of the lightning pains, papillary abnormalities and gastric crises that affect these subjects. Rekindling the interface between rheumatology and neurology, he emphasized the particular joint deformities and arthropathies of tabetics and established their neuropathic origins. Based on careful observations among patients with left shoulder arthropathy, he discovered degeneration in the left cervical spinal cord but without involvement on the other side or in the lower spinal cord. Likewise, he discovered lumbar cord lesions associated with lower extremity joint deformities, usually involving the knee (Charcot, 1872–1873). When he presented these findings

at the International Medical Congress in London in 1881, he traveled with a wide array of photographs, wax casts of deformed joints and anatomical specimens. He was accorded ovations and a scientific triumph before the international audience, and tabetic arthropathy became another neurological sign with the Charcot eponym, Charcot joints (Transactions of the International Medical Congress, 1881).

LIMITATIONS AND FRUSTRATIONS The anatomo-clinical method brought international attention and celebrity to Charcot’s Salpeˆtrie`re service and its leader. The method provided a disciplined and systematic approach that fostered a classification of neurological disease based on the integration of clinical signs and anatomical lesions. In spite of this progress, however, a large category of diseases remained problematically unclassified. Charcot designated all neurological conditions that had no identifiable lesion by current methods as névroses, a term without an English equivalent. Such entities were described with the same clinical rigor, but had consistently proved frustrating to Charcot when the autopsy showed nothing distinctively pathological. Parkinson’s disease was the prototype of this frustration, since Charcot had separated the entity from multiple sclerosis, defined its clinical presentation with clarity, and yet found no lesions to contrast with those encountered in multiple sclerosis. Primary forms of

JEAN-MARTIN CHARCOT AND THE ANATOMO-CLINICAL METHOD OF NEUROLOGY epilepsy similarly frustrated the neurological method. Finally, hysteria, a clear-cut neurological category of diagnosis during the 19th century, showed no pathological lesions in spite of stereotypic signs and clinical patterns of impairment. Although Charcot theorized modestly on the anatomical bases of such disorders, he was scientifically an empiricist and resisted abstractions, continuing to search for lesions. He pursued his studies of hysteria during the late years of his career, but turned away from the solidly grounded discipline of the anatomo-clinical method, drifting dangerously into less sophisticated physiology studies outside his anatomical expertise. Charcot anticipated that further anatomical advances and new technologies would allow well-described clinical syndromes to be removed from the vague névroses category into their own primary diagnostic classification. The eventual identification of the midbrain lesions that typify Parkinson’s disease is only one example of this process, and hysteria became later classified within the psychogenic neurological disorders.

CHARCOT’S MODERN LEGACIES The anatomo-clinical method that became the beacon of Charcot’s Salpeˆtrie`re School during his lifetime extended to become the international anchor of neurology as a medical specialty. The reliance on anatomical localization expanded from gross to histological precision within Charcot’s career and in the later generations to biochemical and molecular anatomy. Further advances have redefined individual diagnostic entities, but the major components of the neurological nosology remain firmly anchored in Charcot’s contributions. His concept of a neurological service that combines clinical expertise with advances from specialists of other scientific fields is echoed in the major university neuroscience programs of the 21st century. Whereas contemporary terms like “translational research” may seem modern, they are reiterations of Charcot’s primary mission. Emphasizing this ultimate point to his students, Charcot stated: We will always have before us a particular case, a patient whom we wish to cure, or at any rate alleviate his suffering. But this end can only be attained by the application of information acquired in the different branches of medicine. True clinical practice has no autonomy: it lives by ideas derived from prior experiences and by their appropriate applications. Without continual infusion with new scientific knowledge, medical practice would soon become a barren and stereotypic routine. (Charcot, 1887, p. 9F, p. 7E)

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REFERENCES Ackerknecht EH (1967). Medicine in the Paris Hospital: 1794–1848. Johns Hopkins University Press, Baltimore, MD. Charcot J-M (1865). Scle´rose des cordons late´raux de la moelle e´pinie`re chez une femme hyste´rique atteinte de contracture permanente des quatre membres. Bull de la Socie´te´ Me´d des Hoˆpit de Paris 2: 24–35. Charcot, J-M (1872–1873). Oeuvres Comple`tes. Vol. 1. Bureaux du Progre`s Me´dical, Paris. [In English: Charcot J-M (1877). Lectures on the Diseases of the Nervous System (transl. G Sigerson). New Sydenham Society, London.] Charcot J-M (1874). Maladies des vieillards: goutte et rhumatisme. Bureaux du Progre`s Me´dical, Paris. [In English: Charcot J-M (1881). Clinical Lessons on Senile and Chronic Diseases (transl. WS Tuke). New Sydenham Society, London.] Charcot, J-M (1877). Oeuvres Comple`tes. Vol. 2. Bureaux du Progre`s Me´dical, Paris. [In English: Charcot J-M (1881). Lectures on Diseases of the Nervous System (transl. G Sigerson). New Sydenham Society, London.] Charcot J-M (1887). Oeuvres Comple`tes. Vol. 3. Bureaux du Progre`s Me´dical, Paris. [In English: Charcot J-M (1889). Clinical Lectures on the Diseases of the Nervous System (transl. T Savill). New Sydenham Society, London.] Charcot J-M (1887–1888). Les Lec¸ons du Mardi: policlinique. Bureau du Progre`s Me´dical, Paris. Charcot J-M, Joffroy A (1869). Deux cas d’atrophie musculaire progressive avec le´sions de la substance grise et de faisceaux ante´rolate´raux de la moelle e´pinie`re. Arch Physiol Norm et Pathol 1: 354–367; 2: 628–649; 3: 744–757. Gelfand T (1994). Charcot me´decin international. Rev Neurolog 150: 517–523. Goetz CG (1987). Charcot The Clinician: The Tuesday Lessons. Raven Press, New York. Goetz CG (1991). Visual art in the neurological career of Jean-Martin Charcot. Arch Neurol 48: 421–425. Goetz CG (2000a). Amyotrophic lateral sclerosis: early contributions of Jean-Martin Charcot. Muscle Nerve 23: 336–343. Goetz CG (2000b). Charcot and Brown-Se´quard on cerebral localization. Neurology 54: 1840–1847. Goetz CG, Bonduelle M (1996). Charcot and aphasia. J Hist Neurosci 5: 108–116. Goetz CG, Bonduelle M, Gelfand T (1995). Constructing Neurology: Jean-Martin Charcot. Oxford University Press, New York. Gombault A (1871–1872). Scle´rose syme´trique des cordon late´raux de la moelle et des pyramides ante´rieurses dans le bulbe. Arch Physiol Norm et Pathol 4: 509–518. Laennec RTH (1819). De l’auscultation me´dicale ou Traite´ du diagnostic des maladies des poumons et du coeur fonde´ principalement sur ce nouveau moyen d’exploration. Paris. Lellouch A (1992). Jean Martin Charcot et les Origines de la Ge´riatrie. Payot, Paris.

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Marie P (1925). E´loge de J-M Charcot. Rev Neurolog 5: 736–745. Michale MS (1985). The Salpeˆtrie`re in the age of Charcot: an institutional perspective on medical history in the nineteenth century. J Contemp His 20: 703–731.

Transactions of the International Medical Congress (1881). London. Weisz G (1987). The posthumus Laennec: creating a modern medical hero. BHM 61: 541–562.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 16

History of the development of the neurological examination EDWARD J. FINE* AND M. ZIAD DARKHABANI Department of Neurology, The Jacobs Neurological Institute at Kaleida, Buffalo General Hospital, Buffalo, NY, USA and the Department of Neurology, University at Buffalo, The State University at Buffalo, USA

INTRODUCTION This chapter reviews the origins of the neurological examination. The task of tracing the history of the development of this examination is arduous. As students we watched attending neurologists examine patients, but heard little or no discussion of when, where, how and by whom the neurological examination was developed. Attending neurologists, perform examinations in front of students and resident physicians without attribution to the pioneers of neurology. Thus, much of the neurological examination has been passed from teachers to students by oral tradition. The authors of this chapter reviewed widely circulated textbooks of neurology and seminal journal articles in reverse chronological order. We discovered through original sources how the tests and techniques of the neurological examination evolved from 1850 to 1930. We found that the pioneers of neurology developed their examinations by correlating signs or symptomes with post-mortem examinations of the patients they examined. They applied the results of stimulation and ablation experiments on laboratory animals to the interpretation of the signs and symptomes (Dalton, 1861; Ferrier, 1876). Examination of widely read textbooks of neurology from 1850 to 1930 revealed that descriptions of methods of neurological examinations appeared in the last 20 years of the 19th century. Textbooks of neurology evolved from simple recordings of their authors’ lectures to medical or postgraduate students. Authors of textbooks before the 1880s indirectly alluded to techniques they used for neurological examination only in the context of describing a disease or syndrome. The American neurologist William A. Hammond (1826–

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1900) did not include an introductory chapter on physical examination; he wrote out instructions on use of an aesthesiometer that resembled a carpenter’s compass to measure tactile sensibility and a dynamometer for documenting muscle power of patients with neurological disorders (Hammond, 1871, pp. xi–xxv). Jean-Martin Charcot (1825–1893) applied the clinical-pathological method of correlating signs and symptomes to morbid anatomy, beginning in the 1850s. Charcot’s students did not document how the master performed his examinations (Charcot, 1877; Goetz et al., 1995, pp. 65–78). Neurologists began exchanging information about the neurological examination of their patients in publications initially in general medical journals, such as the Lancet. The Journal of Nervous and Mental Diseases in the United States and Brain in England, founded in 1874 and 1878, respectively, were publications devoted to neurology and psychiatry that contained articles in which signs and symptomes were correlated with autopsy findings. Publications in these journals distributed knowledge of standardized methods to test the function of the various subsystems of the nervous system. William Richard Gowers (1845–1915) described methods to examine muscular strength, coordination, sensory perception, tone, tremor, reflexes and actions of individual muscles in his textbook (Gowers, 1888, pp. 27–67). Gowers included some methods to evaluate the functions of cranial nerves (Gowers, 1888, pp. 567–707). Charles Karsner Mills (1845–1931) of Philadelphia was the first American neurologist to compose an entire chapter on symptomology and methods of investigation in his textbook of neurology (Mills, 1898,

Correspondence to: Edward J. Fine MD, Associate Professor of Neurology, The Jacobs Neurological Institute, Kaleida Buffalo General Hospital, 100 High Street, Buffalo, NY 14203, USA. E-mail: [email protected], Tel: +1-716-887-5411, Fax: +1-716-887-4385.

214 E.J. FINE AND M.Z. DARKHABANI pp. 142–178). More expansive introductory chapters perturbation of the fantasy, characterized by raving on how to perform a neurological examination first and talking idly” (Pare´, 1634). He associated delirium appeared in American textbooks of neurology at the with fever, wounds, excessive blood loss and gangrene. beginning of the 20th century (Dana, 1901; Church and John Hunter (1728–1793), the Scottish born surgeon, Peterson, 1911). These textbooks disseminated knowldescribed delirium as a “diseased dream, arising from edge about techniques of examination and their relation disturbed sleep.” In delirium, “what the mind thinks to neurological anatomy and physiology. appears to be real to the patient.” He distinguished The organization of this historical review will insanity from delirium by “using a strong stimulus resemble a current neurological examination: beginthat would arouse the delirious person to make him ning with the neurological history and followed by aware of his situation” (Hunter, 1835, p. 33). The the examinations of mental status, cranial nerves, eliinsane person could not be brought to reality (Hunter, citing cutaneous and tendon reflexes, motor strength, 1835, p. 335). sensation, cerebellar assessment and evaluation of gait. An American physician, William Worcester (1859– 1939) came close to our modern perspective of delirNEUROLOGICAL HISTORY ium as failure “to identify surrounding objects and persons, accompanied by sensory disturbances such Systematic examination of the nervous system requires as hallucinations and illusions.” Delirious persons recording the patient’s chief complaints in exact chronmanifested reduced or increased psychomotor activity ological order. The American neurologist Archibald that ranged from “false levity, to despair and even Church (1861–1952) urged physicians to record the terror” (Worcester, 1889). “manifestations of the disease systematically, with full The American neuropsychiatrist Fredrick Peterson attention to remissions and exacerbations” (Church and (1859–1939) graduated from the University of BuffaPeterson, 1911, p. 20). Church also emphasized that lo’s Department of Medicine at age 20. He emphasized knowing the patient’s family history was a critical facthat the mental status examination must include a welltor for diagnosis of Friedreich’s ataxia or Huntington’s defined statement about patients’ consciousness. chorea (Church and Peterson, 1911, pp. 18–22). AppreChurch defined stupor in patients who had diminished ciation of hereditary neurological diseases began with attention, decreased motor activity, and inhibition of Nikolaus Friedreich’s (1825–1882) publications on thought (Church and Peterson, 1911, p. 735). Bernard hereditary ataxia (Friedreich, 1877). George Huntington Sachs identified comatose patients by their lack of (1850–1916) noted that chorea and “nervous exciteany movement to stimuli, absent conjunctival reflexes, ment” were passed “from each generation to another, and dilated pupils that did not react to light (Sachs and unbroken from parent to child” in what we now term Hausman, 1926, pp. 72–73). Gowers examined patients a dominant pattern (Huntington, 1872). in coma, noting that “the pupils may be wide or small, Bernard Sachs (1858–1944), who was born in Baltibut are motionless” to light. He touched the conjuncmore, MD, but received his medical education in Strastiva and concluded that there was no “occurrence of bourg, advocated that a complete developmental any reflex contraction” in deep coma. He noted that history must include information about when an infant “the eyes tend to deviate conjugately” in cerebral followed objects with his or her eyes, cried, smiled, lesions (Gowers, 1888, p. 512). Gowers cautioned his rolled over, crawled, crept, walked and spoke his or readers to remember that “great contractions of the her first words (Sachs and Hausman, 1927, pp. 71–72). pupils occur in opium poisoning, but also in hemorIdentifying debilitating habits of alcohol and tobacco rhage to the pons Variolo” (Gowers, 1888, p. 535). abuse was necessary for accurate diagnosis. ObtainBoston neurologist C. Miller Fisher confirmed that ing details about patients’ occupations provided meiotic pupils are associated with pontine hemorrhages insights into exposure to neurotoxic substances, such (Fisher, 1967). as lead, mercury, arsenic, and carbon disulphide Gowers (1888) stated that depressed consciousness (Church and Peterson, 1911, pp. 18–22). deprives the examiner of direct evidence of motor power. He suggested “a pinch will cause a movement MENTAL STATUS EXAMINATION of a sound limb, but not that which is paralyzed . . . Earlier mental status examinations began with rudiThere is greater flaccidity of the paralyzed limbs” mentary estimations of patients’ responses to their (Gowers, 1888, p. 512). He suggested testing for weaksurroundings, mood, consciousness and memory. ness by lifting the patient’s arms and observing “the Although clear distinctions between lethargy and stuparalyzed arm falls like a dead weight” and the sound por were not made until the end of the 19th century, arm “falls less suddenly . . . The paralyzed cheek may Ambrose Pare´ (1510–1590) recognized delirium as “a flap with respiration” (Gowers, 1888, p. 512).

HISTORY OF THE DEVELOPMENT OF THE NEUROLOGICAL EXAMINATION 215 Smith Ely Jelliffe (1866–1945) and William Alanson convolution, at autopsy of his patient, M. Leborgne. White (1870–1937), American neuropsychiatrists, asked This man was nicknamed “Tan,” because he uttered their patients to recite lists of digits forward and backthis word and some curses, whenever he wished to ward to test attention. For testing “school knowledge,” speak. “Tan,” however, understood commands and these authors asked historical facts, identification of could gesture or point to what he wanted. In 1863, geographical place names, and countries. They listened Broca recognized that the left hemisphere had speto their patients’ stream of thought for clarity, disconcial functions for speech (Finger, 1994, pp. 37–38). nected thoughts, and incoherence. They evaluated Broca examined patients by having them repeat patients’ orientation by asking about their birth dates, words voluntarily, and estimated their rate of produthe present year, and location of a hospital in a city cing words and listened for ungrammatical and state. Unfortunately their mental status examinasentences (Roth, 2002). Broca noted that patients tion lacked a proper examination of speech, because with motor aphasia can understand commands, can they omitted testing repetition of spoken words and anaoften sing along with other persons and curse, when lysis of content (Jelliffe and White, 1929, pp. 126–129). prodded. The mental status examination was expanded and Carl Wernicke (1848–1904) emphasized that speech standardized by borrowing elements from intelligence had a sensory component in his seminal paper on tests. Alfred Binet (1857–1911) developed a test that receptive aphasia that appeared in 1874. Wernicke met the needs of a French government commission to adapted Magendie’s method of analyzing reflexes to identify children who would fail in traditional classcreate a system of evaluating speech disorders. rooms. He tested for tasks of daily living, such as Magendie observed that reflexes have an afferent counting, making change, remembering lists of items sensory input and efferent motor output (Finger, and numbers, and naming objects (Finger, 1994, pp. 1994, pp. 379–380). Wernicke reasoned that decreased 322–323). These elements of Binet’s battery were incormotor output of speech followed destruction of the porated in the Wechsler Adult and Child Intelligence posterior portion of the left frontal third convolution Scales (WAIS or WISC). or the frontal operculum in Broca’s aphasia. Wernicke The Mini-Mental State Examination (MMSE) is the examined patients by having them name objects and most commonly employed bedside test of mental functhen repeat words. He listened for substitutions, paration currently, because it is performed with no special phrasic errors, and incomplete sentences. Wernicke equipment, unlike the WAIS or WISC. Marshall Folstein advised his readers not to use gestures when examin(b. 1941) developed the MMSE as a standardized test to ing such patients, since these motions aid the patients’ detect dementia in patients. The MMSE requires only diminished comprehension. Patients with lesions in the pencil and paper for constructional testing (Folstein speech sensory area could not easily comprehend the et al., 1975). It is divided into two parts: the first “requircontent of speech, recognize errors in their own ing only vocal responses . . . covers orientation, memory speech, or correctly repeat words (Wernicke, 1874; and attention: the maximum score is 21.” The second Roth, 2002). He postulated that the sensory or afferpart gauges “ability to name, follow verbal and written ent area “contained the memory for the acoustic commands, write a complete sentence and copy a comimage” of words and localized the sensory area of plex polygon.” The maximum score is 9. The examiner speech in the posterior part of the superior left temcan use the MMSE to distinguish dementia from poral lobe. depression. Demented patients have combined scores Wernicke also described a third speech disorder, of less than 20; depressed patients score an average of Leitungaphasie, or conduction aphasia. Wernicke iden25 of a total of 30 points (Folstein et al., 1975). (The tified conduction aphasia in patients who had difficulty reader may refer to Victor Henderson’s chapter in this repeating words, but retained understanding and fluvolume for further details about the mental status ency for word production (Finger, 1994, pp. 379–380; examination.) Roth, 2002). Ludwig Lichtheim (1845–1928) adopted Wernicke’s methods of examining patients (Lichtheim, 1885). He EXAMINATIONS FOR APHASIA identified a new class of aphasic disorders in patients Examination for specific defects in language began who could repeat sentences but had difficulty with with the concept that specific areas of the brain are comprehension or word production. The lesions that dedicated to the function of speaking. In 1861, Paul produced these defects were not in the perisylvian Broca (1824–1880) recognized a decreased rate of area. These disorders are currently termed transcortical expression of words as motor aphasia. Broca found (extra-sylvian) sensory and transcortical motor aphasia, the causative lesion, an infarction of the third frontal respectively. (For more on the history of aphasia,

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methods of localization and contributions of Henry Head, the reader is referred to the chapter by Eling and Whitaker in this volume.)

EXAMINATION FOR AGRAPHIA Pure agraphia is the loss of the ability to write in the absence of dementia or paralysis, visual loss, or aphasia. John William Ogle (1824–1905) used this definition to distinguish agraphia from aphasia in 1867. Charles K. Mills cautioned that diagnosis of isolated agraphia must be predicated on knowledge of a patient’s education and “prior ability to write.” He tested his patients’ writing skills by requesting them to write with each hand; because the “true agraphic will not be able to write with either the non-paralyzed or paralyzed hand.” Mills examined his patients’ visual fields and had them write sentences spontaneously and from dictation. “True motor agraphia is not associated with sensory, or visual loss or paralysis” (Mills, 1898, pp. 638–639). He observed that most persons who have motor agraphia also suffer from motor aphasia. An exceptional patient may have “retained speech, but lacks ability to write, since the graphic center is separate from the true speech center” (Mills, 1898, pp. 349–350 and pp. 638– 639). (The history of agraphia and alexia is covered in greater detail by Victor Henderson in this volume.)

CRANIAL NERVES Cranial nerve I: the olfactory nerve In 5th century BC Greece, Alcmaeon proposed that the sense of smell depends upon the aspiration of odorous particles through the nose to the brain (Finger, 1994, p. 176). Plato postulated that smell receptors are located inside the nose (Beare, 1906; Plato, 1952; Finger, 1994). The olfactory nerves (CN I) were described by Galen (c. 130–200), who did not consider them true nerves (Flamm, 1967). The search for the “primary” odors has constituted a plethora of olfaction research. The first odor classification based on chemical structures was developed at the end of the 18th century (Magendie, 1824, pp. 169–176). Non-irritating volatile oils and liquids must be used to test smell. Magendie came to the erroneous conclusion that the trigeminal was the nerve of olfaction when he cut a dogs olfactory nerve and the dog reacted to the smell of ammonia and ether (Magendie, 1824, pp. 169–176). Valentin, Schiff, and Pre´vost pointed out that Magendie used irritating substances that could have activated pain fibers in the trigeminal nerve (Finger, 1994, p. 182). Church recommended testing each nostril separately by firmly closing the opposite anterior nares and having the patient sniff an aromatic volatile oil through

the open nostril (Church and Peterson, 1925, p. 66). Later Jelliffe and White (1929, p. 355) cautioned that “changes in the membrane such as coryza, influenza, maxillary sinusitis and nasal polyps” can “bring about unilateral or bilateral loss of smell.” Scratch and sniff tests supplanted testing olfaction by sniffing varying concentrations of aromatic substances such as oil of cloves.

Cranial nerve II: the optic nerve Galen described the optic nerves and chiasma (Galen, 1968, p. 188). The functions of the optic nerve are examined with tests for visual acuity, field of vision and perception of color.

VISUAL ACUITY In 1738 James Jurin tested his patients’ visual acuity when they read from a book with different print sizes (Jurin, 1738). The Viennese physician, Eduard Jaeger Ritter von Jaxtthal (1818–1884) introduced his SchriftScalen or Test-Types, in 1854, consisting of rows of numbers ranging in size from minute in row 1 to large in row 20. Visual acuity charts that are in widespread use today are named after Dutch ophthalmologist Hermann Snellen (1834–1908), who developed his first chart in 1862. His eye chart consisted of standardized square letters, and he provided rules and a formula for recording acuteness of vision (Snellen, 1862). Hence, a man who tested 20/200 could distinguish letters at 20 feet that normally sighted persons would recognize at 200 feet.

VISUAL

FIELD TESTING

British physiologist David Ferrier (1843–1928) observed homonymous hemianopsia in monkeys, a few days after he had removed portions of their contralateral angular gyrus (Ferrier, 1881). German physiologist Hermann Munk (1839–1912) provided evidence that the angular gyrus was not the locus for vision disputed Ferrier’s claim. Munk observed the behavior of monkeys for up to 5 years after he made lesions in the angular gyrus or in the occipital lobes. Munk concluded that the “critical site of vision” is in the occipital lobe (Munk, 1879). Albrecht von Graefe (1828–1870) introduced visual field examination into daily practice, when he invented campimetry (von Graefe, 1856). He also noted that lesions of the occipital cortex and temporal lobe caused homonymous hemianopsia (von Graefe, 1856). By the 1890s devices were constructed to measure visual field defects accurately. Moses Allen Starr (1854–1932), a New York neurologist, confirmed Munk’s observations from the study of multiple human autopsies of patients with hemianopsia, who had lesions in their occipital lobes (Starr, 1884).

HISTORY OF THE DEVELOPMENT OF THE NEUROLOGICAL EXAMINATION Charles K. Mills noted that bitemporal hemianopsia could be caused by a variety of lesions, such as acromegaly, syphilitic gummata, malignant “sarcomata and an aneurysm of an anomalous artery that destroyed the [optic] chiasm in the median line” (Mills, 1898, p. 761). Gordon Holmes (1918) serially mapped visual fields of dozens of soldiers recovering from gunshot wounds sustained in their occipital lobes. He discovered that the center for macular vision lies in the most posterior portion of the visual cortex, probably on the margins and on the lateral surfaces of the occipital lobes . . . Severe lesions of the visual cortex produce complete blindness in the corresponding portions of the visual fields . . . The defects of vision in the fields of the two eyes are always congruous and superimposable. (Holmes, 1918, pp. 382–383) Modern neurologists check their patients’ visual fields for defects by standing at a distance of one meter separation, closing one eye, and comparing their visual field to their patients’ opposing visual field. Having patients count the examiner’s fingers placed in various quadrants of the field of vision enhances sensitivity of this “confrontation” technique (Welsh, 1961).

FUNDOSCOPY Hermann von Helmholtz (1824–1894) invented the ophthalmoscope between 1850 and 1851 to examine the living retina. He combined a mirror to reflect light onto the retina with a concave lens in a “suitable frame” that he called an Augenspiegel to produce the first ophthalmoscope. Von Helmholtz (1851) described the optic disc and the central retinal artery and vein. The reader can marvel at the extraordinarily detailed plates depicting papilledema or chronic renal failure in Gowers’ (1879) Medical Ophthalmoscopy, drawn by his own artistic hand.

COLOR

VISION

John Dalton (1766–1844) described the inability to see certain hues, including his own problem seeing the color red (Dalton, 1794). Gowers praised the method of Holmgren (1831–1897) of Uppsala, Sweden to detect color blindness: Skeins of wool employed of various colours, pure red, orange, yellow, pure green, greenish-blue . . . pure blue, violet, purple and rose . . . are laid in a heap on a table . . . [The examiner asks] the individual to pick up a skein of wool and then to select all other wools that appear to him to correspond to the selected skein . . . A pale-green skein is the best to select in the first instance . . . because green is . . . most readily confounded

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with grey . . . if the individual is colour blind. (Gowers, 1879, pp. 234–236) Pseudo-isochromatic plates of Ishihara provide more accurate measures of color blindness than matching the hue of wool skeins. The examiner asks the patient to pick out the dotted numbers or figures hidden in a field of dots of a confounding color in these plates. Color blind persons cannot see numbers or figures in the plates corresponding to their specific color blindness.

Cranial nerve III: the oculomotor nerve Galen failed to distinguish this nerve (Goss, 1963). The oculomotor nerve, CN III, was correctly identified by Gabriel Fallopius (1523–1562) in 1561, while working in the anatomical theater at Padua, Italy. Fallopius followed the nerve from its emergence from the midbrain through the superior orbital fissure to divide into two branches. The superior branch “went into the muscle that opens the eye and the muscle that draws the eye upward” (levator palpebrae superioris and rectus superior bulbi muscles). The inferior branch “passes into muscles that drew the eye inward or down” (rectus medialis bulbi, and rectus inferior bulbi). (Fallopius, 1561, p. 148). America’s first trained physiologist, John Call Dalton, Jr. (1825–1889), noted that division of the oculomotor nerve causes the superior eye lid [to] fall down over the pupil owing to the inaction of the levator muscle, so that the eye appears half-shut . . . The movements of the eyeball are nearly suspended and permanent external strabismus takes place owing to the paralysis of the internal rectus muscle (Dalton, 1864, p. 451).

PUPILLARY

REACTIONS

Robert Whytt (1714–1766) made a prescient study of the pupils of humans and domestic animals. He noted the consensual reflex, when he observed that, if a candle is placed to shine upon one eye, without its rays having access to the other pupil, that pupil not exposed to the light becomes somewhat less [in diameter] . . . as if both eyes were equally affected by the light. (Whytt, 1763, pp. 66–67) Whytt also appears to be the first to use cover and uncover tests to detect the consensual reflex when he observed that when one eye is covered, the pupil of the open one becomes wider from the consent between its motions and those of the darkened one. (Whytt, 1763, pp. 66–67) C.K. Mills tested his patients’ pupils by having them look out into the distance, with one eye excluded from

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diffuse daylight, while the other eye is suddenly shaded. If the shaded eye is normal, its pupil should dilate. He tested for consensual light reflex by observing that “the other eye will act in unison with its fellow . . . with both eyes open and then with one eye shaded.” His technique eliminated the confounding effect of constriction of the pupils due to near accommodation (Mills, 1898, pp. 162–163). Marcus Gunn (1850–1909) noticed that if a pupil dilates when a light is shone through the pupil within a dimly lit room, the cause of this apparently paradoxical response is due to an afferent pupillary defect in that eye (Gunn, 1902). This “paradoxical” light reaction is noted when the pupil of the “good” eye dilates due to dark accommodation and drives the Westphal–Edinger nucleus to activate the pupillary dilatory fibers of the “bad” eye. The lack of sufficient afferent input from the “bad” eye for light accommodation fails to overcome the consensual dark accommodation effect from the “good” eye. He cautioned that the patient must look into the distance to eliminate the opposing effect of pupillary constriction caused by near accommodation. Contemporary neurologists swing a small beam of light alternately from one eye to the other to detect afferent pupillary defects (Levatin, 1959; Thompson, 1966). Samuel Wilks (1824–1911) instructed the examiner to observe the pupils closely following an attack of apoplexy (cerebral hemorrhage). “In fatal cases, where blood has burst into the ventricles, or diffused over the base of the brain, the pupils are often minutely contracted” (Wilks, 1878, pp. 435–436). Gowers stimulated the skin of “neck with faradic current. . . so as to produce a sharp painful sensation. . . but in most persons the prick of a needle, and even a pinch is sufficient” to dilate the ipsilateral pupil. This response affirms integrity of sympathetic input upon the pupil (Gowers, 1888, p. 607). In 1869, Douglas Argyll-Robertson (1837–1909), a Scottish ophthalmologist, published a remarkable set of observations about pupils, which he believed would ascertain the diagnosis of tabes dorsalis. He concluded that the retina retained its acuity to detect objects in the tabetic patients. The pupils were small, did not react to light, but constricted to accommodation upon looking at near objects (Argyll-Robertson, 1869). Gowers augmented these astute observations when he noted that pupillary dilatation was absent to painful stimulation of the skin of the neck of many patients afflicted with syphilis of the nervous system. Their pupils “were not perfectly circular and often were unequal” (Gowers, 1888, p. 295). Mills instructed his readers to have patients follow objects with their eyes, with examiners noting loss of ocular movement. When patients diverged their eyes, Mills noted that some had homonymous diplopia:

lateral diplopia implied paralysis of rectus internus (medial rectus) or rectus externa (lateral rectus). He found that the separation of images, when patients looked to their right side, would increase with right rectus externa palsies. “Looking to their left side, greater separation of images would denote a paralysis of the left rectus externa. Covering and then uncovering each eye brought out paresis, because a paretic eye will not move to focus on a nearby object” (Mills, 1898, pp. 813–815). Mills checked convergence and divergence by having patients look at “close objects and far objects situated at the same altitude.” He accepted that convergence was associated with the midline nucleus of Perlia, but later observations cast doubt on this simplistic view (Perlia, 1889; Mills, 1898, p. 801; Warwick, 1955).

Cranial nerve IV: the trochlear nerve This purely motor nerve is the smallest of the cranial nerves. It was overlooked by Vesalius and vaguely described by Realdo Columbo in 1559 (Flamm, 1967). Thomas Willis illustrated a nerve that arose from the dorsal surface of the midbrain and entered the orbit. Willis oddly named it the “pathetick” nerve (Willis, 1681; 7th figure). Later this nerve was given the name trochlear, because it supplied the superior oblique muscle that passed through a pulley-like structure to attach to the ocular globe. The Latin word for pulley is trochlea. After emerging from the dorsal surface of the midbrain, the trochlear nerve winds around the cerebral peduncles and enters the orbit through the superior orbital fissure to supply the superior oblique muscle (Gray and Goss, 1954, p. 986). The primary action of the superior oblique muscle is to draw the eye inward and down. Charles K. Mills detected dysfunction of this nerve, observing: . . . when the action of the superior oblique is lost, the affected eye will be rotated slightly upward and inward. Double images appear when the eyes are turned downward. The diplopia is homonymous and the images are placed one above the other . . . The images become widely separated both vertically and laterally [as] the test object is carried downward and outward . . . The patient inclines to turn the head forward and toward the healthy side to correct the false projection, which is downward and a little outward. (Mills, 1898, p. 826) Modern neurologists employ a modification of Mills’ instruction when we tilt a patient’s head passively, enquire about the separation and elevation of the true and false images, and we observe the lack of compensatory

HISTORY OF THE DEVELOPMENT OF THE NEUROLOGICAL EXAMINATION intorsion of the eye that lost its CN IV innervation (Hofman and Bielschowsky, 1900) (Bielschowsky, 1938).

Cranial nerve V: the trigeminal The trigeminal nerve (CN V), the largest of the cranial nerves, is a mixed nerve, containing motor and sensory functions. Thomas Willis correctly assigned the function of mastication to his 5th nerve pair. “Two nerves of noted magnitude, which after they have passed through the dura mater send for another notable branch on either side straight, with out the skull and are in the Palate, parts of the Mouth and Face” (Willis, 1681, pp. 57–58). The motor portio minor of this nerve emerges rostral and medial to the sensory portio major (Gray and Goss, 1954, p. 954). The combined nerve passes along the temporal bone. The sensory portion “expands into the cresenteric swelling, the Gasserian ganglion . . . The motor portion passes below and exits the skull through the foramen ovale” (Dalton, 1864, pp. 451–455). The motor portion innervates muscles of mastication: masseter, temporalis, internal and external pterygoid, and muscles of deglutition: anterior digastric and mylohyoid (Mills, 1898, pp. 861–862). The sensory branches of the trigeminal nerve are ophthalmic, maxillary and mandibular. Mills recommended testing pain sensation supplying each of the three braches with a clean sharp-tipped object (Mills, 1898, pp. 857–859). Gowers tested for motor dysfunction of CN V by “placing the finger on each masseter or temporal muscle and making the patient bring the teeth forcibly together as in the act of biting. The feebleness or absence of contraction on the affected side is then evident.” Paralysis of the external pterygoid prevents the patient from moving “the jaw toward the unaffected side . . . and . . . when the jaw is depressed, it deviates toward the paralyzed side” (Gowers, 1888, p. 635). These examination techniques remain fully accepted and utilized today.

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of the current examination for determining function of the abducens nerve.

Cranial nerve VII: the facial nerve Galen did not distinguish the separation of the facial nerve from the vestibulo-cochlear nerve; Vesalius’ designation of the cranial nerves did not improve upon Galen. The functions of this nerve were first correctly described by the Scottish surgeon and anatomist, Sir Charles Bell (1774–1842). He meticulously traced the anatomy of the facial nerve to each individual facial muscle in cadavers and drew superb illustrations that challenge today’s atlases of anatomy for clarity and accuracy. Bell’s description of a patient suffering injury to this nerve informs us about his methods of evaluation. Bell recognized that elevation of the upper lid is performed by the attolens (levator) palpebrae superioris, which is innervated by a “branch of the third nerve” (Bell, 1830, Appendix vi–xxvii). He demonstrated a patient whose facial nerve was accidentally crushed by the horn of a bull “at its emergence from the stylomastoid foramen.” He then palpated the orbicularis palpebrae (oculi) muscle while having the patient tightly close his eyelids and commented that the contraction of this muscle was weakened on the side of the facial nerve injury. Figure 16.1 depicts a patient with left facial paralysis attempting to smile and close

Cranial nerve VI: the abducens nerve Fallopius presciently described the abducens nerve as the 6th cranial nerve (Flamm, 1967, pp. 286–288). The nucleus of CN VI arises in the reticular formation of the pons and moves lateral and ventral to exit on the surface of the lateral pons (Gray and Goss, 1954, p. 954). The nerve enters the orbit through the superior orbital fissure above the ophthalmic vein to penetrate and innervate the lateral rectus muscle (Gray and Goss, 1954, p. 999). The eye at rest on the side of an abducens nerve lesion “would have convergent strabismus”; double images are “likewise seen when the eyes are turned in the horizontal plane toward the paralyzed side” (Mills, 1898, p. 827). This technique and observation are part

Fig. 16.1. Left facial palsy-patient trying to close both eyes and show his teeth. (From Dana, 1901.)

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his left eye. Then he asked his patient to pretend to sleep: “the patient’s eye on the paralyzed side of the face rolled up and outward.” Bell also requested his patient to sniff and observed lack of motion of the left nares. Bell tested buccinator muscle strength by having his patient puff out his cheeks against his fingers, noting that air escaped when the weak cheek was compressed. He had the patient laugh and with each “cachinnation the left (weak) cheek was puffed out, flapping like a loose sail” (Bell, 1830, Appendix vii– xiv). Additionally, Bell cut the facial nerve of a monkey and observed the “motions of his eyelids and eyebrows were lost. He could not wink on that side and his lips were drawn to the other, whenever he showed his teeth in rage” (Bell, 1830, pp. 77–78). Georg Herman Monrad-Krohn (1884–1964), a Norwegian neurologist, advocated having patients say “papa, mamma” to test for weakness of the orbicularis oris muscle. Clear articulation of these labial words required full function of this muscle (Monrad-Krohn and Refsum, 1958, pp. 63–81). He postulated that when the emotional smile was inhibited and the forced smile normal, the lesion lay in the opposite hypothalamus (Monrad-Krohn, 1924). This dictum was accepted until Borod and associates noted patients with right hemisphere pathology are less responsive than normal controls when smiling after viewing humorous sketches (Borod et al., 1988). The facial nerve receives afferent fibers from taste receptors on the anterior two-thirds of the tongue through the chorda tympani fibers that initially travel with the lingual nerve of CN V. To test for taste, Monrad-Krohn recommended that salt and sugar be placed on the tongue successively, after washing away the prior test substance with distilled water and blotting the tongue dry. He recommended that patients point to the appropriate words “sweet or salt,” so that talking would not dislocate the test substance. If taste is impaired for these substances, the lesion may lie proximal to the branch of the chorda tympani (Monrad-Krohn and Refsum, 1958, pp. 63–81). Gowers (1888, p. 652) suggested testing for hypersensitivity to noise using low-pitched sounds in patients with suspected facial paralysis. He noted that, in the absence of the action of the stapedius muscle due to a lesion of the facial nerve, the tensor tympani muscle is unopposed.

Cranial nerve VIII: the acousticvestibular nerve Cranial nerve VIII is actually two nerves, serving balance and audition. The vestibular function has its sensors in the semicircular canals, and audition in the cochlea. In 1564, Bartolomeo Eustachio (1524–1574) described

the bony and membranous structures of the semicircular canals and cochlea, the ossicles, and the canal that connects the middle ear to the nasal cavity. Little was known about the receptive organ for sound until Domenico Cotungo (1736–1822) described the membranous portion of the vestibular and cochlear aqueducts and the structure of the auditory labyrinth. In 1789, Antonio Scarpa (1747–1836), while working in Pavia, Italy, described the vestibular ganglion of the VIII nerve and endolymphatic fluid. He correctly postulated that sounds are transmitted through the ossicles to the inner ear (Scarpa, 1789). The function of the vestibular system for maintaining balance was uncertain until Pierre Flourens (1794–1867) showed that lesions of the posterior semicircular canal in pigeons caused them to roll over backwards (Flourens, 1842). Charles Edward Brown-Se´quard (1817–1894) then discovered that cooling the vestibular labyrinth with cold liquids induced vertigo (Brown-Se´quard, 1860, pp. 195– 196). Hungarian physiologist Robert Ba´ra´ny (1876–1936) observed that warming the endolymphatic fluid causes it to expand and induces the quick component of the nystagmus to move the eyes to the same side as the warm irrigated ear (Ba´ra´ny, 1906). Fitzgerald and Hallpike noted when the head is placed 30 above the horizontal line, ice cold water placed in the external auditory canal causes the quick component of the nystagmus to shift the eyes away from the irrigated ear (Fitzgerald and Hallpike, 1942). Positional maneuvers of the head are useful to diagnose causes of intermittent vertigo. Nyle´n (1950) recommended that a patient’s head be displaced rapidly in six different positions to test the functions of the semicircular canals. With lesions of the vestibular canals, when the head is brought down from the sitting up to lateral decubitus position, the induced nystagmus is often rotatory, delayed on onset by at least 2 s, and exhausted with repeated movements from the vertical to the lateral decubitus position. The fast component of nystagmus beats toward the patient’s down-turned ear (Nyle´n, 1950). Contemporary neurologists employ the head impulse test to stimulate maximally the vestibular system with high velocity rotations through 10–15 . This test identifies “acute unilateral peripheral vestibular deficits in patients with vestibular neuronitis or labyrinthitis” (Bronstein, 2003). Bronstein critically evaluated the sensitivity of this maneuver at 34% and commented upon the shortfalls of other positional maneuvers and caloric testing. Whispered words, watch ticks, and tuning forks applied to the mastoid protuberances, and by the ear, have been used traditionally to test hearing (Ng and Jacklar, 1993). Heinrich Rinne (1819–1868) identified conductive hearing loss “when the patient hears the

HISTORY OF THE DEVELOPMENT OF THE NEUROLOGICAL EXAMINATION sound transmitted by bone longer than he hears it through the air” (Rinne, 1855). Gowers explained the physiology of normal persons’ hearing as: Normally as vibrations lessen, they can be heard through the air longer than through the bone . . . This is because the receptive mechanism is more sensitive to vibrations that reach it through the tympanum and the chain of bones than to those it receives from the bones directly. (Gowers, 1888, p. 672) Mills (1898, p. 718) suggested that loss of ability to hear a tuning fork by air conduction and bone conduction equally indicates damage to the cochlear apparatus or cochlear nerve.

Cranial nerve IX: the glossopharyngeal nerve The glossopharyngeal nerve, CN IX, was recognized by Galen; he did not distinguish it from the vagus nerve (Flamm E, 1967). The visceral efferent component of the glossopharyngeal nerve arises in the cells of nucleus ambiguus within the medulla oblongata. The glossopharyngeal nerve leaves the skull via the jugular foramen along with the vagus and hypoglossal nerves (Gray and Goss, 1954, pp. 1004–1012). Special visceral afferent components carrying sensations of taste from the posterior one-third of the tongue end in the nucleus of the tractus solitarius (Brodal, 1981, pp. 460–470). The styloglossus and muscles that elevate the soft palate receive motor innervation from CN IX (Brodal, 1981, pp. 460–470). To check the afferent input of this nerve, the examiner strokes the posterior pharyngeal wall to elicit a gag reflex. Cutting the glossopharyngeal nerve interrupts the afferent supply of the gag reflex. The efferent supply for the gag reflex is the posterior pharyngeal constrictor muscles supplied by the vagus nerve. Section of CN IX resulted in loss of perception of pain in the posterior pharynx and abolished taste from the posterior third of the tongue (Fay, 1927; Lewis and Dandy, 1930). Erickson noted (1936) that, after section of CN IX, a patient complained of a dry mouth due to decreased parasympathetic innervation of the parotid gland for saliva production.

Cranial nerve X: the vagus nerve The vagus nerve (CN X) is also known as the pneumogastric nerve, because of its extensive parasympathetic connections to the heart and digestive tract. Galen recognized this nerve, but he mixed its origins with that of CN IX. CN X emerges from the lateral aspect of the medulla oblongata between the more rostral CN IX

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and the caudal and median hypoglossal nerve (CN XII), in the groove between the restiform and the olivary protuberances. CN X leaves the cranium via the jugular foramen (Dalton, 1864, pp. 461–474). CN X sends a sensory branch to the skin of the ear. Integrity of this branch can be checked when a cough reflex is initiated through this afferent branch (Jacobson’s Nerve) by touching a common cotton-tipped applicator to the skin of the antihelix. Temple Fay (1927) noted that intracranial section of the vagus abolished pain referred to the antitragus and antihelix. John Call Dalton, Jr. noted that swallowing is initiated by pharyngeal constrictor muscles. Section of the esophageal branches of the vagus nerve impaired the “sensibility and motive power of these parts. The food is no longer conveyed readily to the stomach . . . .” Section of the inferior laryngeal nerve abolishes “vocal sound, whereas articulation is controlled by the lips and tongue” (Dalton, 1864, pp. 461–474). The nerve continues to branch extensively in the abdomen to provide parasympathetic supply to the organs therein. Charles Bell’s extraordinary drawings superbly demonstrate the “wandering” of the vagus nerve.

Cranial nerve XI: (spinal) accessory nerve Galen identified the accessory nerve (CN XI). Thomas Willis traced its spinal origin from upper cervical roots (2–4), and identified its exit through the jugular foramen with the glossopharyngeal and vagus nerves (Willis, 1681, figure V; Flamm, 1967). J.C. Dalton, Jr. (1864, pp. 474–476) noted that the accessory nerve originates by many filaments from the side of the medulla oblongata, below the level of the pneumogastric and from lateral portions of the spinal cord between the anterior and posterior roots of the upper five cervical roots. These fibers of spinal origin pass upward uniting in a slender rounded filament which enters the cavity of the cranium by the foramina magnum and is then joined by the fibers which originate from the medulla oblongata. The accessory nerve innervates the sternocleidomastoid muscle and then terminates in the trapezius muscle (Gowers, 1888, pp. 701–703). C.K. Mills tested for weakness of the sternocleidomastoid by noting patients could not move their chin opposite to the side of the weakened muscle. He observed that these patients hold their heads “obliquely with the chin elevated and turned toward the paralyzed side” (Mills, 1898, p. 979). Elevation of the shoulder is reduced ipsilateral to the denervated trapezius, and the scapula “recedes from the

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spine and is rotated, the lower angle inward in consequence of the unopposed action of the rhomboid and levator anguli scapulae muscles” (Gowers, 1888, pp. 701–702).

Cranial nerve XII: the hypoglossal nerve The hypoglossal nerves (CN XII) arise from nuclei close to the midline of the medulla, situated just below the floor of the IV ventricle. These nerves exit between the pyramid and the olivary body. Gowers (1888, pp. 483–485) observed that the tongue lays higher in the mouth ipsilateral to the side of a diseased CN XII. Gowers also appreciated that, when the tongue is protruded with a unilateral lesion of a CN XII, it will deviate away from the side of the paralysis to the normal side. He added that the tongue atrophies ipsilateral to the lesion of the nucleus or in the nerve (Gowers, 1888, pp. 703–704). The severe atrophy of the right half of the tongue was caused by a syphilitic gumma destroying the right hypoglossal nerve (Fig. 16.2).

REFLEXES The concept of reflexes was derived from animal experimentation, nearly a century before myotatic reflexes were described by Wilhelm Erb (1840–1921) and Carl Westphal (1833–1890) in 1875 (Erb, 1875; Westphal, 1875). Jiri Procha´ska (1749–1820) was probably the first physiologist to postulate a theory of the reflexes resembling contemporary concepts, publishing his thoughts in 1784. He described centripetal sensory nerve input into the spinal cord and the centrifugal motor nerve output that produced a motor response in muscle. He used frogs in his experiments to distinguish the structures involved with reflexes from “those that were controlled by the will” (Procha´ska, 1784). In 1822, Magendie recognized that the function of the dorsal roots of the spinal cord is sensory and that its ventral roots subserve motor activity. Twenty years later, Marshall Hall (1790–1857) placed the center of the reflex arc in the “spinal cord marrow” (Hall, 1842). The reflexes traditionally are divided into myotatic (tendon) and cutaneous types. Striking the stretched tendons of muscles in the upper and lower extremities, thorax, or jaw elicits myotatic reflexes. Rubbing or scraping the skin elicits superficial reflexes: over the groin for the cremasteric reflex and over the supraorbital nerves for the blink reflex.

Muscle tendon reflexes

Fig. 16.2. Hemiatrophy of the tongue due to syphilitic gumma affecting the hypoglossal nerve. (From Oppenheim, 1904, opposite p 140.)

The myotatic or tendon reflexes are also called “deep” reflexes to distinguish them from the cutaneous or “superficial” reflexes, such as the abdominal and Babinski reflexes (see below). Wilhelm Heinrich Erb (1840–1921) and Carl Friedrich Westphal (1833–1890) simultaneously reported the patellar tendon or knee reflex in 1875 (Erb, 1875; Westphal, 1875). Erb recognized that reflex action governed extension of the leg, following a sharp blow to the patellar tendon; Westphal thought the extension of the leg was merely due to the elastic property of the quadriceps muscle. The discovery of the patellar myotatic reflexes launched a deluge of reports from 1875 to 1930. Authors named reflexes from almost every muscle in the human body where tendons could be stretched (Wartenberg, 1945, pp. 5–7). Gowers argued convincingly from experimental and clinical evidence that responses to sudden stretching of tendons should be classified as reflexes, because there are afferent fibers in muscles. He noted that patients afflicted with tabes dorsalis, a form of tertiary syphilis affecting the spinal cord, lost lower extremity myotatic reflexes. Gowers (1888, pp. 34–41) postulated that myotatic reflexes were moderated through the spinal cord.

HISTORY OF THE DEVELOPMENT OF THE NEUROLOGICAL EXAMINATION Robert Wartenberg wrote a superlative account of the history and methods for The Examination of the Reflexes (1945). Readers should refer to this exhaustive book to refresh their memories for the names of rarely employed reflexes. We will concentrate our attention on a few of the more commonly used tendon reflexes. Wartenberg (1945, pp. 75–76) recommended that the triceps reflex is best elicited by having patients rest their hands on their hips, abducting their arms as the examiner, standing behind the patient, strikes the triceps tendon just above the olecranon. The reflex pathway is through the radial nerve and involves the C6, C7 and C8 spinal motor neurons. Gowers described a technique to elicit the ankle tendon reflex (triceps surae) by placing the patient’s foot in dorsal flexion, tapping the posterior tibial muscles to elicit plantar flexion of the foot (Gowers, 1880, p. 25). Gowers postulated that the “afferent pathway is from motor neurons that supply L5 and S1 roots; the efferent loop passes back through the same [tibial] nerve to supply the gastrocnemius and soleus muscles” (Gowers, 1880, p. 25). The senior author successfully employed Gowers’ technique of having a patient kneel on a chair seat and struck the patient’s Achilles tendon when other techniques failed to elicit ankle tendon reflexes (Fig. 16.3). The absence of a reflex can be attributed to myelopathy, radiculopathy, plexopathy, or neuropathy. The myotatic reflex is elicited when the percussion hammer suddenly stretches the tendon, activating primary nerve endings of the muscle spindles, which in turn send an afferent volley through 1a fibers ultimately into the dorsal horn of the spinal cord. The 1a fibers form an

Fig. 16.3. Ideal method to maximize ankle reflex by kneeling. (From Dana, 1901.)

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excitatory synapse with the alpha motor neurons in the ventral horn that innervate the previously stretched muscle. Thus, the reflex returns the muscle to its original length after a perturbation of its length (Mathews, 1981). The American Academy of Neurology (AAN) advocated grading tendon reflexes using the National Institute of Neurological Diorders and Stroke (NINDS) scale: 0 = no activity, even with reinforcement of the reflex; 1 = hypoactive; 2 = normal and present in the lower half of the normal range; 3 = present in the upper half of normal range; and 4 = hyperactive, including clonus. Irene Litvan and colleagues (1996) validated the AAN scale for inter-observer reliability.

THE

JAW JERK

American neurologist Morris Lewis (1852–1928) first described the jaw jerk as the sudden elevation of the lower jaw following a blow upon the lower teeth of the chin and is easily produced by striking the parts mentioned in a downward direction with a rubber plexor. The mouth of the patient is of necessity open and the muscles should be relaxed. The masseter or temporalis muscles contract, closing the mouth. (Lewis, 1885, p. 591) Several textbooks of neurology and clinical neurophysiology attribute discovery of the jaw jerk reflex to Armand de Watteville (1846–1925) and not to Lewis (Gowers, 1888, p. 160). Validation of Lewis’ claim of discovery over de Watteville is based upon the American’s description of this reflex in 1885 in both normal subjects and five patients (Fine and Lohr, 2003). De Watteville correctly predicted that the jaw jerk would be valuable to detect disease affecting bulbar nuclei (Beevor, 1886; de Watteville, 1886, pp. 518–519). Clinical neurophysiologists use the jaw jerk reflex to evaluate functions of pontine and mesencephalic pathways. Hopf provides a detailed description for electromyographic recording of the jaw jerk (Hopf, 1994). The afferent input of the jaw reflex is through stretch receptors in the masseter muscles that project to the mesencephalic sensory nucleus of cranial nerve V, where there is a synapse on efferent motor neurons of the trigeminal nerve in the upper pons. Lesions that interrupt the sensory input, such as surgery for control of trigeminal neuralgia, will cause a unilateral loss of the masseter reflex (Hopf, 1994). Modern neurologists use the jaw jerk to confirm diagnosis of motor neuron disease when they observe increased jaw and myotatic reflexes in upper, lower and extremity tendons, and muscular atrophy. In patients with cervical myelopathy,

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myotatic reflexes are increased, but the jaw jerk is not exaggerated. Some caution must be exercised as the masseter reflex increases in patients afflicted with pseudobulbar paralysis (Foix et al., 1926).

MODIFICATION

OF TENDON RESPONSES BY

VARIOUS STIMULI OR MANEUVERS

In 1885, Erno¨ Jendrassik (1858–1921) discovered that tendon reflexes could be reinforced by muscle contractions in other parts of the body. Jendrassik reinforced reflexes of patients with diminished knee tendon reflexes by having them hook their fingers together and pull, while he struck their patellar tendons. American physiologists Henry Pickering Bowditch (1840–1911) and Joseph W. Warren increased the amplitude of the knee reflex by stimulating subjects with small gunpowder explosions, bright light flashes, or having them clench their fists preceding eliciting the knee tendon reflex (Bowditch and Warren, 1890). Nearly a century later, Delwaide and Toulouse (1981) showed that Jendrassik’s maneuver enhanced the amplitude of the Hoffmann reflex, the electrically evoked analogue of the ankle tendon reflex.

Cutaneous reflexes THE BABINSKI

EXTENSOR TOE RESPONSE

Joseph Fe´lix Babinski (1859–1932) described the cutaneous plantar reflex that bears his name to the Biological Society of Paris on 22 February 1896. He noted: In a certain number of cases of hemiplegia or lower limb monoplegia, related to an organic cause there is a disturbance of the cutaneous plantar reflex . . . On the healthy side pricking the sole elicits . . . flexion of the thigh on the pelvis, flexion of the leg on the thigh, the foot on the leg and of the toes on the metatarsals. On the paralyzed side, a similar excitation also results in flexion of the thigh on the pelvis, of the leg on thigh and of the foot on the leg. But the toes instead of flexing, execute an extension movement upon the metatarsus . . . I had the opportunity to observe this derangement in cases of recent hemiplegia as well of cases of spastic hemiplegia of several months duration. (Babinski, 1896, pp. 207–208) Later Babinski (1898) included extension of the great toe and sometimes the second toe as criteria for this reflex. In 1903, Babinski stated that the lesser toes abducted with extension of the great toe. He localized the anatomical lesion that produced the extensor response to the pyramidal tract. Babinski emphasized that the presence of this sign excluded hysteria.

A cascade of publications with modifications of methods to elicit this reflex followed the seminal articles of Babinski. In 1902, Hermann Oppenheim (1858–1919) noted that stroking the tibial surface of the lower portion of the leg caused extension of the great toe and dorsiflexion of the foot (Oppenheim, 1902). Gordon (1904, 1911) squeezed the calf muscles of patients with pyramidal lesions to elicit extension of their great toes. Stransky (1933) observed that forced and mildly painful abduction of the little toe caused extension of the great toe and dorsiflexion of the foot. In 1899, British neurologist James Stansfield Collier (1870–1935) described the presence of a Babinski response with complete traumatic severance of the thoracic spinal cord, epidural abscesses associated with tuberculosis of vertebral bodies, disseminated (multiple) sclerosis, hemiplegia, amyotrophic lateral sclerosis, Friedreich’s ataxia and syringomyelia (Collier, 1899). Kennard and Fulton’s experiments on subhuman primates (1933) and autopsy findings in humans (Leetsma and Norohona, 1976) confirmed Babinski’s remark that lesions within pyramidal tracts from motor cortex to spinal cord cause this reflex to appear. The Babinski response can be elicited in healthy adults and adolescents who are in deep sleep (Collier, 1899; Kleitman, 1923). Collier also observed that he could elicit an extensor toe response by tickling the feet of normal awake infants. Collier postulated that the response in the infant was because the “pyramidal system was not yet fully developed.” The Babinski response can appear in metabolic derangements associated with hepatic or renal failure, and narcotic-induced coma (Walton and Paul, 1900). Figure 16.4 depicts the first photographic recording of the extended great toe after plantar stimulation (Collier, 1899). The contemporary concept of the physiology of the Babinski response is similar to that described by Collier

Fig. 16.4. Babinski’s extensor reflex. (From Collier, 1899.)

HISTORY OF THE DEVELOPMENT OF THE NEUROLOGICAL EXAMINATION in 1899 (Collier, 1899, pp. 73–77). An afferent noxious mechanical stimulus in the receptive zone of the foot elicits the Babinski response. The efferent response is strong contraction of extensor hallucis longus, tibialis anterior, but no activation of flexor hallucis brevis muscle (van Gijn, 1975).

GLABELLAR

REFLEX

Walker Overend (1858–1926) first described “a new cranial reflex,” the glabellar reflex, in a letter to the Editor of the Lancet in 1896. He noted that: When the skin of one-half of the forehead is gently tapped with the edge of an ordinary wooden stethoscope, a twitch in the lower eyelid on the same side may be observed . . . Slight tapping in the midline of the forehead is followed by twitching in both eyelids . . . the region involved is the skin covering the frontal bone . . . The motor pathway is identical to the conjunctival reflex; the sensory channel is in . . . the supraorbital nerve. I believe it is a true skin reflex and “is not produced by communication of physical vibrations . . . or a periosteal reflex.” (Overend, 1896, p. 619) Daniel J. McCarthy (1874–1958), an American neuropsychiatrist, “rediscovered” the supraorbital reflex in 1901 but did not mention Overend’s prior description (McCarthy, 1901). McCarthy elicited the supraorbital reflex by striking “the skin of the forehead up to the hair line with a percussion hammer.” A tap on either side of the midline of the forehead elicited contraction of the ipsilateral orbicularis oculi. McCarthy found that the reflex was eliminated by traumatic division of the supraorbital nerve, general paresis, facial paralysis and ablative surgery for tic doloureux ipsilateral to the side of the surgical intervention or paralysis. Overend concluded that the afferent receptors are cutaneous. The reflex center was in the medulla, similar “to that of the corneal reflex” (Overend, 1902, p. 219). The physiological mechanism of the blink reflex remained unsolved for a half century until Eric Kugelberg (1913–1983), a Swedish neurologist, made an electrophysiological analysis of this reflex. Kugelberg (1952) recorded the “electrical discharges coming from the orbicularis oculi muscles in two groups” in response to a tap on the forehead or electrical stimulation of the supraorbital nerve. He found that the earliest group (Response 1 or R1) consists “of a well-synchronized volley” starting at about 12 ms after electric stimulus and lasting 5–10 ms. “The second group (R2) consists of an asynchronous discharge coming after a latent period of 25–30 ms or more.” The second reflex is

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bilateral, “multi-synaptic and at least some part of it passes over the spinal tract of the trigeminal nerve.” The R2 was associated with closure of eyelids. General anesthesia and trigeminal rhizotomy abolished the electrical blink reflexes confirming Overend’s prescient observations (Kugelberg, 1952). Jun Kimura (b. 1936) substantiated Overend’s observation that, “in moderately severe cases of hemiplegia, the [blink] reflex is absent during the first few days.” Kimura verified Overend’s (1896) statement that the blink reflex is most likely to be absent on the side where there is sensory loss after a stroke (Kimura, 2001). Further information about the history of and neurophysiology of this reflex may be found elsewhere (Fine et al., 1992; Kimura, 2001; Ongeboer de Visser, 1998).

PALMOMENTAL

REFLEX

In 1920, Romanian neurologists Georges Marinesco (1864–1938) and Anghel Radovici (1885–1958) described the abnormal palmomental reflex (PMR) in a 25-year-old woman with amyotrophic lateral sclerosis (ALS). These authors stated that stimulation of the skin over her thenar eminence elicited contraction of the homolateral mentalis, quadratus and triangularis muscles producing a chin retraction and cutaneous folding, corresponding to the insertion of these muscles . . . The entire surface of the arms, legs and thorax were reflexogenic zones . . . This reflex was present in almost all patients with lesions of the pyramidal tract. (Marinesco and Radovici, 1920, pp. 239–240) They defined an abnormal PMR as a slow and sustained contraction of the mentalis muscle. They stated that this reflex is mediated by an ascending “afferent pathway going into the spinal cord in the lateral columns . . . and by collateral fibers reaching the facial nerve nucleus” in the pons. “We are dealing with an indirect and not direct reflex, having an intermediate second order neuron interposed between the first order sensory and first order motor neuron, making possible the stimulation of motor neurons in the pons supplying the chin muscles.” (Marinesco and Radovici, 1920, pp. 240–242) These authors postulated that pyramidal tract lesions or ALS allow the collateral connection to become active. Dalby (1970) found an abnormal PMR in 81%, a normal PMR in 7%, and absent in 12% of patients with pyramidal tract lesions of the central nervous system. Controversy arose about the localizing value of PMR when this reflex was found in 100% of patients

226 E.J. FINE AND M.Z. DARKHABANI demented by neurosyphilis (Thompson, 1945). Molloy A “moderately forceful backward pressure of the and associates (1991) showed no correlation between examiner’s index finger on the subject’s upper lip” the presence or absence of the PMR and impaired cogelicits the snout reflex. The reflex response is “a pucknitive function. Owen and Mulley (2002) concluded ering, protrusion and elevation of the lower lip assothat the PMR is a sign of neurological abnormality, ciated with depression of lateral angles of the mouth” but is not localizing. (Jacobs and Gossman, 1980). The percentage of normal persons exhibiting the snout reflex varies from 17% to ABDOMINAL CUTANEOUS REFLEXES 30% (Klawans et al., 1971; Jacobs and Gossman, 1980). In a group of 240 normal adults, ages 20–40, only 3% Rosenbach described the abdominal skin reflex in 1876 had a suck reflex, 1% had a grasp reflex, and none had (Rosenbach, 1876). Rapidly delivered, “mildly irritating a snout reflex (Schott and Rossor, 2002). The presence strokes with blunt end of a Taylor reflex hammer to of all three reflexes was associated with neurological the skin over the epigastrium causes elevation of the disease (Isakov et al., 1984). Discriminating neuropsyumbilicus and the deviation of the line alba” (Wartenchological testing and high definition magnetic resoberg, 1945, p. 94). This reflex may be absent in normal nance imaging have supplanted use of primitive elderly persons, in people with subcutaneous abdomreflexes to confirm dementia. inal fat, or in young children without disease, during deep anesthesia, and in coma from multiple causes MOTOR STRENGTH (Wartenberg, 1945, p. 98). The abdominal skin reflex is lost soon after the onset of multiple sclerosis and Motor strength was first systematically examined in with lesions in the pyramidal system (Stru¨mpell, patients suffering from neurological trauma. David 1896). The senior author believes that contemporary Ferrier (1876) identified the motor cortex of monkeys neurologists have abandoned this reflex because of risby stimulation and ablation of the Rolandic region. He ing incidence of obesity and widespread use of MRI to found that the region representing the lower extremity detect demyelinating lesions within the spinal cord. was the upper and most medial portion, and for the upper extremity in the middle portion of the Rolandic cortex. Primitive or atavistic reflexes The face and hand are represented on the inferior surface Grasping, sucking, and snouting reflexes are present in of the Rolandic cortex (Ferrier, 1876, pp. 199–205). normal infants, but disappear within 1 year as the cenGowers defined the partial weakness resulting from tral nervous system begins to mature. Therefore some lesions in human Rolandic cortex as hemiparesis, and authors have termed the reappearance of these reflexes complete paralysis as hemiplegia (Gowers, 1888, pp. in adults as primitive or atavistic reflexes. In 1914, 508–524). Gowers stated that paresis of the lower half Samuel A. Kinnier Wilson (1878–1937) and Francis of the face and ipsilateral arm and leg is due to cortical Walshe (1885–1973), affiliated with the National lesions or lesions in the adjacent subcortical white Hospital in London, associated the grasp reflex in an matter. Following the initial paralysis, Gowers recogadult with a frontal lobe tumor. British neurologists nized that the affected limb would become rigid and McDonald Critchley (1900–1997) and William J. Adie have increased tendon reflex activity. (1886–1935) made the distinction of forced grasping Motor power was initially described as “poor, fair, from groping by having the examiner rub the radial good or full strength” in textbooks of neurology aspect of the patient’s palm to obtain grasping flexion and physical therapy (Kendall and Kendall, 1964). of the patient’s fingers around the examiner’s digits. This method of grading muscle strength was unwieldy, These authors noted that some patients with demenpoorly understood, and not reproducible by other tia or frontal lobe lesions would reach around to grope examiners. The method of muscle testing promoted for the examiner’s fingers or hand. Spasticity-induced by the Nerve Injuries Committee of the British groping of the examiner’s hand or fingers will not be Research Council supplanted other systems of grading relieved when the dorsum of the patient’s hand is muscle strength. This method requires the examiner repeatedly stroked, but the primitive or atavistic grasp to position the muscle so that its action would be reflex can be overcome with this maneuver (Adie and the prime mover of the body part. The examiner’s hand Critchley, 1927). Modern neurologists have confirmed applies resistance and the other hand palpates the that the grasp reflex appears ipsilateral or contralateral contracting muscle. The latter maneuver enables to frontal lobe lesions (Schott and Rossor, 2002). the examiner to feel the extent of the contraction Hashimoto and Tanaka (1998) associated lesions in of the muscle and confirm that the patient gave the supplementary motor area and cingulate gyrus full effort. The Committee suggested the following lesions with grasping reflexes. grading system for muscle strength:

HISTORY OF THE DEVELOPMENT OF THE NEUROLOGICAL EXAMINATION 227 No muscular contraction. various thicknesses replaced horse hairs, still called von Frey hairs, to gauge pressure sensitivity. Flicker or trace of muscular contraction. To test temperature sensation accurately, Mills Full active movement with gravity eliminated. suggested that “objects of different temperatures, but Full active movement against gravity. same size and same thermal conductivity,” should be Full active movement against gravity and applied to the skin (Mills, 1898, p. 156). resistance, but the contraction is stopped by Mills and Gowers suggested using the two points of a the examiner’s counterforce. 5 = Normal power – the examiner cannot overcome drawing compass to test the smallest distance at which the contraction of the patient’s muscle. these points can be distinguished as double (Mills, 1898, p. 155; Gowers, 1888, pp. 30–31). They advised that the (Riddoch et al., 1943, p. 1) skin must be touched simultaneously and with equal presThis system of grading muscular strength has been sure to accurately test two-point discrimination. These widely accepted, because it is reproducible and easily authors concurred that the tip of the tongue (1.5 mm) understood. The reader is referred to the Aids to the and finger tips (2–3 mm) were far more sensitive than Examination of the Peripheral Nervous System, 4th the cheeks and the back of the hands (12 mm). edn., for details concerning methods for testing indiviTo control the subjectivity of the sensory examination, dual muscles (O’Brien, 1999, pp. 1–4). Monrad-Krohn advised that the examiner avoid making suggestions and employ various stimuli in a given area of the body in order not to lull the patient into inattention. SENSORY EXAMINATION The patient should point to or draw the line of demarThe sensory examination is the most difficult compocation between decreased and fully sensate areas nent of the neurological examination to perform accu(Monrad-Krohn and Refsum, 1958, pp. 154–156). A sharp rately. It depends on patients’ alertness, audition, end of a broken wooden cotton-tipped applicator stick ability to cooperate and comprehend, and understanding can be used conveniently for testing pain. The cotton-covof questions about subtle differences. Unlike tendon ered remainder is reserved for testing sensitivity to light reflexes or the cranial nerve examinations, the sensory touch. To affirm validity of light touch or pain loss, examination is strictly subjective (DeJong, 1967, pp. DeJong cautioned that the zone of demarcation between 58–61). The sensory examination is optimally performed normal sensation and decreased sensation should be at the mid-point of neurological examination, after the retested with eyes closed (DeJong, 1967, pp. 58–61). possible confounding factors listed above are apparent Gowers’ and Mills’ texts, and the many editions of to the examiner. The elements of the sensory evaluation Church and Peterson up to 1925, did not include vibration are performed preferably in this order: light touch, pain, in their battery of sensory testing. In 1929, Jelliffe and temperature, vibration, position sense, two-point discriWhite listed vibration testing as one of their 20 tests for mination and judging of weights, as the latter three sensation. These authors recommended testing for vibrafunctions depend on the integrity of the first four eletion sense with 64 to 512 Hz tuning forks. Monrad-Krohn ments of the sensory examination (Monrad-Krohn and and Refsum, 1958, (pp. 164–165) noted that the perception Refsum, 1958, pp. 156–161). of vibration disappeared first for 512 Hz rather than lower The multiple types of stimuli employed in the modfrequencies in patients with tabes dorsalis. Vibratory senern sensory examination evolved from several basic sory threshold increases with age (Pearson, 1928). These observations about sensation. Ernest Heinrich Weber authors included tests never used today, such as testicular (1795–1878) distinguished light touch from pain. Weber sensitivity to light and painful pressure (Jelliffe and tested the ability of subjects to distinguish two sharWhite, 1929, pp. 125–126). pened points as two loci of pain. His method of testing Knowledge about the dermatomes, regions of skin supis used today as the so-called two-point discrimination plied by each dorsal root, was roughly mapped by 1900. test of cutaneous sensitivity (Weber, 1846). Charles Sherrington (1857–1952) working primarily with Johannes Mu¨ller (1808–1858) provided the theory of monkeys, cut the roots above and below the one he then specific nerve energies, that a specific nerve carries only tested and mapped (Sherrington, 1898). Otfrid Foerster a specific sensation to the sensorium (Boring, 1942). (1873–1941), a German neurologist and neurosurgeon, cut Max von Frey (1852–1932) postulated that specific dorsal roots in a number of patients suffering from herpes end-organs of cutaneous nerve fibers detect specific zoster or war wounds and mapped out the dermatome sensations. He invented a method of grading pressure schema that we commonly use today (Foerster, 1933). sensitivity with horse hairs that are calibrated to provide Henry Head and Gordon Holmes found that parietal information about the amount of pressure that patients lobe lesions impaired patients’ ability to recognize can detect (von Frey, 1896). Nylon monofilaments of objects placed in their hands (astereognosis), to accurately 0 1 2 3 4

= = = = =

228 E.J. FINE AND M.Z. DARKHABANI discriminate two-point from one-point stimulation, and to The patient with locomotor ataxia localize stimuli applied simultaneously to opposing parts keeps his eyes fixed upon his feet when walking. In of the body (Head and Holmes, 1912). standing . . . he separates the feet to a greater than normal distance. The patient with cerebellar disCEREBELLAR EXAMINATION ease can walk better with his eyes shut than with Knowledge about the function of the cerebellum and its them open . . . but . . . the reverse is true of lococlinical examination were developed from anatomical motor ataxia. (Hammond, 1881, pp. 375–382) dissections, physiological experiments, and observations Gowers attributed reeling gait and difficulty in standof patients who had cerebellar tumors or injuries from ing motionless to disease of the midline vermis of the war. Willis assigned control of involuntary movements, cerebellum. “Unsteadiness of the gait was due to including heartbeat and respiration, to the cerebellum. damage of the middle lobe (vermis) of the cerebellum” He noted that the vagus nerve travels to the viscera (Gowers, 1888, p. 717). and believed its origin was in the “cerebel,” the storeCharles Karsner Mills further delineated symphouse of the “animal spirits” that performed “intestinal tomes caused by focal lesions of the cerebellum (Weicommotions” (Willis, 1681, pp. 121–125). senberg, 1931). Mills noted that patients who fell The Italian physiologist Luigi Rolando (1773–1831) forward and those who fell backward had lesions in made several correct observations about the function their anterior and caudal vermis, respectively. He also of the cerebellum. Rolando performed experiments noted ataxia in a limb, ipsilateral to a lesion of a lateral on animals to prove that there was no loss of conlobe of the cerebellum (Mills, 1898, p. 382). sciousness and decreased voluntary movements followIn 1902, Joseph Babinski described the inability of ing destruction of the cerebellum. He observed that patients with cerebellar lesions to perform rapid succespartial removal of the median lobe of the cerebellum sive, alternating movements. He coined the term from a goat caused the animal to sway and fall to “dysdiadococinesie” from the Greek words “diadocho” one side or the other (Rolando, 1809). (alternating) and “kinesie” (movement), to describe their Marie-Jean-Pierre Flourens (1794–1867), Professor of dysfunction in making alternating movements. Babinski Physiology at the College de France, ablated portions expounded that these patients can “no longer start and of the cerebellum of a dog and a pig. The dog was renstop a movement, because they have lost the combination dered clumsy, bumping into objects; the pig staggered of an excitatory action and an (antagonistic) braking “in a drunken fashion and when it fell over, its efforts action.” Babinski also noted that patients with cerebellar to rise were very awkward.” Flourens concluded that lesions decompose a complex “movement into its sepathe destruction of the cerebellum resulted in movements rate elements” (Babinski, 1902). that “were not regular and coordinated” (Flourens, Gordon Morgan Holmes (1876–1965) and Grainger 1824). Stewart, his resident physician at the National Hospital John Call Dalton, Jr., who studied with Claude at Queen Square, described rebound as a new sign in Bernard in Paris (Fine et al., 2000), reported that, when 1904. They advised that he removed portions of a pigeon’s cerebellum, it “stood and walked though imperfectly.” There was “a to test for this phenomenon, request the patient close and ludicrous resemblance to the effects of to flex an arm as strongly as he can. The elbow intoxication-movements that [were] quite natural in being supported and the movement effectively force and rapidity, but their harmony and certainty resisted by the observer grasping the wrist. The being lost.” Thus Dalton confirmed Flourens’ concluresistance is suddenly relaxed by releasing the sion that the principal function of the cerebellum was wrist. The range of movement is excessive with coordination of voluntary movements. Dalton nursed homolateral cerebellar disease. his pigeons to recovery from acute injuries to the cereStewart and Holmes attributed this rebound phenomenon bellum, and postulated that restoration of coordination to “inability of antagonist muscles to react in tone” to the was due to the remaining cerebellar “portions gradu“sudden loss of resistance in the antagonist muscles.” ally becoming enabled” (Dalton, 1861). The triceps of a patient with a cerebellar hemisphere William A. Hammond noted movements in patients lesion fails to contract when the bicep is suddenly released with cerebellar tumors are not after the bicep was flexed against resistance from the jerking and exaggerated, as they are in locomoexaminer (Stewart and Holmes, 1904, p. 534). tor ataxia . . . Their sensation is unimpaired as From the outbreak of World War I in 1914 to its end, opposed to loss of position, vibratory and pain Holmes served as an army neurologist in hospitals in sensation in locomotor ataxia. France (Penfield, 1967). He observed the effects of

HISTORY OF THE DEVELOPMENT OF THE NEUROLOGICAL EXAMINATION acute cerebellar injuries of some 40 men, noting that cerebellar wounds “can be frequently observed” in combat. Holmes noted whenever the affected limb is “seized and shaken, the more distal segments flop and swing in an unnatural and inert manner,” due to lack of tone (Holmes, 1917, p. 466). Holmes observed that his patients had less strength and speed, especially in their arms, ipsilateral to severe gunshot injuries in a cerebellar hemisphere (Holmes, 1917, pp. 469–471; Holmes, 1922). Some modern neurologists prefer to test the lower extremities for ataxia with the heel-to-knee-to-shin-toknee test (DeJong, 1967, p. 531). But this maneuver has limitations for patients with severe hip disease, proximal muscle weakness and impaired understanding. The cerebellar examination was detailed extensively by Smith Ely Jelliffe and William Alanson White in 1929. These authors traced the phylogenetic development of the cerebellum as a structure that had expanded lateral hemispheres to accommodate the need for coordination of limbs capable of performing increasingly more intricate movements. Their tests for ataxia are in current use (Jelliffe and White, 1929, pp. 679–689).

STATION Modern examiners use Romberg’s maneuver to test patients’ station. They observe patients’ ability to stand with their feet approximated with eyes open and then closed. If patients sway or lose their balance only when their eyes are closed, they have a positive Romberg test. Moritz Heinrich Romberg (1795–1873) mentioned one patient with tabes dorsalis who could not stand with his eyes closed and feet turned out (Romberg, 1853, pp. 395–396). In the pre-treatment era of tertiary syphilis, tabetics commonly presented with the sign of Romberg. Church noted that when tabetic patients stood “with their eyes closed they sway or fall heavily” when their feet are placed closely together (Church and Peterson, 1911, p. 429). The contemporary interpretation of this sign is that patients who exhibit a positive Romberg’s test have a severe neuropathy or a lesion in the posterior columns of the spinal cord (DeJong, 1967, p. 558). In patients with cerebellar hemisphere lesions, “there is swaying with eyes open or closed toward the side of the lesion.” With a cerebellar “vermis lesion, the patient may fall forward or backward” (DeJong, 1967, p. 558).

GAIT The gait examination is made by observing patients walking under natural conditions and with imposed stresses, such as tandem, heel, and toe ambulation. A normal gait depends upon the interaction of the

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cerebellum with the cortex, spinal nerves, muscles, tendons and joints. Diseases or abnormalities in these structures will alter normal gait. For these reasons gait should be tested after completing cerebellar and motor examinations. James Parkinson (1817, p. 6) lucidly described the gait of patients that suffer from the disease that bears his name. As the malady proceeds . . . the propensity to lean forward becomes invincible . . . The patient is thereby forced to step on the toes and the fore part of the feet, whilst the upper part of the body is thrown so far forward to render it difficult to avoid falling on the face. [The patient] becomes irresistibly impelled to take much quicker and shorter steps. As the disease proceeds to its last stage, the patient walks with great difficulty, and unable to support himself with his stick any longer, he dares not venture on this exercise, unless assisted by an attendant who walking backwards before him prevents his falling forward by the pressure of his hands against the fore part of his shoulders. (Parkinson, 1817, pp. 7–8) Church described the spastic gait of the hemiplegic patient: The effected limb is held against the body . . . In the lower extremity extension prevails (on the effected side) . . . the knee is held rigidly extended and the foot rolls over its outer border. The normal leg bears the weight; the rigid leg swings in an arc, like a pendulum toward the sound leg. (Church and Peterson, 1911, pp. 213–215) The ataxic gait was described in the section dealing with cerebellar dysfunction. The normal gait consists of a stance (point where the foot hits the floor) and swing (period in which the leg swings out). Weakness due to peroneal neuropathy or L5 radiculopathy causes slapping of the anterior foot on the floor during transition from swing to stance phases.

SIGNS OF MENINGISMUS Vladimir Milkailovitsch Kernig (1840–1917) of St. Petersburg, Russia, described the sign of meningeal irritation that bears his name in 1882. He noted that when he seated patients with meningitis on the edge of the bed, their necks, trunks and knees became more flexed than when lying supine. When the legs of sitting patients with meningitis were passively extended, the examiner encountered spasm (Kernig, 1882). Josef Polikarp

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Brudzinski (1874–1917) noted that if he passively flexed the hip and knee of a child with meningitis, the child’s other knee and hip flexed (Brudzinski, 1908).

CONCLUSIONS The neurological examination developed as a physiological analysis of patients’ functions. The findings were linked to anatomy by post-mortem pathology and by a lesser extent to physiological experiments with animals. Correlation of signs and symptomes with specific pathologies guided development of logical differential diagnoses. This list of diagnostic possibilities focused the investigation and reduced need for definitive but highly invasive tests, such as myelography or pneumoencephalography, up to the development of computerized tomography (CT) or magnetic resonance imaging (MRI). The neurological examination permits interpretation of anatomical abnormalities revealed by MRI and CT of the brain and spinal cord. Rapid spiral CT without contrast now affords diagnosis of cerebral hemorrhage within minutes. MRI with ever-increasing varieties of scanning modalities and strength magnetic flux at 3T or greater will improve definition of lesions, but can not directly identify the disease or provide any information about function. Hence, technology will not supplant the neurological examination. The neurological examination, with its emphasis on function, will continue to be utilized as the standard procedure for rapid and global analysis of symptomes and neurological signs in the emergency room or at the bedside.

ACKNOWLEDGMENTS The authors thank Linda A. Lohr MA for her assistance in finding many obscure references, and Peter J. Koehler MD, PhD for many useful suggestions that substantially improved this chapter. Debra L. Fine, MA found and prepared the illustrations.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 17

Cognitive assessment in neurology VICTOR W. HENDERSON * Departments of Health Research & Policy (Epidemiology) and of Neurology & Neurological Sciences, Stanford University, Stanford, CA, USA

INTRODUCTION It has long been observed that human intelligence appears to involve different cognitive faculties, factors, or functions. It has not always been apparent, however, that aspects of intelligence might, in some sense, be fractionated or analyzed separately. This possibility arises particularly in diseases of the brain, where some cognitive – or psychological, or mental – abilities may seem to be impaired whereas others may not. In clinical settings, therefore, the task of identifying and characterizing cognitive impairment often devolves first to the neurologist. The purpose of the neurological examination is to determine the health and functional capacity of the nervous system to achieve a diagnosis, gauge disease severity, devise a treatment plan, provide a prognosis, and monitor change resulting from disease progression or therapeutic intervention. Cognitive assessment is one aspect of this examination. It involves direct, controlled observations of the brain-injured patient during the conduct of cognitive tasks. According to the Russian neurologist and neuropsychologist Aleksandr Luria (1902–1977), the patient is best “studied under specially organized conditions whereby the defect can be demonstrated with the greatest possible clarity and whereby its structural features can be analyzed in the greatest detail” (Luria, 1966a, p. 300). Although observed deficits reflect compensatory responses of undamaged brain areas more than residual capabilities of damaged regions (Hughlings Jackson, 1874; Goldstein, 1938; Luria, 1966a), cognitive deficits have topographical correlates. Characterizing these deficits and delineating implicated brain regions are of diagnostic, therapeutic, and prognostic import. The genesis of modern interest in brain and cognition started early in the 19th century, when it began to be appreciated that impairments in intelligence have

*

clinical implications. Working in Vienna and Paris, Franz Gall (1758–1828) developed a theory of mental organology. This neuroanatomist undertook innovative dissections of the human brain and attempted to correlate specific mental faculties with evidence of neuroanatomical variation, which he believed could be revealed by skull features. Based on his analyses, Gall suggested that the cerebrum was composed of discrete organs subserving different mental propensities (Gall and Spurzheim, 1810; Gall, 1825). In one celebrated example, Gall (1825) noted that people with excellent memories for words had prominent eyes. He interpreted ocular prominence as an external indication of focal development, or enlargement, of the brain immediately behind the two orbits, describing this region as an organ for word memory and language sense. His views resonated with faculty psychology as developed by Thomas Reid (1710–1796) and Dugald Stewart (1753– 1828) in Scotland. Although Gall’s organology – and the phrenology fad that it spawned – was scorned by a skeptical scientific establishment, it piqued interest in the relation between delimited mental abilities and discrete cerebral areas.

COGNITIVE ASSESSMENT IN APHASIA Broca’s approach to cognitive assessment Gall’s legacy was to inform and spur the quest to examine brains of patients who had lost the ability to utter words. Publications in the 1860s by the French surgeon Paul Broca (1824–1880) laid groundwork for the conclusion that damage to a circumscribed portion of the left frontal lobe leads to loss of articulate speech, a disorder that he called aphemia (Broca, 1861a, b, 1865). The zeitgeist was right for observations such as Broca’s, and implications of his clinical-

Correspondence to: Victor W. Henderson MD, MS, Stanford University, 259 Campus Drive, Stanford, CA 94305-5405, USA. E-mail: [email protected], Tel: þ1-650-723-5456, Fax: þ1-650-725-6951.

236 V.W. HENDERSON pathological descriptions were both revolutionary and involving language, and general intelligence. Further, he electrifying. cautioned that the examiner should be flexible when distinIn his initial descriptions, Broca emphasized sparing guishing among varieties of speech impairment. The difof the intellect, based on his inference that aphemic ferential diagnosis of aphemia included general paresis patients appeared to understand speech more or less (syphilis), and “psychological analyses” (i.e., cognitive normally. They lacked “only the faculty to articulate assessment) helped with this distinction. According to words. They hear and understand all that one tells them; Broca, intellectual disturbances in the patient with general they possess all their intelligence” (Broca, 1861b, p. 332). paresis were quite different than with aphemia. However, it was soon apparent to him and to other early observers – particularly including the eminent Parisian The early-20th century: Marie, physician Armand Trousseau (1801–1867) – that compreMoutier, and Dejerine hension was in fact often compromised (Trousseau, In the several decades following Broca’s reports, an 1865). In 1868, Broca acknowledged his critics during a enormous amount of research focused on aspects of meeting of the British Association for the Advancement aphasia. Focal injury involving the left frontal lobe of Science in Norwich, UK. This issue, he suggested, (Broca, 1865), left temporal lobe (Wernicke, 1874), was psychological, but the underlying concern was also and left parietal lobe (Dejerine, 1891) were respectively anatomical and physiological: “Do all the parts of the identified with syndromes of Broca’s aphasia, Werconvolutional mass of the brain have the same funcnicke’s aphasia, and alexia with agraphia. At the turn tions, or are there more-or-less circumscribed parts that of the 20th century, key figures were Jules Dejerine are endowed with particular attributes?” (Broca, 1869, (1849–1917) and Pierre Marie (1853–1940), implacable p. 254). rivals with irreconcilable views on aphasia and brain For Broca, the goal of assessing patients with aphasia – organization for language. Both were to hold the presTrousseau’s term for various forms of impaired exprestigious chair in Clinical Diseases of the Nervous Syssion (Trousseau, 1864) – was localization rather than tem at the Salpeˆtrie`re in Paris – a chair originally diagnosis: “The greatest interest in the study of speech created for Jean-Martin Charcot in 1882. Both also prodisorders is research on the site of the faculty of artivided similar, detailed schemes for the assessment of culated language . . . Difficulty with speech can certhe patient with aphasia. tainly be useful in surmising the site of the lesion, but Marie resurrected the contentious perspective that, not in diagnosing the underlying cause” (Broca, 1869, contrary to Broca’s assertions, general intelligence p. 269). Broca distinguished among what he termed was invariably affected in the presence of aphasia: aphemia (roughly corresponding to later concepts of “For all aphasics there exists a trouble, more or less Broca’s aphasia), verbal amnesia (roughly correspondpronounced, in the understanding of spoken language” ing to Wernicke’s aphasia), and other categories of (Marie, 1906, p. 241). Thus, aphasic patients were speech disorders (Henderson, 1986, 1990). For aphemia, unable to carry out complicated orders. Marie detailed the important distinction was with verbal amnesia, where how to assess language and intelligence, cautioning patients had lost a special memory for spoken or written that “one cannot provide an exact account of the menwords. Other forms of memory – for example, that of tal state of an aphasic if one does not conduct a metifaces or location – were spared. When amnesia was culous examination” (Marie, 1917, p. 420). Multistage incomplete, complicated phrases would not be undercommands were especially difficult, as exemplified stood, but phrases that were shorter, simpler, or in by his well-known Three Paper Test (Marie, 1906, common use still might be. Comprehension of words p. 241): was spared even for words that these patients could not produce on their own or repeat. Broca (1869) Of the three unequal pieces of paper placed on suggested that the examiner should vary questions and this table, you will give me largest; you will select those that required unambiguous responses. crumple the middle size and throw it to the floor; Questions involving numbers could also be informative; as for smallest you will put it in your pocket. an aphemic patient should be able to give his age by Marie tested spoken and written language. Evaluation indicating with his fingers, first the number of tens and of the former included both speech comprehension then the number of ones. and production. In testing comprehension, Marie Although Broca (1869) did not outline a systemaobserved that many aphasics were unable to communitized scheme for cognitive assessment, he implied that cate even by nodding or shaking their heads for yes or assessment of the aphasic patient should consider no, or by demonstrating how objects should be used articulation, manual gestures, speech production, (Marie, 1905). To test whether memory was intact for speech comprehension, writing, forms of memory not

COGNITIVE ASSESSMENT IN NEUROLOGY words that the patient could no longer produce, the patient was asked to point to, or take from a table, an object whose name was spoken by the examiner. For this task, Marie used common objects (e.g., a spoon and fork) and toys to represent larger items (e.g., a ladder and saw). Some patients showed the phenomenon of “intoxication” (perseveration), correctly selecting the ladder upon first request but then choosing the ladder again when a different item was named (Marie, 1905). Marie (1917) also used drawings to test naming and understanding. For a rabbit, Marie might ask the patient whether the animal in the picture sang, whether it climbed trees, or whether it could be eaten. Evaluation of speech production included words in series, repetition, and song. Some aphasics found it easy to recite words in series, such as days of the week (Marie, 1905). For repetition, Marie first asked patients to repeat short words or initial syllables of longer words. Familiar words were more easily repeated than words the patient had trouble understanding. Assessment might include the ability to sing spontaneously and to mimic a song sung by the examiner. To test reading, Marie (1905) used posters upon which single words or phrases had been written in large print. The patient was asked to point to an object named on the poster or carry out a simple written command. Letters and numbers were examined separately, and Marie noted that patients with motor (Broca’s) aphasia often read numbers better than letters. Writing tasks included written dictation, the copy of written material, and the transcoding of print to script. Errors often appeared when numbers were copied; 25 might be copied as 26. Spelling with anagram block letters was useful with hemiplegic patients who wrote awkwardly with the left hand (Marie, 1917). Other tasks used to gauge intelligence included gesturing (e.g., showing how to scold a child), identifying colors, understanding the value of money, and giving directions to well-known city landmarks (Marie, 1917). The assessment of aphasic patients was described more systematically by Marie’s intern Franc¸ois Moutier (1881–1961) in his prodigious thesis on Broca’s aphasia (Moutier, 1908). Moutier’s examination was divided into 12 major categories: Auditory Comprehension, Inner Language (unexpressed knowledge about language inferred, for example, by indicating the number of syllables in a word), Speech, Reading, Writing, Mimicry, State of Intelligence, Apraxia, Mobility, Sensation, Swallowing, and Vision. Within each category were subsumed specific tasks. For example, within the Speech category Moutier described tests of spontaneous speech, speech repetition, and singing. Spontaneous speech in turn included naming of objects and body parts; ability to resume speaking after an

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interruption; responding to questions about the patient’s illness or profession; quality and characteristics of speech (e.g., paraphasias, jargon aphasia, agrammatism, dysarthria, stuttering, logorrhea, festination); use of the future tense; word intoxication or swearing; and the ability to produce serial speech (e.g., counting forward and backward, counting by 2s, reciting the alphabet and days of the week). Within his Reading category, Moutier included reading aloud; carrying out simple and complicated orders that were read silently; reading words written vertically or divided horizontally; reading upside down; reading a word whose letters are serially presented one by one; determining if reading is facilitated by first spelling the word or by tracing the shape of letters with a finger; recognizing emblems; telling time and indicating time on a clock; reading a phrase in which words are run together without space in between; reading single and multi-digit numbers; performing arithmetical calculations; reading musical notation; and indicating the names and values of playing cards. Dejerine’s approach to the examination of aphasic patients was similar to Marie’s. Indeed, as contemporary adversaries in the same city, it was inevitable that each should pay attention to the other’s techniques. In his seminal textbook Sémiologie des Affections du Système Nerveux, Dejerine (1914) detailed how to evaluate spoken language (spontaneous speech, repetition, comprehension), singing, reading (reading aloud and reading comprehension), and writing (produced spontaneously, to dictation, and to copy) (Dejerine, 1914). For Dejerine and Marie, many of their recommendations were based on theoretical considerations and on literature reports suggesting that minute distinctions in task performance were sometimes relevant. Their assessment procedures appear exhaustive, but patients were often available for prolonged periods of observation, and it is clear that these investigators did sometimes conduct very detailed analyses of their patients (e.g., Dejerine, 1892; Moutier, 1908). However, it is likely that few aphasics were actually subjected to all enumerated procedures. Rather, following Broca’s (1869) earlier lead, the approach would have been comprehensive yet flexible, intended to sample major categories of language function yet provide minute analyses when there was a clinical or theoretical justification.

Head’s Serial Tests Based on examination of British soldiers who suffered gunshot injuries of the head during World War I, Henry Head (1861–1940) challenged anatomical concepts of aphasia that had developed in the wake of

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Broca’s and Wernicke’s reports. His research is summarized in his monumental Aphasia and kindred disorders of speech (Head, 1926), later extolled as “the finest and the most significant volume in the whole literature of aphasia” (Critchley, 1961, p. 560). Head’s findings are derived from neuropsychological tasks designed to capture impairment of “symbolic thinking and expression,” the defining characteristic of the speech-disordered patient (Head, 1920, 1926). These tests were premised on the observation that cortical lesions lead to an “inconstant response,” creating the need to arrange tasks in a fixed sequence and place each task before the patient in several different ways (Head, 1920, p. 89). Most tests in Head’s battery were new or were employed by Head in a new manner, and he emphasized that they could provide only a partial assessment of a patient’s capacity (Head, 1926). The heart of Head’s battery was the six Serial Tests, some of which were “childishly simple and [could] be carried out perfectly by the stupidest individual” (Head, 1920, p. 93) (Table 17.1). Patients were examined alone in a quiet room, and all remarks (both patient’s and examiner’s) were recorded verbatim. To elicit a patient’s best response, the order of tests could be rearranged if a patient became frustrated or discouraged (Head, 1926). As a general rule, the more choices a task involved, the more apt was a patient to fail; tasks involving a sequential order were more difficult than those that did not. The first of the Serial Tests (Table 17.1) was Naming and Recognition of Common Objects (Head, 1926). This was comprised of several subtests and involved six common objects, such as a pencil and key, which were arranged on a table and screened from a patient’s view. The examiner showed a duplicate of one of the objects (e.g., key), revealed the display upon the table, and asked the patient to point to the object that corresponded to the one just presented. Because patients tended to respond inconsistently, the procedure was repeated at least three times for each of the six items. Next, the patient was asked to name each object as it was indicated to him. As before, each item was designated three times in the same order as in the first serial task. The Naming and Recognition Test proceeded to assess auditory and written comprehension, the ability to write object names, and other skills. The most difficult of the Serial Tests were the Hand, Eye and Ear tests, a series of tasks in which the patient uses his hand to indicate one of his eyes or ears. In the first phase, the patient is placed before a large mirror and instructed to imitate movements of the examiner, who is standing behind the patient. In the next phase, the patient is handed a card on which is drawn a simplified human figure carrying out one of the intended

Table 17.1 Head’s Serial Tests for the examination of the aphasic patient 1. Naming and Recognition of Common Objects (employs six common objects: pencil, key, penny, match-box, scissors, knife) a. Point to the object after a duplicate is shown by the examiner. b. Name the object designated by the examiner. c. Oral commands: point to the object named by the examiner. d. Printed commands: point to the object whose name is given on a card. e. Point to the object corresponding to a duplicate placed in the patient’s hand out of sight. f. Write the name of the object indicated by the examiner. g. Write names of the objects to dictation; copy names from print to script (selected patients). h. Repeat the name of the object spoken by the examiner. i. Point to an object whose name is printed on a card (selected patients). 2. Naming and Recognition of Colours (similar to the Common Objects test, using eight strips of silk of different colors) 3. The Man, Cat and Dog tests (simple tests of reading and writing involving 3-letter words; e.g., reading or writing, “The dog and the man.”) 4. Clock tests (setting clock hands to oral and written commands) 5. Coin-Bowl tests (oral and written commands involving four bowls, in front of which is a penny; e.g., “First penny into third bowl.”) 6. Hand, Eye and Ear tests (tests in which the patient touches an eye or ear with one hand or the other. Tasks include imitating examiner, imitating movements depicted in simplified drawings on cards, and following oral and written commands, such as, “Put your left hand on your left ear.”)

movements (Fig. 17.1). Next, the patient carries out the same movements in response to oral, and then written, commands. Finally, the patient is told to write down movements of the examiner, who may be seated opposite the patient or may be observed in a mirror standing behind the patient. Head (1926) employed further tests in his research which, although not arranged serially, were nonetheless to be applied systematically. These included tests involving alphabet letters and days of the week, explaining a paragraph narrative, picture description, number and arithmetic tasks, tests involving coins, drawing tasks, testing the ability to find the way along a familiar route, assessing the ability to play games, and jigsaw puzzles.

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Fig. 17.1. Four simplified human figures from the Hand, Eye and Ear tests (Head, 1926, p. 161). For this portion of the test, the patient is handed a card depicting a single figure; the patient’s task is to carry out the indicated action. (Copyright by Cambridge University Press; reproduced with permission.)

Head’s extensive examination scheme met with mixed approbation. A colleague described it as “in every way admirable and worthy of universal adoption” (Head, 1921, p. 419), but the tests were also viewed as overly rigid, “time consuming and somewhat repetitive” (Critchley, 1961, p. 558). Kinnier Wilson (1878–1937), Head’s contemporary who shared interests in aphasia (Wilson, 1926), noted that some Serial Tests seemed to assess intellectual capacity rather than “speech activity in the ordinary sense” (Head, 1921, p. 434). And far from being childishly simple, some of Head’s tasks proved difficult even for people without brain damage (Pearson et al., 1928).

Language assessment: later developments WEISENBURG

AND

MCBRIDE

According to Theodore Weisenburg (1876–1934) and Katherine McBride (1904–1976), the Serial Tests did not cover all relevant aspects of cognitive performance; they were not adequately graded in terms of difficulty; and failure on more complex tasks, such as Hand, Eye and Ear Tests, might reflect various sorts of impairment (Weisenburg and McBride, 1935). Spurred by these perceived inadequacies, Weisenburg and McBride (1935) devised a new battery specifically for the assessment of aphasic patients. They selected 60 “clear-cut cases of aphasia” from Philadelphia area hospitals. Two comparison groups were also studied, hospital controls with-

out brain injury and brain-injured patients without aphasia. Because extant tests for adults were limited to the Army Alpha and Beta tests (see below) and to college entrance examinations, their research battery (Table 17.2) was comprised mainly of tasks taken from standardized educational achievement tests in use for children. As an example, Weisenburg and McBride’s Reading Tests included the Gates Word Pronunciation Test, the Gray Oral Reading Paragraphs, the Gates Primary Reading Tests, the Chapman Unspeeded Reading-Comprehension Test, and the Thorndike McCall Reading Scale. Administered during sessions of approximately 1 h, their exhaustive battery took even normal adults 10–15 h to complete; for aphasic patients the average was 19 h (Weisenburg and McBride, 1935).

GOODGLASS

AND

KAPLAN

One of the more popular approaches to aphasia assessment was developed in the 1960s at the Boston Veterans Administration Hospital by Harold Goodglass (1920–2002) and Edith Kaplan. For their Boston Diagnostic Aphasia Examination, these psychologists adopted the strategy of standardized sampling “in as pure a form as possible, all the components of language which have proven useful in identifying aphasic syndroms” (Goodglass and Kaplan, 1972, p. 2). In contrast to researchers (e.g., Hughlings Jackson, 1878; Marie, 1906; Schuell and Jenkins, 1959) who attributed

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Table 17.2 Examination of the aphasic patient: outline of principal tests from the battery of Weisenburg and McBride 1. Spontaneous Speaking 2. Naming (naming tests were Head’s serial tests for Naming and Recognition of Common Objects and Colours) 3. Repeating 4. Understanding Spoken Language (Head’s Hand, Eye, and Ear tests and Marie’s Three Paper Test were included among the language comprehension tasks) 5. Reading 6. Writing 7. Arithmetic 8. Language Intelligence Tests 9. Non-Language Tests (Among the non-language tests were the Knox Cube Imitation Test and the Goodenough test of drawing a man from memory) 10. Reproduction of Verbal Material 11. Handedness Supplemental tests included sound recognition, visual perception, letter cancellation, speed of reading, arithmetic scales, other number tasks, classification test (semantic fluency), word building, sentence construction, picture description, maze test, and mechanical aptitude.

aphasic symptoms to impairment in a general language faculty, Goodglass and Kaplan (1972, p. 2) believed language components could be selectively damaged, providing information about the “anatomical organization of language in the brain” and “the localization of the causative lesion.” The Boston Diagnostic Aphasia Examination incorporated standardized tasks and rating scales to provide quantitative summaries of global severity, oral fluency, auditory comprehension, naming, oral reading, repetition, paraphasia, automatic speech, reading comprehension, writing, music, and supplemental non-language tasks. Their non-language tasks included apraxia tests and a “parietal lobe battery,” designed to assess constructional skills and impairments associated with the Gerstmann syndrome (constructions using sticks and 3-dimensional blocks, drawing, finger identification tasks, left–right orientation, arithmetic, clock setting). Traditional aphasic syndromes were identified and classified on the basis of speech output (fluency) (Goodglass et al., 1964), auditory comprehension, and speech repetition.

TESTS

OF WORD FLUENCY

Word fluency is often evaluated by tasks requiring rapid oral or written word production. Initially referred to as association tests, tests of fluency were used as early measures of memory or general intelligence rather than as measures of language. These word

associations could be elicited under uncontrolled or controlled conditions. For continuous uncontrolled associations, subjects might be instructed to start with any word and then keep saying words as fast as possible so long as they were not part of a sentence. The examiner counted and transcribed responses, and subjects were stopped when they reached 100 words (Whipple, 1915). Scoring was based on time, and transcribed words could be compared to frequency norms or catalogued into such categories as animals, tools, proper names, verbs, or abstract terms. Continuous associations could also be controlled by specifying a semantic category, such as members of the animal kingdom, abstract terms, or articles of clothing. Thus, a subject could be instructed to name words pertaining to clothing, being stopped after 20 words, with scoring based on time (Whipple, 1915). Other controlled association tasks included the Part–Whole Test (name the whole thing of which the word is a part; e.g., for button the subject might respond shirt), the Opposites Test (e.g., give a word that means the opposite of old, or come, or crooked), and the Genus–Species Test (i.e., name something that belongs in the class given on the card; e.g., responding bread for the class food) (Whipple, 1915; Bronner et al., 1927). Scoring was typically in terms of median or mean reaction time, but response accuracy and quality could also be considered. When presented with a list of stimulus words, scoring could be based on the number of words produced within a specified time. Given a list of 50 words, for example, the Opposites Test score was number of written opposites produced within a 5-minute interval. Part–Whole associations and Opposites associations were among the Language Intelligence Tests of Weisenburg and McBride (1935). In developing his theory of primary mental abilities, Louis Thurstone (1887–1955) at the University of Chicago developed a written Word Fluency Task, which required subjects to write four-letter words beginning with the letter S for 5 min and with the letter C for 4 min (Thurstone, 1938). Psychologist Arthur Benton (1909–2006) developed an oral fluency task using the letters F, A, and S in separate 1-min trials. This FAS test was included in the Neurosensory Center Comprehensive Examination for Aphasia (Spreen and Benton, 1977). In the Multilingual Aphasia Examination battery, this task, which used three different initial letters, was referred to as the Controlled Oral Word Association Test (Benton and Hamsher, 1983). Controlled fluency tasks such as the FAS test and tasks of category fluency (e.g., animal names elicited during a 1-min interval) are still commonly used to assess cognitive abilities.

COGNITIVE ASSESSMENT IN NEUROLOGY 241 1916, p. 43). More cynically, intelligence was also defined TOKEN TEST as “the capacity to do well in an intelligence test” or, Early investigators like Trousseau and Marie argued equivalently, intelligence was “what the tests of intellithat intelligence was nearly always affected in patients gence test” (Boring, 1923, pp. 35, 37). A prominent social with aphasia, where one aspect of intelligence was critic described the intelligence test as “fundamentally taken to include the ability to understand speech. In an instrument for classifying a group of people 1962, Ennio De Renzi and Luigi Vignolo described a . . . according to their success in solving problems” new and sensitive test of “receptive disturbances.” (Lippmann, 1922, p. 247). These Italian authors criticized Marie’s Three Paper One of the earliest scales was developed by Alfred Test as requiring the need to remember a complex Binet (1857–1911) and Theodore Simon (1873–1961) in sequence of commands, and Head’s Hand, Eye and response to a governmental directive to identify Parisian Ear tests as being too difficult. The Token Test of school children of “inferior” intelligence, so that they De Renzi and Vignolo (1962) consisted of 62 brief might receive appropriate instruction (Binet and Simon, commands easily performed by healthy people regard1905b, c). Their battery included 30 tasks (Binet and less of intellectual ability. The authors’ primary insight Simon, 1905a) – later expanded to 54 (Binet and Simon, was to eliminate redundancy in each command, requiring 1911a) – arranged in order of difficulty based on findpatients to “[grasp] its significance from the semanings with “average” school-age children. Thus, they tic value of every single word” (De Renzi and Vignolo, determined that an average 5-year-old child could com1962, p. 667). The test employed small tokens of two pare weights of two small boxes with similar appearshapes (circles, rectangles), two sizes, and five colors. ances, copy the drawing of a square, repeat a Tokens were arrayed before a patient, who was then 10-syllable sentence, count four coins, and join together asked to carry out such commands as “Pick up the small two identical right-angled triangles to form a rectangle white rectangle” and “Pick up the large blue circle.” Other (Binet and Simon, 1911a). At age 15, the appropriate commands, using only the large tokens, involved function tasks were to repeat seven digits, find three rhymes words and more complex syntax (e.g., “Put the blue circle for a given word, repeat a 26-syllable sentence, interpret under the white rectangle” and “After picking up the a picture, and interpret a situation (e.g., My neighbor green rectangle, touch the white circle”). Subsequent has just received some unusual visitors. He received experience with this task implied that subtle, or “latent,” one after another a doctor, a lawyer and then a priest. comprehension deficits are present in many aphasic What is going on at my neighbor’s house?) (Binet and patients whose understanding otherwise appears normal Simon, 1911a). Intelligence was summarized as an age, (Boller and Vignolo, 1966). Shorter versions of the or mental, level (Binet and Simon, 1908), an innovation Token Test have appeared in other test batteries, e.g., ballyhooed as perhaps “the most important [discovery] the Multilingual Aphasia Examination (Benton and in all the history of psychology” (Terman, 1916, p. 41). Hamsher, 1983), and continue to be used in clinical and The popularity of the Binet–Simon scale was immense. research settings. Developed for pedagogical purposes, it was soon applied to the diagnosis of low intelligence and mental INTELLIGENCE TESTS retardation (Binet and Simon, 1905a, b, c). During the last two decades of the 19th century, experiIn the 1890s and early 1900s, the United States mental psychologists were increasingly interested in the experienced massive immigration, and the Public identification and measurement of individual differHealth Service was mandated to exclude the “feebleences in mental abilities. Mental testing included not minded” and those “with physical or mental defects only elementary psychophysical properties, such as which might affect their ability to earn a living” (Zenreaction time, simple motor skills, and sensory discriderland, 1998, p. 266). Howard Knox (1885–1949) and mination (Cattell, 1890), but also more complex mental other Public Health Service physicians at Ellis Island, processes (Toulouse et al., 1904). New York, attempted to adopt the tests of Binet and Intelligence scales were developed soon after, using Simon to screen immigrants for “mental deficiency” subtests to yield an overall composite score. These scales or “feeblemindedness” (Knox, 1914, 1915). Many immiwere usually concerned with “general intelligence” grants were illiterate or of limited English proficiency, (Spearman, 1904) rather than more discrete psychological and verbally based tasks, such as those in the Binet– processes. Intelligence was never consistently defined, Simon scale, were thus of scant utility. Even with the but it generally referred to the ability to “judge well, assistance of a translator, “[i]t would be manifestly understand well, [and] reason well” (Binet and Simon, absurd to use educational tests in the case of unedu1905a, p. 197), or to “the sum total of those thought procated persons” (Knox, 1913, p. 105). For this reason, cesses which consist in mental adaptation” (Terman, Knox adapted or designed so-called nonverbal

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“performance tests,” which were “applicable to the educated as well as to the illiterate” (Knox, 1914, p. 742). These were based on “reasoning, judgment, sense of form, perseverance, attention and cooperation.” For some tests, performance was timed and quantified, but there were no standard norms. Borrowing from the work of E´douard Seguin (1812–1880), a pioneer in the education of the mentally retarded, Knox employed form-boards in some tests, which required the fitting of wooden shapes such as an oval or diamond into matching recesses cut into a board. Other tasks administered at Ellis Island included jigsaw puzzles, cube imitation (a serial pointing task involving small wooden blocks; Fig. 17.2), and frame tests (a puzzle task in which wooden blocks were fit into a rectangular frame). Similar to the approach of Binet and Simon (1908), Knox assigned a “mental age” on the basis of the highest level obtained on his scale (Knox, 1915). At the 5-year level, the immigrant was expected to place all 10 wooden pieces into the Seguin form-board, imitate the examiner in tapping the four cubes in a specified sequence (e.g., cubes 1, 2, 3, 4 and then 3), count any number of the examiner’s fingers, copy a square and a circle, and obey a two-step command (e.g., “Shut the door and hand me the pencil”) (Knox, 1914). At about the same time, Stanford University psychologist Lewis Terman (1877–1956) surmised, “The constant and growing use of the Binet–Simon intelligence scale in public schools, institutions for defectives, reform schools, juvenile courts, and police courts is sufficient evidence of the intrinsic worth of the method” (Terman, 1916, p. xi). However, to correct perceived

Fig. 17.2. Knox’s Cube Imitation Test. Prospective immigrant at Ellis Island, New York, being asked to imitate movements of the examiner, who taps the four attached cubes in a specified sequence (Knox, 1915, p. 53). In the foreground is the Feature Profile Test, one of several performance tasks developed by Knox; a similar profile was included in the Object Assembly subtest of the Wechsler– Bellevue Scale.

“imperfections,” Terman undertook a revision in which he defined uniform test procedures, added new tasks for a total of 90, extended the age range to include adults, and developed norms based on the assessment of 2300 children and adults. For a summary measure, he devised a composite intelligence quotient (IQ), defined as the ratio of mental age to chronological age. He observed that girls and boys were similar with respect to mean IQ and IQ distribution (there was a slight mean advantage for girls up to age 13), despite “marked” differences on several tasks. Terman attributed differences that favored children from a “superior” social class to a likely “superiority in original endowment” (Terman, 1916, p. 72) rather than to the “gratuitous assumption” that these children do better “solely by reason of [their] superior home advantages” (p. 115); stated another way, he agreed with many of his era that “their heredity is better” (p. 115). With a test administration time of 60–90 min for adults and under 1 h for children, the Stanford–Binet Intelligence Scale rapidly became the most widely used measure of intelligence in the United States. During World War I, over 1.7 million American soldiers were administered new intelligence scales developed by a team of eminent psychologists headed by Robert Yerkes (1876–1956) (Zenderland, 1998; Boake, 2002). Results were summarized with a “point scale” rather than mental age or IQ (Yerkes and Bridges, 1914). Employing a new multiple choice format, which was scored using a stencil, and rigid standardized administration procedures, the Alpha examination consisted of verbal tasks (Yerkes, 1920). The Beta examination, intended primarily for soldiers lacking English proficiency, was based on performance tasks. The Army Performance Scale was designed to be administered individually to servicemen who had failed the group-administered Alpha and Beta tests. A number of its 10 subtests were derived from batteries of Binet and Simon, and Knox. David Wechsler (1896–1981), an army psychological examiner, came to believe that existing tests, many of which had been developed for children, were restricted in range (Wechsler, 1939). Further, the concept of IQ based on mental age appeared inappropriate for adults. After the war, while at the Bellevue Psychiatric Hospital in New York, he developed the Wechsler–Bellevue Intelligence Scale (Wechsler, 1939). Most Wechsler– Bellevue tasks were borrowed from the Knox battery (Knox, 1914, 1915), the army Alpha and Beta examinations (Yerkes, 1920), and the revised Stanford–Binet battery (Terman and Merrill, 1937). One innovation was to combine verbal and performance tasks into a single scale for calculation of the Wechsler–Bellevue IQ. Of even greater importance was the decision to

COGNITIVE ASSESSMENT IN NEUROLOGY 243 base the IQ on a standard score with the same standard that is, measures of general intelligence with no distribution at each age level. intended distinction between its different phases” Wechsler ignored memory tasks in his intelligence (Babcock, 1930, p. 14). Admittedly, these cognitive scale, perhaps because memory was viewed as “distinct phases can be difficult to disambiguate, but it was and independent of judgment” (Binet and Simon, recognized early that tasks requiring “the fixation of 1905a, p. 197). He published a separate Memory Scale, new data” (Babcock, 1930, p. 58), i.e., episodic which provided a summary memory quotient calcumemory, and those requiring concept formation (e.g., lated in a manner similar to that of the IQ. This scale Goldstein, 1948a), were most sensitive to brain injury. included questions on personal and current informaThe following sections survey several of the more tion, orientation, “mental control” (a series of tasks historically important approaches to assessment involthat tapped attentional and working memory skills), ving delimited realms of cognitive function. logical memory (immediate recall of items from paragraph-length stories), digit span (digits forward Memory and backward), visual reproduction (immediate recall, From research in clinical populations and laboratory demonstrated by drawing three designs presented for animals, it is clear that there are different forms of 10 s each), and associate learning (recall of verbal memory, which can be selectively disrupted by brain paired associates) (Wechsler, 1945). The first edition injury (Squire, 1987). An important early distinction of the Wechsler Intelligence Scale for Children was was between primary memory and secondary memory. marketed shortly thereafter (Wechsler, 1949), and 16 American psychologist William James (1842–1910) years after its debut the Wechsler–Bellevue Intellidescribed primary memory as “belonging to the reargence Scale was revised as the Wechsler Adult Intelliward portion of the present space of time, and not to gence Scale (Wechsler, 1955). the genuine past” (James, 1890, p. 647); secondary memOther revisions to the Wechsler scales followed. ory, or “memory proper,” was the “knowledge of an These scales have achieved immense popularity among event, or fact, of which meantime we have not been clinical and educational psychologists. Although dethinking, with the additional consciousness that we signed and standardized for normal populations, the full have thought or experienced it before” (p. 648). The scales, or, more commonly, abbreviated versions or a terms short-term memory and long-term memory later subset of individual tests, are used often in clinical or came to be applied to describe this dichotomy, and more research settings for the cognitive assessment of neurorecently episodic memory has been used more or less in logical patients. the sense of James’s secondary memory (Squire, 1987). Memory and forgetting had been extensively stuASSESSMENT OF COGNITIVE died by Hermann Ebbinghaus (1850–1909) in Germany ABILITIES OTHER THAN LANGUAGE using lists constructed of nonsense syllables, items A dazzling assortment of cognitive tasks appeared in without preformed associations (Ebbinghaus, 1885). the decade following the initial papers of Binet and Concepts of free recall, the learning curve, primacy Simon (Pyle, 1913; Whipple, 1915), prompting one psyand recency effects, savings score, and recognition chologist to quip, “Of the making of many [mental] date from his epochal investigations. tests there is no end” (Wells, 1927, p. iii). These tests The term memory has always been applied to preprovided an impetus and a means for cognitive testing sumably disparate processes, which are assessed with in clinical settings. One perspective on general intellipatently dissimilar tasks. Early tests of memory (Whipgence testing was “The tests themselves matter little, ple, 1915; Bronner et al., 1927; Wells, 1927) reflected provided that they are numerous” (Binet and Simon, this terminological promiscuity, as do modern tests. 1911b, p. 201). A similar sentiment was implied by the Early tests tapped memory for personal information presumption that “the only intelligence scales worth (e.g., age) and common facts (e.g., number of pints the name draw service freely from all [cognitive] in a quart, name of the President). Memory span tasks ‘functions’” (Kohs, 1920, p. 369). However, the issue included the familiar digit span (Jacobs, 1887) and was obviously quite different for neurological patients, Knox’s cube imitation test (Fig. 17.2), a once popular where it was useful to distinguish among cognitive non-verbal tapping span task that antedated the similar functions disproportionately or differentially affected Corsi block-tapping test (Milner, 1971) by over half a by brain injury. New assessment tools were required century. The Substitution Test, a forerunner of the for the “measurement of mental deterioration,” Digit–Symbol Substitution Test, was “a test of quickbecause, as noted by one psychologist, “intelligence ness of learning” that included digit–symbol and scales are too much exactly what they pretend to be, symbol–digit variants (Pyle, 1913, p. 18). With respect

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to episodic memory, there were various permutations on rote list learning (e.g., lists of concrete nouns or abstract nouns), memory for sentences of increasing length, memory for pictured objects, memory for visual designs, paired-associates learning (e.g., associating the name of an unfamiliar town with the state in which it is located), and logical memory. The latter was sometimes referred to as memory for ideas, or gist learning, and a logical memory task with 19 embedded memory items appeared in the 8-year-old level of the Binet and Simon (1908) battery. Binet and Simon (1905a) included a memory for visual design test (Fig. 17.3) for use at the 10-year level (Binet and Simon, 1911a) that subsequently reappeared with slight changes in several settings, including the Visual Reproduction subtest of the Wechsler Memory Scale (Wechsler, 1945). In patients with neurological disease, it became increasingly apparent that different aspects of memory could be affected differentially. Sergei Korsakoff (1854–1900) described a syndrome of amnesia associated with peripheral neuropathy in alcoholics (Korsakoff, 1890) and pathological alterations in the brainstem and diencephalon in alcoholics (Wernicke, 1881; Gamper, 1928). For patients with this disorder, a young David Wechsler (1917) found normal memory span for digits, words, and sequential pointing (using a modification of Knox’s cube imitation test). However, he demonstrated that Korsakoff patients learned “preformed” (semantically related, e.g., metal–iron, lead–pencil) associates poorly, and they were almost completely unable to learn “new” (semantically unrelated, e.g., crush–dark, cabbage–doll) associates. These results, according to Wechsler (1917, p. 447), showed clearly that “the prime cause of the retention defect in Korsakoff psychosis is the patient’s inability to form new associations.” Most “easy” and “hard” items on the Associate Learning subtest of his 1945 Wechsler Memory Scale derive from this earlier list of preformed and new associates. In the 1950s, it was observed that bilateral surgical resection of medial temporal lobe structures that include the hippocampus – intended to alleviate psychotic behavior or intractable epilepsy – resulted in severe, persistent

Fig. 17.3. Binet–Simon scale, drawing from memory (Binet and Simon, 1905a, p. 216). The child is shown the two designs for 10 s. Immediately following its removal, the child is asked to draw the designs from memory.

difficulty with acquiring new episodic memories while sparing short-term memory (Scoville, 1954; Scoville and Milner, 1957; Penfield and Milner, 1958). Thus, digit span was unaffected, but amnestic deficits were clearly demonstrated on Associate Learning and Logical Memory subtests of the Wechsler Memory Scale. New information could be retained only for a few seconds unless it was continuously rehearsed. When attention was directed away and rehearsal ceased, the information was lost almost immediately. One such patient with epilepsy, known in the literature as H.M., was studied extensively beginning in 1953, when he underwent medial temporal lobe resection (Scoville and Milner, 1957). Decades later, H.M. remained profoundly amnestic (Squire, 2009). Many older adults evince substantial deficits in episodic memory. In comparison to more “benign” forms of forgetfulness, these amnestic symptoms are associated with rapid, progressive clinical decline (Kral, 1962). Recently, the term mild cognitive impairment has been applied to relatively selective deficits in episodic memory, assessed for example with list-learning (Petersen et al., 1999). Mild cognitive impairment is thought to presage Alzheimer’s disease, and episodic memory loss is characteristic of even mild forms of this disorder (Welsh et al., 1991), reflecting early severe pathological alterations in the medial temporal lobes (Hyman et al., 1984).

Visuospatial and visuoconstructive skills Visuospatial, or visuoperceptive, skills are usually assessed with drawing and other formative tests. One exception is the overlapping figures developed by Walther Poppelreuter (1886–1939) after World War I, working with brain-injured German soldiers (Fig. 17.4) (Poppelreuter, 1917). Poppelreuter noted that normal subjects easily named individual objects depicted by the superimposed line drawings, but patients with visual agnosia experienced problems recognizing these figures. Visuoconstructive difficulty, sometimes referred to as constructional apraxia (Kleist, 1934), indicates an impairment in such formative activities as drawing, building, or assembling. Clinical testing may involve copying a line drawing, drawing a picture to command, copying a 2-dimensional design with wooden match sticks, copying a 2-dimensional pattern with colored cubes, or copying a 3-dimensional construction with wooden blocks. “Constructional apraxia in ordinary circumstances is a rather delicate index of disturbed spatial relationships” (Critchley, 1953, p. 191), and normal performance involves visuospatial, praxic, and executive skills. Formative constructions are thus disrupted by a variety of brain lesions, but the most striking deficits were linked in the mid-20th century to

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Fig. 17.4. Poppelreuter’s (1917, p. 190) overlapping figures.

injury of the right cerebral hemisphere (Paterson and Zangwill, 1944; He´caen et al., 1956). Drawing tasks were incorporated into cognitive batteries administered by Moutier (1908) and Head (1926), who were primarily concerned with language disorders, and into early intelligence batteries (Binet and Simon, 1905a; Terman, 1916). Moutier (1908) sometimes asked patients to draw geometric figures (e.g., a circle or square), draw objects from memory (e.g., a boat or elephant) (Fig. 17.5A), to copy simple and complicated non-representational figures in the presence of a model (Fig. 17.5B), or to draw these non-representational figures 10 s after the model had been withdrawn from view. Head (1926) asked patients to draw from a model (e.g., jug, vase, or lamp), to draw from memory (e.g., an elephant), or to draw the floor-plan of a familiar room. Working with children, other investigators attempted to establish a relationship between general intelligence and concept formation inferred from drawings. This approach was perhaps most refined in the Goodenough Intelligence Test (Goodenough, 1926), later referred to as the Goodenough Draw-a-Man Test, in which children were supplied with pencil and paper and were instructed simply to draw the picture of a man (Fig. 17.6). Florence

Goodenough (1886–1959), an American psychologist who trained under Terman, devised an elaborate scoring system and provided age-norms for mental ages 3–13 years. Added impetus for the assessment of drawing abilities came from the Gestalt psychologists, who recognized that stimuli tended to be perceived, grouped, and interpreted as an organized whole, or Gestalt (Ko¨hler, 1929). Pathological processes of the brain interfered with gestalt formation. One of the best known drawing tests was the Visual Motor Gestalt Test – commonly referred to as the Bender Gestalt Test – developed by child psychiatrist Lauretta Bender (1899–1987) at the Bellevue Hospital in New York (Bender, 1938). Her task consisted of nine patterns taken from the work of Max Wertheimer (1880–1943) in Germany (Wertheimer, 1923); accurate copy of these figures reflected in part a patient’s ability to perceive dots or lines as an integrated pattern. Pencil and paper tests continue to be widely used in the assessment of visual perception, constructional skills, and visual memory. Line bisection tasks, introduced a century ago to assess perceptual errors in patients with hemianopia (Liepmann and Kalmus, 1900; Poppelreuter, 1917), are now often used to identify unilateral visual neglect (Albert, 1973). Among standardized tasks, the “complex figure” – a line

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Fig. 17.5. Drawings from two hemiplegic patients with Broca’s aphasia described in the thesis of Moutier (1908, p. 642 and p. 661). (A). Spontaneous drawing of an elephant by a 60-year-old man, using his left hand. (B). Copy of a “complex” figure by a 46-year-old man, using his left hand (model on top and patient’s copy below).

Fig. 17.6. Goodenough Intelligence Test. Drawings of a man by a third-grader girl aged 11 years 7 months (left) and boy aged 10 years 1 month (right) (Goodenough, 1926, p. 114). Copyright by the World Book Company.

COGNITIVE ASSESSMENT IN NEUROLOGY 247 drawing developed by Andre´ Rey (1906–1965) to assess will lick his lips with it” (p. 660). Marie (1905) noted visual perception and memory in developmentally that aphasics were unable to use gestures to describe, delayed and brain-injured patients (Rey, 1941) – is espefor example, their occupations. The concept of apraxia cially well known. Rey’s design, which was much more was most fully developed by Hugo Liepmann (1863– elaborate than, for example, that employed by Moutier 1925) at the beginning of the 20th century, when he (Fig. 17.5B), contained a large central rectangle and 18 described disorders of purposeful movement that embedded details, including diagonals, a circle, a diacould not be attributed to more elementary problems, mond, a square, and hatched lines. Typical administrasuch as weakness, abnormal tone, ataxia, or sensory tion involves copy of the figure followed by an loss (Liepmann, 1900, 1908). The term apraxia is someunannounced recall trial after a short delay (Osterrieth, times extended to embrace a wide range of motor 1945). Other well-known copy and recall tasks are impairments, including disturbed movements required the Visual Reproduction subtest of the Wechsler Memfor speaking (speech apraxia), dressing (dressing ory Scale (see above) and the Visual Retention Test apraxia), drawing (constructional apraxia), and ambu(Benton et al., 1978). lating (gait apraxia). More often, however, apraxia Developed nearly a century ago, the Color Cubes refers to the inability to carry out certain movements test used one-inch cubes available in toy stores under to command or through pantomime (e.g., waving goodthe same name (i.e., Color Cubes). Four sides were bye or pretending to comb one’s hair; referred to by painted a solid color (red, white, blue, or yellow), and Liepmann as ideokinetic apraxia and sometimes called the other two sides were diagonally divided into two ideomotor apraxia), the inability to use objects accordcolors (red and white; blue and yellow) (Kohs, 1920; ing to their intended purpose (e.g., rubbing a cigar on Maxfield, 1925). In a test setting, subjects were the side of a matchbox, as if the cigar were a match; required to match a pattern produced or shown by referred to by Liepmann as ideational apraxia), or the the examiner. As first devised, the examiner’s model inability to mimic non-representational movements perwas constructed from a duplicate set of cubes (Hutt, formed by the examiner (Mayer-Gross, 1935; De Renzi 1925; Maxfield, 1925); another version – referred to et al., 1980). as the Block-Design test – showed a half-scale design Testing for ideomotor apraxia has typically involved printed on a card (Kohs, 1920). The cubes subsequently simple tasks that might be performed at the bedside. Early became known as Kohs blocks, after the test’s author. in the 20th century, Wilson outlined procedures for this Block-Design test scores correlated highly with the purpose. These included movements “conditioned by Binet–Simon intelligence quotient, and performance auditory stimuli” (e.g., “put out your tongue . . . look was claimed to involve mental operations of “analyzing, astonished . . . put your left hand on your right ear . . . combining, comparing, deliberating, completing, discricough . . . make movement of striking a match . . . make minating, judging, criticizing and deciding” (Kohs, movement of counting pennies out of your hand” (Wil1920, p. 370). The original half-hour test consisted of son, 1908, pp. 178–179). Similar tasks were described by 17 designs of graded difficulty. The Block-Design test his contemporary Charles Foix (1882–1927) (e.g., open was included as one of the Wechsler–Bellevue Intelliyour hand, put your finger on your nose, make a military gence Scale performance subtests; in the Wechsler salute, show how to catch a fly, scold a child, cut with Adult Intelligence Scale, Block-Design colors were scissors; tasks with real objects included use of a corkrestricted to red and white. screw and scissors) (Foix, 1916). Moutier (1908), Dejerine (1914), and the American neurologist Johannes Nielsen (1890–1969) indicated that cognitive assessment Praxis should include testing of praxis (Nielsen, 1936). GoodTrousseau (1865) was among the first to recognize glass and Kaplan (1972) developed a short Apraxia Test that aphasic patients were unable to express their that separately assessed commands involving facial, thoughts by gestures. John Hughlings Jackson (1835– limb, and axial musculature. 1911) remarked on the inability of some aphasic To Luria (1966a, p. 328), a task such as the Hand, patients to carry out tasks they seemed to understand. Eye and Ear tests of Head (1920) (Fig. 17.1), in which a One such patient, “instead of opening [his eye for an patient is asked to reproduce particular hand positions, eye examination], he opened his mouth, or screwed could be used to detect “defects in the optic-spatial up his face, or shut his eye” (Hughlings Jackson, organization of the motor act.” He believed that it 1866, p. 660). Another patient “who cannot put out was even more important to test the dynamic organizahis tongue when told will sometimes actually put his tion of the motor act, involving reciprocal coordination fingers in mouth as if to help to get it out; and yet (e.g., simultaneous changing of positions of the left not unfrequently when we are tired of urging him, he and right hands) or involving consecutive components.

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Fig. 17.7. Fist-Edge-Palm test. Three successive hand positions to be learned by imitation and then repeated. From Higher Cortical Functions in Man (Luria, 1966a, p. 334); copyright by Basic Books, Inc.; reprinted by permission of Basic Books, a member of Perseus Books Group.

Luria’s (1966a) Fist-Edge-Palm test is sometimes used by neurologists as a test of praxis, coordination, and the ability to inhibit one motor response and change to another. For this test, the patient is asked to repeat a sequence in which he places his hand in three different positions (Fig. 17.7). A patient with brain damage, particularly that involving the frontal lobes, may have difficulty learning and continuing the sequence smoothly and in an automatic manner.

Executive functions So-called executive functions are involved in concept formation, reasoning, planning, and monitoring of behavior. In the years after World War I, Kurt Goldstein (1878–1965) and his colleagues developed an influential set of constructional and sorting tests for neurological patients (Goldstein and Scheerer, 1941; Weigl, 1941), which might now be viewed as largely focused on executive function (Table 17.3). Table 17.3 Special tests of abstract behavior developed by Goldstein and his colleagues (see Goldstein and Scheerer, 1941) Cube Test (Goldstein and Scheerer) Color Sorting Test (Gelb and Goldstein) Object Sorting Test (Gelb, Goldstein, Weigl, and Scheerer) Color Form Sorting Test (Weigl, Goldstein, and Scheerer) Stick Test (Goldstein and Scheerer)

Goldstein believed that brain injury impairs the capacity for “abstract attitude,” resulting in behaviors that are concrete, rigid, and less capable of shifting to a new, more appropriate mode. The concrete attitude is determined by the “immediate experience of a given thing or situation in its uniqueness” (Goldstein, 1948a, p. 89), whereas the abstract attitude permits action oriented “by a conceptual point of view” (p. 90). For their Cube Test (Table 17.3), modified from the Kohs Block-Design test, Goldstein and Scheerer focused on the patient’s approach to problem solving. A concrete approach failed to involve a “deliberate act of analytical reasoning” (Goldstein and Scheerer, 1941, p. 32), whereas the abstract approach required that the model design be “broken up imaginatively into four [or nine or 16] squares” (p. 33). The Color Sorting Test required a patient to separate woolen skeins of various tints according to a color concept (e.g., category of red or blue). Shades of a color (e.g., dark red and pink) were to be sorted into a single class; a patient with impaired abstract attitude might sort by brightness rather than by hue. The Color Form Sorting Test (Table 17.3), in its simplest arrangement, consisted of 12 figures: four triangles, four squares, and four circles. One of each shape was red, one was green, one was yellow, and one was blue. A patient was told to sort the figures that belonged together. Assuming that these had been grouped either by color or by shape, the patient was then instructed to sort them in a different way

COGNITIVE ASSESSMENT IN NEUROLOGY (Goldstein and Scheerer, 1941). The Object Sorting Test consisted of a series of real and toy objects, with different sets for men and women. The male set included categories of tools, eating utensils, smoking materials, and food items. Other potential groupings included color, form (round or oblong), items that occurred in pairs (e.g., there were two forks and two nails), and material (e.g., metal, wood). Through a series of questions and instructions, the examiner explored the patient’s ability to sort and group objects, or to consider new arrangements of objects, in a manner that demonstrated capacity for abstract thinking. The Stick Test used sticks of two lengths – 3.5 and 5.5 inches. The patient was instructed to copy a model figure and then to reproduce it from memory after it had been removed. Goldstein and Scheerer (1941, p. 131) pointed out that we have become “habituated to handling directional features in space, so that we hardly realize how much abstraction they involve.” Hence, reproducing meaningless figures or geometric figures is demanding for patients with impairments of abstract attitude (Fig. 17.8) (Goldstein, 1948b). Based in part on the Color Form Sorting Test, the more demanding Wisconsin Card-Sorting Test was developed to facilitate quantified scoring (Berg, 1948; Grant and Berg, 1948). It consisted of 64 cards containing one to four identical figures (star, cross,

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triangle, or circle) of a single color (either red, yellow, green, or blue). Each card could be sorted according to form, number, or color. The task began when four stimulus cards were displayed (one red triangle, two green stars, three yellow crosses, and four blue circles). A subject was asked to sort each card onto one of the stimulus cards, being informed only whether the selection was “right” or “wrong.” The initial unannounced category was color, and after the subject learned to sort correctly, the examiner – without warning or explanation – shifted to a new correct category (e.g., number). If the subject successfully shifted categories, the procedure was repeated. Scoring considered the number of sorting errors and perseverative errors. Patients with lesions of the dorsolateral frontal lobe may have particular difficulty with this task (Milner, 1963). In 1935, the American psychologist Ridley Stroop (1897–1973) described naming interference involving colors (Stroop, 1935). Psychologists interested in habit formation and memory had studied ways in which one response might inhibit another. It was also well recognized that serial reading of color names was performed more rapidly than naming of colors. Stroop’s experiments showed that the time to read a series of color names was unaffected by printing the word in a contrasting color rather than in black (e.g., reading aloud

Fig. 17.8. Stick Test. Samples from a woman with Pick’s disease, showing impairment of abstract attitude (Goldstein, 1948a, p. 162). Her comments are given in the right column. The patient copied and recalled figures recognized as concrete objects but not those that appeared meaningless. Some errors represent reification of a less meaningful model. Adapted from Language and Language Disturbances (Goldstein, 1948b, p. 162), copyright by Grune and Stratton (1948), and reproduced by permission of Elsevier.

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“red,” for the word red printed in blue ink). However, naming the ink color was markedly slower for contrasting color names (e.g., saying “blue” for the word red printed in blue ink) than for colored squares (e.g., saying “blue” for a blue square). Although Stroop himself took little interest in his experimental findings, the Stroop effect – prolonged naming when color names are printed in inks of a different color – has been widely adapted for use in a variety of clinical and experimental settings (McLeod, 1991). The familiar Trail Making Test had its origin as the Taylor Number Series, a timed motor performance task consisting of the numbers 1–50 scattered on a sheet of paper, which were to be connected in sequence (Brown et al., 1958). It was recast as the Partington Pathways Test, and during World War II it was incorporated into the Army Individual Test battery in a two-part format (Anonymous, 1944), where it was referred to as the Trail Making Test. Part A consisted of the numbers 1–25, which were to be connected in sequence. The more complex Part B consisted of a series of randomly distributed circles; in the center of each circle was either a number or letter. Instructions were to draw a line from 1 to A, from A to 2, from 2 to B, from B to 3, and so on. Presumed to assess the “ability to plan” and the “ability to ‘shift’ [set],” this pencil and paper test was subsequently found useful in discriminating brain-injured patients from controls (Armitage, 1946, p. 31). Working with patients with frontal lobectomies, frontal lobotomies, and traumatic head injuries, the psychologist Ward Halstead (1908–1968) borrowed, adapted, and devised tasks sensitive to “brain injury” from which he derived an “impairment index” (Halstead, 1947). He favorably contrasted his quantitative techniques to the “impressionistic approach” of neurologists, psychiatrists, and psychoanalysts. Several of Halstead’s tasks were assembled into a fixed battery (Halstead–Reitan Battery), which included the Halstead Category Test and the Halstead Tactual-Performance Test (Reitan, 1955). The latter was a timed form board task presented nonvisually. The Category Test was a nonverbal multiple-choice test involving the ability to group, or abstract, according to “organizing principles” (Halstead, 1947, p. 57) such as size, shape, number, position, brightness, and color. The original test comprised 336 items organized into nine subtests. Groups of stimulus figures were projected onto a boxed viewing screen, and subjects responded using an electrical response box (Halstead and Settlage, 1943). Other tasks, such as the Trail Making Test and the Wechsler–Bellevue Scale, were incorporated into the Halstead–Reitan Battery. Variations of this battery have proven adept at distinguishing neurological patients from people without brain injury.

SHORT STANDARDIZED COGNITIVE INSTRUMENTS FOR DEMENTIA In the second half of the 20th century, short standardized batteries for cognitive assessment were developed for use primarily in the setting of geriatric assessment to identify older adults with suspected dementia, distinguish demented patients from other patient groups, distinguish among dementia diagnoses, or monitor cognitive function over time. Among early batteries were the 10-item Mental Status Questionnaire and the 10-item Short Portable Mental Status Questionnaire. The former offered “a gross measure of ‘overall’ organic impairment” (Kahn et al., 1960, p. 434) among nursing home and mental hospital residents, and the latter provided “quantitative measures of mental functioning related to cerebral impairment” (Pfeiffer, 1975, p. 326) in a geriatric outpatient setting. Particularly popular were the Information–Memory– Concentration Test and the Mini-Mental State examination (below). As might be expected, there is considerable overlap in approach and content in these batteries and others designed for similar purposes.

Information–Memory–Concentration Test and Orientation–Memory– Concentration Test The Information–Memory–Concentration Test, intended “to apply quantitative measures . . . to the phenomena of mental deterioration,” was described in a landmark article by Garry Blessed, Bernard Tomlinson, and Martin Roth (1917–2006) working in Newcastle-upon-Tyne (Blessed et al., 1968, p. 798). This test was devised for a clinicalpathological study of old-age dementia (Roth et al., 1966; Blessed et al., 1968), because existing standardized neuropsychological tasks exceeded the capabilities of elderly hospitalized patients targeted by their research. Their instrument included two quantitative scales under the rubric of “Dementia Scale.” The first, a functional scale, concerned the ability to deal with practical tasks encountered in everyday life. The cognitively oriented second part was based on “performance in a number of simple psychological tests of orientation, remote memory, recent memory, and concentration” (Blessed et al., 1968, p. 799). Referred to as the Information–Memory– Concentration Test, it included items on temporal and geographic orientation, personal memory (e.g., date of birth, occupation), non-personal memory (e.g., date of World War II, 5-min recall of a name and address), and concentration (e.g., months of year backwards, counting from 1 to 20). Analyses were based on 60 clinically heterogeneous cases with post-mortem findings. Both the functional score and the Information–Memory–Concentration score were significantly related to post-mortem

COGNITIVE ASSESSMENT IN NEUROLOGY 251 brain pathology (plaque count in the cerebral cortex) findings systematically. She admonished him to write (Blessed et al., 1968). down exactly what he wanted; and the two of them The two-part Dementia Scale was used in an influenthen devised a short battery that incorporated items tial follow-up study that helped confirm the relation that M. Folstein had found clinically useful and easily between neurofibrillary tangles and senile dementia scored (Folstein, 1990). The resulting instrument con(i.e., Alzheimer’s disease) (Tomlinson et al., 1970). This tained 11 questions and included items on orientation, article contributed greatly to fostering interest in registration (repeating names of three objects), attendementia for a new generation of neuroscientists and tion and calculation (serial subtraction of 7s from 100 clinicians. As the concept of Alzheimer’s disease or spelling world backward), recall of three object evolved from an obscure disorder of the presenium to names, language (e.g., name a pencil and a watch; folone whose importance and late-life prevalence were low a 3-stage command), and copy of an interlocking increasingly recognized, the Information–Memory– pentagon figure. Concentration Test was widely applied in clinical and Reasons for the tremendous popularity of the MMS research settings. A decade and a half later, Robert include its brevity and ease of bedside administration. Katzman (1925–2008) and colleagues in New York It was shorter, for example, than the Information– described a shortened version, validated against postMemory–Concentration Test and better suited for mortem cortical plaque counts in 38 nursing home American patients. Unlike some of its predecessors, patients (Katzman et al., 1983). Sometimes referred to the MMS included items related to language and as the Short Blessed Test or the Orientation–Memory– drawing ability. Perhaps such items conveyed the Concentration Test, this version consists of only six appearance of broad applicability and the unintentional items. Orientation items are year, month, and time of impression that the MMS could be used as a selfday; memory items are based on recall of a rehearsed contained mental status examination. The initial publiname and address; and concentration items are counting cation demonstrated that the MMS score distinguished backwards from 20 to 1 and reciting months of the year among clinical groups (e.g., dementia, depression), in reverse order. correlated significantly with scores from the Wechsler Beginning in 1984, the National Institutes of Health in Adult Intelligence Scale, and showed high test–retest the United States established a series of Alzheimer’s Disand inter-rater reliabilities. As such, the MMS was ease Centers devoted to the understanding of Alzheimer’s indeed “a quantified assessment of cognitive state of disease and related disorders. Shortly thereafter, the Condemonstrable reliability and validity, [making objecsortium to Establish a Registry for Alzheimer’s Disease tive] what is commonly a vague and subjective impres(CERAD) was funded, in part to develop standardized sion of cognitive disability” (Folstein et al., 1975, instruments for the assessment of dementia. The Orientap. 195). tion–Memory–Concentration Test was incorporated as Equally important to success of the MMS was its part of the standardized CERAD assessment employed timing. The MMS was published as American psychiaby neurologists and other physicians in the evaluation of try was shifting to a more explicitly biological mode, patients with suspected dementia (Morris et al., 1989). and the quantitative approach of the MMS fit this Validated versions of CERAD Test instruments are availnew orientation. Further, for neurologists as well as able in a number of languages. psychiatrists, disorders of aging and dementia were beginning to assume prominence in clinical and research arenas. Like other brief batteries, the MMS Mini-Mental State examination found its greatest application in patients with geriatric Of the short standardized assessment instruments, dementia, but it did so without shedding its aura as a none is better known than the Mini-Mental State useful and sometimes obligatory component of the (MMS) examination, published as “a practical method routine mental status examination in other clinical setfor grading the cognitive state of patients for the clintings. Other short batteries were never perceived as so ician” (Folstein et al., 1975, p. 189). At the time of its applicable to a broad spectrum of neurological and inception, lead author Marshal Folstein was a young psychiatric patients. biological psychiatrist trained in neurology; co-author Like the Orientation–Memory–Concentration Test, Paul McHugh was his more senior mentor; and cothe MMS was included in the CERAD battery, but in author Susan Folstein, Marshal’s wife, was a resident the section on neuropsychological assessment rather physician who had not yet completed specialty training than clinical assessment (Morris et al., 1989). The in psychiatry. When S. Folstein presented examination MMS has been translated into more than 50 languages, findings of her hospital patients, M. Folstein someand its items have been fully incorporated into larger times complained that she failed to report cognitive batteries. In January 2006, the original publication

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was feted by Current Contents among the 50 most cited scientific articles, having garnered over 18 000 citations during the preceding 30 years.

CONCLUDING PERSPECTIVES A fertile tradition of cognitive assessment in neurological patients dates back to germinal considerations of brain–behavior relationships in the early and mid19th century. With roots in experimental and educational psychology, the intelligence testing movement added techniques and tools that were later applied within a neurological arena. Subsequent advances in clinical psychology and neurology, and in the cognate clinical neurosciences, have further enriched assessment options. The experienced clinician, according to American neurologist Norman Geschwind (1926–1984), should be able to “obtain vital [cognitive] information rapidly and efficiently” (Strub and Black, 1977, p. vi). The time-limited nature of the neurologist’s cognitive examination at the bedside or in the clinic suggests the frequent need to refocus assessment procedures during the examination (Luria, 1966a). Flexibility in the service of neurological diagnosis or syndrome identification has long been advocated. According to Broca (1869, p. 268), examination of the aphasic patient “cannot be subject to a formal rule; it must be left to the observer’s wisdom.” Nielsen (1936, p. 91) emphasized that “no amount of outline or preparation or following of a scheme will take the place of or compensate for ingenuity and perspicacity on the part of the examiner.” Assessment procedures, he wrote, are tailored to the clinical situation: “A case never occurs requiring all the tests here given” (Table 17.4). In evaluating abstract behavior, Goldstein thought that the examiner “should feel free to probe further by varying the experimental procedure according to his needs” (Goldstein, 1948b, p. 155). Even Head (1926, vol. 1, p. 165) indicated that his Serial Tests “must be strictly adapted to the capacity of the patient and should not be applied in a routine way.” The flexible approach seems at variance with assessment relying upon formal batteries, such as the Wechsler scales, or standard sets of psychological tests. The British psychologist Malcolm Piercy (1959, p. 491) remarked, “One of the most important disadvantages of any standardized test of brain damage is that much information tends to be missed that otherwise might be utilized.” In the brain-injured patient, the concern is that such assessment is ill-suited for determining qualitative features of the cognitive disturbance or analyzing fundamental underlying defects. Indeed, Luria (1966a, p. 302) believed that “application of these

[psychometric] tests to the diagnosis of circumscribed brain lesions has completely failed to justify the confidence placed in them.” Halstead (1947, p. 14) may have been correct when he carped that “the neurologist’s working approach to intelligence has traditionally been impressionistic rather than mensurate.” However, the latter approach, i.e., “pursuit of a mathematical model . . . may ignore the existence of the brain entirely” (McFie, 1975, p. 1). Further, standard tests intended to investigate particular functions (e.g., language or memory) do not necessarily reflect the form that mental disturbances take after brain lesions (Luria, 1966a). Cognitive assessment, as practiced by most neurologists, is usually more informal, more flexible, quicker, and less quantitative than that of most psychologists. In part, this tendency reflects neurologists’ emphasis on syndrome identification in the diagnostic process. A particular symptom-complex in turn may implicate particular brain regions and disease processes. Because lesions in various brain regions can manifest similarly (e.g., as agraphia or memory loss),

Table 17.4 Nielsen’s (1936) syndrome based approach to cognitive assessment 1. Testing for agnosias a. Visual agnosia b. Recognition and naming of letters, mathematical figures, words, musical notes, other symbols, colors c. Acoustic (auditory) agnosia d. Tactile agnosia 2. Testing for apraxias a. Kinetic apraxia (loss of dexterity) b. Ideomotor apraxia c. Ideational apraxia 3. Testing for aphasias (“lower level”) a. Emissive (spontaneous) speech b. Speech repetition (e.g., spared in transcortical motor aphasia) c. Singing d. Character of speech (e.g., paraphasias; agrammatism) e. Object naming (e.g., to identify amnesic aphasia) f. Reading, including reading comprehension g. Intonation 4. Testing for aphasias (“higher level”) a. Testing for semantic aphasia b. Testing for acalculia c. Writing (spontaneously, to dictation, to copy) 5. Miscellaneous syndromes a. Simultanagnosia b. Other forms of agnosia c. Charcot–Wilbrand syndrome (inability to revisualize previous visual impressions)

COGNITIVE ASSESSMENT IN NEUROLOGY it is the constellation of associated impairments that constitutes a diagnostic syndrome (Luria, 1966b). A few neurologists have explicitly organized their cognitive examination around syndrome identification (Nielsen, 1936), although this approach to neurological assessment is open to criticism (Hughlings Jackson, 1873). Other goals of cognitive assessment – for example, grading severity, monitoring disease progression, and evaluating effects of treatment – are more readily realized with standardized, quantitative measures. Further, modified administration of standardized tests might help the examiner discern strategies and processes involved in performing particular neuropsychological tasks (Kaplan, 1988). Many psychologists now employ flexible batteries when examining brain-injured patients, and some instruments emphasize a qualitative, hypothesis-testing approach to cognitive assessment (Christensen, 1975). The purpose of cognitive assessment depends, of course, on questions being asked. For some – but not all – questions posed by the neurologist, a flexible process-driven approach that considers syndrome identification is most revealing. For the clearly formulated question, a myriad of options for cognitive assessment are at the neurologist’s disposal, reflecting the feracious contributions of neurologists, psychologists, and others from the 19th century forward.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 18

The origins of functional brain imaging in humans MARCUS E. RAICHLE * Department of Radiology and Neurology, Washington University School of Medicine, St. Louis, MO, USA

INTRODUCTION Functional brain imaging, as we know it today, began when the experimental strategies of cognitive psychology were combined with brain imaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to examine how brain function supports mental activities (Posner and Raichle, 1994). For over three decades now, functional brain imaging has been an important growth area in neuroscience. It has more recently expanded to include experimental strategies from a broad range of the social sciences (Cacioppo et al., 2006). It is easy to conclude that much of this work has transpired over the past few decades because of its prominence at scientific meetings, in the scientific literature, and in the media. In truth, critical work has been occurring for more than a century. In order to place current work in its proper perspective, this review presents a brief history of some of the events and personalities that have shaped functional brain imaging as we know it today. More detailed historical reviews are available for the interested reader (e.g., Webb, 1990; Kevles, 1997; Raichle, 2000). Before beginning, it is useful to consider the intended goal of functional brain imaging. This may seem selfevident to most. Yet, interpretations frequently stated or implied about functional imaging data suggest that, if not careful, functional brain imaging could be viewed as no more than a modern version of phrenology. It was Korbinian Brodmann (1909) whose perspective I find appealing. He wrote: Indeed, recently theories have abounded which, like phrenology, attempt to localize complex mental activity such as memory, will, fantasy, intelligence or spatial qualities such as appreciation of shape and position to circumscribed cortical zones. *

He went on to state: These mental faculties are notions used to designate extraordinarily involved complexes of mental functions . . . One cannot think of their taking place in any other way than through an infinitely complex and involved interaction and cooperation of numerous elementary activities . . . in each particular case [these] supposed elementary functional loci are active in differing numbers, in differing degrees and in differing combinations . . . Such activities are . . . always the result . . . of the function of a large number of suborgans distributed more or less widely over the cortical surface . . . (Trans. in Garey, 1994, pp. 254–255) With this prescient admonition in mind, the task of functional brain imaging becomes clear: identify regions of the brain and their temporal relationships associated with the performance of well-designed and well-understood tasks. The brain instantiation of these tasks will emerge from an understanding of the elementary operations performed within such networks. The great strength of functional brain imaging is that it is uniquely equipped to undertake such a task and can do so in the brain of most interest to us, the human brain.

PHYSIOLOGY Blood flow Functional brain imaging with PET and MRI is made possible because blood flow changes locally in the brain in relation to changes in cellular activity (Raichle and Mintun, 2006). While the blood flow response is delayed somewhat in time, due to a sluggish response

Correspondence to: Marcus E. Raichle, Washington University School of Medicine, 4525 Scott Avenue, St. Louis, MO 63110, USA. E-mail: [email protected], Tel: +1-314-362-6915, Fax: +1-314-362-6110.

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of blood vessels to changes in neuronal activity, it is remarkable how reliable it appears to be in reflecting changes in cellular activity in the normal brain. The idea that local blood flow within the brain is intimately related to brain function is surprisingly old. One has only to consult William James’ (1890) monumental two-volume text, Principles of Psychology, to find reference to changes in human brain blood flow during mental activities. In a chapter titled “On some general conditions of brain activity under the subheading cerebral blood supply” (Vol. 1, beginning p. 97), he states that “All parts of the cortex, when electrically excited, produce alterations both of respiration and circulation.” This is a remarkably foresighted statement for its time. James references the work of the Italian physiologist Angelo Mosso detailed in a book titled Ueber Den Kreislauf Des Blutes Im Menschlichen Gehirn (“Concerning the Circulation of the Blood in the Human Brain”; Mosso, 1881). Mosso had ingeniously monitored the pulsations of the brain in adults through neurosurgically created defects in the skulls of patients. He noted that the pulsations of the brain increased locally when his subjects engaged in tasks, such as mathematical calculations. Such observations led him to conclude, presciently, that blood flow to the brain followed function. The actual physiological relationship between brain function and blood flow was first explored 12 years later by Charles Roy and Charles Sherrington, then working in the pathology laboratory at the University of Cambridge, UK (Roy and Sherrington, 1890). Despite a promising beginning, interest in the relationship between brain function and brain blood flow virtually ceased during the first quarter of the 20th century. Undoubtedly, this was due in part to a lack of tools sufficiently sophisticated to pursue this line of research. In addition, the work of Leonard Hill (1896), Hunterian Professor of the Royal College of Surgeons of England, was probably influential. His eminence as a physiologist overshadowed the inadequacy of his own experiments, which wrongly led him to conclude that no relationship exists between brain function and brain circulation. Work on brain circulation and metabolism did not resume in earnest until the close of World War II, when Seymour Kety and his colleagues opened the next chapter on studies of brain circulation and metabolism. Working initially with Carl Schmidt of the University of Pennsylvania, Kety developed the first quantitative method for measuring whole brain blood flow and metabolism in humans, using nitrous oxide as a freely diffusible tracer (Kety and Schmidt, 1948). With this newly developed technique, Lou Sokoloff, Charles Kennedy, and others working with Kety

actually performed, in 13 subjects, a sophisticated version of the experiment originally performed in a single subject by Angelo Mosso (Mosso, 1881; Sokoloff et al., 1955; see above). In contrast to Mosso, they observed no change in brain blood flow or oxidative metabolism with mental arithmetic. The important difference between the two experiments was that, crude as his measurements were, Mosso’s observations were based on regional measurements, serendipitously made over the right prefrontal cortex, whereas those of Sokoloff and his colleagues were of the whole brain. Much subsequent data has confirmed the fact that whole brain metabolism and blood flow change little during the performance of most tasks employed in functional brain imaging. The changes are strikingly localized and include both increases and decreases from a level of baseline activity (Raichle and Mintun, 2006). The introduction of an in vivo tissue autoradiographic measurement of regional blood flow in laboratory animals by Kety’s group provided the first glimpse of quantitative changes in blood flow in the brain related directly to brain function (Landau et al., 1955; Kety, 1960). This relatively simple technique involved the intravenous injection of the diffusible tracer trifluoroiodomethane labeled with 131I. The animal (originally a cat) was decapitated one minute after the injection. The brain was removed and cut into thin sections, which were laid on X-ray film. The resulting images were a detailed map of blood flow in the brain. Comparing cats exposed to visual stimulation prior to decapitation with cats not similarly exposed revealed clear changes in blood flow to the visual cortex. Derivatives of this technique many years later became important for the measurement of blood flow in humans with PET (see below). Surprisingly little research was done with the blood flow autoradiographic technique developed in the Kety laboratory. This was likely due to the dominance of neurophysiological techniques that were used for the study of the regional activity of neurons in the brains of experimental animals. The situation began to change in 1977 with the introduction of the C14-deoxyglucose autoradiographic technique for the study of regional brain metabolism in laboratory animals (Sokoloff et al., 1977). Deoxyglucose is an analogue of glucose that is trapped in the brain in proportion to the brain’s local metabolic rate. Studies with this technique were able to bridge the gap between electrophysiological studies and studies of brain metabolism (Sokoloff, 1984). Comparisons between the two approaches (i.e., electrophysiological versus metabolic) provided strong evidence that studies of brain metabolism and brain blood flow had the potential to contribute to our

THE ORIGINS OF FUNCTIONAL BRAIN IMAGING IN HUMANS knowledge of functional brain organization in important and, as we shall see, unique ways. The beginnings of human measurements of regional brain circulation antedated the introduction of the deoxyglucose method in animals by many years. Soon after Kety and his colleagues introduced their quantitative methods for measuring whole brain blood flow and metabolism in humans, David Ingvar, Neils Lassen and their Scandinavian colleagues introduced methods applicable to man that permitted regional blood flow measurements to be made using scintillation detectors arrayed like a helmet over the head. They subsequently demonstrated directly that blood flow changed regionally during changes in brain functional activity in normal human subjects (for a summary of their early work, see Lassen et al., 1978).

Metabolism Until 1986, it was assumed that behaviorally induced increases in local blood flow would be coupled with local increases in the oxidative metabolism of glucose (Siesjo, 1978). With this hypothesis, functionally induced increases in blood flow should be accompanied by quantitatively similar changes in oxygen consumption. While widely held, this hypothesis was based on rather scanty data (Raichle et al., 1976). It was seriously challenged by much more substantial quantitative data from PET (Fox and Raichle, 1986; Fox et al., 1988b). These data demonstrated conclusively that functionally induced increases in blood flow in normal humans, while accompanied by parallel increases in glucose utilization, are not accompanied by changes of similar magnitude in oxygen consumption. The importance of this finding for the development of functional brain imaging with MRI will be discussed later in this review.

IMAGING X-ray computed tomography (CT) In 1971, Godfrey Hounsfield first introduced X-ray computed tomography, or CT as it is now called, at Atkinson Morley’s Hospital in London. The first patent on Hounsfield’s invention was actually filed in 1968. Hounsfield was a self-taught engineering genius working for London-based EMI (Electrical and Musical Industries Ltd.). In creating CT, Hounsfield had arrived at a practical solution to the problem of creating 3-dimensional transaxial tomographic images of an intact object with data arising from a large number of projections through the object. Hounsfield’s invention received enormous attention and quite literally changed the practice of medicine. For this work, he and Alan Cormack, who had earlier developed the

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theoretical basis for CT, received the 1979 Nobel Prize for Physiology or Medicine (for detailed reviews leading to the development of X-ray CT see Webb, 1990; Kevles, 1997). Hounsfield’s success was, in part, due to collaboration with EMI and the British Medical Research Council’s Department of Health and Social Services (DHSS). Funding for the project within EMI was apparently insufficient, due to corporate uncertainty about the market prospects for such a device (Kevles, 1997). It was the brain that eventually prevailed. The idea that the device would permit a safe and comfortable (for the patient) look at accurate tomographic representations of the living human brain was apparently far more appealing to the DHSS than the ability to detect small tumors in the body, as first proposed by Hounsfield and EMI. Overnight, CT changed the way in which we looked at the human brain. Gone were difficult to interpret, unpleasant, and sometimes dangerous techniques, like pneumoencephalography, or PEG as it was known. Cerebral angiography, likewise, was no longer needed to determine the presence of mass lesions in and around the brain. Suddenly, there was a safe technique, easily tolerated by patients and far easier for physicians to interpret. Likewise for neuropsychologists, correlations between specific behaviors and localized lesions due to strokes and other diseases no longer needed to await the demise of the patient. Such information was available immediately. CT was not, however, a direct avenue to looking at the functions of the brain. It was an anatomical tool. Function was to be the province of PET and MRI.

Positron emission tomography (PET) INSTRUMENTATION PET derives its name and its fundamental properties from a group of radionuclides (15O, 11C, 18F and 13N), whose properties include short half-lives (15O = 2 min; 13 N = 10 min; 11C = 20 min; and 18F = 110 min), a unique decay scheme, and chemical properties with relevance to studies in biology and medicine that arise from the fact that carbon, nitrogen, and oxygen are the building blocks of most biological molecules, and fluorine can be substituted for hydrogen in some molecules (for a review of PET fundamentals, see Raichle, 1983). Each of these features had caught the attention of investigators long before the introduction of CT, but the routine implementation of these cyclotronproduced isotopes in the practice of nuclear medicine was inhibited by the large infrastructure required in the form of on-site cyclotrons and specialized chemistry laboratories.

260 M.E. RAICHLE The first post-World War II cyclotron dedicated their work continued up through the introduction of exclusively to biomedical research and radiation therPET. While they did not achieve true 3D-image reconapy in nuclear medicine was authorized by the British struction using filtered backprojection, their work Medical Research Council and installed at the Hamdemonstrated the validity of the hypothesis put forth mersmith Hospital in London. A second cyclotron for by Wrenn and his colleagues (Wrenn et al., 1951). biomedical research was installed at the Mallinckrodt Alan Cormack, who was to win a Nobel Prize along Institute of Radiology of the Washington University with Godfrey Hounsfield in connection with the invenSchool of Medicine in 1965. From these important tion of X-ray CT (see above), was also aware of the beginnings in London and St. Louis, cyclotrons that potential of positron-emitting radionuclides for imawere dedicated to the production of positron-emitting ging, writing: radionuclides for biomedical research began to appear The precise determination of body attenuation for in medical centers around the world. Importantly, X-rays or its stopping power for heavy charged quantitative techniques were developed for the use of particles, positron annihilation scanning, and, to these techniques for the measurement of brain blood a lesser extent, single g ray scanning all contain flow, oxygen consumption, and blood volume. Howthe same mathematical problem, namely, to deterever, their use was restricted to patients undergoing mine a density distribution in space from its known carotid angiography for diagnostic purposes, because projections on to one or more planes. (Cormack, they had to be administered by carotid artery injection. 1973) All of that changed when PET was invented. One of the critical aspects in the emergence of PET Enter a young Assistant Professor of Radiology for quantitative in vivo autoradiography in humans recruited by Ter-Pogossian by the name of Michael E. was the unique decay scheme of positron-emitting Phelps. Before joining the Ter-Pogossian laboratory, radionuclides that produces two 511 KeV photons, leavhe had received his PhD in nuclear chemistry from ing the site of the positron-electron annihilation travelWashington University. Stimulated by the introduction ing in almost exactly opposite directions (Raichle, of CT, Phelps, through discussions with others at 1983). The importance of this decay scheme in the Washington University (namely Jerome Cox and in vivo detection of these radionuclides was recognized Donald Snyder of the School of Engineering), came early in a paper from Duke University by Frank Wrenn to understand what Alan Cormack had realized before. Jr., a neurosurgical resident doing a research elective, Namely, if an image of the density of a transverse secand his senior research colleagues (Wrenn et al., tion of the body could be reconstructed from the mea1951). They captured what was to become widely sured attenuation of highly collimated X-ray beams appreciated in the years to come in the following presprojected through the section, then the distribution of cient comment: a radionuclide within the section (especially ones that decayed by positron emission) could be accurately . . . it seemed that an additional method of deliand quantitatively reconstructed from its emissions. miting areas of concentrated radioactivity from The elements necessary for the ultimate success of within the intact skull might be possible. It is this idea were readily available to Phelps at Washington known that the 2 gamma-quanta resulting from University: positron-emitting radionuclides, with abunpositron annihilation emerge simultaneously dant experience in producing and utilizing them; and oppositely directed, with a precision of 1/ mechanical engineers and machinists, honed by years 137 radian. From a consideration of this anguof designing and machining cyclotron targetry and lar correlation, it appeared that if one were to detector systems, and who were capable of producing count these 2 gamma rays in coincidence, the an imaging device; a sophisticated algorithm with the source of activity must then lie somewhere on a people who not only developed it but could modify it straight line joining the 2 counters. In the for PET; and computers with enough power to implement absence of scattering no lead collimator should the algorithm, as well as the people to program them. be required, since the directional characteristic Armed with a modified reconstruction algorithm of the system is inherent in the radiation itself originally designed by Jerome Cox and Donald Snyder and independent of the detector. for X-ray CT, much youthful enthusiasm, and the It was Gordon Brownell and his neurosurgical colleaassistance of then postdoctoral student Edward Hoffgue William Sweet at the Massachusetts General Hosman, Phelps assembled the necessary equipment from pital who pursued this idea in depth (see Raichle, odds and ends in the laboratory and commenced col2000, for additional details). Beginning almost immelecting pilot data. Much of this work was done on diately after the paper by Wrenn and his colleagues, nights and weekends, because of the low priority it

THE ORIGINS OF FUNCTIONAL BRAIN IMAGING IN HUMANS was initially given. His resulting data converted an attitude of initial indifference within the laboratory into a galvanized, inter-departmental effort, which led to the production of the first PET camera, PETT III (TerPogossian et al., 1975; Hoffman et al., 1976). With PET, we had a tool that brought quantitative tissue autoradiography from the laboratory into the clinic. Such things as brain blood flow, blood volume, oxygen consumption, and glucose utilization, not to mention tissue pH and receptor pharmacology, could now be measured safely in humans. However, unlike the anatomical information provided by CT, these new measurements had never been a part of the clinical practice of medicine. An understanding of how to use such information in the clinical care of patients had to be developed. Pneumoencephalography and arteriography had paved the way for CT. PET had no such ancestry. An exception to the above scenario, of course, was in the area of the neural correlates of human behavior. The wonderful relationship between blood flow and neuronal activity (see Physiology), and the accuracy and simplicity of adapting autoradiographic techniques for the measurement of blood flow and glucose metabolism in laboratory animals to PET, facilitated a rapid entry of PET into this area of research. Additionally, the questions that could now be addressed in humans were immensely interesting and important. In this area, PET was not a technique in search of a question.

METABOLISM

VERSUS BLOOD FLOW

Work on the neural correlates of human behaviors with PET began with studies of brain glucose metabolism and the tracer 18F-2-fluoro-2-deoxy-D-glucose or “FDG” as it is often called. Extension of the autoradiographic deoxyglucose technique developed by Sokoloff and his colleagues (1977) for studies in laboratory animals was an obvious way to begin. Sokoloff had demonstrated the sensitivity of this technique to functional changes in neuronal activity in a wide-ranging group of animal experiments (for an excellent early summary, see Sokoloff, 1984). Early PET cameras were inherently slow in their ability to acquire data, limited in part by the inability of their sodium iodide detectors and their associated electronics to handle very high counting rates. This was not a problem with the PET adaptations of the deoxyglucose technique employing FDG. Typically, at least 30 min are allowed following tracer administration for non-metabolized FDG to clear from the brain. Because that which remains is assumed to be metabolically trapped as 18F-fluorodeoxyglucose-6-phosphate, and hence stationary within the tissue, imaging can

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proceed at a leisurely pace. The fact that 18F has a 110 min half-life also aids the imaging process. Typically, 20–40 min was used for image acquisition. Using this technique, investigators were able to provide a number of interesting demonstrations of functionally induced, regional changes in human brain glucose metabolism. While imaging functional activity in the human brain with FDG confirmed much that animal work had shown with the original deoxyglucose technique, functional brain imaging as we know it today would not have developed on the basis of this approach alone. The critical determinants became the speed of data acquisition and repeatability in the measurements of brain function. Whereas human brain function could be assessed with either blood flow or glucose metabolism, blood flow became the technique of choice with PET because it could be measured quickly ( concept of inhibitation

Willis 1664

Lieutaud 1742

Smooth muscle vessels controlled by nerves

Ernst Heinrich/ Eduard Weber 1845

Brain is machine Descartes 1630

Henle 1840

Vessel contraction by stimulation or cut of nerve endings

Humors of one organ are able to influence another

First to propose “Hypophysis” Organic nervous system (to the viscera) in the sympathetic ganglia/ animal Nervous system (NS) (to the external world) formed by education in the brain

Thyroid secretion into blood

Mohr 1840

Obesity due to hypophyseal tumor

Remak 1840

Ganglia in heart and bladder

Schiff 1856

Diencephalon lesion induces gastric perforation, blocked by vagotomy, but not by spinal section stimulation of splanchnic vessels

Bezold 1862

Motor heart center of the medulla oblongata

Schiff 1867

Counterbalance of sympathetic/ parasympathetic with effect on lesion stomach

Köhler 1886

Lesion lateral hypothalamus induces diabetes insipidus

Nothnagel 1879

Discrepancy between emotional expression and voluntary movement after lesion in diencephalon

Fig. 23.9. Time line of the scientists and their findings discussed in this chapter. (Continued)

Bechterew 1887

Bramwell 1888

Langley 1889

Ott 1891

Goltz 1892

His 1893

Diencephalon contains centers of automatic and reflectory functions of the brain, connected to emotions

Tumor in the base of the brain results in adiposogenital syndrome/lipodystrophy

Effect of stimulation of the hypothalamus, on heat production, breathing and blood vessel tone

Cajal 1909

Innervation of neurohypophysis

Blair-Bell 1909

First to mention “hypothalamus”

Probst 1898

Lesion posterior hypothalamus induces obesity

Babinski/ Fröhlich 1900

Fröhlich syndrome

Erdheim 1904

Obesity by hypophysial tumors induced by compression of hypothalamus Posterior lobe extract induces milk ejection

Dale 1906

Oxytocic effect on uterus

Herring 1908

Peculiar hyaline bodies

Posterior lobe extract has oxytocic effect Mechanical, electrical and pharmacological stimulation of the hypothalamus induces glycosuria, hypertension as well as urinary bladder and uterus contraction

Aschner 1909

Decortication leads to rage

Extract of the posterior lobe of the hypophysis leads to vasoconstriction

Fig. 23.9. Cont’d.

Stimulation of hypothalamus induces pupil reflex

Antagonism of the autonomic nervous system on heart, stomach

Howell 1898

Ott/Scott 1905

Karplus/ Kreidl 1909

Adiposogen syndrome not due to hypophysis, but due to hypothalamus

Hypophysectomized animals survive

Lichtenstern 1912

Stimulation of hypothalamus induces urinary bladder contraction

Camus/ Roussy 1913

Hypophysectomy alone does not induce obesity, only if the hypothalamus has been lesioned

Vd Velden/ Farini 1913

Posterior lobe extract has an antidiuretic effect

Isenschmid 1914

Tiber cinereum is body heat center

Speidel 1917

Concept of neurosecretion

Banting/ Best 1921

Discovery of insulin

Banting/ Best 1922

Insulin overrules effect of Bernard's brain stem lesion

Klien 1921

Lipodystrophy induced by separate trophic/atrophic centers in HYP

Starling/ Verney 1921

E Scharrer 1928

Pituitrin : ADH effect on isolated kidney

Hypothalamic neurosecretion with effect on hypophysial function

Ranson/Kabat/ Magoun 1934

Stimulation of the lateral hypothalamus with the stereotact induces pupil dilatation, hypertension and tachypnoe. Stimulation of the preoptic area of the hypothalamus leads to urinary bladder contraction, decreased heart rate and bradypnoe

Collin 1928

Droplets in hypothalamus originate in hypophysis

Wang 1928

Confirmation of Karplus by galvanic skin response

Raab 1934

Intracerebroventricular pituitin induces fatty liver, which is abolished by spinal cord section or denervation of the splanchnic nerve

Lewy 1928

Electrical stimulation of the hypothalamus with Horsley-Clarke apparatus

Houssay 1935

Toad: blood flow downward from hypothalamus to hypophysis

Bard 1928

Sham rage

Grafe 1929

Lesion posterior hypothalamus induces obesity

Cannon 1929

Sympathetic reaction in fear

Himwich 1930

Popa/ Fielding 1930

Beattie 1930

Hess 1930

Cushing 1932

Fig. 23.9. Cont’d.

Electrical stimulation of hypothalamus induces hyperglycemia

Blood upward from pituitary to hypothalamus through portal vessels Stimulation of posterior hypothalamus induces adrenergic secretion and changed heart conduction, even after adrenalectomy. Stimulation of tuber cinereum induces GE activity, increased urinary bladder tone. Conclusion: posterior hypothalamus projects to the sympathetic nervous system, the anterior hypothalamus to the parasympathetic Stimulation of conscious free-moving rats Concept of hypothalamic integration Hypophysis controls the Hypothalamus

Selye 1936

Gellhorn 1940

Scharrer/ Scharrer 1940

Adrenal induction by stress Faradic stimulation of the lateral mammilary body even after adrenalectomy induces hyperglycemia, which is diminished by vagotomy

Hypothalamic neurosecretion present throughout the animal kingdom

Bronk 1940

Hypothalamic control of cardiovascular reactions shown by sympathetic nerve discharge

Hetherington 1943

Hypothalamic obesity independent from hypophysial lesions

Heinbecker 1944

“PVN” > “Induction of obesity by lesion of the Paraventricular Nucleus of Hypothalamus”

Green/ Harris 1947

Microscope observation of flow from hypothalamus to hypophysis

Asher 1949

Neurophysin

Bargmann 1949

Gamori-positive axons from hypothalamus to posterior lobe

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 24

The coming of molecular biology and its impact on clinical neurology CHRISTOPHER U.M. SMITH * Vision Sciences, Aston University; Universities of Aston and Birmingham, Birmingham, UK

INTRODUCTION In the long history of clinical neurology the chemical study of the nervous system is comparatively recent. Thudichum is generally regarded as founding the subject in the late 19th century with the publication of his book The Chemical Constitution of the Brain (Thudichum, 1884; for a review see McIlwain, 1958). This rather recent origin has, of course, to do with the great difficulty of studying chemical processes in the brain. Biochemistry itself, although originating in the 19th century, only began to gather momentum in the early decades of the 20th. So far as molecular biology is concerned it is customary to take 1953, when Watson and Crick published their short article in Nature, to be decisive (Watson and Crick, 1953). But the impact of molecular biology on clinical neurology came later still. In this chapter the history of this impact in the last half of the 20th and very beginning of the 21st century will be reviewed (for time line see Appendix). First, one needs to be clear about what is meant by “molecular biology.” In this chapter it will refer to the study of large biological molecules, in particular the proteins and nucleic acids. Hence, this chapter will not discuss, for instance, the history of ideas about dysfunctioning amino-acid metabolism, of which the best-known case is afforded by phenylketonuria (PKU). These conditions have a genetic basis and, in many cases, are due to single gene defects that affect the proper functioning of enzymes essential to amino-acid metabolic pathways. But they fall under the heading of brain biochemistry rather than molecular biology. Nor will this chapter have anything to add about the various reflexes and syndromes that form so large a part of clinical neurology. Jendrassik’s

*

maneuver or the Babinski sign, Broca’s aphasia or the Brown–Se´quard syndrome, may well have a molecular dimension at some depth of analysis, but molecular biology has yet to have an impact on understanding these conditions or their treatment. In contrast, a number of diseases well known to clinical neurologists do have an increasingly understood molecular basis. In general (but not always) these conditions have strong genetic components. They are thus open to investigation via the classical molecular biological paradigm involving the transfer of information (in this case defective information) between DNA and protein.

ORIGINS OF MOLECULAR MEDICINE AND MOLECULAR NEUROSCIENCE Although, as noted above, the origins of molecular biology can be traced back far into the past, it only came of age in the 1950s and, most importantly, at the Unit for Molecular Biology established by the Medical Research Council, Cambridge, UK, in 1947. It was here, in 1957, that Vernon Ingram earned the title of “Father of Molecular Medicine” by showing that the cause of sickle cell anemia was a single amino-acid substitution in the b-chains of hemoglobin (Ingram, 1957). Ingram showed that at position 6 on hemoglobin’s b-chains valine was present rather than the normal glutamine. Later the “point mutation” on the b-globin gene on chromosome 11 was detected. It was shown that in sickle cell anemia adenine is substituted by thymine in codon 6 of the gene, thus encoding the “wrong” amino acid. This substitution, a seemingly tiny alteration, generates a hydrophobic region in the molecule which, in sticking to a similar hydrophobic region in

Correspondence to: C.U.M. Smith, Vision Sciences, Aston University, Birmingham B4 7ET, UK. E-mail: [email protected], Tel: +44-121-454-1443, Fax: +44-121-204-4048.

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an adjacent hemoglobin molecule, causes a molecular clumping within the red blood cell. This, in turn, leads to the sickling deformation of the cell, which is easily observed under a microscope. Individuals homozygous for the mutation suffer from chronic anemia and periodic pain because the abnormally shaped cells cannot squeeze through small capillaries. Sickle cell anemia, together with a number of other blood diseases caused by defective hemoglobin, has thus been traced to its molecular root. It is interesting to note that in the latter part of his career Ingram turned to molecular neuroscience and ended by investigating the molecular roots of Alzheimer’s disease. If Vernon Ingram can be called the “Father of Molecular Medicine” who, if anyone, should be called the “Father of Molecular Neuroscience?” There is no straightforward answer to this question. In a previous paper I discussed the role of physicists in the origins of molecular neurobiology (Smith, 2005) and it is certainly the case that, after the great influx of physicists into biology in the 1950s, many turned their attention to what seemed the ultimate prize, the brain and then the mind. They used the techniques and mental approach that had proved so successful in originating molecular biology to tackle what seemed to many of them this ultimate problem. However, if any single person can take credit for originating molecular neuroscience it has to be Francis O. Schmitt. Indeed he is credited with introducing the term “neuroscience” itself. In the 1920s Schmitt forsook his intended path toward a career in medicine in favor of working for a PhD with Joseph Erlanger at Washington University in St. Louis, and thus became associated with a group of pioneering neurophysiologists using a wide variety of physical techniques: X-ray diffraction, polarization optics, electrophysiological recording etc. This interest in interdisciplinarity, especially in the application of physical and biochemical techniques to solve biological problems, stayed with Schmitt for the rest of his life. His interdisciplinary convictions led him to gather a group of scientists from many different backgrounds and disciplines to form the “Intensive Study Program in Biophysics” at MIT. The outcome of this initiative was published in 1959 by John Wiley as the highly influential monograph Biophysical Science: A Study Program (Schmitt et al., 1959). A few years later Schmitt used a similar procedure to create the discipline of neuroscience. Scientists from a wide variety of different disciplines met to create the four Neurosciences Research Programs (1965, 1970, 1973, 1978). These were crucial in establishing neuroscience and molecular neuroscience as disciplines (Quarton et al., 1967; Schmitt and Worden, 1974, 1979). Francis Schmitt could see connections where

others only saw disciplinary and technical barriers. It has been said that discussions with him were like taking a drinking cup to a fire hydrant! Schmitt’s early interest in the biophysics of the nerve impulse and the nature of biomembranes forms one of the starting points of molecular neurobiology and its application to clinical neurology. A large number of neurological diseases are, at root, due to defective membranes. Molecular abnormality at this level multiplies up through the levels of biological complexity, just as did the single base alteration in sickle cell anemia, to produce major malfunctions of the entire organism. This, as will be shown, is the case with the numerous channelopathies known nowadays, and with the similarly numerous gap-junction deficiencies. In order to understand these neurological conditions, and to effect cures, it is first necessary to understand their roots in molecular abnormalities.

BIOMEMBRANES The understanding of biomembranes has come a long way since James Robertson worked on his unit membrane model in Schmitt’s MIT laboratory (Robertson, 1960, 1966). This model, developed from earlier ideas due to Davson and Danielli (1943), suggested that biomembranes consisted of a bilayer of phospholipid molecules (plus a few cholesterols and other lipids) with protein molecules electrostatically attached to the charged phosphate groups of the phospholipids. This concept seemed to fit the electron-microscopical observations, where osmium-stained biomembranes appear as two dark lines separated by a translucent area. Sjo¨strand (1967) suggested that the dark lines were due to the osmium electron-stain binding preferentially to the phosopholipid phosphates and charged amino-acid side chains. The problem with these lipid bilayer models is that they make biomembranes seem merely passive structures, merely containers for the hive of activity within. This, however, is not how things are. Biomembranes are extremely active structures. Somehow water-soluble ions and other substances flow through these hydrophobic barriers. This is particularly the case with the membranes of neurons. The Hodgkin/Huxley/Katz theory of the action potential and Eccles’ theory of postsynaptic potentials (the EPSPs and IPSPs) depend on the precise and controlled movements of hydrophilic ions into and out of the neuron. In spite of various suggestions, the way in which this could occur remained a mystery until, first, a new electron microscope technique and, second, more advanced molecular biological and biophysical methods came to the rescue.

THE COMING OF MOLECULAR BIOLOGY AND ITS IMPACT ON CLINICAL NEUROLOGY 363 The new electron microscope technique, freezep. 12). In this case the special organisms, electric fish fracture etching, developed by Steere (1957) and such as Gymnotus, the electric eel, and Torpedo, the Moore et al. (1961), enabled a far more detailed examelectric ray, had fascinated and been studied by experiination of biomembranes to be undertaken. It gave rise mental natural philosophers, including John Walsh, John to the fluid-mosaic model (Singer and Nicholson, Hunter, Jan Ingenhousz, Henry Cavendish, and even 1972), which showed proteins embedded in the lipid Luigi Galvani two centuries earlier. Indeed, they had bilayer, not restricted to the inner and/or outer surbeen crucial to some of the major breakthroughs in faces. It was no difficult step to recognize that it was 18th century neurophysiology (see Piccolino, 2007, these proteins that gave biomembranes their vital propCh. 9). It is noteworthy that they have once again played erties. But how could these proteins be analyzed and a crucial role, this time in the molecular breakthroughs understood? Membrane biophysicists looked enviously of the 1970s. at the precise techniques of the protein crystallographers. The detailed and revealing structures of Pauling ANALYSIS OF MEMBRANE PROTEINS and Corey’s b-pleated sheets and a-helices (1951a, b), In 1937 Nachmansohn visited the World Fair in Paris Kendrew et al.’s myoglobin (1958), Perutz et al.’s and saw for the first time living specimens of Torpedo hemoglobin (1960) etc. had all been elucidated by crystalmarmorata. When the Fair had finished, he obtained a lographic techniques. But all of these structural trifew fish and assessed their electric organs for acetylumphs depended on an initial delicate crystallization of cholinesterase (AChE). He was “astonished” to find the protein from an aqueous solution. The non-aqueous that the AChE activity of their electric organs was nature of the membrane in which neurobiological pro“prodigious” (Nachmansohn, 1972). Each electric organ teins were embedded made this initial step difficult if consists of a stack of electric cells, or electrocytes, and not impossible. each electrocyte is covered on one of its surfaces by Progress toward understanding the detailed struchuge numbers of nicotinic cholinergic nerve endings. ture and thus function (function at this level depends They thus form extremely rich sources of AChE. on structure) of membrane proteins seemed to have Where there is AChE there is ACh, and where there reached an impasse. Nevertheless, work in other areas is ACh there are bound to be membrane-embedded of molecular biology proceeded apace. In the 1960s acetylcholine receptors, in this case nicotinic acetylchoNirenberg, Ochoa, Crick and others worked out the line receptors (nAChRs). Indeed, electron-microscopy genetic code. The biochemistry of transcription and of electrocyte membranes shows them to be covered with translation was unraveled. Recombinant DNA technolrow upon row of nAChRs (see Hirokawa et al., 1983). ogy was mastered and various cloning techniques During the late 1970s and early 1980s, a large group invented. The ways in which the primary structure of of investigators in Japan was able to isolate and purify proteins, that is their amino-acid sequence, folded to milligram quantities of receptors from this source – sufgive higher structures – the b-pleated sheets, the ficient to allow biochemical analysis. Chromatography a-helices, the TIM barrels etc. – began to be undershowed each receptor to consist of four subunits – stood. It became possible, given a nucleotide sequence, a, b, g, and d – in order of increasing molecular weight. to predict not only the primary structure of the protein Next, small amino-acid sequences from each subunit for which it was the code, but also the probable way in were determined and then, using oligonucleotide probes which, in physiological conditions, it wound itself up to deduced from these sequences, the nAChR gene form secondary, tertiary and higher structures. Comwas isolated, cloned, and its nucleotide sequence deterputer analysis of electron microscope images also mined. Once this had been done, application of the began to provide information about the 3-dimensional genetic “code book” enabled the amino-acid sequence conformation of channel proteins (see Brisson and (primary structure) of the receptor subunits to be Unwin, 1985). Finally the patch-clamp technique for deduced (Noda et al., 1982, 1983). studying the biophysical characteristics of single chanIt remained to identify hydrophobic regions in these nels was invented by Neher and Sakmann (1976). amino-acid sequences. These are likely to be memBy the mid-1970s it was possible to return to the probbrane-spanning regions. It is usually the case that these lem of membrane proteins with a fresh armamentarhydrophobic sequences take the form of a-helices with ium of techniques and approaches. As is so often the hydrophobic residues projecting outward into the memcase in the biological sciences, advance also depended brane’s lipophilic interior. It turned out that in each of on finding and using the right organism. As Nachmanthe subunits the amino-acid sequence had four hydrosohn says, quoting August Krogh, “Nature has created phobic sequences separated by runs of hydrophilic quite a few animals with the special purpose to help residues. In consequence it was initially thought that biologists solve their problems” (Nachmansohn, 1972,

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each subunit possessed four membrane-spanning a-helices (Fig. 24.1A). More recently, evidence has accumulated suggesting that there is only one membranespanning a-helix and that the other three transmembrane segments take the form of b-strands. The complete nACh receptor consists of five of these subunits – 2a, 1b, 1g, and 1d subunits (Fig. 24.1B and C). The nAChR is only the first of many ligand-activated ion channels to have their molecular structure “run into the ground.” Other ligand-controlled channels include GABAA receptors (GABAARs), glycine receptors (GlyRs), ionotropic glutamate receptors (iGluRs), purinoreceptors, to name just a few. Most of these channels are themselves members of large families.

Over 400 ligand-gated ion channel subunits are listed on the ion-channel website. Detailed analyses of these receptors have revealed their biophysical and biochemical characteristics. Site-directed mutation and other techniques have allowed these characteristics, especially the characteristics of their channels, to be altered at will. In addition to ligand-gated channels, nerve cell membranes contain other equally important types of neurotransmitter receptor. These are the G-proteincoupled receptors and include muscarinic acetylcholine receptors (mAChRs), adrenergic receptors (ARs), metabotropic glutamate receptors (mGluRs), neurokinin receptors (NKRs), canabinoid receptors (CBRs) and

A B

C Fig. 24.1. (A) Disposition of the a-subunit in a biomembrane. The first 210 residues are located in the extracellular space. The four transmembrane segments are symbolized by dark cylinders. Glycosylation occurs at residue 141 and phosophorylation between the positions marked P on the second intracellular loop. The binding site for acetylcholine is close to residue 192. (From Smith, 2002, with permission.) (B) Plan view of the complete receptor. The pentameric structure (2a, 1b, 1g, 1d) viewed from above. The second transmembrane segment of each subunit takes the form of an a-helix and forms the lining of the central pore. (From Smith, 2002, with permission.) (C) Side view of complete receptor. The five subunits are labeled and the ligand (ACh) or neurotoxin binding sites indicated. (From Stroud, 1981, with permission.)

THE COMING OF MOLECULAR BIOLOGY AND ITS IMPACT ON CLINICAL NEUROLOGY many others. The receptors specialized to detect visible photons, the rod and cone opsins of the retina, are also included in this category. In the mid-1980s the first of these ubiquitous receptors, the b2-adrenergic receptor, was sequenced and its molecular anatomy established (Dixon et al., 1986). It was shown that its polypeptide chain makes seven passes through the membrane. In this it resembled the opsins of prokaryotic and eukaryotic photoreceptors. After the structure of the b2-adrenergic receptor had been solved, the structures of a large number of other G-protein-coupled receptors were determined. It turned out that they all share a common feature. In every case the polypeptide chain, like that of the b2-adrenergic receptor, makes seven passes through the membrane. They are thus often known as the seven-transmembrane (7TM) or “serpentine” receptors. Defects in their complex “collision-coupling” G-protein biochemistry are associated with a number of pathologies. Mutations of the cognate opsin 7TM receptor of rod and cone cells are implicated in retinitis pigmentosa. However, the truly definitive channels of nerve cell and striated muscle fiber membranes are those which are controlled by transmembrane voltage. These include the Na+ and K+ channels responsible for action

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potentials and also the Ca2+ and Cl
channels which are fundamental to synaptic transmission. Molecular biologists, using variants of the techniques described above for working out the structure of the nAChR, and many other techniques, have now a good understanding of the structure of all of these mostly multimeric proteins (for detailed accounts see Ashcroft, 2000; Smith, 2002). The first to have its molecular structure elucidated was the Na+-channel. The large Japanese group that had solved the structure of the nAChR applied similar recombinant techniques to sequence the a-subunit (the major subunit) of the Na+-channel harvested from Electrophorus electroplax (Noda et al., 1984). They revealed a huge protein of some 1820 amino acids containing four homologous zones of about 300 amino acids each (Fig. 24.2). With the rapid growth in knowledge of genomes it has become possible to search gene libraries for sequences similar to those already known to code for channel proteins. In very recent years molecular biologists using this technique discovered a sequence coding for a potassium channel in a gram-positive soil bacterium: Streptomyces lividans. This bacterium can be engineered to over-express this gene and, because it is possible to culture large quantities of the bacterium,

Fig. 24.2. Disposition of the Na+-channel subunits in a membrane. The a-subunit is by far the largest of the subunits and consists of four homologous domains each of which has six transmembrane segments. The b1 and b2 subunits make only one pass through the membrane and have an immunoglobulin-like extracellular domain. M indicates the modulation loop (by phosophorylation) and I indicates the inactivation sequence. a- and b-ScTx indicate where scorpiotoxins attach. (From Smith, 2002, with permission.)

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sufficient channel protein can be harvested to allow crystallization and “traditional” X-ray diffraction. MacKinnon and coworkers succeeded in “picturing” this potassium channel (the KcsA channel) at 3.2 ˚ resolution (Doyle et al., 1998) and then at 2 A ˚ resoA lution (Zhou et al., 2001). These 3-dimensional images, which even show a line of K+ ions passing through the pore, not only complete the 50-year search for a channel-protein equivalent of Perutz’ hemoglobin, but also help greatly in understanding the detail of voltage-gated channels in general. The multidisciplinary nature of contemporary molecular neurobiology (sometimes many dozen names author a paper; in the case of the Huntington gene well over 50 names working in Boston, London, California, Michigan and Cardiff) shows it to be a true descendant of Francis Schmitt’s vision of half a century ago.

THE CHANNELOPATHIES But if we have a neurobiological equivalent of hemoglobin, do we yet have a neurobiological equivalent of Ingram’s molecular medicine – his running of the devastating condition of sickle cell anemia into the molecular ground? The answer to this question is in the affirmative. A large number of neurological conditions are nowadays known to be due to mutations of genes that code for membrane channel proteins. These so-called channelopathies mainly affect the sarcolemmas of muscle fibers rather than neurolemmas of nerve cells. This, of course, does not make them any less interesting to the neurologist. Some of the best-researched channelopathies involve the Na+ channels in the sarcolemmas of striated muscle. The most well known of these are due to mutations on the SCN4A gene which encodes the a-subunit of the Na+ channel. These mutations fall into three groups. Members of the first group affect one of the transmembrane segments of the protein, members of the second group affect the inactivation loop between domains III and IV, whilst members of the third group affect the inactivation sequence at the cytoplasmic end of the molecule (see Fig. 24.2). All of these mutations are single nucleotide substitutions leading to single amino-acid changes. The most common mutations belong to the third group. They slow the rate at which the Na+ channel is inactivated thus allowing a persisting inward current of Na+ ions. The muscle membrane is thus depolarized for longer than usual and this, in turn, causes various types of periodic paralysis. The best known of these paralyses is hereditary hyperkalemic periodic paralysis (HyperKPP) which is characterized by muscle hyperexcitability and delayed relaxation. Other mutations

belonging to this group cause paramyotonia congenita (PC) and a diverse group of disorders known as potassium-aggravated myotonias (PAMs). Other mutations affect other channel proteins. Episodic ataxia (EA1), characterized by imbalance and vertigo usually accompanied by nausea and headache, and Anderson’s syndrome, a rare condition showing periodic muscle paralysis, cardiac arrhythmia and abnormal growth, are caused by mutations of one of the K+ channel genes. Mutations of one of the 10 Ca2+-channel genes (CACNA1A) leads to a group of conditions including familial hemiplegic migraine (FHM), mainly a childhood disorder, type 2 episodic ataxia (EA2) and spinocerebellar ataxia, type 6 (SCA6). Mutation of another Ca2+-channel gene (CACNL1A3) is associated with hypokalemic periodic paralysis (HypoPP). In this condition patients suffer skeletal muscle weakness when serum K+ is low. The disease is inherited as an autosomal dominant and may be triggered by carbohydrate-rich meals, strenuous exercise etc. Finally, turning to the large family of Cl
channel genes, it has been shown that a G ! A transition at position 689 on the ClCN-1 gene leads to the substitution of Glu for Gly at position 180 in sarcolemmal chloride-channel proteins. This reduces their Cl
conductance and causes congenital myotonia (Thomsen’s disease), characterized by muscle stiffness after prolonged rest. At least four other point-mutations on the ClCN-1 gene are now known to cause congenital myotonias. Voltage-gated channels are, of course, not the only type of channel subject to mutational alteration. Mutations affecting ligand-gated channels also multiply up through the complexities of the nervous system to generate neurological disorders. For instance, a single nucleotide change on the gene coding for the a-subunit of the nAChR causes an amino-acid substitution in the subunit’s pore-lining domain. This leads to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), a rare condition showing clustered epileptic episodes during sleep. Another example is provided by a GABAA receptor (GABAAR) gene. A deletion on chromosome 15 leads to the loss of the gene coding for the b3-subunit of the GABAAR. This leads to a condition known as Angelman Syndrome (AS). The condition is quite severe. Symptoms include not only craniofacial abnormalities but also severe mental retardation accompanied by puppet-like ataxic movements. It is clear that the molecular approach to neurology at the least allows the causes of a number of neurological disorders to be understood at a fundamental level. Although the prospects of effective therapy for these conditions still seem remote, just as they still do for sickle cell anemia (unless genetic therapies can be

THE COMING OF MOLECULAR BIOLOGY AND ITS IMPACT ON CLINICAL NEUROLOGY 367 devised), knowing the cause at least prevents misdiagnosis A G ! A transition in the gene coding for Cx26 and inappropriate prescription. Exhaustive accounts of leads to a defective connexin being incorporated in cells ion channels and their pathologies may be found at of the stria vascularis, basement membrane, limbus and http://www.neuro.wustl.edu/neuromuscular/mother/chan. spiral prominence of the cochlea. The resulting disruphtml and in the four volumes of The Ion Channel Facts tion of the physiology of the organ of Corti causes deafBook (Conley and Brammar, 1996–1999). ness. Another, and quite different, cause of profound deafness is due to mutation of a gene coding for MinK, a b-subunit of a K+ channel also located in stria vascuGAP-JUNCTION PATHOLOGIES laris. This disrupts the electrolyte balance in the cochlea Before leaving the neuropathologies caused by disturin much the same way as mutated Cx26 and, again, bances of biomembranes and their constituents, someinactivates the organ of Corti. thing must be added about the neurological conditions Several mutations of genes coding for Cx50 and caused by defective gap-junctions. These junctions were Cx46 affect gap-junctions between lens fibers. This first discovered in the central nervous systems of crayleads to patchy, dust-like, opacities in the lens, a condifish where they function as electrical synapses (Furshpan tion known as pulverulant cataract. and Potter, 1957). They have since been found in a wide A number of mutations of the gene coding for Cx32 variety of tissues and organisms, including mammalian lead to the rather rare condition known as type 2 Charbrain. They have been shown to consist of proteins cot-Marie-Tooth disease (CMT2). In this condition neuknown as connexins, which develop in the membranes rons in the anterior horn of the gray matter and in the of both adposed cells. posterior root ganglia are lost. It is believed that Cx32 is When isolated, connexins can be shown to vary in expressed in the uncompacted myelin near nodes of Ranmolecular weight from 26 kDa to 50 kDa and this has vier and Schmidt–Lauterman incisions. The gap-junctions been used to provide a nomenclature – Cx26, Cx50 etc. in these positions normally allow communication between Six connexins are arranged to form a cylinder adposed Schwann cell cytoplasm and the spaces between the to another hexagonal cylinder in the opposing cell. Each uncompacted myelin whorls. Disruption of this channel hexagonal cylinder is called a connexon and contains a of communication has disastrous consequences for the hydrophilic pore. Gap-junctions usually consist of large Schwann cell and the myelin it forms and thus, eventually, clusters of connexons and thus provide a way of transferaxonal degeneration and neuron loss. The symptoms vary ring hydrophilic metabolites of a molecular weight of up from mild to severe and in the latter case the patient may to 1.5 kDa from one cell to the next and also a low resisbe confined to a wheelchair. tance pathway for electrical signaling. Finally, because gap-junctions function as communiThe first connexins to have their primary structure cation channels between cells, they have been suspected analyzed were from the liver (Paul, 1986). The technique of being involved in cortical spreading depression, assoemployed was similar to that described above for the ciated with migraine (Reilly, 2002), and its opposite, analysis of nAChRs. From a purified preparation of cortical spreading hyperexcitability (epilepsy). This susliver gap-junctions a 19 amino-acid sequence was deterpicion has been supported by finding that some forms mined and a matching oligonucleotide probe syntheof epilepsy are associated with increased expression sized. This was then used to screen a library of liver of Cx43 (Fonseca et al., 2002) in cerebral glial cells, cDNA. It hybridized with a cDNA of 1494 base pairs. whilst inactivation of the connexin has the opposite The coding sequence of this cDNA was shown to speeffect, being associated with cortical spreading deprescify a polypeptide of 283 amino acids. When this sion (Theis et al., 2003). sequence was scanned for hydropathic segments, it So far in this chapter we have been reviewing the neuwas found that it resembled the subunits of ligand-gated rological disorders caused by defective cell membranes channels in possessing four such regions. Each connexin and, in particular, the protein constituents of those memthus has four membrane-spanning a-helices or b-strands branes. These are, of course, far from the only neurolike the subunits of nAChRs (see Fig. 24.1A). pathologies caused by malfunctions at the molecular At least 15 connexin genes have been identified in level. It is, however, arguable that they provide the most mammals and mutations are now known to cause a clear-cut instances of the cause-and-effect sequence from number of neuropathologies. These include some molecule to neurological symptom. In many of the other, forms of genetic deafness, some forms of cataract, often better known, neurological conditions the line of and type 2 Charcot-Marie-Tooth disease (CMT2). causation between molecular defect and neuropathology Connexin mutations are also associated with cortical is highly complex and still subject to dispute. In the next spreading depression (CSD) (hypoexcitability) and sections of this chapter some of the better known of these epilepsy (spreading hyperexcitability). conditions will be examined.

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TRINUCLEOTIDE REPEAT EXPANSION DISEASES (TREDS) There are now believed to be over a dozen neurological disorders due to trinucleotide repeat expansions. These include Fragile X syndrome (FRaX), Huntington’s disease (HD), Friedrich’s ataxia, spinobulbar muscular atrophy and myotonic dystrophy. TREDs, as their name suggests, have their root in faulty DNA replication. When the two strands of the “maternal” DNA fall apart and new “daughter” strands are synthesized alongside, extra nucleotide triplets, sometimes many hundreds, are inserted. The first neurological condition to be traced to this molecular defect was Fragile X syndrome (Kremer et al., 1991). In this condition, which develops in one in every 2000 males and one in every 4000 females, the first exon of the FRM1 gene, located on the long arm of the Xchromosome, contains a CGG repeat. In normal individuals the repeat number is 29; in fully affected individuals the repeat number is over 200 and may be up to 600 and even 1000. The protein encoded by the FRM1 gene, known as FRMP, is widely expressed, not only in the brain, but also in other parts of the body, especially the testicles, where macro-orchidism is often found. Both males and females also suffer connective tissue problems and the neurological symptoms include low intelligence and often autism. How lack of FRMP causes this widespread disorder is as yet not known in detail. As mentioned above, the lines of cause and effect run through the mazes of cellular biochemistry. There is some evidence, however, that FRMP is involved in the regulation of protein synthesis and it may be involved in the maturation of synapses. But why should a stuttering increase in the number of CGG triplets affect transcription of the FRM1 gene? It appears that when the number of repeats exceeds about 230 the cytosines start to become methylated and soon every cytosine in the entire sequence acquires a methyl group. Ultimately this invades a regulatory site near the FMR1 gene and prevents transcription. One final point of interest to note in FRaX (and in other TREDs) is that age of onset diminishes and severity increases with each generation. This is due to the CGG repeat number increasing with each replication event. Huntington’s Disease (HD) or Chorea is one of a group of disorders of the basal ganglia, especially the corpus striatum, which lead to rapid, jerky, involuntary movements. Earlier victims of the condition were probably classified as suffering from “St. Vitus’ dance,” a term covering a variety of movement disorders. Indeed the term “chorea” is derived from a Greek root meaning “dance,” so these disorders have been known for millennia. HD affects 5–10 people in every 100 000 and is inherited as an autosomal dominant. The disease

typically starts in a small way as, perhaps, a facial twitch but gradually develops to include the whole body, including hallucinations, memory disorders and mood swings, so that the sufferer’s life becomes intolerable and is only relieved by death, some 15 years after the first symptoms appear. In the early 1980s molecular biological techniques involving the analysis of restriction fragment length polymorphisms (RFLPs) of a patient’s DNA allowed Gusella and coworkers (1983) to map the offending gene to the short arm of chromosome 4. Further analysis, using some of the more recent molecular biological techniques, allowed a large group of investigators to home in on the gene itself (HDCRG, 1993). The gene was named HD and was shown to encode a protein designated huntingtin. Once again the exact role this protein plays is somewhat obscure. It is not confined to striatal cells, or even the brain, but is widely distributed throughout the anatomy. However, evidence is beginning to suggest that it is involved in the regulation of transcription and that one of the transcriptional systems it affects in the brain is that for neurotransmitter receptors. It may also be involved in axonal transport and membrane recycling. Once again the lines of cause and effect lead into the mazes of neurobiochemistry. However, returning to the topic of TREDs, it has been shown that, like the FraX FRM1 gene, HD is subject to trinucleotide repeats. In this case the trinucleotide is CAG. In normal individuals the repeat number is 11–34 (median 19) whilst HD patients show 37–86 repeats (median 45). Once again the number of repeats increases and the age of onset decreases, especially with males, in each generation. The fact that the effect is seen most strongly in the male line suggests that the insertion of extra CAGs occurs mostly during spermatogenesis. Finally, it is interesting to note that experiments with transgenic mice showing neurological symptoms that closely mimic human HD have provided evidence that enriched sensory environments can delay the onset of the disease (Van Dellen et al., 2000). If such findings can be replicated in humans it may be that occupational therapy can play a role in at least delaying the onset of the disease in humans.

PRIONS AND PRION DISEASES The prion diseases that have attracted so much attention in recent years – Creutzfeldt–Jacob disease (CJD), variant Creutzfeldt–Jacob disease (vCJD), Gerstmann–Stra¨ussler–Scheinker syndrome (GSS), Kuru, fatal familial insomnia (FFI) etc. and a number of animal conditions, Bovine Spongiform Encephalopathy (BSE), Scrapie etc. – are believed to be due to protein misfolding. Prusiner, who had believed for many years that these diseases were

THE COMING OF MOLECULAR BIOLOGY AND ITS IMPACT ON CLINICAL NEUROLOGY 369 caused by a “slow virus,” eventually showed that no understood. Other neuropathologies, such as bipolar nucleic acid is involved but that the neurodegenerations disorder (where the Old Order Amish population has are caused by something quite outwith orthodox molecuprovided an invaluable case study [Law et al., 1992; lar biology – replicative proteins – which he named Ginns et al., 1996]), neurofibromatosis type 1 (von Reck“proteinaceous infectious particles” or “prions” for short linghausen’s disease) and type 2 and the various forms of (Prusiner, 1982). motor neuron disease (MNDs), have all had their genetics Normal prion protein (PrPC) appears to be a common analyzed and suspect genes identified. However, limitaconstituent of cell membranes. However, when the gene tions of space preclude tracing the history of attempts encoding this protein, named PRNP, mutates (and up to to understand the molecular bases of these debilitating 20 different mutations have been identified) an abnormal conditions through the last 50 years. prion protein (PrPSc) is synthesized. Three-stranded bsheets replace regions where a-helical segments would CONCLUDING REMARKS normally occur. To cut a long story very short, this new This account of the history of molecular approaches to the conformation has, very unusually for a protein, self-repliproblems encountered in clinical neurology is obviously catory ability. PrPSc spreads throughout the brain and causes the spongiform degeneration, plaques and reactive little more than a brief, selective summary. The literature gliosis characteristic of the disease, leading to progressive is now huge, as is shown, for instance, by the ion-channel loss of neural function and eventually death. website cited at the end of the section on channelopathies. Once again it can be seen that a fundamental underThe subject advances on many fronts, like an incoming standing of these terrible neuropathologies depends on tide sweeping up an uneven beach. deep insight into molecular biology, in this case Nevertheless, some general features can be seen. the molecular biology of proteins and the different First, perhaps, that the days when papers were published 3-dimensional conformations they can assume. under the name of a single author (as was the case with Vernon Ingram’s ground-breaking paper) or even two (as was the case with Watson and Crick’s 1953 paper) OTHER NEUROPATHOLOGIES are mostly now long gone. Several of the papers listed The coming of molecular biology has also thrown light on in the references are authored by well over a dozen the etiology of many other neurological disorders. names, and the sequencing of genomes is usually done Myasthenia gravis, for instance, finds an explanation at by international consortia, in the case of the yeast genthe molecular level. As early as 1973 Patrick and Lindome by over 100 laboratories (see Appendix: Time line). strom had realized that the condition is an autoimmune This reflects the enormous technical complexity of condisease involving the nicotinic-acetylcholine receptor at temporary molecular biology. Biology has gone from a neuromuscular junctions. It was, however, only in the small to a big science in a generation. early 1990s that the offending region of the nAChR was Second, a review of the 50 years since Watson and found (Tzartos et al., 1991). It has been called the main Crick’s epochal paper shows that there was a considerimmunogenic region (MIR) and is constituted by residues able lag before the molecular approach could be 44–59 and 66–79 of the a-subunit. For some, as yet applied to neuroscience (see Appendix: Time line). It unknown, reason antibodies are synthesized against this was not until the late 1970s and early 1980s that techniregion. As the nAChRs are progressively destroyed, ques became available to understand the molecular transmission between nerve and muscle is affected and physiology of nerve and muscle membranes. Once muscular activity becomes progressively weaker. these techniques had been developed, progress became Myasthenia gravis is far from the only autoimmune almost exponential. The molecular roots of numerous disease to which the neuromuscular system is subject. neurological conditions soon became apparent. Another well-known instance is provided by multiple Third, just at the end of this 50-year period, the era of sclerosis (MS). Here the body’s antibodies attack one genomics began. The first Genome Mapping and Sequenof the most important proteins holding the spiral cing Meeting was held at Cold Spring Harbor in 1988 and whorls of myelin together (myelin basic protein by 2000 the genomes of 31 Eubacteria, 7 Archaea, 1 fun[MBP]) and the resultant disruption, in affecting gus, 3 animals and 1 plant had been completely sequenced. impulse transmission in myelinated fibers, is responsiIn 2001 the first draft of the human genome was pubble for the disabling symptoms of the condition. lished and in 2003, to mark the Watson/Crick anniversary, Molecular biology has also thrown much light on the final 99.99% accurate draft became available. Already two well-known neurodegenerations of old age – Parthis has proved invaluable for tracing the genes responsikinson’s and Alzheimer’s disease – although all the ble for many neuropathologies. The OMIM (Online Mencomplexities at the molecular level have yet to be delian Inheritance in Man) website lists 163 genes

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responsible for neurodegenerations, 353 for different forms and variants of epilepsy, 207 for depression, 132 for schizophrenia etc. Furthermore, it has been shown that many of these genes have their counterparts in the genomes of Drosophila and even the tiny nematode worm, Caenorhabditis elegans. Genomics constitutes the gathering of a second wave of advance fully comparable to that which characterized the 1980s. The onrush of molecular biological approaches to neuroscience shows no sign of slackening. Although the torrent of detail pouring from the laboratories (see The Ion Channel Facts Book mentioned earlier) sometimes threatens to overwhelm the non-specialist, it is nevertheless possible to hope for ultimate clarification. When the full causative chain (from gene to protein to cell to organism to symptom) has finally been elucidated a more accurate classification of neurological disorders (and hence diagnosis and therapy) will become possible. A case in point is provided by the Charcot-Marie-Tooth (CMT) neuropathies (see Ho¨rst et al., 2006). Although the symptoms of Type 1 and Type 2 CMTs are not greatly dissimilar – a slowly progressive symmetrical weakness of the upper and then lower limbs – the causes are different. Whilst Type 1 CMT is caused by an autosomal dominant mutation affecting a 22 kDa peripheral myelin protein (PMP22) and/or myelin protein P0 (MPZ), Type 2 CMT is often X-linked and affects, as we noted above, connexin 32 (Cx32) on Schwann cell membranes. Similar remarks might be made about the two dissimilar causes of profound deafness, which were outlined in the section on gap-junction pathologies. Molecular biological analysis allows the disentangling of symptomatically very similar disorders and thus (hopefully) the design of more rational therapies. The design of these therapies is, nevertheless, still largely a hope for the future. From the historical viewpoint this is no new thing. Joseph Needham points out that although great advances in understanding human physiology (including neurophysiology) were made in the 19th century, their application to medical practice hardly occurred before the 20th (Needham, 2004, p. 36). In a similar way, the fundamental molecular biology worked out in the 20th century may have to await the middle of the 21st to find its application in neurology. However, if, as Francis Bacon said long ago, “knowledge is power,” it can surely be predicted that this new knowledge will ultimately be harnessed to cure or at least help ameliorate the human suffering seen in the neurological ward and clinic.

to help understand the many ills known to clinical neurologists. This understanding begins to accumulate toward the bottom of the time line and (hopefully) will inform therapies on into the 21st century. 1951 Protein secondary structures. Pauling and Corey 1953 DNA. Watson and Crick 1957 Molecular medicine (HbS). Ingram 1957 Crayfish electrical synapse. Furshpan 1957 Freeze-fracture-etch. EM. Steere 1958 Tertiary structure of myoglobin. Kendrew et al. 1959 Biophysical Science. Schmitt 1960 Tertiary structure of hemoglobin. Perutz et al. 1960 “Unit membrane”. Robertson 1965 Genetic code. Nirenberg et al. 1965 Neuroscience Research Program. Schmitt 1976 Patch-clamp technique. Neher and Sakmann 1982 Structure of first ligand-gated channel (nAChR). Noda et al. 1982 Prions. Prusiner 1983 Huntington’s disease marker. Gusella et al. 1984 Structure of first voltage-gated channel (Na+ channel). Noda et al. 1986 Structure of first G-protein-coupled receptor (b2-adrenergic). Dixon et al. 1986 Gap-junction structure. Paul 1987 Structure of first K+-channel (Drosophila shaker). Papazian et al. 1987 Structure of first Ca2+-channel. Tanabe et al. 1988 First Genome Mapping and Sequencing Meeting. Cold Spring Harbor 1990 Structure of first Cl
-channel. Jentsch et al. 1991 FRaX trinucleotide repeat. Kremer et al. 1992 Linkage analysis of bipolar disorder. Law et al. 1993 Huntington gene (HD). Huntington’s Disease Collaborative Research Group (HDCRG) 1996 First eukaryotic genome (yeast). Goffeau et al. 1998 First metazoan genome (Caenorhabditis elegans). Sanger Institute/Washington University School of Medicine (SI/WUSM) ˚ ). 1998 First X-ray analysis of K+-channel (3.2 A Doyle et al. 2000 Drosophila genome. Howard Hughes Medical Institute; Celera Genomics Corporation (HHMI/Celera) 2000 First draft human genome. International Human Genome Sequencing Consortium/Celera Genomics Corporation (IHGSC/Celera) ˚ ). Zhou et al. 2001 X-ray analysis of K+-channel (2 A 2003 Final draft human genome. IHGSC

APPENDIX: TIME LINE

HDRC, Huntington’s disease Collaborative Research Group; HHMI/Celera, Howard Hughes Medical Institute/Celera Genomics Corporation; IHGSC, International Human Genome Sequencing Consortiun/Celera Genomics Corporation; SI/WUSM, Sanger Institute/Washington University School of Medicine.

This chronology gives some of the significant “milestones” in the history of molecular biology as it applies to neuroscience and neurology. The fundamental science had to be established before it could be applied

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 25

Headache: an historical outline GIORGIO ZANCHIN * Headache Center, Department of Neuroscience, and Pinali’s Library Ancient Section, University of Padua Medical School, Padua, Italy

AT THE ORIGINS Between mythology and magicaltheurgic-empirical attitudes Disease and pain have accompanied humanity since its origins and, undoubtedly, there is no suffering experience more widespread than headache. Its emotional participation is particularly intense due to the peculiar features of head pain, so totally involving and yet intimately perceived and elusively subjective. For these reasons, an historical outline of this fascinating chapter of medicine reflects, perhaps more than for other illnesses, beliefs, conceptions, knowledge, and cultural and social backgrounds of different epochs. It involves widespread experience, both geographically, and, as we are going to see now, chronologically. On the level of remote literary traditions, a reference to migraine is suggested as early as the myth of Athena’s birth from the head of Zeus. Metis, the Titaness, being courted by Zeus, attempts to escape by assuming very different forms. Taken, she remains pregnant. The oracle predicts the birth of a daughter, but should one day Metis become pregnant a second time, she will bear a son who will oust Zeus from power. Worried, the king of the gods hypocritically welcomes Metis to his bed, and swallows her. Struck by a terrible headache, he is freed from it thanks to the help of Hephaestus, god of fire, who with a blow from an axe splits Zeus’s head in half, from which Athena appears, fully dressed in a suit of armor complete with lance and spiked shield (Lucianus, 1743). For the physician, this description contains evident elements that suggest a migraine attack. The intensity of the headache; the “heroic” nature of the therapeutic intervention (the blow of a battle-axe); the division of the head into two halves, a possible reference to the *

unilaterality of migraine pain; the powers of therapist Hephaestus, god of fire, perhaps a reference to vegetative accompanying symptoms; the goddess’s rather unique clothing for a newborn, likely an implicit reference to the heavy and piercing character of the pain; and finally the triggering factor: overeating, a whole Titaness indeed! But let us now summarize some historical aspects. At the origins of medicine is the instinct of selfprotection and conservation, common among other animals. Two main components were parts of the early story of medical knowledge, the magical-theurgic and the empirical, for the most part in reciprocal connection, as we can recognize, for example, in cranial trepanation, practiced even by prehistoric man (Arnott et al., 2003, see Chapter 1). The first attempts date back to the Mesolithic age, around 10 000 BC, but the operation became widespread in Europe, Asia and in pre-Incaic Peru between 3000 BC and 2000 BC. Many of the skulls treated with trepanation show signs of reparative bone growth and therefore document the survival of the patient. It is not possible to establish the motivation behind the operation: among the varied hypotheses, the origin could be the primitive empiric observation of an improvement of clinical conditions after lifting the fragments of a depressed cranial fracture; the use could then be extended, by analogy, to other ailments, such as head pain; or yet again, the overlapping of a transposition in a religious sense could have ritualized the act, performed to release the demons causing the disease. Thus, the motives for craniotomy have been explained based on opposite interpretations, some favoring the empiric, and others the magical, a debate that puts us in front of a continuous intertwining, and a reciprocal influence, of the various

Correspondence to: Dr. Giorgio Zanchin, Associate Professor of Neurology, Department of Neuroscience, Padua University. Via Giustiniani, 5, Padova, I-35128, Italy. E-mail: [email protected], Tel: +39-49-821-3626, Fax: +39-49-875-1770.

376 G. ZANCHIN methods with which man has sought to protect himself body is sick or healthy. It is sick when there is from suffering. too much or too little of one of these elements, Another pertinent example is given by the therapy or if one has become separated in the body and suggested in an Egyptian sacral prescription of about not mixed with the others. (Zanchin, 1992) 1000 BC: “The physician shall take a crocodile made Hippocrates (c. 460–370 BC) gives vivid descriptions of clay, with an eye of faience, and with sacred grain of strong pain affecting the head. Unexpectedly, howin its mouth; he shall strap it to the head of the sufferer ever, among the rich harvest of careful and original with a strip of fine linen upon which are the name of clinical observations, which the “Corpus Hippocratithe gods; and he shall pray” (Edmeads, 1988). This is cum” contains, we cannot find any clear reference to another demonstration of how an empirical experience, migraine, or to other primary headaches, but the foli.e., the alleviating action of compression and cold lowing description, that has been interpreted as a possigiven by the ceramic artifact, was interpreted in a relible reference to migraine with aura (Pearce, 1986): gious dimension, as the effect of the holy animal, the crocodile, and of the help of the deity. . . . To Phoenician seemed to see something shining before him like a light, usually in the right eye; after a while, a violent pain superGREEK-ROMAN CIVILIZATION vened in the right temple, then in all the head Clinical approach and headache and neck . . . ; when he tried to move the head classification or to open the mouth, he suffered like he was feeling a strong contraction. Vomiting, when it The magical-theurgic heritage, with all of its relational became possible, was able to divert the pain implications, and the empirically acquired one are both and render it more moderate . . . (Littre´, 1861) recognizable in the great civilizations of the past; and they blended typically in the therapeutic procedures of the In most cases, headache appears to be a symptom of sanctuaries devoted to Asklepios, the asklepieions. an organic underlying disease, and therefore of secIf the search for a protection from headache, as for ondary origin. Interestingly, the relevance of emotions other illnesses, began in an instinctive-empiric dimenis fully understood, since when the attack is related to sion, mixed with a magical-ritualistic and religious an irritated or depressed mood, Hippocrates suggests one, only the advent of classical Greek civilization treating the soul first. saw the beginning of a lay-rational approach. That Headache should have been a widespread experience path, continued until modern times, has brought cliniamong ancient Romans, since the encyclopedist Plinius cal and therapeutic progress that today allows us to (23–79 AD) in his Naturalis Historia, by no means a help cephalalgic patients in an effective, evidencespecialized medical work, gives a kind of topographical based manner. classification of the aches of the head: capitis dolores A descendant of a family of doctor-priests of Aescu(pain of the entire head) and capitis dolores fervoresque lapius, according to tradition, Hippocrates of Kos in the (accompanied by sense of warmth); temporum dolores 5th century BC embedded this empiric heritage, passed (localized to the temples); cervicis dolores (when the down in these temples, into the first system of rational nape is involved). Capitis dolores veteres, chronic headmedicine. The Hippocratic doctrine presents as a fundaache, is listed too (Plinius, 1982). mental element the interpretation of disease as a natural The contemporary Aulus Cornelius Celsus (1st cenevent, without sacred interventions, and as a general tury AD) devoted Chapter 2 of the 4th book of his phenomenon of the organism. We read in this quotation De medicina to the headache: the birth certificate of rational medicine: Sometimes in the head an acute, unbearable About the disease which is called sacred [epileppain, may supervene, called “Kefalaia” sia] this is the truth. It does not at all appear to [Cephalaia] by Greeks. This pain comes along me that this disease is more divine or sacred a series of dangerous symptoms, from vomiting than other illness, but it has a natural structure to faintness . . . to alienation of mind and loss of and rational causes. (Zanchin, 1992) speech. In other instances the head may be affected by a long weakness of the head, but Its pathophysiology was based on the doctrine of the neither severe nor dangerous, through the whole four humors of man’s body, the blood, yellow bile, life. Sometimes the pain is more violent, but black bile, and phlegm: short, yet not fatal; which is brought about The human body itself contains blood, phlegm, either by drinking wine, or indigestion, or cold, yellow bile and black bile; because of these the or heat of a fire, or because of the sun. And all

HEADACHE: AN HISTORICAL OUTLINE of these pains are sometimes accompanied with a fever, and sometimes not; sometimes they affect the whole head, at other times a part of it. (Celsus, 1960) As therapeutic measures, purging, bloodletting, diet, and applications of warm or cold water, are recommended. He reports that some patients get relief from tightening a rope around the head, or compressing it with a pillow. As an extreme measure, cauterization can be adopted. In the 2nd century AD, Aretaeus the Cappadocian (Koehler and van de Wiel, 2001) in his De causis et notis diuturnorum affectuum first gave order to headache nomenclature, proposing this classification: “Cephalalgia,” episodic, moderate; “Cephalea,” chronic, severe; “Eterocrania,” located in half of the head. If an individual has a sudden headache attack following an unimportant cause of brief duration, this affection is called with the Greek terminology “Cephalalgia,” even if the crisis is prolonged for more days. But, if the disturbance is of lasting duration, for long, often recurrent periods, and if, in time, the head pain becomes more intense and unbearable showing resistance to treatment, then the Greek term is “Cephalea” . . . The pain affects sometimes the entire head, other times it localises on the right, other times on the left or on the forehead . . . and at times the attacks change site during the same day . . . The specific name of this affection is “Eterocrania,” an illness by no means mild, even though it intermits, and although it appears to be slight . . . it sets in acutely, it occasions unseemly and dreadful symptoms . . . nausea; vomiting of bilious matters, collapse of the patient, but, if the affect be protracted, the patient will die; or if more light and not deadly, it becomes chronic; there is a great deal of listlessness, heaviness of the head, anxiety and weariness: [the patients] escape the light, darkness alleviates their suffering: . . . their sense of smell is vitiated. (Aretaeus, 1581) Therefore Aretaeus gives the first almost complete clinical description of a migrainous attack; however, the deadly outcome he considers leads us to guess that the term “eterocrania” most probably includes onesided secondary headaches as well. As far as therapeutic measures are concerned, there are many similarities with those suggested by Celsus, such as bleeding, purging, and cauterization. Galen (c. 129–199 AD), the great organizer of classical medical knowledge, integrated the humoral theory in his complex physiopathological construction, passing it down for centuries to come. He treats the headaches in De locis affectibus and De medicamentorum compo-

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sitione secundum locos (Ku¨hn, 1965). He called today’s migraine “hemicrania,” a synonym which prevailed in Aretaeus’ “eterocrania,” and described it as: “ . . . a painful disorder affecting approximately one half of the head, either the right or the left side, and which extends along the length of the longitudinal suture” (Ku¨hn, 1965). Migraine is due to the irritation of the brain by an excessive humoral amount of yellow bile; this is prevented from flowing through the whole brain by the falx, hence it characteristically affects only one half of the head. Consequently, on the therapeutic side Galen continues to indicate the measures, such as purgatives and diaphoretics, which are considered suitable to eliminate the offending humor. He recommends also rest, silence, darkness, diet and avoidance of wine. In the same period, therapies are suggested that clearly show their popular origin. In his Liber medicinalis, Quintus Serenus Sammonicus (2nd century AD) writes: During acute pain that affects part of the head, garlic wrapped in wool, and in the same way, the balms introduced in the ear on the opposite side, or massage with three garlic cloves and three grains of pepper minced together: this treatment will surely contribute to recovery. (Celsus and Sammonicus, 1750) Magic-ritual elements are evidently present, such as the number three and the introduction of the healing preparation on the opposite site of pain location (Zanchin, 2004). Caelius Aurelianus (c. 5th century AD) holds that . . . often the headaches are caused by cold, sun, sleep deprivation. Curiously, women are affected more often because they insist too much on hair washing and combing. (Caelius Aurelianus, 1567) Humoral interpretation prevailed for centuries; as a consequence, the remedies had to eliminate the “guilty” humor, as suggested by the Byzantine Alexander Trallianus (523–605) in the 6th century AD: If therefore headache frequently arises on account of superfluity of bilious humour, the cure of it must be effected by means of remedies which purge and draw away the bilious humour. (Sacks, 1985) Another theory was based on “sympathy,” that is a connection not anatomically defined, called “sympatheia” by Greeks and “consensus” by Romans, between peripheral organs, mostly the uterus, and intestine, stomach (Sacks, 1985), and the head (“mirum inter caput et viscera commercium,” the remarkable influence

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between the viscera and the head). The pain could originate in some instances from ascending vapors. This theory would have a reappraisal in the 18th century, but involving peripheral nerves.

MEDIEVAL MEDICINE AND HEADACHE The Salernitan Medical School, which flourished mostly from the 10th to the 12th century, follows traditional Hippocratic–Galenic humoral theory. It keeps migraine distinct from other headaches, which are also considered. Indeed, migraine remains nosographically apart in respect of other forms of headache, even during these centuries: in Fig. 25.1 we see an illuminated iconography of a migraine sufferer, from a medieval manuscript of the Pseudo-Apuleius, one of the late classical works on “materia medica” (i.e., pharmacology). In comparison with the setting of other cases, described as “ad capitis dolorem” (indicated for the ache of the head), in this scene with the indication “ad imicraniam” (for migraine), we see a visibly incapacitated patient, lying down in bed, assisted by two women, one using a fan to refresh him, the other putting a presumably wet handkerchief on his forehead. This peculiar assistance and the herb prescribed, the opium-containing “papaver silvaticum” (wild poppy – for the other cases, lighter remedies such as valerian and anetus are suggested), underlines the distinction made by the anonymous illuminator between migraine and a more generic, milder headache. An interesting character of that period is the nun Hildegard von Bingen (1098–1170), who deals with head-

Fig. 25.1. This illuminated scene, with the indication papaver silvaticum and ad imicraniam, comes from the PseudoApuleius, a late classical work mainly on the medical use of plants, reproduced in the Codex Vindobonensis 93, written around the first half of the 12th century. The intensity and the accompanying symptoms of a migraine attack are well represented. From Codex Vindobonensis 93, p. 65, verso. Facsimile vol. XXVII. Reproduced courtesy of Akademische Druck, u. Verlagsanstalt, Graz, Austria, 1972.

aches in her work Causae et curae. In her opinion, migraine is a chronic condition, difficult to heal and mainly due to black bile. The explanation of the unilaterality of its attacks is really curious in its teleologism: “[Migraine] is so strong to become unbearable, should it involve the whole head ” (von Bingen, 1903). Another humor that can cause headache is the phlegm which, when present in exceeding amounts, accumulates in the head and, shaking the vessels, makes the front painful. Hildegard is known also for her visions, which have been hypothesized as possibly being complex, visual migraine auras. Many aspects of classical medical culture, including humoral theory, were acquired by Muslims after their conquest extended to large portions of the Byzantine Empire. Rhazes (c. 864–935) thinks that the headache is due to the accumulation of yellow bile in the gut. The surgeon Albucasis (936–1013) advocates invasive therapeutic measures, such as the sectioning of the artery of the temple, or cauterization, in keeping with the Medieval Arabic tradition. Indeed, cauterization is very effective in order to eliminate “the excess of wetness and coldness of the brain, which causes headache” (Penso, 1991). Avicenna (980–1037), who with his treatise Canon made Galenic theories very influential in the Arabic world, maintains that headache comes from an excess of phlegm and/or black bile affecting the brain, and can be caused by diseases of other organs or of the whole body, such as fevers. The stomach is very relevant and causes a headache that is usually located in the frontal region. He distinguishes also forms that can be more sensitive to smell and light, and even triggered by these stimuli. But noxious vapors may originate in the brain, too. As a general consideration, besides migraine, for many centuries there was only a broad division between dangerous and not dangerous headaches; only in recent times were the symptomatic forms accurately separated from the primary forms and, among the latter group, a further distinction was made among different essential headaches. This explains the difficulty in recognizing the various types of headache in the ancient texts.

THE RENAISSANCE Reappraisal of the traditional Galenic system, new view and original observations With the return of interest in the study of nature, the Renaissance was able to rapidly enrich clinical knowledge, also with respect to new observations on headache. Charles Le Pois (1563–1633), who considered

HEADACHE: AN HISTORICAL OUTLINE 379 migraine to be an intracranial disorder, was the first to THE 18TH CENTURY give a clear report of the aura, with a clinical descripEmphasis on the neurovegetative system, tion of what he calls “hemicraniae insultus”: a paron working conditions, and on domestic esthesia of one hand and arm, diffusing like a breeze therapy during the enlightenment and resembling crawling ants: During the 18th century a modern theory of “sympa. . . the patient felt dizzy and a little while later thy,” now mediated by peripheral nerves, was supported numbness in the little finger of the left hand, like and developed by Samuel Tissot (1728–1797). He extena sensation and movement of wandering antsr sively writes on headache in his Traité des Nerfs (Tissot, (which started from the same finger and spread 1768–1770): to the whole arm and advanced in the same way of a shiver), and immediately afterwards it it can no longer be doubted that most migraines spread to the ring finger, to the middle finger are the consequence of an irritating cause within in succession, and likewise then a sort of the stomach that acts on the nerve branches, hindrance presented itself in the whole which are distributed to the anterior and lateral arm. (Le Pois, 1733). region of the head. Only later Johann Jakob Wepfer (1620–1695) described a case with visual aura. He also gave the first report of migrainous stroke and of basilar migraine (Isler, 1985). This period saw the development of new but also of older theories, often connected with the Hippocratic–Galenic view: mainly that involving the cerebral circulation and that of “sympathy,” which, as already stated, identified the origin of migraine in a peripheral disturbance, in turn affecting the brain. The first two chapters of Thomas Willis’ De Anima Brutorum (1694) treat the headache (De Cephalalgia). The role of brain vessels was considered by Willis, who linked intracranial vasoconstriction with following dilatation, anticipating in part the vascular theories to be developed in the 19th century. That of “sympathy” was also one of Willis’ different pathophysiologic theories: “Headache attacks may originate per consensum from other organs, such as from uterus, spleen, stomach . . .” It attained a strong influence in the following century thanks to the emphasis, put in general in that period, on the role of the vegetative nervous system in the development of diseases. Among the more determined supporters of this view was Tissot. Brain vessels and vegetative nervous system roles were, in a sense, integrated in the theories to be developed in the 19th century by Du Bois-Reymond, Mo¨llendorf, Eulenburg, and Latham, among others. Among the remedies, Willis suggested the use of Tanacetum parthenium (feverfew) and of the recently introduced coffee, which are considered useful even today. He is also quoted for possibly one of the earliest descriptions of cluster headache: . . . it is common for the attacks to increase around equinoxes and solstices, often in “subordinate periods,” they usually infest at certain fixed hours within the space of every day and night. (Willis, 1694)

On the therapeutic side, he is pretty convinced that on migraine, almost only the drugs are effective, which act favourably on the condition of the stomach. (Tissot, 1768–1770) He also takes into consideration a type of headache characterized by a pain similar to a nail (“clou”), related to psychic conditions; these forms probably correspond to tension-type headache. Tissot, with his book Avis au Peuple sur la Santé (1761) initiated a series of public education manuals. In line with the ideals of the Enlightenment, the aim was to satisfy the needs of people who had no opportunity of consulting a physician by providing them with significant information about the symptoms and treatments of the most common diseases, including headache (Maggioni et al., 1998). A typical character of the Enlightenment is Bernardino Ramazzini (1633–1714), who demonstrated a great interest in the causes and prevention of headache. The second, larger and final edition (1713) of his most important work De Morbis Artificum Diatriba (A dissertation on the diseases of workers) (see Ramazzini, 1742), which marks the birth of modern occupational medicine, reports headache as work-related in 12 of 69 activities described (Zanchin et al., 1996). His remarks on headache are typical of his way of collecting first-hand experience of working conditions, and they underline the importance of occupational hazards in the assessment of headache. Not only is this disturbance listed as a symptom, but the author always endeavors to give causal explanation and also often adds preventative suggestions. For instance, he writes that among the pharmacists, carpenters, brewers, tobacco workers and oil producers, the headache is a consequence of the inhalation of particularly intense and/or bad odors or toxic substances. Among the confectioners, there is that “pestiferous force,” which is caused by working for

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hours in front of burning coals, and which is identified as gas sylvestre (today’s carbon dioxide). In the headaches that afflict desk workers and stenographers, the cause is found in long hours of intense attention; we would define this as a tension-type headache. Possible etiopathogenic factors are given also for other professional categories: wet-nurses (“exhaustion,” insufficient sleep); clerks, menders (“intense and incessant attention”); footmen, singers (blood plethora in the brain); hunters, sailors (temperature fluctuations); wine producers, brewers (an excess of animal spirits). Very specific is Ramazzini’s interest in the role of smells, as when he deals with the professional diseases of the pharmacists: In spring when they prepare infusions of roses for golden syrups, and when the whole shop smells of the rose beds of Paestum, I have heard some complain of severe headache, others of diarrhea. (Ramazzini, 1742) Such attention can be due to personal reasons: indeed from what he reports about his own experience with irritating, unbearable odors when visiting grimy shops, Ramazzini seems to have been a migraineur himself, for whom bad smells could have had a triggering role in attacks: There are also many other work-shops that are a plague for the noses . . . Whenever I set foot in this kind of place I should say I suffered from an upsetting of my stomach that was far from mild, and I could not stand the depraved smell for long without a headache and some retching. (Ramazzini, 1742)

OLD AND NEW DRUGS FOR HEADACHE From traditional to spagyric remedies Migraine therapy has seen many different approaches. Since antiquity many plants, animal extracts and minerals have been utilized to treat headaches. We will now examine a few of the most representative texts of pharmacopoeia of the 17th–18th centuries, in light of the therapies proposed for treating headaches, although it is not easy to establish a correspondence between the various forms of headache listed and those of modern classification; in particular it is often difficult to distinguish migrainous and tension-type forms. Let us begin with the Nuovo et Universale Theatro Farmaceutico (1667) by Antonio De Sgobbis, prior of art and owner of the pharmacy with the insignia “To the ostrich” in Venice. This work is an exhaustive encyclopedia of pharmaceutical knowledge of its time: “. . .based on the pharmaceutical preparations written

Fig. 25.2. Original lead individual dispensers of Venetian theriaca (17th century). On the cover, the seal has been struck of the authorized pharmacy ( farmacia teriacante). Personal collection.

by Greek and Arab physicians of antiquity, principally by Galen and Mesue” (De Sgobbis, 1667). A specialty of De Sgobbis was the “theriaca of Andromaco the Elder, according to Galen,” a remedy remaining in use until the middle of the 1800s (Fig. 25.2). It was a multidrug composed of more than 60 vegetal, animal, and mineral ingredients. The principal component that distinguished it from another important electuary, the mithridate, was the presence of viper meat in its composition. Among its other virtues and medical indications, the theriaca was also used for “aches of the head.” Of its several components, those possessing probable pharmaceutical activity in this sense were mainly opium, then valerian, aristolochia, agaric and cretic dittany. First published in 1641 at Ulm, the Pharmacopoeia Medico-Chymica is another fundamental work of the 17th century. The author, the physician Johann Schro¨der, born in Westphalia, was also chief surgeon in the Swedish Army. In the 1681 edition, we find listed under the heading “cephalic” various plants (e.g., verbena, valerian, cinnamon, nigella, aloe) and animals (e. g., sheep, pigeon, hen, upupa, crab and, curiously enough, stork feces). In addition “ileal pills of Rasis” are proposed which “relieve aches of the head and migraine” and contain colocynth, sagapenum, scammony, leek juice; and a “priestly salt,” composed of common salt, pepper, cinnamon, zedoary, ginger, and cumin seeds, which “dolorem capitis medetur” (alleviate the pain of the head) (Schro¨der, 1681). The following century brought the Pharmaceuticalchemical Lexicon (first published in 1728), a very fortunate work that was in current use even in the first decades of the 1800s. The author Giovanbattista Capello familiarizes

HEADACHE: AN HISTORICAL OUTLINE 381 us with a large number of drugs against headache. of older beliefs in favor of the chemical theories of LavoiMultidrug formulas also predominate in this work, sier; and on the other side by the refinement of technology, however, with distinct emphasis upon chemical prewhich permited the isolation of the active ingredients of parations, documenting the definitive acceptance of substances. Then in the middle of the 1800s the race for spagyric drugs, which are a pharmacopoeia of mineral the synthesis of drugs non-existent in nature erupted, prinsubstances, promoted since the 16th century mainly by cipally by German chemists who produced a series of new Paracelsus: “Lunar bezoar” (a concretion found in the molecules, among which were many with analgesic stomach of ruminants composed mainly of ingested properties. hair), containing “butter” of antimony and silver, “desIn 1804 in Einbeck, Hanover, the pharmacist Sertu¨rtined by druggists for aches of the head, believing that ner discovered morphine. In 1820 Runge identified cafthe moon offered striking protection through this comfeine, while the preparation of potassium bromide pound ”; “diaphoretic mercury” composed of gold and (1826) was attributed to Balard, a pharmacist at Montmercury “useful as a remedy for migraine”; “the pills of pellier. In 1843 Gerhardt prepared acetanilid from which Silvius,” composed of storax, licorice juice, incense, phenacetin was derived in 1887 by Kast and Hinsberg. In myrrh, opium, crocus, and poppy syrup, that “calm the 1882 sodium salicylate and the benzoate of caffeine and aches of any part”; “the volatile aromatic salt,” composed sodium were introduced. The field of analgesic antipyreof ammoniac salt, calcined tartrate, and lavender oil, tics was one of the most fruitful sectors of the rich pro“profitable in the lethargic conditions and aches of duction of synthetic drugs characterizing the end of the the head”; “distilled lemon balm” (another Venetian 19th century. We remember antipyrine and pyrazolone, specialty), that “dispels headache” (Capello, 1797). synthesized respectively by Knorr in 1883 and by Stolz What was the efficacy of these drugs in the optic of in 1896. The same period saw the synthesis of one of current knowledge? For many of these substances, more the most successful remedies, acetylsalicylic acid or ingredients than drugs, therapeutic utility seems to be aspirin, which appeared in 1899 as the substitute for nil. It is probable that their success was founded on sodium salicylate. In 1903 Fisher and Mehring prepared the placebo effect, which even today constitutes an ever veronal, the precursor of a series of diethylbarbituric present problem in the evaluation of the effectiveness, derivatives, which a few years later found application being able to influence, in some instance with a weight in anticephalgic preparations like Starkenstein’s veraof about 40%, the results obtained with anticephalgic mon, which associates veronal with pyramidone. In condrugs; even more so for complex and costly comcluding this concise review, we remember the 1918 pounds, like the theriaca, which was prepared with a isolation by Stoll of ergotamine in pure chemical form, suggestive ritual and the guarantee of public authority. more than 50 years after the introduction of ergot deriAlongside this aspect, for some preparations, a synergic vatives as antimigraine agents. But we will deal further action among the various components possessing modand more specifically on this, given the relevance of est therapeutic activity alone cannot be excluded; or an ergot to the study of migraine. indirect action, favoring the absorption of other compoTo possess a vision of how new synthetic anticenents, an hypothesis developed, for example, for viper phalgic drugs were, already at the end of the century, meat contained in the theriaca (Fig. 25.2). Nonetheless, included in the clinical outlines, it is useful to linger there remains a group of substances whose pharmacolobriefly upon the paragraph on migraine therapy in the gical activity is recognized even today. These can be disManual of Diseases of the Nervous System, published tinguished in two categories: the first includes drugs by Gowers (1888), where a series of analgesics of with vasoactive properties, like caffeine. Among the recent introduction are cited, including antipyrine, second, characterized by analgesic-sedative properties, acetanilid, and phenacetin. we can list hellebore, valerian, and opium (and the therTo summarize the development of pharmaceutical iaca, of which opium appears to be the major active knowledge briefly, it can be said that from the assercomponent); and again mandrake which, like belladonna tion in the 1600s of the spagyric pharmacopoeia, which and henbane, contains the hyoscyamine, scopolamine, assumes an ever increasing predominant role aside the and atropine alkaloids. older remedies of the Galenic–Arab tradition, we pass to the second half of the 1700s to the acceptance of THE 19TH CENTURY the new chemical theories, elaborated principally by Lavoisier. In a short time the new conceptual frame The advancements of pharmacology permitted, for the first time, the isolation in pure form By the end of the 1700s a progressive and unrelenting of different substances equipped with therapeutic properevolution of pharmaceutical knowledge was witnessed, ties and, most importantly, in the second half of the 1800s which now was supported on one side by the abandonment the chemical synthesis of drugs not present in nature.

382 G. ZANCHIN Referring to the specific theme of the evolution of the shared, among others, by Hughlings Jackson and pharmacopoeia for headache, in parallel with the historiGowers. Liveing explains the migraine attack as a cal journey of pharmacology, to remedies of prevalent recurrent vegetal origin (e.g., poppy, mandrake, valerian, opium), accumulation and discharge of nerve force . . . and, to a lesser extent, of animal origin in correspondence [due to] . . . a morbid disposition: There is another to the classical tradition, are added in the course of the point of view, . . . from which megrim and other 1600–1700s the first protochemical and then chemical paroxysmal nervous affections of the same class preparations. These culminated in the course of the 19th may be regarded: it is that which considers them century with the isolation of active ingredients (such as in the light of Nerve-storms . . . On this theory, then caffeine and morphine); and later with the laboratory the fundamental cause . . . is to be found, not in any preparation of synthetic molecules among which are irritation of the visceral or cutaneous periphery, many present analgesic and antipyretic properties. nor in any disorders of irregularity of circulation,

Conflicting vasogenic versus neurogenic, “nerve storm,” theories The second half of the 19th century saw a lengthy debate on migraine pathogenesis. A pioneer of electrophysiology, Du Bois-Reymond, considered the attack as consequent to an irritation of the sympathetic nervous system, causing angiospasm. This view was influenced also by his personal experience as a migraineur, since during his crises he became pale. In the same years, Mo¨llendorf, instead, supported the opposite view, seeing migraine as a cerebral angioparalysis, consequent to a transitory defect of the sympathetic system, since he observed that the face of many patients became red. Other authors, such as Eulenburg and Latham, tried to integrate the two mechanisms. This position was supported by the efficacy of parentheral ergot derivatives, interpreted as the result of the drug-induced vasoconstriction counteracting the vasodilatation due to angioparalysis. The use of ergot in different forms became widespread. So, in the Italian Pharmacopoeia of 1880, Morelli writes that “the ergots snuffed like tobacco are recommended for migraine.” Ruata in the National Pharmacopoeia of 1883 indicates ergot as “warmly recommended for migraine in general.” Ergotin in migraine attack is also suggested, although with less enthusiasm, by Gowers, who attributes its efficacy, judged partial, to the capacity of the drug of calming the pulsating intensity of the pain. Another view on migraine pathogenesis was Liveing’s theory of “nerve storm.” Putting emphasis on the analogy between migraine and epilepsy advanced by Sieveking 15 years before, Edward Liveing (1832– 1919) proposed an original concept, that of migraine as a cerebral disorder, fully structured in his treatise On Megrim, Sick Headache and Some Allied Disorders (1873), which contains also the first printed iconography of the migraine visual aura in its development (Fig. 25.3). Migraine is considered to be “primarily nervous” and any modification on the cerebral vessels is a consequence of nervous discharge. This view was

but in a primary and often hereditary vice of morbid disposition of the nervous system itself; this consists in a tendency on the part of the nervous system centres to the irregular accumulation and discharges of nerve force. The immediate antecedent of an attack is a condition of unstable equilibrium and gradually accumulating tension in the parts of the nervous system immediately concerned, while the paroxysm itself may be linked to a storm, by which this condition is dispersed and equilibrium for the time restored. (Liveing, 1873) On the therapeutic side, he is convinced that there are measures, general and specific, which can relieve this condition. He deems very relevant the treatment of megrim by measures directed to the improvement of the general health, or the correction of faulty hygienic conditions since the greater number of patients who seek for medical advice are those with whom it has been first awakened, or greatly aggravated, by failing health from other causes, or some injurious habits of life. (Liveing, 1873) Among the drugs recommended as preventative are tonics and sedatives, in particular belladonna and jusquiam. During the attack, any effort or movement is to be avoided along with sensorial stimuli; bed-rest can be very effective. A curious suggestion is to drink a dose of brandy, at the very beginning of the attack. Other useful remedies are bromides, coffee, tea, and caffeine containing guarana´. Liveing considers useful the action of the emetics, since vomiting may stop the attacks. Good results, although short-lived, can be expected from the inhalation of chloroform, too. As we have said, among the supporters of Liveing’s “nerve storm” theory was Sir William Gowers, professor at London University College. In his classic Manual of Diseases of the Nervous System he treats migraine

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Fig. 25.3. This colored lithography, taken from Dr. Hubert Airy’s paper “On a distinct form of transient hemiopsia” (1870), is reported in Edward Liveing’s On Megrim, Sick Headache and Some Allied Disorders (Churchill, London, 1873), the first comprehensive treatise devoted to migraine. This picture is the first printed representation of a visual aura, in this case on the left side (sinistral teichopsia), in its progressive development.

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extensively. He prefers the “nerve storm” theory of Liveing to Du Bois-Reymond’s vasospasm theory, which gives a clue also to the connection between migraine and epilepsy. He points out the importance of avoiding the favorable causes of migraine, and gives particular regard to the regularity of meals, sleep, and lifestyle: If any error in mode of life, or defect in general health can be traced, the removal of this is the first and most essential step in treatment . . . Of special importance are increased rest, regularity in meals, attention to diet; whatever is known to induce a paroxysm should be carefully avoided. (Gowers, 1888) With a modern approach he clearly distinguishes the “intermediate treatment,” equivalent in this day to prophylactic therapy, and the “treatment of the attack.” For the prophylaxis he indicates bromide; or if “facial redness” is associated, a combination of bromide and ergot. In cases in which there is “conspicuous pallor,” nitroglycerine is recommended, but its use is contraindicated during the painful crisis. In the course of the attack, the suggested remedies are mainly sedatives: bromide, possibly associated with tincture of Indian hemp, valerian, chloral, or even morphine. As already mentioned, a number of recently synthesized analgesics are listed. Noticeably, caution is given on their repeated use, which could determine reduction of effectiveness. Instead, a fashionable approach of that time, electrotherapy, is deemed useless: Faradaism usually does harm. The voltaic current passed through the head occasionally gives transient, but rarely permanent relief. After migraine, Gowers takes into consideration other headaches, which patients describe as a “sense of pressure,” caused by “brain-work.” The suggested cure is psychological: The only method of treatment that is effective is to make the patient realise the unimportant nature of the sensations, and try to neglect them by directing his attention to other subjects. Thus, we can easily see that the clinical-therapeutical differences between migraine and tension-type headache are already well delineated. As a general consideration, it can be noticed that from the classic theories involving the patient as a whole, such as with the humoral and sympathy doctrines, we have moved to more restricted, organ-based, hypotheses, such as the vascular and “nerve storm” views.

THE 20TH CENTURY Alternative profile This period sees fundamental developments in the headache field up to contemporary advancements. The principal domains are nosography, physiopathology, and therapy. Furthermore, in the second part of the century, headache scientific societies are established and specialized journals published. We will try to give just a brief outline of the vast amount of information on this subject. As far as physiopathology is concerned, during the first half of the century the emphasis was on vascular research, also fueled by the isolation by Stoll in 1919 of pure ergotamine. In 1928 Trautmann, in one of the first controlled pharmacological trials, demonstrated it to be more effective than placebo. In 1937 Graham and Wolff, measuring the pulse amplitude over the temporal artery, showed that ergotamine relieved the pain of migraine thanks to its vasoconstrictive action on dilated cranial vessels (Graham and Wolff, 1938). In the 1960s, in Florence (Sicuteri et al., 1961) and in Sydney (Curran et al., 1965), the role of serotonin became evident: migraine appeared to be a biochemical syndrome caused by the depletion of this neurotransmitter. Indeed, its administration is able to interrupt the attack. But this therapeutical measure appeared unsuitable, mainly because of its short-lived action. In the following years, the discovery of a series of serotonin receptors allowed the first serotonin-like molecule to be successfully synthesized, a specific agonist later called sumatriptan (Humphrey et al., 1989). A new class of drugs, the triptans, very effective for acute treatment, has since become available, replacing ergot derivatives, which act unspecifically on many receptors, causing a number of adverse events. In the early 1980s, pioneering studies with Xenon133 on regional cerebral blood flow resulted in favor of neurogenic theory (Olesen et al., 1981). During the development of visual aura, starting from the occipital pole, a short hyperemia takes place, followed by a decrease of blood flow. Since this phenomenon trespassed the areas of distribution of the blood vessels and traversed the cortex forward at a speed of 2–3 mm/min, it appeared far from being caused by a vessel spasm and similarly, instead, to the neurogenic cortical spreading depression, described in the animal by Leao in the forties (Leao, 1944). Further supports to neurogenic theory came in those years from the finding of Lance, showing that the stimulation of the locus coeruleus could cause blood flow alterations similar to those observed during a migraine attack. A relevant contribution to a better understanding of migraine pathophysiology and of the pharmacologic

HEADACHE: AN HISTORICAL OUTLINE action of the tryptans has been given by studies of the trigemino-vascular system (Moskowitz, 1992). More recently, innovative technologies like magnetoencephalography, functional magnetic resonance and positron emission tomography, have shown the probable origin, not only of migraine from brainstem (Weiller et al., 1995), but also of other primary headaches from specific brain sites, such as the hypothalamus in the case of cluster headache (May et al., 1998). Considering nosography, a series of modern classifications have been used in the last 50 years, from that of the Ad Hoc Committee (1962), based mainly on physiopathology, to the first international classification of headache disorders (ICHD, 1988), which has been recently updated (ICHD-II, 2004). The extreme usefulness of sharing a common nosographic terminology is demonstrated by the possibility of introducing improvements, modifications and scientifically documented new entities, such as chronic migraine, hypnic headache, and new daily persistent headache, which have been included in the ICHD-II. Finally, diffusion of knowledge in the headache field has seen the publication of journals devoted to this discipline, such as Headache (1961), organ of the American Association of Headache; Cephalalgia (1980), journal of the International Headache Society; and the Journal of Headache and Pain, founded in 2000 as the organ of the Italian Society for the Study of Headache and since 2006 the official journal of the European Headache Federation. The first foundation and national headache societies were established (Migraine Trust, 1965; American Association of Headache, 1973; Italian Society for the Study of Headache, 1976), followed by many countries and by the institution of international organizations: the International Headache Society (1980), and the European Headache Federation (1992).

REFERENCES Airy H (1870). On a distinct form of transient hemiopsia. Phil Trans R Soc Lond p. 247. Aretaeus (1581). Liber III. In: Medici Antiqui Graeci Aretaeus, Palladius Ruffus, Theophilus: Physici & Chirurgi. Ex officina Petri Pernae, Basileae, pp. 31–32. Arnott E, Finger S, Smith CUM (Eds.) (2003). Trepanation: History, Discovery, Theory. Swets & Zeitlinger, Lisse. Caelius Aurelianus (1567). Opera. Apud G. Rovillium, Lugduni. Capello GB (1797). Lessico farmaceutico-chimico. Appresso Pietro Savioni, Venezia, pp. 100, 121, 139, 164. Celsus AC (1960). De Medicina. William Heinemann, London and Harvard University Press, Cambridge, MA, pp. 363–365. Celsus AC, Samonicus QS (1750). De Medicina. Josephus Cominus, Patavii, p. 340.

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Curran DA, Hinterberger H, Lance JW (1965). Total plasma serotonin, 5-hydroxindoleacetic acid and p-hydroxy-m-methoxymandelic acid excretion in normal and migrainous subjects. Brain 88: 997–1010. De Sgobbis A (1667). Nuovo et Universale Theatro Farmaceutico. Stamparia Juliana, Venetia. Edmeads J (1988). Treating the head in headache. Headache 28: 496–497. Gowers W (1888). A Manual of Diseases of the Nervous System. Churchill, London, pp. 793–803. Graham JR, Wolff HG (1938). Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry 39: 737–763. Humphrey PP, Feniuk W, Perren MJ, et al. (1989). The pharmacology of the novel 5-HT1-like receptor agonist GR43175. Cephalalgia 9: 23–33. Isler H (1985). Johann Jakob Wepfer (1620–1695). Discoveries in headache. Cephalalgia 5: 424–425. Koehler PJ, van de Wiel TW (2001). Aretaeus on migraine and headache. J Hist Neurosci 10: 253–261. Ku¨hn CG (1965). Claudii Galeni Opera omnia. Tomus VIII. Georg Olms Verlaugsbuchhandlung, Hildesheim, p. 206. Leao A (1944). Spreading depression of activity in the cerebral cortex. J Neurophysiol 7: 359–390. Le Pois C (Carolus Piso) (1733). Selectiorum observationum et consiliorum de praetervisis hactenus morbis affectibusque praeter naturam, ab aqua seu serosa colluvie, et diluvie ortis, liber singularis. Apud Gerardum Potuliet, Lugduni Batavorum. This observation was first published in 1618. Littre¯ E (1861). Oeuvres comple`tes d’Hippocrate. Septie`me Livre. Baillie`re, Paris, pp. 445–447. Liveing E (1873). On Megrim, Sick Headache and Some Allied Disorders: A Contribution to the Pathology of Nerve Storm. Churchill, London, p. 335. Lucianus S (1743). Opera. Cum Nova Versione. Tomus I. Sumptibus Jacobi Westenii, Amstelodami, pp. 224–225. Maggioni F, Occhipinti C, Zanchin G (1998). The Headache in Domestic Medicine by William Buchan. Ital J Neurol Sci 19: 109–115. May A, Bahra A, Buchel C, et al. (1998). First direct evidence for hypothalamic activation in cluster headache attacks. Lancet 352: 275–278. Moskowitz MA (1992). Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol Sci 13: 307–311. Olesen J, Larsen B, Lauritzen M (1981). Focal hyperemia followed by spreading oligemia and impaired activation of r-CBF in classical migraine. Ann Neurol 7: 344–352. Pearce JMS (1986). Historical aspects of migraine. J Neurol Neurosurg Psychiatry 49: 1097–1103. Penso G (1991). La Medicina Medioevale. Ciba-Geigy Edizioni, Saronno. Plinius G (1982). Storia Naturale. XXVII libro, par. 138. Einaudi Editore, Torino. Ramazzini B (1742). Opera Omnia, Vol. II. Apud Paulum et Isaacum Vaillant, Londini.

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Sacks O (1985). Migraine. Understanding a Common Disorder. University of California Press, Berkeley, CA and Los Angeles, CA, p. 3. Schro¨der J (1681). Pharmacopoeia medico-chymica, sive thesaurus pharmacologicus. Sumpt Petri Borde. Joan et Petri Arnaud, Lugduni, p. 149. Sicuteri F, Testi A, Anselmi B (1961). Biochemical investigations in headache: increase in hydroxyindoleacetic acid excretion during migraine attacks. Int Arch Allergy Appl Immunol 19: 55–58. Tissot SA (1761). Avis au Peuple sur la Sante´, Didot le jeune, Lausanne, Paris. Tissot SA (1768–1770). Traite´ des Nerfs et de leurs maladies, p. 120, chapnis et Didot le jeune, Lausanne, Paris.

Von Bingen H (1903). Causae et curae. In: P Kaiser (Ed.), Aedibus. BG Teubneri, Lipsiae, p. 90. Weiller C, May A, Limmroth V, et al. (1995). Brain stem activation in spontaneous human migraine attacks. Nat Med 1: 658–660. Willis T (1694). De anima brutorum exercitationes duas. In: Opera Omnia Tomus Secundus. Gasparis Storti, Coloniae, p. 357. First published in 1672. Zanchin G (1992). Considerations on “the sacred disease” by Hippocrates. J Hist Neurosci 1: 91–95. Zanchin G (2004). Sources. J Headache Pain 5: 261–264. Zanchin G, Rossi P, Isler H, et al. (1996). Headache as an occupational illness in the treatise “De Morbis Artificum Diatriba” of Bernardino Ramazzini. Cephalalgia 16: 87–92.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 26

A history of seizures and epilepsies: from the falling disease to dysrhythmias of the brain DAVID MILLETT * Department of Neurology, Keck School of Medicine at USC, Los Angeles, CA, USA

INTRODUCTION Among the myriad of human afflictions, perhaps none has terrified, amazed and inspired more than epilepsy. For those who have witnessed a grand mal seizure, the reasons are obvious: the unpredictable convulsion that may begin with a brief period of unresponsiveness but is quickly followed by deviation of the eyes and violent muscle contractions, a prolonged period of stupor and, finally, a return of normal functions is one of the most dramatic events in the course of human life. Two essential elements of a generalized convulsion or bilateral tonic–clonic seizure – namely the fall that results from a loss of muscle control and the alteration of consciousness – have remained core features in the recognition of seizures throughout history. The history of seizure disorders might be roughly divided into three eras. The “early” period dates from antiquity to the medieval period and includes descriptions of seizures and their associated auras, as well as observations about the natural history of seizure disorders (later referred to as epilepsies). This early period, during which convulsions were widely regarded as an attack, possession or “seizure” of human victims by a supernatural being, is briefly summarized here. Interested readers may consult the scholarly study of The Falling Sickness by Temkin (1971) and more recent reviews (e.g., Eadie and Bladin, 2001) and translations (e.g., Stol, 1993). During the “classical” period of epileptology, from the Renaissance until the mid-19th century, there were many important developments in anatomy, physiology, and medicine, with a latent impact on the understanding of seizures and seizure disorders. During the early classical period, naturalistic explanations of brain function and cerebral disease coexisted with lay beliefs

*

in supernatural possession. By the 18th and early-19th centuries, however, epileptology began to blossom with a dramatic expansion in the recognition of different types of seizures, refinements in the classification of seizures, delimitation of epilepsy from other neurological and psychiatric disorders, and greater attention to anatomical pathology (Temkin, 1971). Many hospitals, colonies and other institutions dedicated to the care and observation of persons with epilepsy opened during the 19th century (Holmes, 1954; Temkin, 1971; Sander et al., 1993; Fine et al., 1995; Friedlander, 2001), and a great variety of archaic treatments were abandoned (Temkin, 1971; Scott, 1993). The “modern” era of epileptology can be traced to the 1860s, when the critical studies of John Hughlings Jackson initiated a remarkable transformation in the medical and physiological understanding of seizures (Taylor, 1958; Temkin, 1971; Critchley, 1998; York and Steinberg, 2006). This shift was initially a conceptual one, beginning with Jackson’s prescient notion of the “discharging lesion,” an idea rooted in his own clinical-pathological correlations, and supported by early animal experiments with electrical stimulation of the “excitable cortex.” Development of the electroencephalogram (EEG) during the 1930s rendered such discharges visible for the first time and this new technique rapidly revolutionized the understanding, diagnosis, classification and treatment of seizures and the epilepsies. The 20th century witnessed a series of spectacular technological breakthroughs, including an explosion of neuroimaging techniques, the creation of animal models that recapitulate human seizures and epilepsy syndromes, and the identification of many ion channels and genes responsible for some genetic epilepsy syndromes.

Correspondence to: David Millett MD, PhD, Keck School of Medicine at USC, 1510 San Pablo Street, Suite 643, Los Angeles, CA 90033, USA. E-mail: [email protected], Tel: +1-323-442-7686, Fax: +1-323-442-7689.

388 D. MILLETT It is important to recognize that descriptions, definifallen upon him he says ‘It is he!’: the roving epilepsy tions and classifications of seizures and epilepsies have has seized him; he will be saved” (translation in Stol, changed substantially over the centuries (Eadie and 1993, p. 57). Interestingly, the presence of a warning Bladin, 2001). Until the late-18th century, the terms that precedes an impending seizure (later referred to “seizure” and “epilepsy” were essentially synonymous as an “aura” by Galen; see below) carried important (both referring to the paroxysmal attack) and there was diagnostic and prognostic value in the pre-Hippocratic little appreciation of the facts that: (1) seizures are freperiod. The ancient Babylonian text also describes a quently a symptom of an underlying biological disorder; variety of other behaviors and movements that were and (2) the epilepsies consist of various disorders with difalso recognized as epileptic manifestations: ferent etiologies, natural histories, and effective treatIf a fall falls upon him and it overwhelms him ments. Perhaps the most significant changes in repeatedly, seven times on that (same) day; after epileptology occurred during the early-modern period it has released him he feels good: Hand of a from the late-19th to the mid-20th century, as new conmurderer; he will die [serial seizures; status cepts and technologies revolutionized our understanding epilepticus] . . . (Translation in Stol, 1993, p. 59) of epileptic seizures. Indeed, the impact of this revolution If his fit overwhelms him and his hands and feet in epileptology is immediately apparent when the Galenic curve [unilateral tonic seizure] . . . (Transladefinition of epilepsy as “convulsions of the whole body tion in Stol, 1993, p. 60) [with] interruption of the leading functions” is contrasted If at the time it overcomes him, his limbs are with current definitions proposed by the International dissolving, his innards seize him time and again, League Against Epilepsy (ILAE): his bowels move [incontinence] . . . (TranslaAn epileptic seizure is a transient occurrence of signs tion in Stol, 1993, p. 61) and/or symptomes due to abnormal excessive or If, at the time it overwhelms him, his torso (?) is synchronous neuronal activity in the brain. heavy for him and gives him sharp pains; later Epilepsy is a disorder of the brain characterized by on it overwhelms him and he forgets himself: an enduring predisposition to generate epileptic antasˇubba [limbic aura, complex partial seizure] seizures and by the neurobiologic, cognitive, . . . (Translation in Stol, 1993, p. 62) psychological, and social consequences of this If he, time and again, gets into [and] throws away condition. The definition of epilepsy requires his garments, he . . . time and again [talks(?)] the occurrence of at least one epileptic seizure. much, he does not eat bread or beer any more (Fisher et al., 2005, p. 471) and he does not sleep; Hand of the Goddess; With the rapid and continuing development of neurohe will live [behavioral automatisms, post-ictal imaging and genetics, we must also recognize that modpsychosis?] . . . (Translation in Stol, 1993, p. 70) ern epileptology is a lively and evolving field, and that If, at the time it has seized him, he shouts time these terms continue to adapt to a changing environment and again “My belly, my belly!,” he opens and of medical technology, knowledge and practice. closes his eyes . . . he scratches the tip of his nose, the tips of his fingers and toes being cold; THE EARLY PERIOD: ANTIQUITY if you make that patient “talk” and he does not TO THE MEDIEVAL PERIOD respond: Hand of incubus [limbic aura, postictal automatisms and aphasia] . . . (TranslaAncient medical writings describe a remarkable variety tion in Stol, 1993, p. 67) of seizures, despite the paucity of surviving texts. Until the mid-20th century, the most celebrated ancient text That such diverse behaviors were all recognized as that dealt with epilepsy was the Hippocratic essay, On manifestations of epilepsy within the Babylonian text the Sacred Disease (Temkin, 1971). In recent years, is remarkable, particularly in light of the more however, other ancient texts have been discovered restricted definition of epilepsy found in the Hippoand/or translated, revealing a more sophisticated cratic texts and in the more enduring writings of Galen. appreciation of epileptic phenomena during the preDescriptions of a variety of seizures can also be Hippocratic era (Stol, 1993; Eadie and Bladin, 2001). found in a variety of other pre-Hippocratic texts, such The oldest known description of an epileptic seizure as the Chinese Huang Di Nei Jing (The Yellow Emper(antašubba, lit., “fallen from heaven”) can be found in or’s Classic of Internal Medicine, 770–221 BCE) (transthe Assyrian-Babylonian diagnostic handbook Sakkiku lation in Veith, 2002), and the Ayurvedic Indian (lit., symptomes) compiled between 1067 and 1046 Charaka Samhita (6th century BCE) (Manyam, 1992; BCE. “If a fall falls upon him and at the time it has Eadie and Bladin, 2001).

A HISTORY OF SEIZURES AND EPILEPSIES 389 One of the earliest medical systems was established Ares then gets the blame. But terrors which hapin India, where epilepsy was referred to as Apasmara pen during the night, and fevers, and delirium, (Apa = without; Smara = consciousness, recollection), and jumpings out of bed, and frightful apparia chronic disease that was both dangerous and difficult tions, and fleeing away – all these they hold to to treat. Various auras, or warnings that immediately be the plots of Hecate . . . (F. Adams translaprecede a seizure, were also described in ancient Ayurtion, www.grtbooks.com) vedic texts, including perceptions of sounds, darkening Rejecting the widespread appeal to supernatural causes, of vision, and even a dream-like state, anticipating the Hippocratic writers suggested that epilepsy involves Jackson’s description of the “dreamy state” and its irregularities in the liquefaction of phlegm. This humoral connection with temporal lobe epilepsy by over 2000 defect was not unique to epilepsy: an excessive influx of years (Manyam, 1992). phlegm to the heart, lungs, or bowels was associated with Ancient terms such as antašubba or miqit šamê palpitations, dyspnea, or diarrhea, respectively. In the case (fallen from heaven) attest to the religious interpretaof the epileptic attack, however, the sudden build-up of tion of seizures during the pre-Hippocratic period. phlegm within the brain erupts into the blood vessels Indeed, seizures were associated with several deities and, upon reaching various organs of the body, produces in Babylonian culture, including Sˇulpea (second rank the various manifestations of a convulsion: god of Jupiter) and Lugal-urra (lit., Lord of the roof, demon of epilepsy; possibly due to the upward deviaAnd if, being shut out from all these outlets, its tion of the eyes that frequently accompanies a convuldefluxion be determined to the veins I have sive seizure), as well as lesser demons such as the formerly mentioned, the patient loses his speech, incubus and succubus (Stol, 1993). and chokes, and foam issues by the mouth, the The common belief in supernatural possession falls teeth are fixed, the hands are contracted, the eyes under attack in one of the most celebrated ancient texts distorted, he becomes insensible, and in some concerning epilepsy, the Hippocratic monograph On the cases the bowels are evacuated. (F. Adams Sacred Disease (c. 400 BCE; www.grtbooks.com). translation, www.grtbooks.com) The title of this monograph is a sardonic reference to Many other aspects of the natural history of epilepsy the widespread understanding of seizures advanced by drew the attention of ancient physicians. The Hippo“conjurors, purificators, mountebanks, and charlatans,” cratic text notes that, in many cases, epilepsy is a congewho advocated a variety of dietary and hygienic pracnital disease, and that children and adults have differing tices aimed at evicting demonic possessors. The principrognoses. The onset of seizures during childhood was pal goal of the Hippocratic writer(s) was to argue, for frequently fatal, and when the child survived the disthe first time in recorded history, that epilepsy has a natease was associated with hemiplegia; adults, on the ural or physical cause, like all other diseases, and that other hand, typically survive their seizures and do not this cause lies within the brain (Temkin, 1971). After crimanifest neurological deficits. Hippocrates also notes ticizing the baseless therapeutic regimens prescribed by that persons “habituated to the disease know beforethese “charlatans,” the Hippocratic writer(s) confront hand when they are about to be seized and flee from those who hide their ignorance of the natural cause of men,” not from fear of possession but from embarrassseizures behind religious attributions and ment and shame. Whatever the impact of this naturalistic interpretation of seizures in the ancient medical invent many and various things, and devise many world, the notion of demonic possession persisted well contrivances for all other things, and for this into the 17th century (Temkin, 1971). disease, in every phase of the disease, assigning There is little detailed discussion of specific the cause to a god . . . For, if they imitate a goat, warnings that may herald a seizure in the Sacred Disor grind their teeth, or if their right side be conease, although numerous auras are mentioned by a vulsed, they say that the mother of the gods is the 2nd-century Greek physician, Soranus, in On Chronic cause. But if they speak in a sharper and more Diseases: intense tone, they resemble this state to a horse, and say that Poseidon is the cause. Or if any Heaviness and giddiness in the head, an inner excrement be passed, which is often the case, noise, which is felt in the occiput too, tension owing to the violence of the disease, the appellain the eyes, ringing in the ears or difficulty in tion of Enodia is adhibited; or, if it be passed in hearing; and together with the vertigo, dimness smaller and denser masses, like bird’s, it is said of the eyesight or something hanging down before to be from Apollo Nomius. But if foam be emitted the eyes, as it were, either similar to the spots of by the mouth, and the patient kick with his feet, marble which the Greeks call “armarygmata” or

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“marmarygas,” or similar to spider webs or to very thin clouds . . . rigor of the throat and a concomitant precordial distention . . . (Translation by Temkin, 1971, p. 38) The occurrence of a brief period of amnesia – “forgetfulness of what has been done shortly beforehand” – is also described by Soranus, as well as a prodrome of depression or “a ready disposition for things causing gloom” (translation by Temkin, 1971, p. 38). A number of common triggers, i.e., feelings or experiences that can provoke a seizure, are described here for the first time, including sleep deprivation and fear. Interestingly, fear has been recognized as a potent trigger for seizures throughout much of the history of seizures and epilepsy. While fear may in fact trigger seizures in some patients, fear is now a well-recognized aura – really an early feature of seizures arising from the limbic system (Gloor et al., 1982) – and was likely misinterpreted as an emotional trigger by early writers. The most influential figure in this early period of epileptology is arguably the Greek physician Galen of Pergamum (129–c. 200 AD), heir to the Hippocratic tradition of humoral medicine (Brock, 1929). Four major developments in the history of epileptology can be directly traced to the teachings of Galen (Brock, 1929; Temkin, 1971; Eadie and Bladin, 2001). First, Galen plainly articulated a much more restrictive definition of epilepsy than his predecessors: “If there is not only convulsion of the whole body, but also interruption of the leading functions, then this is called ‘epilepsy’” (translation by Temkin, 1971, p. 36). This necessary conjunction of convulsive movements and an alteration in “leading functions” excluded a variety of behaviors that earlier Babylonian and later Post-Renaissance writers recognized as epileptic. Thus, absence or petit mal, simple partial seizures, complex partial seizures with or without automatisms, and unilateral tonic or clonic seizures (see www.ilae.org for glossary and descriptions) all fall outside Galen’s strict definition of seizures. This stringent definition was to reign virtually unchallenged until the Renaissance, when a broader range of stereotyped behaviors were once again recognized as manifestations of epileptic seizures. Second, Galen understood all human diseases, including epilepsy, in terms of the four basic humors – blood, phlegm, and black and yellow bile – and he integrated this humoral theory with newer concepts of brain structure and function that emphasized the importance of the cerebral ventricles for various psychological functions. By the 2nd century CE, the pneuma was considered a lifesustaining substance that was created in the lungs and acquired “psychic” properties in the cerebral ventricles. Galen postulated that it was the accumulation of viscous

humor – either phlegm or black bile – in the ventricles that impeded the flow of psychic pneuma through the ventricular system. This congestion of pneuma within the ventricles, where the “leading faculties” of volition and memory reside, produced the loss of awareness and memory that accompany a seizure. At the same time, the viscous humor itself was thought to irritate the roots of the nerves, which shake violently in an effort to free themselves or “repulse whatever is brought up to it from the primarily affected part” (Galen, On the Parts Affected, translated in Brock, 1929, p. 224). Galen postulated that this violent shaking of the nerves is transmitted to skeletal muscles, thereby producing the convulsive movements. This concept of a physical event – a twitch, chemical reaction, explosion, or discharge – beginning within the central nervous system and propagating to the periphery, can be traced from Galen through the modern period. Third, Galen developed the first system of classification for seizure disorders based on the behavioral manifestations or semiology of a seizure. In many patients, he noted that seizures began during childhood and consisted of convulsive attacks without any preceding signs or symptoms. Galen believed that such cases constituted a cerebral or idiopathic form of epilepsy, in which the principal disturbance in natural humors was located within the brain itself. In contrast, other patients reported symptoms such as palpitations or abdominal sensations prior to their seizures. Galen referred to such cases as sympathetic epilepsy, in which an excessive production of bile in the viscera or an aberration of the heart disturbed the pneuma, with seizures occurring when this perturbation reached the brain. Finally, cases in which seizures began with a sensation or movement of an extremity suggested that some cases of sympathetic epilepsy could result from a distal disturbance in the pneuma, and Galen suggested that the initial symptoms of numbness, tingling, or abnormal movements resulted from propagation of abnormal pneuma from an affected limb to the brain. One case of sympathetic epilepsy involved a young boy presented to Galen with an unusual warning before his seizures: I heard the boy relate that the condition began in his leg, and rose thence straight up through his thigh, superjacent flanks, sides and neck, right to his head, and that as soon as it reached this, he could no longer follow it. Asked, however, by the doctors what sort of thing it was that rose to his head, the boy was unable to say. Another young lad, however . . . said that what rose up was like a cold current of air [aura = lit. breeze]. (Brock, 1929, p. 222)

A HISTORY OF SEIZURES AND EPILEPSIES 391 Galen recognized the importance of such a stereoA remarkable number of flowers, berries, leaves, and typed warning of an impending seizure, and used the roots, as well as internal and external organs of virtually term aura to refer to such symptoms. The expression every type of animal – from elephant liver to crocodile “aura” retained this specific connotation of a cold intestine – were used at some point in time to treat breeze or vapor until the early-19th century. The rarity seizures or epilepsy (Scott, 1993). of this peculiar type of warning was noted by Pritchard in 1822 (cited in Temkin, 1971), and descriptions of THE CLASSICAL PERIOD: RENAISSANCE auras as well as seizures broadened during the lateTO THE 19TH CENTURY classical period to include virtually any subjective and Remarkable advances in neuroanatomy took place durstereotyped warning before a seizure. ing the 16th and 17th centuries, as illustrated by wellIt is no exaggeration to state that Galen’s writings known drawings of Vesalius, Leonardo da Vinci, and dominated the medical understanding of seizures and Thomas Willis. Yet there were few substantial changes epilepsy for over a millennium. Late-medieval physiin the definition, description or understanding of seicians, such as Arnold of Villanova (1235–1313 CE), zures during the early-classical period, and lay beliefs understood epilepsy as “an occlusion of the chief venabout demonic possession persisted alongside naturatricles of the brain, with loss of sensation and motion; listic theories of brain function (Temkin, 1971). It is or, epilepsy is a non-continuous spasm of the whole important to remember that the terrifying and grobody” (Von Storch and Von Storch, 1938, p. 253). tesque appearance of convulsive seizures was not the Galen’s basic division between idiopathic and sympaonly factor that raised the specter of possession during thetic seizures also endured well into the classical perthis period. Indeed, seizures occur more frequently in iod, although a few newer terms were introduced. persons suffering from schizophrenia and organic Thus, during the medieval period the term analepsy brain diseases such as tertiary syphilis (i.e., general parreferred to seizures arising from the stomach, while esis of the insane), and persons with uncontrolled seithe ancient term catalepsy was used to refer to seizures were at greater risk of developing psychosis zures beginning in another part of the body, typically and other psychiatric complications of epilepsy, further an extremity. All in all, however, Galenic views domiblurring the boundary between epilepsy and madness nated medical writings on seizures and epilepsy until until the mid-19th century (Berrios, 1984). the Renaissance: Despite the persistence of supernatural beliefs, a To sum up, it can be said that the Middle Ages number of “classical” descriptions of distinct seizure added little to the physiological understanding types appeared during this period. In 1597, for example, of epilepsy. Yet at a time when the vague conMartinus Rulandus detailed the case of a 10-year-old ception of the falling evil prevailed among the boy who most likely suffered from benign childhood people and when even the educated were epilepsy with centrotemporal spikes (previously known included to mistake a disease for demonic posas benign Rolandic epilepsy): session, it was no small merit for the medieval During the seizure the left eye, the mouth, and the physicians to have kept alive the tradition of left hand convulsed, he lost speech, and his left epilepsy as a natural disease caused by natural arm became paralyzed. The seizure, however, factors. (Temkin, 1971, p. 133) passed off quickly and the boy came round without I shall only briefly mention the various treatments for having fallen as occurs in more serious form of seizures and epilepsy during this early period, which epilepsy. (Translation in Van Huffelen, 1989, depended primarily on whether the practitioner was p. 447) inclined toward a superstitious or naturalistic underAnother type of focal seizure, later eponymously standing of the disease (Temkin, 1971; Scott, 1993; Eadie designated “Jacksonian” seizures by Charcot, was also and Bladin, 2001). In the case of the former, treatment described in detail during this period. In this type of frequently involved prayer or exorcism, as in the biblical seizure, clonic activity typically begins in the face or story of the young boy with epilepsy who was cured hand and progressively involves adjacent or highly speafter Jesus supposedly expelled the evil spirit from cialized muscle groups. Briefly mentioned in the Sakhim (Mark 9:14–29). For those practitioners who subkiku, these focal motor seizures disappeared from the scribed to a naturalistic view, treatments during the medical literature until the mid-17th century, when the early period of epileptology included a variety of philosopher John Locke (who briefly studied medicine herbs and plants thought to have sedative properties, under Thomas Willis) described a “hysteric patient” cathartics and emetics, as well as blood-letting and/or seen by his colleague: blood consumption (Moog and Karenberg, 2003).

392 D. MILLETT First, she would have a convulsive motion of her In 1772, the Swiss neurologist Samuel August Tissot thumb, then would be added to it that of her provided the first detailed description of absence seiforefinger, then that of her middle finger, then zures, the subtle arrest of behavior that is seen in a that of her ring finger, then all the fingers, then common type of childhood syndrome, childhood that of the joint of the hand, the wrist, then of absence epilepsy. Here, the case of a seven-year-old the elbow, and then the whole arm. This ceasing, girl is described: the like convulsive motion would begin in the Some movement of the eyelids was observed thumb of the other hand and make the same prowhich was taken at first to be a tic but soon gress on the other side, which being ended, it was recognized as being convulsive . . . About would seize in order the foot, leg, and thigh on four months later real epileptic attacks began, one side, and then of the other. After that it quite violent and frequent. In the intervals would seize the muscles of the neck and turn between the convulsions (grands acce`s) there the head from one side to the other almost quite were petits, very frequent but very short, almost round, and from thence make its progress to the of an instant’s duration, which were marked only breast. This he saw several times, beginning by a momentary loss of consciousness, cutting always with the same thumb and so regularly from short her speech, and by a slight trembling of one place to the other keeping with same the eyes. After regaining consciousness she course. (Cited in Eadie and Bladin, 2001, p. 40) would finish her interrupted sentence but occasionally she had forgotten it. On other occasions Similar descriptions of such “epileptiform” attacks can these very brief fits used to come only when she be found in the early papers of John Hughlings Jackwas walking; she would then stop during the few son (reprinted in Taylor, 1958), who largely drew on seconds of unconsciousness and have slight his correlation of these focal motor seizure onsets convulsive movements of the leg which was and their associated brain lesions in laying the foundaadvanced for the next step . . . (Tissot, translations of modern epileptology. In 1684, an important tion in Lennox and Lennox, 1960, p. 69) monograph by Thomas Willis appeared, Pathology of the Brain and Nervous Stock: On Convulsive Diseases, Gradually, increased recognition of these subtle manicontaining detailed descriptions of both epileptic seifestations of seizures and the rising importance of zures and a variety of movement disorders. Here we medical classification forced a broadening of the defifind the first detailed description of a complex partial nition of epilepsy. By the late-18th century, epilepsy seizure (i.e., arising from a focal region in the brain was no longer strictly associated with a convulsion, and associated with an alteration of consciousness): fall, and the loss of “leading functions.” In his First A fair Maid . . . began to complain of her head being ill: And first of all, she felt near the forepart of the head, by fits, a vertigo or giddiness, whereby all things seemed to run around; and also while this symptom continued, she was wont to talk idlely, and to forget what she had but just done. (Willis, 1684, cited in Eadie and Bladin, 2001, p. 38) In this case, seizures consisted of brief paroxysms of amnesia accompanied by incoherent speech that began shortly after menarche and occurred once or twice per month, all suggestive of temporal lobe epilepsy, the most common cause of medically intractable epilepsy. Consistent with the Galenic teaching, however, Willis only arrived at a diagnosis of epilepsy 6 months after the onset of these spells, “her Brain being daily more weakened, this giddiness or turning round was plainly changed into the Epilepsy, that the sick being struck down to the ground at every fit, was affected with Insensibility, and horrid convulsions, and also with foam at the mouth” (cited in Eadie and Bladin, 2001, p. 38).

Lines of the Practice of Physic (1789), William Cullen explains that epilepsy “may be defined, as consisting in convulsions of the greater part of the muscles of voluntary motion, attended with a loss of sense, and ending in a state of insensibility and seeming sleep,” but may also involve “convulsions which are . . . more partial: that is, affecting certain parts of the body only, and by their not being attended with a loss of sense, nor ending in such a comatose state as epilepsy always does” (cited in Eadie and Bladin, 2001, p. 42). Heightened awareness of the range of seizure manifestations was partly due to more systematic and longitudinal observations of patients with chronic epilepsy both in the clinic and the asylum (Temkin, 1971; Berrios, 1984). Patients suffering from chronic seizures were initially segregated from criminals and the insane in asylums and large hospitals in Europe beginning in the early-19th century. Furthermore, during the second half of the century, a number of dedicated colonies and hospitals were established to house and care for patients with epilepsy, including Bethel (Bielefeld); Blackwell’s Island (New York); Ohio State Hospital for

A HISTORY OF SEIZURES AND EPILEPSIES Epileptics (Gallapolis); Chalfont (St. Peter, UK); and the National Hospital for the Paralysed and Epileptic, Queen Square (London) (see, e.g., Holmes, 1954; Barclay, 1992; Friedlander, 2001; Lannon, 2002). Clinicians of this period collected their observations in a number of monographs that focused on epilepsy and seizures. These include Tissot’s Traité de l’épilepsie (1770), Maisonneuve’s Recherches et observations sur l’épilepsie (1805), Bravais’ Recherces sur les sympto^mes et traitment de l’épilepsie hémiplégique (1824), Pritchard’s A Treatise on Disease of the Nervous System (1822), and Herpin’s Des acces incomplets d’épilepsie (1867). These detailed clinical studies introduced a new lexicon to describe seizures, and many of these terms, such as absence, petit mal and grand mal, have survived to the present. In 1815, the famous French psychiatrist Jean-E´tienne Dominique Esquirol remarked on the wellknown distinction between “le grand and le petit mal in the hospitals,” terms also recognized by Tissot (Temkin, 1971). Petit mal referred to seizures with milder movements than the bilateral tonic–clonic activity typically seen in the grand mal attacks. Louis-Florentin Calmiel first employed the term absence to describe a seizure that consists of a brief arrest of behavior without abnormal movements or other physical manifestation, and he described the ominous état de mal (i.e., status epilepticus), a condition that was frequently fatal until the introduction of intravenous anticonvulsant medications in the mid20th century. A gradation of seizure severity was emphasized by Louis Jean-Franc¸ois Delasiauve, who ranked seizure types in order of increased severity: absences, vertiges, acces intermediaries, and acces complets. Similarly, a renewed interest in the anatomical pathology of epilepsy led many to revisit the classification of the epilepsies, introducing important distinctions between types of epilepsy. As autopsies were increasingly performed in the late-17th century and a predicted brain lesion could not be found, Tissot (1770) introduced the term “essential” epilepsy to refer to epilepsy resulting from “without any doubt a fault in [the brain’s] organization, but a fault which escapes our senses.” Such cases were frequently referred to as “idiopathic” epilepsy during the 19th century. This connotation of “idiopathic” – recurrent seizures without structural lesion in the brain – is still in wide usage today. As the classical period came to a close, many physicians focused their attention on the clinical features of idiopathic epilepsy, believing that a more thorough understanding of this pure form of epilepsy would cast light on “epileptoid” or “epileptiform” attacks, i.e., partial or focal seizures that are “symptomatic” of a brain lesion (Russell, 1861; Gowers, 1881). Finally, we must acknowledge the discovery of the first effective pharmacotherapy for epilepsy during

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the late 1850s (Scott, 1993; Friedlander, 2000). It was Charles Locock who, after learning that administration of bromide of potassium produced temporary impotence or “torpidity of the genital organs” in men, decided to see whether this compound might suppress seizures in young women with catamenial epilepsy (i.e., seizures associated with the menstrual cycle). To his surprise, he found that bromide therapy “cured” 13 of the 14 patients who received it. Although side effects were common and frequently limited the duration of treatment, bromides provided the first effective pharmacological treatment for epilepsy, later shown to provide a 70% reduction of seizures by Edouard Se´guin (1878), and were enthusiastically prescribed in the 1860s (Friedlander, 2000). Reflecting on the consumption of bromide by patients at the National Hospital for the Paralysed and Epileptic at the end of the 19th century, Gowers recalled that “many patients who are not cured, nevertheless cannot do without bromide . . . and the amount used at the hospital during the year 1899 was almost two tons” (Gowers, 1901).

THE MODERN PERIOD: FROM JACKSON’S DISCHARGING LESION TO THE EEG AND BEYOND The modern period of epileptology began in the late19th century, and may even be pinpointed to 1870, the year in which a seminal Study of Convulsions (reprinted in Taylor, 1958) was published by the brilliant English neurologist, John Hughlings Jackson. To appreciate just how dramatic was the transition from classical views to the modern era, consider the fact that in 1861 the great London neurologist, Russell Reynolds, encouraged his colleagues to focus on the “natural history of this idiopathic disease,” avoiding any discussion of focal or unilateral seizures in his influential Epilepsy: Its Symptoms, Treatment, and Relation to Other Chronic Convulsive Diseases (Reynolds, 1861). Jackson (1870), however, pursued exactly the opposite approach, believing that careful examination of focal seizures would provide clues about the functional organization of the brain and the cause of seizures. The combination of Jackson’s meticulous correlation of seizure semiology and anatomical pathology, his powerful belief in functional organization within the brain, and critical analyses of both clinical and experimental data established a firm foundation for the modern study of seizures and epilepsy (York and Steinberg, 2006). When he began examining cases of epilepsy in the early 1860s, Jackson shared the widely held belief that bilateral convulsions arose from the medulla and that “unilateral convulsions” arose from lesions around

394 D. MILLETT the corpus striatum (the basal ganglia and internal distinguish idiopathic from sympathetic or symptocapsule). Yet, he quickly realized that if aphasia or matic epilepsy. hemiplegia – signs that indicated a loss of function – freThis was an attractive and influential theory that has quently resulted from tumor, stroke, or other “destroycaptivated generations of neurologists (Walshe, 1943; ing lesion” within the cerebral hemispheres, then Bladin, 2005), and Jackson’s approach led to the disconvulsions might result from a “discharging lesion” covery that complex partial seizures with a particular within the cerebral hemispheres as well. semiology are frequently associated with lesions of the anterior temporal lobe or uncus (Jackson and In very many cases of epilepsy, and especially in Colman, 1898; Jackson and Stewart, 1899). syphilitic epilepsy, the convulsions are limited to one side of the body; and, as autopsies of patients I have . . . suggested for these cases the name of who have died after syphilitic epilepsy appear to Uncinate Group of Fits; this was on the hypothshow, the cause is obvious organic disease on esis that the discharge lesions in these cases are the side of the brain, opposite to the side of the made up of some cells, not of the uncinate group body convulsed, frequently on the surface of the alone, but of some cells of different parts of a hemisphere. (Jackson, 1863, p. 111) region of which this gyrus is part . . . In cases of this group there is at the onset of the paroxysms By the end of the 1860s, Jackson had collected several a crude sensation of smell or one of taste, or there cases in which partial seizures began with sensations or are movements of chewing, smacking of the lips, movements in the face or an extremity, and hemispheric etc. (sometimes there is spitting). In some cases lesions were discovered at autopsy. Jackson soon found of this group there is a warning of what is known experimental support for his concept of the “discharging as the epigastric sensation . . . (Jackson and lesion” in the pioneering work of Fritsch and Hitzig Stewart, 1899; reprinted in Taylor, 1958, p. 467) (1870), and later by Jackson’s colleague David Ferrier (1873, 1875, 1876), who discovered that discrete moveJackson was not the first person to describe gross ment of an extremity or even frank seizures could be lesions of the brain associated with chronic seizures produced with electrical stimulation of the cerebral corof a particular type: indeed, detailed descriptions tex in dogs, cats, and, eventually, the macaque. Ferrier of lesions within the temporal lobe associated with was himself motivated to undertake experimental work “genuine” epilepsy were first reported by Bouchet based on Jackson’s concept of the “discharging lesion,” and Cazauvieilh (1825), and focal motor seizures beginand his discoveries paved the way for the first neurosurning in the face or extremities were correlated with gical operations directed at removing an epileptogenic gross lesions of the hemispheres by Bravais (1827) lesion (Walker, 1951). By the mid-1870s, Jackson’s modand Bright (1831). Jackson was the first, however, to ern, physiological concept of epilepsy had crystallized: use these observations as data in the service of a new “Epilepsy is the name for occasional, sudden, excessive, integrative theory of brain function and a physiological rapid, and local discharges of grey matter” (Jackson, approach to understanding seizures. 1873; reprinted in Taylor, 1958, p. 100). In addition, the circumstances were ripe for testing When it came to identifying the seizure focus within Jackson’s hypothesis both in the laboratory and the the brain, Jackson assumed that the principle of funcoperating theater. The experimental work of Ferrier tional specialization based on evolutionary principles during the mid-1870s was mentioned above, and this would provide a reliable guide to localization of the nexus of neurological theory and experiment quickly discharging lesion (York and Steinberg, 1994). In other bore fruit: by the end of the decade, a Glasgow surgwords, the more specialized the movement, sensation eon named William Macewen (1879) had localized or thought associated with a seizure, the “higher” up and removed a tumor of the motor cortex in a teenage the neuroanatomic hierarchy the lesion would be locapatient, based solely on the presence of focal motor lized. Thus, regardless of whether or not a structural seizures involving the arm and face (Macmillan, 2004, lesion could be demonstrated, Jackson argued that sei2005; Jefferson, 1960). The 1880s are widely regarded zures resulted from focal dysfunctions of brain tissue. as the birth of “modern” neurosurgery, with pioneers An important corollary of Jackson’s definition of episuch as Rickman Godlee and Victor Horsley working lepsy was that it postulated a common underlying closely with neurologists such as Ferrier and Jackson, mechanism for all seizures, i.e., “discharging lesions.” who became increasingly confident of the ability to By substituting the issue of localization for the seelocalize tumors and other epileptogenic lesions after mingly intractable problem of the different types of careful study of seizure semiology and associated neupathology associated with seizures, Jackson’s approach rological defects (Bennett and Godlee, 1885; Horsley, transcended the classifications used since antiquity to 1886, 1887; Millett, 2001a; see also Ch. 14).

A HISTORY OF SEIZURES AND EPILEPSIES

THE TECHNOLOGICAL ERA Over 50 years had elapsed before Jackson’s “discharging” lesion could be captured on paper or film, and around the beginning of the 20th century many researchers returned to the study of cerebral blood flow, chemical or metabolic derangements to help clarify the pathophysiology of seizures (Lennox and Cobb, 1928). When the proper technique unexpectedly arrived in the form of the human electroencephalogram (EEG), Jackson’s definition of “occasional, sudden, excessive, rapid, and local discharges of grey matter” was one of the most compelling definitions of a seizure, but clinically irrelevant. All that changed during the 1930s with the rapid development of electroencephalography. The human EEG was developed by German neuropsychiatrist Hans Berger during the late 1920s (Berger, 1929; Millett, 2001b), but the application of this new technology to patients with epilepsy began during the mid-1930s (Millett, forthcoming). In Boston, a series of EEG demonstrations on normal subjects took place during 1934 in Hallowell Davis’ physiology laboratory at Harvard University, capturing the attention of three young epileptologists, William Lennox, Frederic Gibbs and Erna Gibbs. After observing EEG demonstrations with normal subjects, Lennox took a young woman with frequent “petit mal” (i.e., absence) seizures to Davis’ laboratory to record the electrical activity of her brain. She had a brief seizure during hyperventilation, and the Davis–Lennox–Gibbs team recorded what was soon known as the “spike and dome” EEG pattern of petit mal seizures (Gibbs et al., 1935). Energized by this remarkable discovery, Gibbs, Gibbs and Lennox mounted a scientific campaign with their powerful new technique. By 1937, they had distinguished different EEG patterns for the three major types of clinical seizure: petit mal, grand mal, and psychomotor seizures (i.e., complex partial seizures arising from the temporal lobe) (Gibbs et al., 1937). This last type frequently presented a diagnostic dilemma, as patients appeared unaware of their environment for a few minutes while they engaged in bizarre and stereotyped behaviors. While many of these patients had been diagnosed as “hysterical” prior to the introduction of the EEG, Lennox and Gibbs were the first to show that episodes involving “automatic but purposeful acts, such as dressing and undressing or urinating in the room,” were definitely accompanied by an “electrical storm” in the brain. If a patient has a tonic–clonic convulsion during which he shows no abnormalities of cortical activity, he can be put down as either hysterical or a malingerer, for the disturbance in grand mal involves the entire cortex and is therefore readily detected with electrodes on any part of

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the head. The absence of electrical abnormalities does not permit a differential diagnosis between hysteria and certain bizarre forms of epilepsy. The presence of abnormalities of the electroencephalogram may, however, demonstrate that certain cases of unexplained muscle jerkings, temper tantrums, or moments of abstraction are really minute petit mal or psychomotor seizures (Gibbs et al., 1937, pp. 379–380). Furthermore, they discovered that the interictal EEG (i.e., in between clinical seizures) of many epilepsy patients was frequently abnormal and that the abnormal discharges recorded during these periods closely resembled the rhythmic discharges that occurred during a seizure. This was a remarkably useful finding, in that it often permitted the clinician to diagnose a particular type of seizure or epilepsy syndrome based on a clinical history, neurological examination, and routine EEG, without observing a seizure first-hand. Within a few years, the EEG was quickly transformed from a scientific curiosity into a promising clinical tool (Millett, forthcoming). Early reports from the Boston group also demonstrated that patients sometimes experience subclinical seizures, in which pathological brain activity occurs without associated symptoms or signs of a seizure. Careful inspection of abnormal slow waves in the EEG also suggested that the EEG could be used for seizure prediction (Gibbs et al., 1937), a concept that continues to shape the development of biomedical devices designed for patients with intractable epilepsy. In a remarkably bold statement, the Boston team redefined the “sacred” disease in modern, electrical terms: epilepsy was a “paroxysmal cerebral dysrhythmia” (Gibbs et al., 1937). These were breathtaking developments for any field of medicine, but particularly so for the epilepsies, which drew this pessimistic assessment in a popular textbook of clinical neurology: “Every present-day discussion of the cause of epilepsy should begin with the confession that it is unknown and end with the logical phrase, not proved” (Wechsler, 1940, p. 636). An equally important aspect of this early technological advance was the use of EEG in the precise localization of the “discharging lesion” for surgical treatment of intractable seizures. In the late 1930s, a young physiologist at Brown University, Herbert Jasper, published the first criteria for localizing an epileptogenic lesion based on EEG recordings from the scalp (Jasper and Hawke, 1938). That same year, Jasper joined the prominent neurosurgeon Wilder Penfield, director of the new Montreal Neurological Institute, and established the first EEG laboratory in North America. Surgical treatment for intractable epilepsy had previously been limited to patients with evidence of a

396 D. MILLETT focal trauma, typically with a superficial scar, focal Systematic EEG studies of patients with epilepsy made neurological deficit, or abnormal X-rays. Yet, after just such a physiological taxonomy possible by the 1960s. some persuasion, Penfield agreed to operate on two The most important distinction that emerged with of Jasper’s patients whose EEG recordings alone sugroutine use of the EEG was that between patients with gested a focal abnormality. With Jasper looking on primary generalized seizures associated with idiopathic from the observation room, the predicted lesion was epilepsy on the one hand, and those with partial or discovered at surgery, heralding a new era in the surgifocal seizures associated with symptomatic epilepsy cal treatment of intractable seizures, in which surgical syndromes on the other. In the case of generalized seitreatment is guided primarily on EEG recordings, and zures such as absence seizures, myoclonic seizures supplemented by radiological studies. By the time the (brief jerks of the extremities or trunk), and primary US had entered World War II, two landmark reviews generalized tonic–clonic seizures, abnormal EEG activhad appeared – the Gibbs’s Atlas of Electroenceity appears simultaneously over both hemispheres durphalography (Gibbs and Gibbs, 1941) and Penfield ing the ictal (seizure) and during interictal discharges. and Erickson’s (1941) Epilepsy and Cerebral LocalizaWith symptomatic epilepsies, discharges are located tion, the latter with an authoritative chapter on electroover one hemisphere, frequently localized to a particuencephalography (Jasper, 1941). lar lobe, for example, in cases of temporal lobe The EEG revolution of the mid-20th century had a epilepsy. Thus, the EEG corroborated the historical disprofound impact on every aspect of epileptology, from tinction between idiopathic and sympathetic epilepsies, our understanding of the pathophysiology of seizures and it became a fundamental axis in the first classificato the classification, diagnosis, and medical and surgical tion system adopted by the ILAE in 1969 (Gastaut, treatment of epilepsies. Invasive EEG recordings from 1969). This distinction between generalized and partial deep brain structures in patients with absence seizures epilepsies remains one of the cornerstones of epileptolled to the early discovery that the bilateral 3 Hz spikeogy, since these two categories are now known to have and-wave rhythm associated with these seizures was prodifferent etiologies, prognoses, and responses to medduced by a circuit that involved the cerebral cortex and ical and/or surgical therapies. the thalamus (Penfield and Erickson, 1941), later Both medical and surgical treatments of the epilepreferred to as the thalamocortical circuit. Experimental sies were profoundly shaped by the application of the findings, such as the discovery that slow electrical stimuEEG. While Lennox, Gibbs and Gibbs were recording lation of the intralaminar nucleus of the thalamus proEEGs from patients with epilepsy in the neurological duces a “recruiting response” in the cerebral cortex research laboratory at Boston City Hospital, Tracy Put(Morison and Dempsey, 1941), and the development of nam and Houston Merritt embarked on their systematic the penicillin model of absence seizures (Prince and survey of potential anticonvulsants in 1935 (Friedlander, Farrell, 1969), produced conflicting evidence about where 1986). Putnam later recalled it was Gibbs’s belief that these types of seizure begin. Nevertheless, Penfield him“every true seizure is attended by an electrical ‘storm’ self proposed the concept of “centro-encephalic” seizures, in the brain,” which led to the adoption of an electrocona category that included petit mal or absence, petit mal vulsive threshold model (rather than a variety of chemiwith automatisms, myoclonic petit mal, grand mal, and cal models) for screening hundreds of Parke–Davis “psychomotor” automatisms, which arise from thalamic compounds for anticonvulsant properties. This search “neurone systems which are symmetrically connected to quickly led to the enormously important discovery of both cerebral hemispheres” (Penfield, 1950). Penfield’s the anticonvulsant properties of diphenylhydantoin (pheconcept of a centro-encephalic system was fiercely nytoin), one of the most important neurological treatattacked during the 1950s, and revived later with Pierre ments of the 20th century. Gloor’s concept of “generalized corticoreticular epilepsies” The impact of EEG on the surgical treatment of (Gloor, 1968), but the question of whether these generalized intractable epilepsy was equally momentous. During spike-and-wave seizures originate in the thalamus and his early work in Montreal, Jasper clearly demonstrated cortex remains unresolved (Blumenfeld, 2002, 2003). the added value of EEG in the surgical evaluation of In terms of the classification of the epilepsies, the EEG patients with intractable seizures: routine preoperative has remained an essential, if controversial, tool. While screening with the EEG and intraoperative EEG clinical distinctions between minor and major types of sei(i.e., electrocorticography) significantly increased the zures had existed for centuries, Craig Colony president F. number of successful surgical procedures resulting in Peterson lamented in 1897 that a physiological taxonomy seizure freedom, and dramatically decreased the numof seizures “is not possible . . . in light of the present ber of “negative explorations” (failed surgery exploraknowledge . . . [but] would be more scientific and valutions). Furthermore, in many cases, Jasper was able to able” than traditional systems (Friedlander, 2001, p. 70). pinpoint a cerebral lesion to within a few centimeters

A HISTORY OF SEIZURES AND EPILEPSIES 397 of the discharge focus obtained from preoperative scalp and benign occipital epilepsy of childhood. Thus, while EEG (Penfield and Jasper, 1940). most classification systems from ancient times until Penfield’s surgical studies, in which he electrically the 1970s have distinguished different types of seizures, stimulated the cerebral cortex over different areas of supplemented with information derived from the EEG the brain, confirmed and extended many correlations by the 1940s (see Gastaut, 1970; Masland, 1970; ILAE, between seizure type and their associated brain regions 1981), the ILAE introduced a separate classification of (Penfield and Jasper, 1954). Stimulation of the temepilepsy syndromes in 1989 (ILAE, 1989). poral lobe, for example, would occasionally reproduce a particular memory or a déjà vu feeling, consistent RECENT DEVELOPMENTS with Jackson’s hypothesis that this region was the During the second half of the 20th century, three major source of the “uncinate fits” (Penfield and Boldrey, advances have had a significant impact on the under1937; reviewed in Penfield and Jasper, 1954). Then, in standing, diagnosis and treatment of seizure disorders. 1948, Gibbs and Gibbs reported a study of over 300 The most pervasive change in the landscape of clinical patients with “psychomotor” seizures, in which disepileptology has been the development of numerous charges could frequently be recorded in the EEG over effective antiepileptic medications (Krall et al., 1978; the anterior temporal lobe and that, since this type of Scott, 1993; French et al., 1998; Kupferberg, 2001). epilepsy was highly resistant to pharmacotherapy, “surThe novel agents trimethadione (troxidone) and ethogical removal of the discharging region” was recomsuximide, both developed based on a pentylenetetramended (Gibbs et al., 1948). zole animal model of epilepsy, proved to be effective As a number of surgeons turned their attention to treatments for childhood absence epilepsy. Pharmaceuthe temporal lobe during the mid-20th century, they tical research on antipsychotic agents during the early reported limited, but promising, results, initially with 1950s led to the synthesis of carbamazepine. Benzodiaa success rate of just over 50% in 1950 (Morris, 1950; zepines were also introduced at this time, initially prePenfield and Flanigin, 1950; Bailey and Gibbs, 1951). scribed for their antipsychotic and anxiolytic/sedative Gradually, limited surgeries that involved the removal properties, but rapidly became critical agents for the of just one or two temporal convolutions gave way to management of epilepsy and the treatment of status larger but more effective resections, which included epilepticus. During the 1960s, the anticonvulsant mesial temporal structures (i.e., the hippocampus and effects of valproic acid, used as an organic solvent amygdala) (Morris, 1950), as well as the temporal pole, since the late-19th century, were discovered. Within a uncus, and lateral structures (Penfield and Baldwin, decade, valproic acid became the first “wide spectrum” 1952). By the late 1950s, surgical resection had become antiepileptic agent, highly effective at preventing both a safe and effective treatment for mesial temporal lobe generalized and focal-onset seizures. During the last epilepsy, with high rates of surgical cure (70–80% 30 years, the development of several animal models seizure-free outcomes in well selected patients) and of human seizures and epilepsy syndromes, such as low rates of morbidity and mortality that have not sigthe tottering mouse, the photosensitive baboon, and nificantly changed during the last few decades. the genetic absence epilepsy rats from Strasbourg The post-World War II period saw the rise of (GAERS), has facilitated the screening of many thouseveral European schools of epileptology, the most sands of potential antiepileptic medications, over a notable being the Marseille school. Henri Gastaut and dozen of which have been successfully marketed his colleagues intensively explored the correlation (French et al., 1998; Kupferberg, 2001). between clinical seizure type, epilepsy syndrome, and Another major advance in the modern development EEG pattern during the 1950s (Gastaut, 1970, see of epileptology has been the pursuit of cellular, moleCh. 40). While some epilepsy syndromes, such as West cular and genetic mechanisms in the production of seisyndrome or benign Rolandic epilepsy, had been zures. These contributions are too numerous, and the described during the classical period, Gastaut focused mechanisms they have revealed are too complex, to on the recognition of specific epilepsy syndromes with summarize here. I shall mention just a few milestones. common features such as age of seizure onset, seizure First, during the 1960s, research on the feline penitype(s), EEG pattern, degree of progression, underlycillin model of epilepsy revealed that interictal dising etiology or pathology, and therapeutic features. charges in the EEG – the thumbprint of an This work led to the description of many imporepileptogenic lesion – are associated with a high-amplitant epileptic syndromes including photoparoxysmal epitude, prolonged depolarization (referred to as the parlepsy, startle epilepsy, hemiconvulsive-hemiplegic oxysmal depolarization shift) and a superimposed epilepsy, severe encephalopathy of children with epiburst of high-frequency spikes in cortical neurons lepsy (eponymously named Lennox–Gastaut syndrome),

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(Matsumoto and Ajmone-Marsan, 1964; reviewed in Prince, 1978). Second, investigation of the mechanisms that drive normal brain oscillations during sleep, such as the 12–14 Hz sleep spindles, led to the discovery that spike-and-wave EEG discharges associated with generalized seizures and epilepsy syndromes probably result from corruption of the normal feedback networks between the thalamus and cortex that govern brain oscillations during sleep (Steriade et al., 1994; reviewed in Blumenfeld, 2005). Third, an explosion in genetic techniques has implicated particular ion channels (and the genes that code for them) in a number of human epilepsy syndromes (reviewed by Berkovic et al., 2006), presenting enormous challenges to the current generation of epileptologists in terms of understanding the relationship between genes, seizures, and epilepsy syndromes. Lastly, the rise of neuroimaging has profoundly impacted the diagnosis, classification, and treatment of the epilepsies. The advent of computerized tomography (CT) during the mid-1970s rendered many gross lesions, particularly those associated with dense calcifications (seen in some tumors, vascular malformations, and infectious processes), visible for the first time in vivo. The introduction of magnetic resonance imaging (MRI) during the 1980s, however, and subsequent advances in MRI technique have had a more profound impact on the diagnosis and treatment of medically intractable epilepsy. Indeed, with the routine use of MRI it is now possible to identify a wide variety of brain lesions – including hippocampal sclerosis, low grade tumors, and malformations of cortical development (MCDs) – early in the course of the disease. Some of these lesions, such as MCDs, were previously considered rare (and previously contributed to the substantial number of “cryptogenic” epilepsy cases), but are now readily visualized on high resolution MRI (Barkovich, 2002). Indeed, new techniques such as functional MRI, positron emission tomography (PET), and magnetoencephalography (MEG) continue to improve our ability to detect epileptogenic lesions and offer surgical therapy in the setting of medically intractable epilepsy.

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Millett D (forthcoming). Brain Waves: EEG and the History of Modern Neuroscience. Oxford University Press, New York. Moog FP, Karenberg A (2003). Between horror and hope: gladiator’s blood as a cure for epileptics in ancient medicine. J Hist Neurosci 12: 137–143. Morison RS, Dempsey EW (1941). A study of thalamocortical relations. Am J Physiol 135: 281–292. Morris AA (1950). Temporal lobectomy with removal of uncus, hippocampus and amygdala. Results for psychomotor epilepsy three to nine years after operation. AMA Arch Neurol Psychiatry 76: 479–496. Penfield W (1950). Epileptic automatisms and centrencephalic integrating system. Res Nerv Mem Dis Proc 30: 513–528. Penfield W, Baldwin M (1952). Temporal lobe seizures and the technique of subtotal temporal lobectomy. Ann Surg 136: 625–634. Penfield W, Boldrey I (1937). Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain 60: 398–443. Penfield W, Erickson TC (1941). Epilepsy and Cerebral Localization: A Study of the Mechanism, Treatment and Prevention of Epileptic Seizures. Charles C Thomas, Springfield. Penfield W, Flanigin H (1950). Surgical therapy of temporal lobe seizures. Arch Neurol Psychiatry 64: 491–500. Penfield W, Jasper H (1940). Electroencephalography in focal epilepsy. Trans Am Neurol Assoc 66: 26–30. Penfield W, Jasper H (1954). Epilepsy and the functional anatomy of the human brain. Little Brown, Little Brown, Boston. Prince D (1978). Neurophysiology of Epilepsy. Ann Rev Neurosci 1: 395–415. Prince D and Farrell D (1969). “Centrencephalic” spikewave discharges following parenteral penicillin injection in the cat. Neurology 19: 309–310. Pritchard JC (1822). A Treatise on Disease of the Nervous System. Thomas and George Underwood, London. Reynolds JR (1861). Epilepsy: Its Symptoms, Treatment, and Relation to Other Chronic Convulsive Diseases. John Churchill, London. Russell JR (1961). Epilepsy: Its Symptoms, Treatment, and Relation to Other Chronic Convulsive Diseases. John Churchill, London.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 27

A history of cerebrovascular disease CATHERINE E. STOREY 1 * AND HANS POLS 2 Department of Neurology, Royal North Shore Hospital, St. Leonards, Australia 2 Unit for History and Philosophy of Science, University of Sydney, Sydney, Australia 1

INTRODUCTION The term cerebrovascular disease is relatively new. It was first listed in the 8th edition of the International Classification of Disease (ICD 8) in 1965, where it is included under diseases of the circulation and distinct from diseases of the nervous system. However, the medical conditions which are included under this heading (and which are generally linked by the familiar term “stroke”) have attracted medical attention since time and memorial. Stroke has been recognized and described since ancient times when it was included within the complex syndrome known as apoplexy. Hippocrates defined apoplexy solely by its catastrophic presentation: a sudden loss of consciousness, motion, and sensation, and not by any presumed common vascular etiology, as stroke is currently defined in contemporary practice. This ancient conception of apoplexy had a remarkable longevity. The term was still in use and the condition defined by the same characteristics when the London physician Dr. John Cooke (1756–1838) wrote his comprehensive Treatise of Nervous Disease in 1820. In this work, all the hitherto known concepts of this disease from antiquity to the time of his own contemporary practice are reviewed. On the basis of this review, Cooke provided a conclusive definition of apoplexy, which he proposed in these terms: The term apoplexia was employed by the Greeks, and is still used, to denote a disease in which the patient falls to the ground, often suddenly, and lies without sense or voluntary motion. Persons, instantaneously thus affected, as if struck by lightning, were, by the ancients, denominated, attoniti aut, syderati [struck by lightning; tempest]. (Cooke, 1820, p. 157)

*

Today, apoplexy is no longer a familiar medical term and has largely been replaced in clinical practice by “stroke.” Nevertheless, the term “stroke” also has earlier origins. According to the medical historian Francis Schiller, the first synonym for “stroke of the palsy” in the Oxford English Dictionary of 1599 is given as “stroke of God’s hands” (Schiller, 1970, p. 115). The term implied that the condition was caused by divine intervention; the patient appeared to be struck by lightning or by the “hand of God.” An alternative term, “cerebrovascular accident,” colloquially named a “CVA,” was introduced in the early-20th century. This was a period of growing awareness and acceptance of vascular theories and of the recognition of the consequences of a sudden disruption in the vascular supply of the brain. There is no better explanation than the one provided by Schiller in his history of stroke, which explains the likely genesis of this term: That rather blurry and pompous piece of nomenclature must have issued from the well-meant tendency to soften the blow to patients and their relatives, also from a desire to replace “stroke,” a pithy term that may sound unscientific and lacking gentility. “Cerebrovascular accident (CVA)” can be traced to the early 1930s – between 1932, to be exact, when it was still absent from the 15th edition of Dorland’s Medical Dictionary, and the following edition of 1936 where it first appeared. (Schiller, 1970, p. 129) In the modern understanding of stroke (or cerebrovascular diseases) the term “accident” is to be discouraged.

Correspondence to: Catherine Storey, Department of Neurology, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia. E-mail: [email protected], Tel: +61-2-94391993, Fax: +61-2-94384919.

402 C.E. STOREY AND H. POLS Covered by the term “stroke” there are several subHe [Hippocrates] says, “A person in health is groups, which include hemorrhagic (further subdivided suddenly seized with a pain about the head, the according to location as intracerebral, subdural, or subvoice is immediately intercepted, he snores arachnoid), ischemic, and lacunar stroke, all defined by and gapes, and if spoken to or moved, he only their morbid pathology, and transient ischemic attack sighs; [he] is insensible, and makes a great deal (TIA), defined according to its clinical presentation. of water without knowing it. If he becomes A wide variety of patho-physiological mechanisms are mute and snores, he dies within seven days, known to underlie these sub-types. The singular comunless a fever comes on, and then he generally mon factor that defines the term stroke in modern recovers . . . This kind of disease generally hapmedical usage is that all strokes are known to result pens to people advanced in years, [rather] than from a disturbance of the vascular supply of the brain. to young subjects; but the most usual time of The terms stroke and cerebrovascular diseases have attack, is betwixt forty and fifty years of age. It thereby become synonymous. is more common in winter and rainy seasons. A history of stroke must begin with the ancient texts of The brain suffers and becomes morbid, and if Greece and Rome, in particular the Hippocratic writings eroded sustains a violent derangement; hence of the 5th century BC and the extensive texts of Galen delirium, the brain is convulsed, and involves of Pergamum of the 2nd century AD, and will therefore the whole man in the same perturbation; he cover a period in excess of two millennia. By necessity, becomes incapable of speaking, and suffocation this history has to be written as a series of defining events ensues . . . If apoplectic patients are attacked with or discoveries that, viewed retrospectively, identify those the piles, the symptom is favourable, if with chiltheories that align with our modern vascular understandling and torpor, it is a bad sign . . . It is impossible ing of stroke. Generally, such overview histories assume to cure a vehement apoplexy; nor is a weak one that rank-and-file medical practitioners followed each very easily cured”. (Kirkland, 1792, pp. 5–9) new discovery with immediate acceptance of new theories Much of this summary of Hippocratic theory still and treatment methods. This assumption is, in most cases, provided the basis of the clinical concept of apoplexy unjustified. Long intervals separate the proposal of a new at the time this 1792 monograph was published. theory from its incorporation into clinical practice. From Apoplexy, in the Hippocratic writings, is presented the discarding of humoral theories of the Galenic tradias a disease in which the brain suffers as a consetion in centuries past to the introduction of thrombolysis quence of an imbalance in the four humors of the for ischemic stroke in modern medical practice, long perbody, blood, phlegm, black bile, and yellow bile, while iods separate theoretical innovation from changes in bedtherapeutic options of purging and blood-letting are side management. proposed as interventions that serve to correct these In this history of stroke, we therefore attempt to humoral imbalances (Clarke, 1963). highlight medical innovations and breakthroughs that Galen of Pergamum (129–201 AD), one of the most eventually led to changes in everyday medical practice. prolific medical writers of antiquity, who left a legacy This account will attempt to identify those landmark of written works, elaborated on the clinical concepts events that, during this long period under review, were contained in the Hippocratic aphorisms and suppleresponsible for the nominal and conceptual transition mented them from his own clinical and animal dissecfrom apoplexy to stroke over two millennia, concludtion experience. His works contain numerous ing with the point at which “cerebrovascular disease” references to apoplexy. Galen constructed a complex entered the official terminology. neural physiology, which included an explanation for both the signs and symptoms of apoplexy (Freemon, APOPLEXY: EARLY CONCEPTS 1994; Karenberg, 1994). According to Galen’s theory (400 BC^1600 AD) of neural function, “vital spirits” (vital pneuma), formed in the heart and transported to the brain via The term “apoplexy” was introduced in the Hippocratic the blood, first underwent transformation in the “rete writings (c. 400–200 BC), with many scattered refermirabile,” an arterial plexus he identified at the base ences to this medical disorder found throughout the of the brain in his animal dissection specimens. “Anicorpus (Clarke, 1963). One of the most succinct mal spirits” so formed were stored within the cerebral abstracts of the opinions held by the Hippocratic physiventricles, the postulated center of cerebral function cians is found in the monograph, A Commentary on (only later was the cerebral cortex identified as the Apoplectic and Paralytic Affections, which was pubfunctional component), until required for transmitting lished by the 18th-century English physician Thomas movement to the rest of the body (Karenberg, 1994). Kirkland, who summarized these ideas:

A HISTORY OF CEREBROVASCULAR DISEASE 403 Galen thus reasoned that apoplexy might result from autopsy failed to demonstrate the anticipated phlegm a failure of flow of these “animal spirits,” caused by an in the ventricles; in this case, Galen’s argument was accumulation of thick phlegm within the ventricles. For difficult to sustain. The apoplexy, Fernel reasoned, physicians at this time, the provision of a correct progoccurred, not as a consequence of an obstruction of nosis rather than a diagnosis was of paramount imporanimal spirits from the ventricles, but as a result of a tance; medical attention was therefore directed toward clot of blood obstructing flow of the vital spirits in the signs that were thought to influence outcomes. the arterial formation at the base of the brain. (Fernel’s Galen proposed that a severe attack characterized by case was reported in the substantial pathological collecsignificant respiratory compromise was invariably fatal, tion of The´ophile Bonet’s Sepulchretum of 1679; while an attack accompanied with only minimal respiraSchutta and Howe have extensively reviewed Bonet’s tory signs improved the chances of recovery. Clinical contribution to the understanding of apoplexy in a assessment of vital signs played an important part in recent publication, 2006). the physician’s ability to recognize and to prognosticate Further challenges to Galenic views emerged from such patients with apoplexy. the great Renaissance anatomists. Andreas Vesalius Remnants of these principles were still in evidence (1514–1564) demonstrated that other aspects of Galenic when Cooke offered this clinical definition in 1820: theory were erroneous. In 1543, in his detailed descriptive and illustrative anatomy of the human brain, [Apoplexy] is a disease in which the animal De Humani Corporis Fabrica, the myth of the rete functions are suspended, while the vital and mirabile was dispelled with the conclusion that this is natural functions continue; respiration being not a structure identifiable at the base of the human generally laborious, and frequently attended brain (Vesalius, 1543). Despite the excellence of his with stertor. (Cooke, 1820, p. 166) anatomical illustrations, Vesalius failed to include Following Galen’s extensive writings on medical accurate depictions of the hexagonal ring of communiaspects of apoplexy, there has been a general consencating vessels that came to play such a pivotal role dursus amongst authors of histories of stroke that ing the next period of the vascular history of the brain. “although a few additional clinical features had been The description of the circulation of the blood by presented during the Middle Ages and Renaissance, litWilliam Harvey (1578–1657) in 1628 introduced signifitle was added to the ancient descriptions and concepts cant elements that would later contribute to a re-concepof apoplexy” (McHenry, 1969, p. 374). Galen’s authortualization of apoplexy, as older theoretical concepts itative doctrines formed the basis of medical opinion gave way to those derived from physiological experiand remained the core of medical knowledge well into mentation. Harvey’s discovery, although not universally the Middle Ages and beyond (detailed reviews of medembraced within the medical community at the time, ieval doctrines of apoplexy can be found in Karenberg provided the catalyst for two physician-anatomists of and Hort, 1998a, b, c). the 17th century, Johann Jacob Wepfer (1620–1695), from Schaffhausen, and Thomas Willis (1621–1675), from Oxford, to investigate apoplexy as a possible VASCULAR ORIGINS OF APOPLEXY cerebrovascular event. (1600^1700) Although Willis was a very accomplished clinician In exploring the origins of the conception of apoplexy and had written extensively on a broad range of neuroas a vascular disease, it is important to understand logical conditions, it is undoubtedly the arterial anastoGalen’s recognition of the vascular network at the base mosis at the base of the brain for which he is best (and of the brain, the rete mirabile, and the role Galen eponymously) known (Symonds, 1955; Meyer and assigned this structure in human neural physiology Hierons, 1962; Dewhurst, 1999; for a full description (the historical importance of this structure is reviewed of Willis’ clinical neurology see Eadie, 2003a, b). In by Viale, 2006). Unfortunately, this is a structure that 1664, Willis published De Cerebri Anatome, the most Galen erroneously extrapolated to the human brain complete and accurate account of the nervous system from his animal dissections. up to that time (Willis, 1664). This work included an Starting in the 16th century, an increasing number illustration of the complete anastomosis, later referred of challenges were leveled against traditions that had to as the “Circle of Willis.” Priority for the description long dominated medicine, including concepts of apoof this structure, albeit incomplete, is generally given plexy. In 1544, the French philosopher, physician, and to Gabriel Fallopius (1523–1562), who described the leading Galenic opponent of his time, Jean Fernel complex arterial circle in 1561; others further described (1497–1558), presented a case of a patient who died or illustrated the incomplete circle well before Willis of apoplexy as a consequence of a head injury. The (Casserio, 1627; Vesling, 1647; Wepfer, 1658). It was

404 C.E. STOREY AND H. POLS Willis, however, who recognized its physiological sigI once opened the dead carcass of one wasted nificance and suggested a functional basis for this vasaway, in which the right Arteries, both the Carocular structure (Symonds, 1955; Meyer and Hierons, tid and the Vertebral, within the skull, were 1962). He deduced that the most important function become bony and impervious, and did shut for of the anastomosis lay in its ability to provide a collatthe blood from that side, notwithstanding the sick eral arterial supply in the event of occlusion of one person was not troubled with the astonishing artery, thus preventing apoplexy. Disease [apoplexy]; wherefore it may be doubted, Willis reasoned as follows: whether the blood excluded from the Brain, by reason of some Arteries being obstructed or comBut there is another reason far greater than this pressed, doth bring forth this Disease. Certainly [mixing of blood] of these manifold ingraftings there is more of danger that the cause of the of the Vessels, to wit, that there may be a maniApoplexy, should be from its too great incursion fold way, and that more certain, for the blood and extravasation within the brain. (Willis, about to go into divers Regions of the brain, laid 1684; cited by Spillane, 1981, p. 69) open for each; so that if by chance one or two The wealth of sometimes-contradictory pathological should be stopt, there might easily be found findings in this “astonishing disease” precluded Willis another passage instead of them: as for example, from establishing a definite connection between arterial if the Carotid of one side should be obstructed, occlusion and apoplexy. Nevertheless, the contributions then the Vessels of the other side might provide of Willis and his Oxford colleague Richard Lower for either Province . . . Further, if both the (1631–1691) advanced the study of apoplexy into one Carotids should be stopt, the offices of each might of experimental physiology and clinico-pathological be supplied through the Vertebrals. (Willis, correlation (Spillane, 1981). 1684; cited in Symonds, 1955, p. 122) Credit for having been the first to propose that He followed with a clinical example: occlusion of a vessel might result in apoplexy is generally assigned to an earlier author, Gregor Nymann It is not long since we dissected the dead body of (1594–1638) of Wittenberg (McHenry, 1969). In what a certain man . . . When his Skull was opened, we is recognized as the first monograph on apoplexy, pubbeheld those things belonging to the Head, and lished in 1619, Nymann reasoned that apoplexy might found the right Carotid, rising within the Skull result from a lack of flow of “vital spirits” obstructed plainly bony or rather stony, its cavity being by the occlusion of a carotid artery, a transition almost wholly shut up; so that the influx of the between the humoral theories of the past and the blood being denied by this passage, it seemed future vascular basis of this disease. wonderful, wherefore this sick person had not In 1658, prior to Willis, Johann Wepfer had also dyed before of an Apoplexy: which indeed he made an important observation with relation to apowas so far from, that he enjoyed to the last plexy. Wepfer is today remembered for being the first moment of his life, the free exercise of his mind person to demonstrate a relationship between the conand animal function . . . This Gentleman, about dition of apoplexy and intra-cerebral hemorrhage the beginning of his sickness, was tormented with (Pearce, 1997). Wepfer published a treatise, Historiae a cruel pain of the Head towards the left side. The Apoplectorum, which would be reprinted in five writcause whereof I know not how better to explain, ings between 1658 and 1724, an influential and authorthan that the blood excluded from the right Carotid itative work, and one quoted well into the 19th century Artery, when at first it rushed more impetuously (Wepfer, 1658). In it, he presented four reports in the left, had distended the Membrane. (Willis, of patients who, in life, presented the clinical picture 1684; cited in Symonds, 1955, p. 122) of apoplexy and at post-mortem showed massive intraWillis, challenged by a clinical scenario, provided a cranial hemorrhages. rational physiological explanation based on his personal Although history records Wepfer’s contribution as interpretation of the cerebral vascular anatomy. He his identification of cerebral hemorrhage, it has been made reference to the arterial changes in both the caroargued that Wepfer contributed much more to the tid and vertebral arteries, and to the occlusion of the understanding of the pathogenesis of apoplexy than arteries that resulted from these pathologies. Observing his description of hemorrhage alone (Mani, 1982; vascular occlusion without apoplexy at the same time, Karenberg, 2004). Wepfer also explained apoplexy as however, Willis seemed reluctant to conclude that there a potentially occlusive vascular disease. Thus, as a was a definitive causal relationship, writing: direct result of Harvey’s earlier explanation of the

A HISTORY OF CEREBROVASCULAR DISEASE 405 circulation of the blood, Wepfer provided both a phyWhile many isolated case reports of apoplexy were siological interpretation and pathological explanation recorded from the 15th century on, these were often for the disease of apoplexy (Mani, 1982). Wepfer difficult to source or of limited practical value for reasoned that apoplexy might result either from the physician. In 1679, The´ophile Bonet (1620–1689) obstruction of inflow through the carotid arteries, suphad published in Geneva the first extensive collection ported by the finding of small fibrous bodies (corpora of all diseases, including both case reports and autopsy fibrosa) partially occluding the cerebral arteries; by a findings. Most of the published cases of apoplexy up delay to egress of flow through the jugular veins; in to his time were included in his Sepulchretum sive Anaaddition to the rupture of arteries and effusion of tomia Practica (literally, “Burial Vault of Practical blood into the cerebral cortex. Anatomy”) to which Bonet added his own notes as well Arterial changes had now been well described, but it as additional personal material (Schutta and Howe, was Franc¸ois Bayle (1622–1709) of Toulouse who, in 2006). This collection, enlarged and edited by Johann 1677, described the changes of arteriosclerosis within Mangentus in 1700, remained an important reference the arterial wall and linked this finding to apoplexy source until replaced in 1761 by the more extensive col(Bayle, 1677; McHenry, 1969). The actual term “arteriolection of Giovanni Battista Morgagni (1682–1771). sclerosis” was a much later term introduced by These works of Bonet and Morgagni form the the German-born French pathologist Jean Lobstein basis of John Cooke’s reference material when writing (1777–1835) in 1829 (Schiller, 1970). A Treatise on Nervous Diseases (1820). At the conclusion of the 17th century, a link had Morgagni, in the long-standing anatomical tradition been established between apoplexy and intracranial of the University of Padua, sought to determine the hemorrhage. Prominent researchers had also identified “seats and causes of disease investigated by anatomy,” disease within the cerebral arteries and established a and published his findings as De Sedibus et Causis clinical association with apoplexy. The cerebral arteries Morborum per Anatomen Indagatis (Morgagni, 1761). were now assuming an important role in the pathogenThis work, a foundation for the modern study of esis of apoplexy. Mani, who researched Wepfer’s pathology, provided an impressive, systematic arrangemid-century contribution to the patho-physiological ment and logical synthesis of a massive collection of explanation of apoplexy, has written: “From a process material based on a lifetime of clinico-pathological of humoral pathology in the form of obstruction or observations, and was published when Morgagni was repletion of the cerebral ventricles, apoplexy became 79! Written in the format of “observations” or letters a vascular and circulatory disease of the brain” (Mani, to a young colleague, this work categorized diseases 1982, p. 52). according to the affected organ and the pathology In practice, following the influential writings of deemed responsible. Wepfer and Willis, intracerebral hemorrhage became The first of his five books he devoted to Diseases of the most favored explanation for apoplexy. But the Head, which included most of the cases of apogeneral acceptance in actual clinical practice of apoplexy. These he divided systematically, according to plexy as primarily a cerebrovascular disease was still macroscopic findings, into “sanguineous,” in which a in the future. collection of blood was identified, “serous,” in which a collection of fluid with the characteristics of serum was recognized, and others, a diverse group that A FOCUS ON PATHOLOGY AND included cases of tumors and abscesses, amongst other THE CHARACTERISTICS OF conditions. DISEASE (1700^1860) In this work, apoplexy remained defined according In spite of the burst of activity in medical research durto clinical presentation. Rather than providing radical ing the 17th century, there is general agreement among new insights, Morgagni consolidated the findings of the authors of histories of stroke that there were no his predecessors. He too made reference to the dismajor discoveries that would radically change the eased arteries observed in apoplexy. He also confirmed course of cerebrovascular disease during the 18th an earlier theory proposed and illustrated by Domencio century (McHenry, 1969; Fields and Lemak, 1989). Mistichelli, of Pisa, who had suggested that paralysis There were, however, several developments that would will occur contralateral to the side of the lesion (Mistirefocus clinical attention on this disorder, and this prochelli, 1709). Although no new or radical insights into gress would lay the foundations for later medical the causation of apoplexy were proposed, it can be said research, establishing clinico-pathological correlations that Morgagni provided a structure for the potential for apoplexy, as well as systems of classification to re-classification of the condition of apoplexy according aid bedside recognition of this disease. to underlying pathological findings.

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In 1769, within a few years of the publication of De Sedibus, Scottish physician William Cullen (1710–1790) published his Synopsis Nosologicae Methodica, a comprehensive, albeit to the modern eye cumbersome, symptom-based nosology of all human diseases. This new classification was fashioned on a framework used in the cataloguing of botanical material. In this work, apoplexy was divided according to the clinical characteristics that separated patients, not the pathology-based approach that had characterized Morgagni’s work. Cullen provided no reference to any cerebrovascular connection. Apoplexy (and paralysis as a separate disease entity) was classified within the class Neuroses, into the order Comata, “Of comata, or the loss of voluntary motion.” Apoplexy was further classified according to its distinguishing clinical features. Thus Cullen identified the sanguinea, marked by clinical features of a ruddy complexion; serosa, occurring in those with “leukophlegmatic habits” in the elderly; traumatica for those associated with head injury; mentalis produced by “passions of the mind”; atrabiliara “in persons of the melancholic temperament,” amongst others; hydrocephalica in children; and venerata from sedatives (Kendell, 1993). An examination of Cullen’s classification demonstrates a diversity of etiologies, with no suggestion of progression toward a single vascular cause. While most histories of stroke suggest that there was steady progress of ideas, based on a modern division into hemorrhagic and ischemic stroke, this dichotomy did not emerge until well into the 19th century. Although Cullen’s nosology was an immediate, widely adopted success, and was reprinted in many editions until 1823, his classification lost favor following his death. In 1820, when John Cooke wrote of the practical classification of apoplexy, he outlined Cullen’s classification in some detail, but clarified his own accord that now “many eminent modern physicians have approved the distinction of apoplexy into the sanguineous and the serous” (Cooke, 1820, p. 257–258): The sanguineous, they say, is marked by plethora, especially in the head, a strong robust constitution, suddenness of the attack, a swelled, red or purple countenance, a full, strong pulse, laborious stertorous breathing, prominence and inflammation of the eyes, and in increased heat of body, the disease happening not unfrequently in the vigour of life. The serous apoplexy takes place, they say, more especially in advanced, or old age, in debilitated or leucophlegmatic habits, and makes its attack more gradually than the sanguineous. In this species the countenance

is said to be pale; the pulse weak, and often irregular. (Cooke, 1820, pp. 257–258) The distinction between sanguineous and serous apoplexy seemed to be generally accepted in Cooke’s time, suggesting that a vascular dichotomy was emerging, at least in theory. There were, however, some notable dissenters. Cooke noted the objections voiced by French anatomist Antoine Portal (1742–1832), who considered it impossible to distinguish between the two forms in life (Portal, 1781). Cooke acknowledged this difficulty, but supported the clinical fact that serous apoplexy was generally seen with a more gradual clinical onset, in the older patient, while an intracranial hemorrhage was the expected post-mortem finding in cases of sudden onset of apoplexy, and added that diseased arteries were a frequent accompaniment. This association had been well described some years before. The English pathologist Matthew Baillie, in 1793, had specifically referred to diseased arteries of the elderly brain in the final chapter of his Morbid Anatomy on “Diseased appearances of the brain and its mechanisms” (Baillie, 1793). The diseased arteries he had conclusively related to the occurrence of intracerebral hemorrhage. He also described a “bony or earthy matter being deposited in the coats of the arteries, by which they lose a part of their contractile and distensible powers, as well as of their tenacity,” and went on to reason that: The vessels of the brain under such circumstances of disease are much more liable to be ruptured than in a healthy state. Whenever blood is accumulated in unusual quantity, or the circulation is going on in them with unusual vigor, they are liable to this accident, and accordingly in either of these states ruptures frequently happen. (Baillie, 1793; quoted in McHenry, 1969, p. 130) In the early-19th century, the clinical presentation of apoplexy, in the minds of most physicians, was equated with an intracranial hemorrhage. What then had become of Morgagni’s alternative pathological finding, that of “serous apoplexy”? In his comprehensive review of 1820, Cooke stated that, while contemporary opinion suggested that “serous” apoplexy was rare in comparison to “sanguineous,” there were some, including the notable Scottish physician John Abercrombie (1780–1844), who questioned its very existence as a pathological entity. According to Schiller’s history of stroke, “serous apoplexy” was “the great enigma, the early pathologist’s no-man’s-land lying between hemorrhage and other palpable causes of brain disease, called ‘apoplexy’ when sudden and fatal” (Schiller, 1970,

A HISTORY OF CEREBROVASCULAR DISEASE 407 p. 119). While a relationship had been firmly established the pathological studies of his French contemporaries, between hemorrhage and arterial disease, there was no proposed (as early as 1837) that “we cannot preserve suitable explanation for those cases that had been the term ‘Apoplexy’ any longer in Science.” He justidesignated as “serous.” Non-hemorrhagic causes were fied his decision with the explanation that: often not considered in terms of arterial obstruction It is too vague, it does not indicate with precision or occlusion, but rather within the popular theory of the material change in the organ, but, like all other “vascular congestion” (Morgagni, 1761; Portal, 1781; similar terms capable of various interpretations, it Burrows, 1848). lends itself to every theory, and in the end serves no Some resolution occurred in 1820, when French real purpose but that of covering our ignorance. pathologist Le´on Rostan (1790–1866), then at the SalpeˆFor observe how many different affections of the trie`re hospital, described a pathological process that brain give rise to the same symptoms as apoplexy, would rival hemorrhage as a cause of apoplexy (Rostan, – viz., sudden loss of consciousness and motion. 1823; Poirier and Derouesne´, 2000). Rostan had first been See how the effects of simple congestion, of ramolpuzzled when a patient who had presented with the clinilissement, etc., are equally comprised under this cal features of apoplexy failed to show the anticipated generic term. (Andral, 1836, p. 523) hemorrhage at post-mortem. During the next few years, Rostan examined a series of such patients, in whom he It was a change in emphasis on disease pathology, found, at macroscopic level, the appearance of softening rather than symptoms, which led Andral to support of the brain tissue, to which he assigned the name the abandonment of the time-honored term apoplexy. “ramollissement” (Poirier and Derouesne´, 2000). Such There is recognizable acknowledgment that various “softenings” were commonly found in the region of the pathological processes were responsible for the sympcorpus striatum, the thalamus, and centrum ovale. toms of apoplexy, which had served to describe a speRostan considered “softening” to be a more common cific clinical presentation. It is also acknowledged that occurrence than hemorrhage. He reasoned, contrary to the mechanisms that led to such observed pathologies prevailing opinion, that this “softening” was not inflamwere still poorly understood. Magendie also questioned matory in nature. But although he recognized ossification the terminology of sanguineous and serous apoplexy, of arteries in many of these cases, he failed to associate citing a lack of precision in determining the underlying these findings with, or determine a pathogenesis for, cause or nature of the lesion as his disillusionment with “ramollissement.” these terms. He reasoned: These thoughts were not lost on Rostan’s French I would willingly abandon the term “apoplexy,” a contemporaries. The highly respected French physioloterm which is evidently unsuitable, which bears gist Franc¸ois Magendie (1783–1855), in a lecture of no relation whatever to the cause or nature of 1837, stated: “how much superior to determine the the disease, for, as the etymology indicates, it exact nature of the modifications, without thinking merely refers to one of the circumstances under the thing is complete when we have pronounced the which the disease is developed, namely, that of word ‘ramollissement’ ” (Magendie, 1837, p. 551). striking suddenly (besides, this phenomenon is A causal relationship between arterial occlusive disby no means a constant one), and I would adopt ease and softenings was first suggested by the Scottish in its place any word which expresses accumulaphysician John Abercrombie (Abercrombie, 1828) and tion of fluid. (Magendie, 1837, p. 551) later confirmed by other British physicians (Bright, 1831; Carswell, 1838). It would, however, be another century before the term Overall, the clinicians of the 18th and early-19th centuwould leave the medical vocabulary, during which time ries, who sought to correlate clinical presentations with pathologists and clinicians continued to contribute to pathology findings, had made significant progress toward the understanding of the pathogenesis of what Willis an understanding of the condition that had hitherto been had called this “astonishing disease.” referred to as apoplexy. It can be said, however, that a One such pathologist was Carl Rokitansky (1804– variety of radically different pathological conditions had 1878). Working in Vienna during the 1840s, he drew become subsumed under the heading of apoplexy. attention to the common association of apoplexy and In a series of lectures delivered during the 1835– cardiac enlargement. While many apoplexies were 1836 academic year of the University of Paris, Profesassumed to be due to congestion associated with dilatasor Gabriel Andral (1797–1876) presented a comprehention of the right ventricle, left ventricular hypertrophy sive account of all known diseases of the nervous and an increased “impulse” were also recognized system from a clinico-pathological perspective. In his as common associations with cerebral hemorrhage discussion on apoplexy Andral, greatly influenced by (Schiller, 1970).

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C.E. STOREY AND H. POLS stream as far as they can go. (Virchow, 1847; quoted by Schiller, 1970, p. 127) Thus Virchow demonstrated that arterial occlusion could be caused by a clot formed in situ in the intracranial artery (thrombosis) or by a clot formed at a distance and transported via blood vessels (embolism). The theory of an embolus occluding a vessel distant from the site of origin was not a novel concept (Pearce, 2002). Gerard van Swieten had suggested this mechanism as a potential cause of apoplexy when, in his 1754 commentaries on Boerhaave, he had written a century earlier: It has been established by many observations that these polyps occasionally attach themselves as excrescences to the columnae carneae of the heart, and perhaps then separate from it and are propelled, along with the blood, into the pulmonary artery or the aorta, and its branches . . . were they thrown into the carotid or vertebral arteries, could disturb – or if they completely blocked all approach of arterial blood to the brain–utterly abolish the functions of the brain. (van Swieten, 1754; cited in McHenry, 1978, p. 9)

Fig. 27.1. Rudolf Virchow (1821–1902). (Courtesy of the Clendening History of Medicine Library, University of Kansas Medical Center.)

It was Rudolf Virchow (1821–1902), a mid-19thcentury German pathologist (Fig. 27.1), who would expand the vascular theories of occlusive stroke with the introduction of the terms “thrombosis” and “embolus” into the medical literature (Schiller, 1970). In doing so, he focused attention on the physiological mechanisms that underpinned the processes of stroke. Virchow reasoned that thrombosis (a clot) could occur, not as the result of an inflammatory process, as was generally assumed by pathologists at this time, but rather as a consequence of local arterial changes. An inflammatory response was a secondary and not primary event. Thus, he revived the term arteriosclerosis, introduced by Lobstein in 1829, to explain the local fatty streaks within the arterial wall, which he identified at the site of thrombosis in situ. Virchow also proposed an alternate means of vessel occlusion, a process that he called “embolism”: In contrast to that kind of obliterating clot we find another kind. Here there is either no essential change in the vessel wall and its surroundings, or this is ostensibly secondary. I feel perfectly justified in claiming that these clots never originated in the local circulation but that they are torn off at a distance and carried along in the blood

Both thrombosis and embolism had the potential to occlude arterial flow, which Virchow acknowledged was responsible for cerebral softening. When Schiller considered the impact of this work on the progress of stroke, he reasoned: Virchow’s role must be seen in the decisive switch from the vitalist concept of inflammation to the demonstrable fact of a mechanism, as fundamental and modern as plumbing. (Schiller, 1970, p. 127) Virchow’s re-classification of apoplexy now included sanguinea (with an intracerebral hemorrhage) and ischaemica (his term). With regard to ischemic apoplexy, he considered embolism the most common cause, usually affecting the middle, anterior cerebral arteries, the carotid arteries, or the vertebral arteries. When English physician William Kirkes (1822–1864) read a paper before the Medico-Chirurgical Society in 1852, he reported the clinical findings on three patients with cardiac disease and apoplexy, providing the first detailed clinical and pathological description of cerebral embolism (Kirkes, 1852; Pearce, 2003). Within a short period of time, clinicians generally accepted the concept of embolic occlusion, with the potential for diagnosis in life, rather than just at the post-mortem table (Anon, 1860; Gowers, 1875). By the late-19th century, the various pathologies associated with apoplexy and their modes of presentation

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had become accepted in routine clinical practice. On the one hand, it was accepted that those patients with a sudden explosive onset were most likely to have suffered an intracerebral hemorrhage, and that arterial disease and left ventricular hypertrophy were common associations. On the other hand, an alternative pathological finding was that of cerebral softening, a result of occlusive arterial disease, presumed due to either local intracranial arterial thrombosis or from a distal embolic source. The term apoplexy had become largely but not exclusively synonymous with intracerebral hemorrhage.

VASCULAR ANATOMY (1860^1950) By the second half of the 19th century, physicians and researchers, encouraged by the contemporary interest in cerebral localization, looked to occlusive cerebrovascular events as a means to study vascular anatomy and to correlate these findings with specific clinical syndromes (Tatu et al., 2005). The study of functional vascular anatomy began with the research of Henri Duret (1849–1921) in Charcot’s laboratories at the Salpeˆtrie`re (1874). Duret mapped the areas of supply of the major cerebral vessels, while also describing, with Charcot, the lenticulo-striate artery or “artery of cerebral haemorrhage.” Important contributions followed from Otto Huebner (1843–1926) in Germany (Huebner, 1872), Charles Beevor (1854–1908), an English anatomist (Beevor, 1907), and two Australian anatomists: Joseph Shellshear (1885–1958) and Andrew Abbie (1905–1976) (Shellshear, 1927; Abbie, 1933, 1937). Major contributions to understanding the vascular anatomy relating to stroke syndromes were made by Charles Foix (1882–1927) (Fig. 27.2), who, according to Caplan, deserves the title “the first modern stroke neurologist” (Caplan, 1990). With his co-workers in the 1920s, Foix was largely responsible for an “awakening interest in stroke.” They studied the distribution of a wide variety of cerebral softenings, making a detailed and systematic study of the arteries responsible, while correlating these findings with clinical presentations. By these means, Foix and his colleagues provided descriptions of the clinical syndromes of occlusion in the territories of the middle cerebral artery, and sylvian infarcts (Foix and Levy, 1927), posterior cerebral artery (Foix and Masson, 1923), anterior cerebral artery (Foix and Hillemand, 1929), and the vertebro-basilar territory (Foix and Hillemand, 1925). The emphasis lay in clinico-pathological correlation and clinical phenomenology. (For a more extensive review on Charles Foix, see Caplan, 1990, 2006a,b.) Just weeks prior to his premature death in 1927, Foix changed his focus from a descriptive analysis to a

Fig. 27.2. Charles Foix (1882–1927).

consideration of the physiological mechanisms of stroke. In a preliminary report to the Medical Society of the Hospitals of Paris, he presented the results of the vascular pathology identified in 56 cases (Foix et al., 1927a; Caplan, 1990). The artery responsible for the region of softening was found totally occluded in only 12 patients, partially occluded in 14, while the artery remained patent in 30. These researches redirected attention from pure pathological description in an innovative direction, which would lead to speculation about the possible mechanisms responsible for arterial occlusion and, in turn, cerebral softening (ramollissement). Foix proposed four possible explanations: (1) that occlusion may follow softening and therefore had insufficient time to develop in some cases prior to death; (2) that an embolus was responsible but had progressed distally since occlusion; (3) a period of arterial insufficiency had resulted from a more proximal circulatory failure (“l’insuffisance cardio-arte´rielle”); or (4) that arterial vasospasm had occurred (“spasme arte´riel”) (Foix et al., 1927a). Vasospasm would become a popular theory of occlusion in later decades. Subsequent studies correlating clinical with pathological findings included reviews of basilar artery

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occlusion (Kubik and Adams, 1946), internal carotid occlusion (Fisher, 1951), cerebral hemorrhage (Fisher, 1961a), and lacunar infarcts (Fisher, 1965). The clinician, prior to the age of technology, was provided with knowledge of the clinical patterns with which to interpret the anticipated pathological processes responsible for a given stroke. With a developing clinical interest in stroke, it would be only a short time before researchers would develop methods of visualizing these pathologies in life. Treatment of stroke, which up to this time still showed remnants of correction of humoral imbalance best characterized by the long-held tradition of blood letting, would undergo the most radical revisions, as shall now be shown.

THE ORIGINS OF MODERN STROKE MEDICINE (1950^1975) The carotid artery In 1951, Charles Miller Fisher (b. 1913), in the tradition of the pathologist-clinician, drew attention to the extracranial carotid artery as a potential cause of stroke, or apoplexy as Fisher still often referred to the condition in this report (Fisher, 1951). This landmark paper would transform not only the way in which stroke was viewed as a vascular disease but would herald a new era in the management of stroke. Fisher followed with a report in which he correlated these lesions with attacks of contralateral hemiplegia and ipsilateral monocular blindness (Fisher, 1952). Earlier clinicians were aware of the extracranial carotid artery. Hans Chiari, a Viennese pathologist, had, in 1905, first suggested that the extracranial portion of the carotid artery was a potential embologenic source (Chiari, 1905). Chiari had described in a series of patients pathological changes at the carotid bifurcation, which he referred to as “arteriosclerosis nodosa” or “endarteritis chronica deformans.” These irregularities, he postulated, in turn resulted in thrombosis at the extracranial site from which cerebral emboli had led to the demise of four patients. As early as 1914, the New York neurologist J. Ramsay-Hunt had similarly drawn attention to the neck vessels as having a potential role in cerebrovascular events (Hunt, 1914). In his description of the syndrome of internal carotid occlusion he prefaced his remarks by writing: The object of the present study is to emphasise the importance of obstructive lesions of the main arteries of the neck, in the causation of softening of the brain, and more especially to urge the routine examination of these vessels in all cases presenting cerebral symptoms of vascular origin. In other words, the writer would advocate the

same attitude of mind towards this group of cases as towards intermittent claudication, gangrene, and other vascular symptoms of the extremities, and never omit a detailed examination of the main arterial stem. (Hunt, 1914; cited by Eastcott et al., 1954, p. 994) While Fisher acknowledged these former authors, he lamented the fact that their advice had been largely disregarded. The examination of the carotid artery in life was made technically possible when Egas Moniz, a Portuguese neurosurgeon and future Nobel Laureate, demonstrated the technique of cerebral angiography (Moniz, 1927a). Initially, the technique was developed for the identification of intracranial pathologies such as tumors (Moniz, 1927b). In a later contribution, Moniz described the occlusion by thrombosis of the cervical portion of the carotid artery, reporting this observation in 1937 (Moniz et al., 1937).

Transient ischemic attack (TIA) and potential treatment options Fisher took advantage of the technology to examine the previously neglected extracranial segment of the carotid artery. His stated aim was to “furnish important clues to the mechanisms of many heretofore puzzling cerebral symptoms, especially transient episodes of blindness, aphasia, paresthesia and paralysis” (Fisher, 1951, p. 347). A transient cerebral symptom as a harbinger of stroke was not a new concept (the historical development of the transient ischemic attack is covered by Hachinski, 1982; Mohr, 2004). Reference had been made to warning events when Hippocrates wrote that “attacks of numbness and anaesthesia are signs of impending apoplexy” (Clarke, 1963), while later authors made reference to this detail supported by their own clinical experience. One of the most descriptive explanations of such events is found in the text of Kinnier Wilson who writes: Whether such symptoms constitute minor antecedent attacks or merely indicate general vascular trouble is immaterial; they are the straws which show how the intracranial wind is blowing. (Wilson, 1940, p. 1088) At the time of Fisher’s landmark article of 1951, vasospasm was considered the most likely cause of a transient ischemic attack (TIA), with hemodynamic and thrombotic events as less common alternative causes (Hachinski, 1982). Fisher reported that, in 1950, 70% of completed ischemic strokes were considered to be due to vasospasm (Fisher, 2001). Thus, the extrapolation to TIA was understandable.

A HISTORY OF CEREBROVASCULAR DISEASE 411 The presumption of vasospasm as a major cause of This report served as a great impetus for surgeons stroke led to treatments to effect vaso-dilatation. Stelto attempt comparable procedures. The operation late ganglion block, first proposed in 1936 (Leriche and gained in acceptance and was refined by both vascular Fontaine, 1936), was popularized “in an attempt to and neurosurgeons. The popularity of the procedure influence the zone of vasoconstriction around an was evident; in 1985, over 107 000 procedures had been ischaemic area” (Millikan et al., 1961, p. 192), or to performed in the United States alone (Estol, 1996). dilate a narrowed vessel rapidly for the treatment of It would be some years until the publication of methocases of “intermittent insufficiency.” Vasopressor dically sound trials of the benefits of such surgery agents were still in use in 1972 in the management of (NASCET, 1991; ACAS, 1995). acute ischemic stroke (Wise et al., 1972) but the rationale for their usage and the efficacy of such therapy Stroke emerges as a specialty was under scrutiny (Browne and Poskanzer, 1969). Fisher’s results, however, suggested an alternate Potential therapeutic options in a specialty that hitherto mechanism for transient ischemic attacks: thrombohad lacked successful treatments, in combination with embolic disease. Fisher was somewhat reserved but new diagnostic angiographic techniques to determine prophetic when it came to discussing therapy. He the underlying pathology in life and not at post-morbegan his discussion by stating that “on this subject tem examination, led to a renewed enthusiasm for there is little definite to state,” although he continued: research on stroke in the 1950s. Recognition of a need to research deeper into the causes and treatment of It is even conceivable that some day vascular stroke led to the formation of the Joint Council surgery will find a way to by-pass the occluded Subcommittee on Cerebrovascular Disease of the portion of the artery during the period of omiAmerican Heart Association (AHA). nous fleeting symptoms. (Fisher, 1951, p. 377) The first in a series of formal conferences on cerebrovascular disease, soon to become known as the Princeton Conferences, was held in 1954. These events Carotid surgery brought together those at the forefront of cerebrovascuHistory has proven Fisher’s speculation to be correct. lar research and clinical practice. By 1964, the AHA had Fisher’s work directly promoted the carotid artery as formed an ad hoc Coordinating Committee for a an important site of interest for stroke research, therNationwide Stroke Program, with Irving Wright, a cardiapy, and clinical opinion (Millikan et al., 1955; Acheson ologist, as chairman. In 1967, the committee emerged as and Hutchinson, 1964; Marshall, 1964; Estol, 1996). the Council on Cerebrovascular Disease of the AHA, Once the clinician was aware of the risk profile for a and the Stroke Council was born (Caplan, 2006b). TIA, and the ability to identify a lesion by angiography In an historical review of the early days of the was widely available, the next logical step was prevenStroke Council, Bob Siekert, a founding member, tive interventional surgery (reviews of the history of summed up the position on stroke in the 1950s, stating: carotid artery surgery can be found in Thompson, The importance of the early Princeton Conferences 1996; Robertson, 1998; Heros and Morcos, 2000). cannot be overemphasised. By 1950, or so, investiAfter reading about Fisher’s explanations of carotid gative work had begun on stroke-related topics pathology, the first carotid surgery was performed in such as atherosclerosis of the large extracranial Buenos Aires in 1951, although not reported in the medical arteries, related cardiac disorders, and increasing press until 1955 (Carrea et al., 1955). The first successful use of arteriography, but the medical profession in carotid endarterectomy (CEA) was performed by Michael general remained aloof from the study of the subDe Bakey on 7 August 1953, with the publication of his ject. The first conference [held in 1954] clearly report delayed until 1975 (De Bakey, 1975). At St. Mary’s indicated a desire to go forward. The second [held Hospital, London, H.H.G. Eastcott, George Pickering and in 1956] and third [held in 1961] conferences Charles Rob contributed to the innovative carotid reconbrought forth previously unknown individuals, struction operation in 1954 (Eastcott et al., 1954; Eastcott, new insights in viewing stroke, and talk of therapy. 1994). These authors reported the case of a woman aged By this time, neurologists showed interest in the 66, who, after 33 episodes of right hemiparesis, left field. (Siekert, 1995, p. 1490) amaurosis, and speech disturbances, successfully underwent carotid reconstruction with complete resolution of Through the exchanges at these conferences, new her symptoms. She was reported to be alive and well when approaches were encouraged, and clinical expertise last examined at age 86. was shared.

412 C.E. STOREY AND H. POLS Up to this time, clinical and pathological examinaprevention and acute stroke management. (The developtions had provided an increasing understanding of the ment of stroke initiatives during the 20th century is problem of the spectrum of stroke. Angiography comprehensively recorded by Caplan, 2006a, b.) allowed the clinician to visualize the cerebral arteries, but clinical signs alone determined whether the patient CONCLUSIONS was considered to have either an ischemic or hemorrhaThe history of stroke covers a period of over two millengic stroke (Aring and Meritt, 1935; Fisher, 1961a). In nia. Known in antiquity as apoplexy, the term included a 1972, however, a technological development occurred vast array of medical conditions, which had in common that would revolutionize the management, investigathe presentation with a catastrophic loss of motor and tion and understanding of patients with stroke. At the sensory function. The term took on a new meaning in Annual Congress of the British Institute of Radiology, the 17th century, when apoplexy was first demonstrated Godfrey Hounsfield, of the Central Research Laborato result from an intracranial hemorrhage and thereby tories of EMI, delivered an account of the technique became a “vascular disease.” The disease was further of computerized tomography (CT scan) (Hounsfield, refined by the clinico-pathological correlations that 1973). Commercial CT scanners followed soon after began in the 16th century and culminated in the great (Fields and Lemak, 1989), and even the deeper parts work of Morgagni in the mid-18th century. of the brain became visible in the living. As a conseThere followed a period during which clinicians quence, various types of stroke and stroke mimics, sought to understand these processes and identify the such as tumors, could now be distinguished with accumechanisms of the disease. By the mid-19th century, racy in life. The investigation and management of apoplexy was truly a cerebrovascular disease with the patients entered a different epoch. establishment of the importance of diseased arteries What then had happened to apoplexy? The term, in the genesis of hemorrhage and the occlusion of first questioned by the French physicians in the first arteries by the processes of emboli and thrombosis. half of the 19th century, lost favor during the later cenThe correlation of clinical features with the topography tury. Apoplexy, with its original understanding of a of arterial supply in the early-20th century confirmed sudden catastrophic presentation, became synonymous the importance of vascular anatomy in the understandwith an intracerebral hemorrhage. ing of stroke. Epidemiological studies have identified that, during When the extracranial portion of the carotid artery the period from 1877 to 1961, there was a gradual was found to be the culprit in many stroke syndromes, decline in the incidence of cerebral hemorrhage, with and with the possibility of intervention, the therapeutic a reversal in the ratio of cerebral thrombosis to hemornihilism that had so dominated stroke management for rhage (Yates, 1964). This was largely a consequence of two millennia faded. This generated a substantial and the new attention given to the identification and treatcontinuing interest in stroke. ment of hypertension (Hamilton and Kellett, 1969). As This history of cerebrovascular disease will conclude the catastrophic presentations became less common, so at the time that the term “cerebrovascular disease” too did the term apoplexy, which was finally omitted entered the official classification of the ICD coding, from the WHO classification of cerebrovascular disorin 1967. With the introduction of the journal Stroke in ders in 1965, and replaced in the lay and medical verna1970, stroke as a medical specialty had come of age. cular by the term stroke and in official classifications The aims of the journal outlined in the introductory by cerebrovascular disease. pages of its first issue summarize the contemporary The 20th century has seen enormous progress in position of stroke: stroke management and vastly improved outcomes for patients, improved means of investigation, and improveStroke: A Journal of Cerebral Circulation brings ments in the understanding of pathogenesis. Large comtogether reports of clinical and basic investiputerized databases and stroke registers that developed gation of any category of cerebrovascular disease, from the early 1970s have advanced the epidemiological or the cerebral circulation, from many discistroke data (Mohr et al., 1978); advances in ultrasonoplines including neurology, internal medicine, graphy and radiology permit visualization of the vascuradiology, pathology, vascular physiology, rehabilar tree; echocardiography aids investigation of litation, neuro-ophthalmology, neurosurgery, neuassociated cardiac disease; while stroke management ropsychology, and vascular surgery. (Millikan, has been revolutionized by the development of stroke 2001, p. 4) units, coordinated by stroke teams. The randomized Stroke has emerged from a long history to the present, controlled trial has led to the safe adoption of treatment where it is now a disease with multiple facets and strategies and expanded treatment options for stroke

A HISTORY OF CEREBROVASCULAR DISEASE multi-disciplinary involvements. Nevertheless, we still have a long way to go in the quest to achieve a full understanding of the mechanisms that underlie cerebrovascular disease.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 28

A history of bacterial meningitis KENNETH L. TYLER * Department of Neurology, University of Colorado Denver Health Sciences Center and the Denver Veterans Affairs Medical Center, Denver, CO, USA

INTRODUCTION Central nervous system (CNS) infections are likely as old as humankind. Evidence of CNS infections is featured in archeological artifacts and anthropologic specimens that antedate written records. For example, a Neolithic skeleton dated to 5000 BCE shows evidence of spinal tuberculosis (Morse, 1961), as do several Egyptian skeletons dating to 3500 BCE and earlier (Chalke, 1959; Morse et al., 1964). We can infer that ancient civilizations were familiar with many infectious diseases known to affect the CNS, and in some cases we can make “modern” diagnoses based on depictions of illness in ancient monuments or other art forms. One of the earliest and most famous likely depictions of the sequelae of a CNS infection appears in an Egyptian funeral stele dating from the 18th dynasty (1580–1350 BCE), which is in the Carlsberg Glyptothek in Copenhagen. The stele depicts a priest with a staff whose right leg is withered and atrophic and who almost certainly suffered from poliomyelitis (Paul, 1971). The Greek and Roman writers of the pre-Christian era were also clearly aware of rabies (Steele, 1975). Short remarks about rabies in both humans and other animals, including dogs, can be found in Aristotle and the Hippocratic writers. It was the Romans who utilized the Latin word “virus” (literally “poison”) to describe the disease-causing agent. Celsus wrote a major monograph on the disease, clearly identifying saliva as the key agent for its transmission. He noted that “it was a most wretched disease, in which the sick person is tormented at the same time with thirst and the fear of water, and in which there is but little hope” (Steele, 1975, p. 2). Many descriptions of the combination of severe headache and febrile illnesses with various additional *

symptoms including mental status alterations can also be found in the Hippocratic writings, and almost certainly include cases that today would be considered as having encephalitis and/or meningitis. It is on this subset of infectious disease, predominantly what would later be recognized as “bacterial meningitis,” that the remainder of this chapter is focused. This narrow perspective is justified, as bacterial meningitis is arguably the “archetype” of all CNS infections, and one of the easiest CNS infectious diseases to trace through early historical records because of the relative stereotypy of its cardinal clinical manifestations of headache, fever, and altered sensorium. Focal suppurative infections including brain abscess and empyema are briefly covered elsewhere in this volume, as attempts to surgically treat them played a seminal role in fostering the development of modern neurosurgery (see Ch. 14).

ENGLISH AND SCOTTISH CONTRIBUTIONS 17th century: Thomas Willis (1621–1675) Writers in the 17th and 18th centuries frequently referred to brain fever, “phrenitis,” and “cephalitis,” undoubtedly including under these diagnostic labels patients who today would be classified as having encephalitis or meningitis. These labels were generally used to refer to patients with combinations of symptoms including headache, fever, and delirium. The English physician Thomas Willis (1621–1675) is increasingly recognized as a seminal figure in the history of neurology and the neurosciences. Not only was he a great cerebral anatomist whose eponym still is associated with the arterial circle at the base of the brain (“Circle of Willis”), but he also pioneered the use of the experimental approach

Correspondence to: Kenneth L. Tyler MD, Reuler-Lewin Family Professor of Neurology, Professor of Medicine, Microbiology & Immunology, University of Colorado Health Sciences Center and the Denver Veterans Affairs Medical Center, Denver, CO, USA. E-mail: [email protected], Tel: +1-303-393-2874, Fax: +1-303-393-4686.

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to the analysis of the nervous system, and he repeatedly tried to correlate his clinical observations of disease with his knowledge of neuroanatomy and even with results he obtained in studies of experimental physiology. Many of his clinical observations were included in his London Practice of Physick (Willis, 1685), an English translation of several of Willis’ Latin works that appeared 10 years after his death. The Physick contains a section entitled “Of the Phrensy,” noting “The Phrensy is defin’d: That it is a continual raving, or a depravation of the chief faculties of the brain, arising from an inflammation of the meninges with a continual fever” (Willis, 1685, p. 452, emphasis in original). This ancient sense of a hyperactive and at times almost maniacal state is preserved in our modern word “frenzy.” Willis was clearly aware, based on his own clinical observations, that many patients with “phrensy” never had hyperactive features and often progressed clinically into a hypoactive state of lethargy or coma that could lead to death. He developed a pathophysiological explanation for the differences between hyper- and hypoactive forms of “phrensy”: “Inflamm’d Meninges, and much more swollen, greatly compress the Brain, and stop the passages of the Spirits, which causes a Lethargy; whereas in a Phrensy the Spirits are dilated above measure, the Pores of the Brain being all open’d. . .” (Willis, 1685, p. 452). He noted that:

18th century: Robert Whytt (1714–1766) and the Edinburgh School In the 18th century, Robert Whytt (1714–1766) (Fig. 28.1) and his contemporaries developed and characterized a new nosological category of disease referred to as “acute hydrocephalus (hydrocephalus acuta)” or “dropsy in the brain.” Whytt became one of the stars of what is often referred to as the Edinburgh school, a group of 18th century physicians born, educated, or practicing in that area. Whytt himself ultimately became the President of Edinburgh’s Royal College of Physicians and served from 1747 until his death as Professor of the Theory of Medicine at the University of Edinburgh’s medical school. His major medical writings, including those of neurological interest, were collected and published posthumously by his son in 1768. It is in this collection that his Observations on the Most Frequent Species of the Hydrocephalus Internus, viz: the Dropsy of the Ventricles of the Brain appeared for the first time. Although some of these patients suffered from congenital or other causes of obstruction to CSF flow or absorption, it is likely that

Every Man knows that Convulsions sometimes happen to Persons in Fevers, and from thence a very great Prognostick is taken of death or danger . . . a Vertigo or Delirium arise from the Morbisick Matter’s being depos’d from the Blood in the Brain; so from the same fall’n into the Genus Nervosum, Contractions and Twitchings of the Muscles and Tendons, and also sudden shakings of the Members and Limbs, and sometimes horrible stiff extensions in the whole Body ensue, which sorts of Convulsive affects happen for the most part about the height of Fevers, when the Morbisick Matter, first heap’t together in the blood, is convey’d thence into the Brain, and that being either presently past through, or infected together with it, carried into the Systema Nervosum, and thence Convulsive affects, with or without a Delirium are rais’d. (Willis, 1685, p. 271) Willis followed his descriptions of “phrensy” with a section entitled “An account of an Epidemick Fever, reigning An. 1661. Which chiefly infested the Brain and the Genus Nervosum” (Willis, 1685, pp. 273–278). This was likely one of the earliest descriptions of an epidemic of meningococcal meningitis (see below).

Fig. 28.1. Robert Whytt (1714–1766). (From L. McHenry, Garrison’s History of Neurology, 1969, p. 115, with permission of Charles C. Thomas, publisher.)

A HISTORY OF BACTERIAL MENINGITIS 419 a great many had hydrocephalus resulting from meninor Dropsy in the Brain (Cheyne, 1808) dedicated to gitis, particularly tuberculous meningitis. Charles Bell. As implied in his monograph’s title, Whytt is generally credited with the first clear Cheyne focused on cases of hydrocephalus in which descriptions of this disease. He was aware of earlier the clinical course was rapid. His cases resembled descriptions of similar cases dating back to Hippothose that had been described by another prominent crates and Celsus, but noted that no one had “favored member of the Edinburgh school, the physician Wilus with the signs by which we may distinguish dropsy liam Cullen (1710–1790), under the name “apoplexia of the ventricles of the brain from other diseases hydrocephalica.” Cullen’s (1777) textbook, First Lines affecting that organ” (Whytt, 1768, p. 726). He then of the Practice of Physic, was a landmark in the claswent on to remedy this deficiency, dividing the sympsification of disease (nosology) and widely used as an toms of dropsy in the brain into three stages. In the authoritative text throughout Europe in the late 18th first stage, which began 4–6 weeks before death, “At and early 19th centuries. Cullen had described an illfirst they [children] lose their appetite and spirits; they ness that he called “apoplexia hydrocephalica” that look pale, and fall away in flesh; they have always a “arises gradually in children, and affects them with quick pulse, and some degree of fever” (Whytt, 1768, lassitude, feverishness, and pain in the head; afterp. 729). He then went on “They complain of a pain in wards with slowness of pulse, dilation of the pupil the crown of their head, or in the forehead above their of the eyes, and somnolency” (Cullen; quoted by eyes . . . They cannot easily bear the light, and complain Cooke, 1820, p. 379). Cheyne also referred to this illwhen a candle is brought before their eyes.” In the secness as “internal acute hydrocephalus” (hydrocephaond stage, which typically began 2–3 weeks before lus acutus) and noted like Cullen that it occurred death, the pulse slowed and became irregular. The chiefly in children and was associated with fever and symptoms present in the first stage continued, and an altered sensorium (consciousness) and generally the children became increasingly drowsy. He clearly terminated in death. In these fatal cases, “the ventridescribed paralysis of extra-ocular movements and cles of the brain are found enlarged and full of the appearance of palsies of the oculomotor nerve. lymph” (Cheyne, 1808, p. 11). However, somewhat in “Their eyes are often turned toward their nose, or they contrast to both Whytt and Fothergill, he felt that squint outwards, and sometimes they complain of seethe excess fluid in the brain was not the primary proing objects double” (Whytt, 1768, p. 732). In the final cess in the disease, but instead a reaction to some stage children became drowsy and ultimately comaantecedent event, which he speculated might be disortose. Whytt (1768, p. 733) noted that “Frequently one dered vascular circulation. “In dissection of the brain eye-lid loses its motion, and afterwards the other after Hydrocephalus, the most striking appearance is becomes also paralytic. About this time, or rather the fluid contained in the ventricles; but, in reasoning sooner, the pupil of one or both eyes ceases to conon the immediate causes of the symptoms, the importract, and remains dilated in the greatest light.” tance of this effusion appears to me to be over-rated. Whytt’s colleague David MacBride (1726–1778) (MacWhat is only an effect, a mere symptom, is assumed Bride, 1772) made similar observations to Whytt’s on cases as the cause of all symptoms” (Cheyne, 1808, pp. 56– he called “hydrocephalus internus with fever.” Another 57). Later he elaborates: “It is obvious that, before contemporary, John Fothergill (1712–1780), generally the dropsical effusion [in the ventricles] takes place, agreed with Whytt’s description, noting that the patients the condition of the part, as it exists in health, must complained of “an acute deep seated pain in the head, be altered; and that this antecedent condition is part extending across the forehead from temple to temple, of the disease. Accelerated circulation as certainly and he is generally very sick, exclaiming alternately, ‘Oh precedes the effusion of the lymph . . . as it does the my head! Oh, I am sick!’. . .” (Fothergill, 1783–1784, Vol. formation of purulent matter” (Cheyne, 1808, p. 57). II, p. 69; also quoted by Cooke, 1820, pp. 393–394). Pain In some aspects Cheyne’s theory had been anticipated could also occur below the head “most commonly about by Charles Quin, who had noted that hydrocephalus the nape of the neck” (Fothergill; quoted by Cooke, 1820, “owes its origin to morbid accumulation of the blood p. 393). The symptoms included “dilation of the pupils of in the vessels of the brain, sometimes preceding to a the eye, with paralysis of the eyelids; aversion to light; an degree of inflammation, and generally (but not always) inability to bear any but the horizontal posture, one or both producing an extravasation of watery fluid [in the ventrihands being commonly about the head; great heat of the cles] before death” (Quin, 1779). head and body, with profuse sweats. . .” (Fothergill, 1783– In addition to his contribution to pathology and 1784, Vol. II, p. 69). pathogenesis, Cheyne also refined the clinical descripThe Edinburgh physician John Cheyne (1777–1836) tion of disease first advanced by Whytt. He separated wrote a monograph entitled Hydrocephalus Acutus, out a rapid form of disease that might last only a

420 K.L. TYLER few days from the more chronic forms (described by effusion in the ventricles, and the brain in other Whytt) that could last 4–6 weeks. In the acute cases respects was healthy” (from Case VII, p. 53). Aber“There is a sudden change to a fever, attended, even crombie’s studies played a critical role in shifting the from the first, with a great degree of pyrexia. . .severe emphasis from ventricular pathology (e.g., hydrocephaheadache. . .we are led to suspect some deeply-seated lus) to meningeal inflammation as the primary patholoevil, from the frantic screams, and complaints of the gical substrate for meningitis. head and the belly, alternating with stupor. . .” (Cheyne, 1808, pp. 14–15). Cheyne revised Whytt’s three 18TH AND 19TH CENTURY GENEVAN stages into those of increased sensibility, decreased (SWISS) PHYSICIANS AND THE FIRST sensibility (torpor), and a terminal paralytic or convulREPORTS OF EPIDEMIC MENINGITIS sive stage (Cheyne, 1808, pp. 89–90). In the stage of Several physicians from Geneva extended the earlier increased sensibility there was “great aversion to light observations of Whytt and his colleagues of the “Edinand sounds.” In the second stage of decreased sensibilburgh School” (Mullener, 1965). Jean-Franc¸ois Coindet ity the child was “not easily roused, his pupil is dilated, (1774–1834) identified a subtype of hydrocephalus charhis pulse is slow, he is lethargic. . .” The final stage was acterized by violent head pains and extreme fever and characterized by “squinting, rolling of the head, raving, tachycardia. He described the patient’s sensitivity to stupor, convulsions . . .” light, plaintive crying, and rapid progression to death, Another Edinburgh physician, John Abercrombie often in just over a week’s time. Credit for the recogni(1781–1844) (Pitman, 1991), is often credited with writtion of the importance of meningeal suppuration in ing the first textbook of neuropathology (Abercrombie, patients with meningitis likely belongs to another Gen1828). He devotes a section of this book to “Inflammaevan physician, Louis Odier (1748–1814) (Odier, 1779; tion of the arachnoid and pia mater” (Section IV, pp. Mullener, 1965), although the use of the term “menin49–71). He notes in introducing this section, “To pregitis” to describe this process did not come into general vent circumlocution, I shall employ the term Meningiuse until later (see below). Odier described an epidemic tis to express the disease, meaning thereby the that occurred in Geneva in 1789, including 16 cases inflammation of the arachnoid, or pia mater, or both, with 12 deaths. He commented that the disease was as distinct from inflammation of the dura mater” not rare and that 12 or 13 infants died of it each year (Abercrombie, 1828, p. 51). Although the term meningiin the Geneva area. He noted the frequency of a pretis was likely first employed by Herpin in 1803 (see ceding febrile illness and the common association of Mullener, 1965), it was not until after Abercrombie’s abnormal pupillary reflexes. He described hippus (flucwork, which was widely disseminated, that it came into tuating size of the pupil despite maintained exposure general usage. In describing the clinical correlates of to a light source). He felt this sign was pathognomonic meningitis he notes: of “internal hydrocephalus” as he had not seen it in any Some degree of this affection frequently accomother disease (Odier, 1779, p. 198; Mullener, 1965). panies other acute diseases of the brain, but we Describing the post-mortem appearance of the brain very often find it uncombined, so that we are from a patient who had died Odier noted: enabled to mark the symptoms more immediately The pia mater was largely inflamed. Between it and connected with it. In these, however, there does the arachnoid was a semitransparent gelatinous not appear to be any uniformity. In some cases, substance which covered one of the lobes [of the it comes on with a headache, vomiting, fever brain] almost entirely and impinged considerably and impatience of light; but I think the more on the other one. On the first lobe a portion approxicommon form in which the attack takes place, mately two thumbs length long was suppurating. is by a sudden and long continued paroxysm of (Odier, 1779; quoted in Mullener, 1965, p. 7) convulsion. (Abercrombie, 1828, p. 50) Abercrombie divided cases of meningitis into several subtypes based on the extent of the inflammatory process and its location. He recognized types in which inflammation predominantly involved the base of the brain, the surface of the brain, and in which meningitis was combined with suppuration within the ventricles. He clearly recognized the importance of the inflammatory process in the meninges as the predominant pathological lesion, noting in many cases that “there was no

Surprisingly, despite Odier’s frequent observations of frank suppuration including a vivid description of green and yellow pus combined with dilated meningeal vessels in the case of an 8-month-old girl who died, he was reluctant to attribute a primary role to the meningitic process alone – instead concluding that the meningeal inflammation led to the hydrocephalus which was the central pathogenetic facet of the disease (Mullener, 1965).

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FRENCH CONTRIBUTIONS In 1803, the French army surgeon Franc¸ois Herpin (Herpin, 1803) wrote a thesis on “meningitis” which he referred to as an “inflammation of the membranes of the brain.” This likely represents the first use of the term meningitis in its modern sense (Mullener, 1965). Herpin was describing cases of CNS infection complicating military traumatic head injuries. He explicitly described the presence of purulence in the meninges at autopsy in these cases. Some of the afflicted soldiers did not have prominent delirium, which was generally considered a cardinal feature of “phrenitis,” and this led Herpin to coin the new term “meningitis” to describe his cases. By 1839, Louis Guersent (1777–1848) was able to propose a classification of meningitis that began to reflect modern views of the disease, separating out acute meningitis, chronic meningitis, meningitis due to trauma, epidemic meningitis, and a final subset of cases associated with mental illness (these likely including cases of the syndrome of syphilitic general paresis that had recently been described by Antoine Bayle [1799–1858] in 1822) (Mullener, 1965): 1. Tuberculous meningitis, characterized by a more or less distinct preliminary phase which ends in a rather sudden outburst of the typical symptoms, and by the pathological-anatomical finding of tubercles in the meninges as well as other organs. 2. Simple, non-tuberculous meningitis. A.: Acute form, occurring after injuries of the head, epidemically or without evident reason . . . B.: Chronic form, with or without mental illness. (Guersent, 1839; quoted by Mullener, 1965)

THE EMERGENCE OF CLINICAL SUBTYPES OF MENINGITIS Epidemic meningitis The Genevan physician Gaspard Vieusseux (1746–1814; Fig. 28.2) is often credited with having written the earliest comprehensive clinical description of epidemic meningitis, describing cases that were almost certainly due to meningococcal infection (Vieusseux, 1805). Vieusseux reported on an epidemic that appeared in January 1805 near Geneva, ultimately leading to 33 fatal cases during a 3-month period. It began in a most peculiar and terrifying manner at a very small distance from the town [Geneva] in a district inhabited by poor people, dirty, and in whom the manner of life favored the development of every contagious disease . . . At the end of January, in a family composed of a woman and three children, two of the children

Fig. 28.2. Gaspard Vieusseux (1746–1814). (From E.-R. Mullener, Six Geneva physicians on meningitis, J Hist Med Allied Health Sci 20: 1–26, 1965, with permission of Oxford University Press, publisher.)

were attacked and died in less than forty-eight hours. Fifteen days later the disease appeared in another family in the neighborhood, [four infants] were attacked at almost the same time, and all died . . . after having been sick fourteen to fifteen hours with striking symptoms of malignancy . . . It commences suddenly with prostration of strength, often extreme; the face is distorted, the pulse feeble, small and frequent. . . . There appears a violent pain in the head, especially over the forehead; then there comes . . . vomiting of greenish material, of stiffness of the spine, and in infants, convulsions. In the cases which were fatal, loss of consciousness followed. The course of the disease is very rapid, termination by death or by cure . . . In most of the patients who died in twenty-four hours or a little after, the body is covered with purple spots . . . Examination of the body showed most frequently a sanguinous engorgement in the brain without any particular alteration of the other viscera . . . this disease has certain singular characteristics, especially in the grave cases. These characteristics are the sudden invasion, the violence of the headache, the vomiting, and especially the rapidity of the termination. It forms then, a distinct species, and the name of cerebral malignant, non-contagious (sic) fever is that which appears the best. The brain is the only

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organ in which post-mortem inspection has shown any alteration; the affection of the other parts appears to come only from the brain, and all the symptoms of it are nervous. (Vieusseux, 1806; translated by Major, 1945, pp. 188–189) Vieusseux’s colleague Andre´ Matthey (1778–1842) reported on the same epidemic the following year, including a clear description of the cardinal pathological features including basilar accumulation of pus and congestion of the meningeal vessels. The vessels of the meninges were notably congested. A gelatinous humour covering the brain was markedly tinged with blood. There was fluid in the ventricles . . . The base of the brain was covered by a yellow puriform matter, with no obvious change in the underlying cerebral tissue. This exudation covered the optic chiasma and extended backwards towards the cerebellum, reaching for the space of an inch down the vertebral canal. (Matthey, 1806; quoted in Foster and Gaskell, 1916, pp. 2–3) Virtually identical outbreaks to the one in Geneva occurred in America in Massachusetts in 1806 and in Connecticut in 1807. Credit for the first American description of meningococcal meningitis is often given to Elisha North (1771–1843; Fig. 28.3) for his description of the Connecticut outbreak in his Treatise on a Malignant Epidemic Commonly Called Spotted Fever (North, 1811; Pleadwell, 1924). North seemed to have had a particular interest in neurological diseases, as he subsequently wrote two books on phrenology (Pleadwell, 1924). Earlier but less complete descriptions had appeared in the graduation thesis of another Connecticut physician, Nathan Strong Jr. (1781–1837) (Strong, 1810; see Grady, 1965), and in a report in 1806 by two Massachusetts physicians, Danielson and Mann, of nine affected children who became ill in March of 1806 (see Danielson and Mann, 1806). Without any apparent previous predisposition, the patient is suddenly taken with violent pain in the head and stomach, succeeded by cold chills, and followed by nausea and puking . . . the heat of the skin soon becomes much increased. . . [after six to nine hours], when coma (suppression of sense and voluntary motion) commences . . . livid spots resembling petechiae (purple spots which appear in the last stages of certain fevers) appear under the skin, on the face, neck, and extremities . . . (Danielson and Mann, 1806; as quoted in Grady, 1965; Scheld, 2001, p. 4)

Fig. 28.3. Elisha North (1771–1843). (From R.H. Major, Classic Descriptions of Disease, 3rd edn., 1945, p. 190, with permission of Charles C. Thomas, publisher.)

Pathological features were described in five cases, including a 10-year-old boy: On removing the cranium and dividing the dura mater, there was discharged by estimation, half an ounce of serous fluid. The dura and pia mater in several places adhere together, and both to the substance of the brain. The vessels of the brain were uncommonly turgid . . . and the substance of the brain itself remarkably soft, offering scarcely any resistance to the finger when thrust into it . . . (Danielson and Mann, 1806; as quoted in Grady, 1965; Scheld, 2001, p. 4)

Tuberculous meningitis Two decades after Gaspard Vieusseux described meningococcal meningitis, the French physician Louis Senn (1799–1873) (Senn, 1825) would describe a more chronic type of basilar meningitis that occurred in children. Although Robert Whytt in England had described cases that likely represented tuberculous meningitis in 1768 (see above), Senn’s cases are unequivocal. Several of the afflicted children were found at autopsy to have

A HISTORY OF BACTERIAL MENINGITIS 423 pulmonary cavitation, miliary disease, or even frank and its coverings. The ability to definitively brain tubercles diagnostic of tuberculosis. At autopsy, diagnose meningitis ante-mortem, and to further subpatients were noted to have “little lenticular plaques” categorize its types, was dramatically expanded by or “little yellowish plaques” within the brain tissue, typithe introduction of cerebrospinal fluid (CSF) examinacally adjacent to vessels. These plaques were almost certion as a routine part of the neurological diagnostic tainly tubercles. The meninges in these cases, especially armamentarium. at the base of the brain, were thickened, opaque, and The examination of the spinal fluid, first performed granulated. Senn distinguished between a “simple” type by James Leonard Corning (1855–1923) in 1885, led to of meningitis that included non-tuberculous cases and a the introduction of the modern lumbar puncture by “complicated” form associated with hydrocephalus, Heinrich Quincke (1842–1922) (Fig. 28.6). Virtually contubercles, and involvement of the brain parenchyma. It temporaneously with Quincke’s efforts, both Walter was this later complicated type that took the form of a Wynter (1860–1945) and Charles Morton (1860–??) “basilar” meningitis so characteristic of tuberculosis. had attempted therapeutic drainages of lumbar spinal Senn’s report is even more remarkable as it appeared fluid in patients with tuberculous meningitis (Morton, in the same year as Pierre Louis’ (1787–1872) seminal 1891; Wynter, 1891). Wynter’s technique was more cumstudies on pulmonary tuberculosis (Louis, 1825). A pupil bersome than Quincke’s and involved making a small of Louis’, the American physician William Gerhard incision down to the dura and then inserting a small (1809–1872) (Gerhard, 1833), described a similar series rubber tube. of cases based on his personal experiences with 10 chilQuincke’s studies included examination of the CSF dren, and an additional 20 cases collected from his colin patients with purulent meningitis, and he was the leagues at the Hospital for Sick Children in Paris first to recognize the presence of pleocytosis and hypo(Hoˆpital des Enfants Malades). He clearly identified glycorrhachia as well as to identify bacteria in CSF the presence of headache, vomiting, seizures, cognitive obtained by lumbar puncture (Quincke, 1891, 1893, impairment, and focal neurological findings including 1895). In his first reports of CSF examination, Quincke paralyses and pupillary abnormalities. Gerhard recogmeticulously recorded the amounts of CSF withdrawn nized that these cases could occur in the absence of (typically 40–75 cc), its specific gravity, and its opening hydrocephalus, in distinction to the earlier focus on this pressure as well as change in pressure as fluid was aspect of the disease by Whytt. removed. Quincke’s initial studies, begun in 1888, Purulent basilar meningitis was clearly illustrated by involved removal of CSF from the ventricles after treRobert Hooper (1773–1835) in his classic atlas The Morbid phination. His first lumbar puncture was performed in Anatomy of the Human Brain (Hooper, 1826). The atlas December of 1890 in a boy 1 year 9 months of age with contains a section devoted to “inflammation of the pia presumed tuberculous meningitis. mater and tunica arachnoids” (Hooper, 1826, pp. 17–18). I punctured the subarachnoid space in the lumIn the first of the two plates in this section (Plate III precedbar area, passing a very fine cannula 2 cm deep ing p. 17), Hooper shows that “The vessels of the pia mater between the third and fourth lumbar spinal are enlarged and turgid with blood; there is a considerable arches and drop by drop I drained a few cubic quantity of puriform albumen in patches between the two centimeters of watery fluid . . . (Quincke, membranes; and the tunica arachnoids is, in many places, 1891; quoted by Pearce, 2003a, p. 204) thickened and opaque” (Hooper, 1826, p. 17). In the figure He described one of his first adult cases as having been legend he describes “Yellow patches or portions of albudone in April of 1891. In describing the technique men between the pia mater and tunica arachnoides, which employed he noted: very much resemble pus” (Hooper, 1826, p. 17). This is even more dramatically shown in Plate IV (Hooper, 1826, folThe patient lies on his left side with a markedly lowing p. 18) (Fig. 28.4) in which yellow-green patches of anteriorly flexed lumbar spine; with coma, espe“puriform albumen” are dramatically shown overlying cially in the child, anesthesia is not necessary. most of the base of the brain. A virtually identical figure The puncture is done with a thin cannula below was still in use nearly a century later (Fig. 28.5; Foster and the third and fourth lumbar arches . . . it is better Gaskell, 1916, Plate VIII). to puncture some millimeters lateral from the midline and to direct the needle in a way that EXAMINATION OF CEREBROSPINAL it reaches the midline on the posterior wall of FLUID IN MENINGITIS the dural sac. In the adult (and sometimes even Until the end of the 19th century, the diagnosis of in older children). . .this can be reached best meningitis was purely clinical, with confirmation by starting at the level of the lower third of the depending on post-mortem examination of the brain spinal process and a little lateral to it . . . and

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Fig. 28.4. Bacterial meningitis from J. Hooper, Morbid Anatomy of the Human Brain, Longman, Rees, Orme, Brown and Green, London, 1826, showing the green colored purulent exudates at the base of the brain.

pointing the needle somewhat upward . . . It is necessary to be led somewhat by sensation during the puncture. The emergence of fluid shows that one has reached the subarachnoid space. (Quincke, 1891; translated by Wilkins, 1965, pp. 306–307)

The association of bacterial meningitis with a low CSF glucose and pleocytosis was established in early reports by Ludwig Lichtheim (1845–1928) (Lichtheim, 1893), Georges Deniges (1859–1951), Jean Sabrazes (1867–1940) (Deniges and Sabrazes, 1896), and Arnold Netter (1855–1936) (Netter, 1898), and confirmed by William

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Fig. 28.5. Bacterial meningitis as illustrated in M. Foster and J.F. Gaskell, Cerebro-Spinal Fever, 1916, Plate VIII, London, with permission from Cambridge University Press.

Mestrezat (1883–1928) in his comprehensive studies of the chemical constituents of CSF (Mestrezat, 1912). It was Mestrezat who suggested that hypoglycorrhac likely resulted from both consumption of glucose by bacteria in the CSF and by its degradation by the associated cellular exudates, an opinion that predominated until studies in the 20th century suggested that interference with the action of glucose transporters was the more likely cause (Swartz and Dodge, 1965). The classic reference on CSF profiles in infectious and other neurological diseases was prepared by

H. Houston Merritt (1902–1979) and Frank FremontSmith (1895–1974), based on their exhaustive analyses of thousands of spinal fluid specimens sent to their Cerebrospinal Fluid Laboratory at Boston City Hospital. In their report (Merritt and Fremont-Smith, 1937) on CSF findings from 4074 patients with various diseases, they noted that in 152 cases of purulent meningitis, 147 had cell counts > 200 and four cases between 50 and 200 cells/ mm3. A more precise breakdown indicated that 1% had < 100 cells, 12% had 100–1000 cells, 72% 1000–10000 cells, 10% 10000–20000 cells, and 5% > 20000 cells,

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IDENTIFICATION OF THE MOST SIGNIFICANT BACTERIAL ETIOLOGIES OF MENINGITIS

Fig. 28.6. Heinrich Quincke (1842–1922). (From R.H. Major, Classic Descriptions of Disease, 3rd edn., 1945, p. 624, with permission of Charles C. Thomas, publisher.)

with the highest count recorded being 52000 from a patient with meningococcal meningitis. In looking at the sugar content of the CSF in these patients, Merritt and Fremont-Smith found that 23% had a glucose concentration of < 10 mg/dl, 57% between 10 and 40 mg/dl and 20% > 40 mg/dl. Protein elevations 100 mg/dl were found in 86%. They succinctly noted that: The changes in the cerebrospinal fluid are essentially the same regardless of the organism and consist chiefly of an increase in pressure, a pleocytosis, an increase in protein, and a decrease in the sugar and chloride contents. (Merritt and Fremont-Smith, 1937, p. 94) A low sugar content is of great diagnostic significance. A low sugar content in a purulent fluid is strong presumptive evidence of a bacterial meningitis, and organisms will nearly always be found on smear or culture. If the sugar content of a purulent fluid is normal or high and remains so on repeated punctures, bacterial meningitis is unlikely . . . (Merritt and Fremont-Smith, 1937, p. 98)

Modern series have repeatedly shown that the majority of cases of community-acquired acute bacterial meningitis result from infection by Neisseria meningitidis (meningococcus), Streptococcus pneumoniae (pneumococcus), and Listeria monocytogenes. Haemophilus influenzae was an important cause of bacterial meningitis prior to the introduction of the Hib vaccine. Mycobacterium tuberculosis continues to cause large numbers of acute and chronic meningitis cases in many parts of the world. These organisms, with the exception of Listeria, were each identified and associated with specific diseases, including meningitis, during the later part of the 19th century. Louis Pasteur (1822–1895) identified the pneumococcus in 1881 (“microbe septice´mique de la salive”) from the saliva of a child who had died of rabies, and found that inoculation of this child’s saliva could induce septicemia in rabbits (Pasteur, 1881). Almost simultaneously the American microbiologist George Sternberg (1838– 1915) had discovered the same organism (“Micrococcus pasteuri”) (Sternberg, 1881; Flaumenhaft and Flaumenhaft, 1993). However, truly definitive identification of the pneumococcus came from the studies of Albert Fraenkel (1848–1916) (Fraenkel, 1886) and Anton Weichselbaum (1845–1920) (Weichselbaum, 1887). The organism was subsequently assigned to the genus Diplococcus, but was reclassified as Streptococcus pneumoniae in the modern era (1974). Hugo Schottmuller (1867–1936) (Schottmuller, 1903) described the ability of certain strains to produce clear zones of lysis on blood agar plates and noted that other strains produced greenish zones of discoloration. This became the basis for distinguishing Streptococccus hemolyticus from Streptococcus viridans, a distinction that has survived with some modifications into the modern era. Friedrich Neufeld (1869–1945) (Neufeld, 1900, 1902) described the quelling reaction of the bacterial capsular polysaccharides. Use of the quelling reaction led ultimately to procedures for distinguishing different pneumococcal serotypes devised by Frederick Lister (1875–1939) (Lister, 1913), and the later classification by Lancefield (1928) that has survived into the modern era. Anton Weichselbaum (1845–1920) identified Neisseria meningitidis (originally referred to as Diplococcus intracellularis meningitides of Weichselbaum) from the CSF of patients with cerebrospinal meningitis in 1887 (Weichselbaum, 1887). Meningococcal serotypes were initially classified by Mervyn Gordon (1872–1953) (Gordon, 1915), although this has been modified somewhat in the modern era (see Branham, 1953).

A HISTORY OF BACTERIAL MENINGITIS

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In 1892–1893, Richard Pfeiffer (1858–1945) reported on the isolation of what would later be called Haemophilus influenzae from lung and sputum specimens obtained from patients dying during the influenza pandemics of 1889–1892. The name reflects the erroneous assumption that these bacteria were responsible for influenza, a misapprehension corrected when the influenza virus was shown to be the actual cause of the disease. The bacteria were subsequently cultured post mortem from brains of children who had died of meningitis and isolated from CSF obtained by lumbar puncture (Slawyk, 1899). Although Listeria was first isolated by Nyfeldt in 1929 (Nyfeldt, 1929), it was not until 1934 that it was recognized as a cause of CNS disease (Burn, 1934), although earlier cases of CNS Listeriosis had likely been described (see Heck, 1978). Jean-Antoine Villemin (1827–1892) (see Villemin, 1868) established the transmissibility of tuberculosis, and in 1882 Robert Koch (1843–1910) identified Mycobacterium tuberculosis in tuberculous lesions in infected human tissues (Koch, 1882). Koch also developed a method to stain mycobacteria that utilized long immersions in alkaline solutions of methylene blue. This was subsequently modified by Franz Ziehl (1859–1926) and Friedrich Neelsen (1854–1894) (Ziehl, 1882; Neelsen, 1883), leading to the modern Ziehl–Neelsen stain.

CLINICAL SIGNS OF MENINGEAL IRRITATION Neck stiffness (nuchal rigidity), one of the cardinal features of bacterial meningitis, may have been recognized by Hippocratic writers in the 5th century BCE, and was possibly described by Vesalius, and depicted artistically by William Blake (see Scheld, 2001). Although many clinical aspects of meningitis had been well described in the middle 19th century, the major eponymic signs so closely linked to the disease (Kernig’s and Brudzinski’s signs) were first described at the end of the 19th century (Verghese and Gallemore, 1987; Pearce, 2003b). In 1882, Vladimir Kernig (1840–1917) described his sign (Fig. 28.7) to a meeting of Russian physicians in St. Petersburg. I have observed for a number of years in cases of meningitis a symptom which is apparently rarely recognized although it is, in my opinion, of significant practical value. I am referring to flexion contracture of the legs or occasionally also in the arms which becomes evident only after the patient sits up. . . If [with the patient sitting on the edge of the bed and legs dangling] one attempts to extend the patient’s knees one will succeed only to an angle of approximately 135

Fig. 28.7. Kernig’s sign. (From M. Foster and J.F. Gaskell, Cerebro-Spinal Fever, 1916, Plate VI, London, with permission from Cambridge University Press.)

degrees. In cases in which this phenomenon is pronounced, the angle may even remain at 90 degrees. (Kernig, 1884; quoted by Pearce, 2003b, p. 365) Josef Brudzinski (1874–1917) described several different physical signs of meningitis (Verghese and Gallemore, 1987), but his most famous was his neck sign, originally described in 1909: I have noted a new sign in cases of meningitis: passive flexion of the neck causes the lower extremities to flex at the knees and the pelvis . . . With the child in the supine position, the examiner flexes the neck of the child with the left hand while resting his right hand on the patient’s chest to prevent it from rising. (Brudzinski, 1909; quoted by Pearce, 2003b, p. 366)

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K.L. TYLER 1685, p. 456). Blood-letting was felt to decrease the CLINICAL CONTRIBUTIONS IN THE “immoderate flame of the blood,” which was felt to 20TH CENTURY contribute to the agitated state seen in phrensy. ClyGreat epidemics of meningococcal meningitis in the early sters were prescribed to keep the bowel “soluble” and part of the 20th century, including an outbreak of almost to prevent the “violent recourse of the febrile matter 7000 cases in the New York area between 1904 and 1906, in the viscera” from spreading to the head. A variety large outbreaks in military encampments during World of “juleps” made from fruits, flowers, grasses, and War I, and later epidemics in Detroit, Milwaukee, and grains were advised to appease the “boylings of the Indianapolis between 1928 and 1931, provided abundant Blood and the excandescence of the Spirits” (Willis, clinical and pathological material for study, and provided 1685, p. 457). Narcotics including liquid Laudanum or great impetus for early trials of immunotherapy (Brana drink made of poppy seeds and sugar candy were ham, 1956; Bell and Silber, 1971). Classic studies on the of value too, but required care as they might produce clinical features of bacterial meningitis caused by specific insomnia or agitation rather than the desired soporific organisms include Humphry Rolleston’s (1862–1944) and sedating effects. Topical treatments were often review (Rolleston, 1919) of cerebrospinal fever and Thoprescribed for local application to different parts of mas Rivers’ (1887–1963) review (Rivers, 1922) of over the skull, which was often shaved. These local applica220 cases of Hemophilus influenza meningitis. It is striktions often contained exotic ingredients including “the ing to remember that in the pre-antibiotic era the mortality warm lungs of a Lamb” or “pigeons or chickens cut from virtually all types of bacterial meningitis was often in two” or “great Burr-duck bruised and mixt with greater than 90% (Rivers, 1922; Fothergill, 1936; Finland Womans milk” (Willis, 1685, p. 458). et al., 1938; Swartz, 2002). For example, in a review of Whytt noted that the prognosis in hydrocephalus the experience with pneumococcal meningitis seen at the cases (which as noted encompassed meningitis) was Boston Children’s Hospital between 1920 and 1936, Maxuniformly dismal. “I freely own that I have never been well Finland (1902–1987) reported that none of the 99 so lucky as to cure one patient who has those sympcases had survived! (Finland et al., 1938). A contemporatoms which with certainty denote this disease; and I neous review of meningitis due to Hemophilus influenza suspect that those who imagine they have been more was equally bleak. During a 12-year period in which 78 successful have mistaken another distemper for this” cases had been seen prior to use of serum therapy or anti(Whytt, 1768, p. 745). Whytt advised treatment with biotics, there was only a single survivor (Fothergill, 1936). purgatives, diuretics, and bleeding (Whytt, 1768, H. Houston Merritt (1902–1979) and Merill Moore p. 744). Fothergill agreed with Whytt concerning prog(1903–1957) provided a comprehensive review of acute nosis, noting “I must own to you that it is not in my syphilitic meningitis (Merritt and Moore, 1935). Raymond power to suggest any probable means of curing the disAdams and Charles Kubik (1891–1982) provided an ease of which I treat; it has baffled all my attempts, updated review of the clinical and pathological features both when confided in alone, and in consultation with of Hemophilus influenza meningitis in 1948 (Adams, the ablest of the faculty” (Fothergill, 1783–1784, vol. 1948). Arnold Rich (1893–1968) and Howard McCordock II, p. 72; also quoted by Cooke, 1820, p. 437). Cooke (1895–1938) performed decisive pathological studies on agreed with the unfavorable prognosis, but advised tuberculous meningitis in the 1930s, which led to the purging, blood-letting, blisters. He also used “refrigerrecognition that disease typically resulted from discharge ants externally applied” and used sedatives including of mycobacteria into the subarachnoid space from a local opium (Cooke, 1820, pp. 437–438), and commented caseous focus in either the brain or meninges (Rich and “The prognosis in hydrocephalus must always be unfaMcCordock, 1933). In the modern era the clinical features, vourable, unless we should be fortunate enough to diagnosis, and therapy of bacterial meningitis were comdetect its presence at an early period. It seldom happrehensively reviewed in classic papers by Carpenter pens that the disorder is cured, if it has made such proand Robert Petersdorf (1926–2006) (Carpenter and gress as to say with certainty that it actually exists” Petersdorf, 1962) and Swartz and Dodge (1965). (Cooke, 1820, p. 433). In the early 19th century some of the emphasis on TREATMENT FOR BACTERIAL bleeding, diuretics, and purgatives for treatment of MENINGITIS meningitis and encephalitis was replaced by interest in the use of stimulants. North (1811, p. 99) felt that 17th and 18th centuries death in meningitis resulted from “sudden and violent Willis, like most physicians of the 17th century, felt prostration of the energy of the brain and nervous systhat phlebotomy should “seldom or never” be omitted tem,” and was an early proponent of the use of stimuin treatment of phrensy associated with fever (Willis, lants. He claimed to have lost only two of nearly 200

A HISTORY OF BACTERIAL MENINGITIS 429 patients he had treated with “spotted fever,” a result coccal meningitis and a patient with meningoccal sepsis which if it is to be credited would challenge even mod(Schwentker et al., 1937; Scheld and Mandell, 1984). ern antibiotic therapy! Only one of the 11 cases died (9% mortality), a phenomenally successful result that far exceeded the best Introduction of serum therapy reports of serum therapy (Swartz, 2002) (see above). in the 19th century Following the sulfonamides, penicillin became the next major breakthrough in antiobiotic treatment of The first successful specific treatments of bacterial bacterial meningitis (Tauber and Sande, 1984). The meningitis involved the use of equine antisera by effects of penicillin on CNS infections including StaGeorg Jochmann (1874–1915) in Germany and Simon phylococcal meningitis, epidural abscess, and cases of Flexner (1863–1946) in the United States for treatment meningitis caused by Pneumococci and hemolytic of meningococcal meningitis (Jochmann, 1906; Flexner, Streptococci were included in a large series of 500 1907, 1913; Flexner and Jobling, 1908). This work was cases described in 1943 by Chester Keefer (1897–1972) based on pioneering studies by George and Felix Klem(Keefer et al., 1943). One of the larger treatment perer, showing that immunization of mice with pneugroups included 23 patients with pneumococcal meninmococci protected them against subsequent challenge, gitis, two of whom had associated endocarditis. Of this and that this protection could be transferred to naı¨ve set of patients only seven survived, despite penicillin mice by serum (Klemperer and Klemperer, 1891). therapy. The results were considerably better in a landEarly serum treatment regimens using only a subcumark study by David Rosenberg (1903–??) and Phillip taneous or intravenous route met with limited success, Arling (1908–??) (Rosenberg and Arling, 1944) on the and ultimately the cornerstone of therapy became effects of penicillin in the treatment of meningococcal intrathecal (and less commonly intracisternal or even meningitis (65 cases) and six additional cases of meninintraventricular) therapy. Typical regimens might gitis due to hemolytic Streptococci (six cases) in miliinvolve administration of 20–30 ml of equine serum tary recruits. Of this total group of 71 patients, only daily for 4 or more days. Flexner’s report of the sucone died after receiving penicillin therapy! cessful use of serum treatment in 1300 cases of epiIn these early trials of penicillin therapy patients demic meningitis, reducing mortality to 31% for this were typically treated by a combination of intrathecal previously largely fatal disease, remains a landmark and intravenous or intramuscular routes using doses in medical history (Flexner, 1913; Swartz, 2002). Modthat are miniscule by modern standards. A typical regiest success was also reported in treatment of Hemophimen might include 10 000 units of intrathecal penicillin lus influenza meningitis with serum specific for G every 24 h combined with 5000 units/h intravenously Hemophilus influenza type B (Ward and Fothergill, or 15 000 units every 3 h intramuscularly (Rosenberg 1932; Fothergill, 1936). However, the results of serum and Arling, 1944). The first two treated patients therapy were considerably less impressive than for received 9 and 11 daily intrathecal treatments, but as meningococcal meningitis, with a mortality rate of efficacy became more apparent this was reduced to 85% in treated children with Hemophilus influenza one or two treatments (given to 60% of those treated). meningitis, compared to 98% in those untreated No patient received a cumulative dose of more than (Fothergill, 1936; Swartz, 2002). 900 000 units, and nearly half got a total dose of 100000 units or less! The availability of larger quanti20th century: introduction of ties of penicillin in the period after World War II antibiotic therapy enabled trials of higher doses of penicillin. In 1949, one Serum therapy for bacterial meningitis was ultimately study reported a 38% mortality in patients with pneumosuperseded by the use of antibiotics, beginning with coccal meningitis treated with what was described as the the introduction of sulfonamides. Gerhard Domagk “massive” dose of 12 million units/day of penicillin (1895–1964) isolated sulfachrysoidine (Prontonsil) in (1 million units q 2 h intramuscularly) (Dowling et al., 1933 as part of his research at AG Bayer on aniline 1949). Even this dose is low in comparison to modern dyes (Domagk, 1935). Following the successful use of recommendations for treatment of susceptible cases of this first “antibiotic” and its later derivatives to treat meningitis with 24 million units/day of intravenous peniserious human bacterial infections, Domagk received cillin for a minimum of 7 days – a potential cumulative the Nobel Prize in Physiology or Medicine (1939). The dose of 168 million units! – more than 1000 times greater first reports of the successful use of other sulfonathan what most patients received in the original penicillin mides (e.g., sulfanilamide) in the treatment of meningitreatment trials. tis came with Franc¸ois Schwentker’s (1904–1954) Low dose penicillin treatment was less efficacious description of its effects in 10 patients with meningothan treatment with sulfonamides for meningococcal

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meningitis (Beeson and Westerman, 1943), and sulfonamide and its derivatives remained the treatment of choice in meningococcal meningitis until sulfonamideresistant strains were isolated from cases of meningitis in military recruits at the San Diego naval base and Fort Ord in California in the early 1960s (Leedom et al., 1965). The emergence of resistant meningococci prompted the transition to high dose penicillin and later third generation cephalosporin therapy. The efficacy of antibiotics in the prophylaxis of meningococcal meningitis was first demonstrated by using sulfadiazine in 1943 (Kuhns et al., 1943), a regimen that was subsequently replaced by the use of rifampin (Deal and Sanders, 1969). Maxwell Finland (1902–1987) provided one of the earliest reports of the efficacy of sulfanilamide in pneumococcal meningitis, noting that the mortality rate dropped to 40% in a small group of 10 treated patients, compared to a 100% mortality rate prior to chemotherapy (Finland et al., 1938). Although the earliest results in the treatment of pneumococcal meningitis with the low doses of penicillin initially available (Keefer et al., 1943) were actually inferior to those of sulfanilamide, the availability of higher doses of penicillin and its derivatives became the treatment of choice for pneumococcal meningitis and remained so until the emergence of penicillin-resistant strains was first identified in three cases of meningitis in South Africa (Koornhof et al., 1978). As pneumococcal resistance to both penicillin and cephalosporins became more widespread, modern treatment evolved to include the addition of vancomycin in cases of pneumococcal meningitis, to provide coverage for these resistant strains. After World War II, the first report of the successful treatment of tuberculous meningitis in a 1-year-old infant with the antibiotic streptomycin appeared (Cooke et al., 1946), a result that was soon confirmed in larger scale treatment trials of combined intramuscular and intrathecal therapy (Medical Research Council, 1948; Smith et al., 1948). Isoniazid (INH) was introduced in 1952 and soon became the mainstay in the treatment of tuberculosis. Steroid therapy in tuberculous meningitis was first described in the early 1950s (Shane et al., 1952), when it was shown that cortisone treatment of patients with tuberculous meningitis resulted in a more rapid resolution of CSF pleocytosis and elevations in protein concentration.

Vaccines to prevent meningitis The first attempts to reduce the frequency and severity of bacterial meningitis through vaccination were probably studies performed among the black South African gold miners of the Witwatersrand in whom pneumo-

coccal infections were rampant and often fatal (Wright et al., 1914; Lister, 1916; Orenstein, 1931; Finland, 1942; Austrian, 1981a and b). Early trials of prophylactic vaccination began during World War I, and set the stage for the introduction of the polyvalent pneumococcal vaccines in current use. The first large scale field trials of a meningococcal vaccine in military recruits were carried out in the late 1960s (see Artenstein et al., 1970; Gold and Artenstein, 1971). In one large field trial of meningococcal Group C vaccine, only two of 28 245 vaccinated patients as compared to 73 of 114 481 unvaccinated controls developed meningococcal meningitis (Artenstein et al., 1970; Gold and Artenstein, 1971). A meningococcal conjugate vaccine (Menactra) against Neisseria meningitidis groups A, C, Y, and W-135 is now part of the recommended vaccination schedule for children and young adults. Large field trials in Finland in over 100 000 children established the efficacy of the Hemophilus influenzae type b vaccine (Peltola et al., 1977). The first Hemophilus influenza vaccine was licensed in the United States by the FDA in 1985, and later replaced by more effective conjugate vaccines in the late 1980s. The Hemophilus influenzae type b (Hib) vaccine is now a standard part of childhood immunization schedules, and its efficacy has virtually eliminated Hemophilus influenza as a major cause of meningitis in the developed world. The effective immunization against Hemophilus influenzae type b has been called “the greatest achievement in pediatric infectious diseases in this generation” (Scheld, 2001).

CONCLUSION In this chapter we have reviewed the development of ideas concerning the classification, clinical features, and pathology of bacterial meningitis. Bacterial meningitis can arguably be considered one of the great archetypes of all CNS infections, and tracing the historical development of meningitis both provides a background for understanding the historical development of other bacterial infections of the CNS (e.g., abscess, empyema) and sets the stage for the later identification of cases of “aseptic meningitis” in which viruses rather than bacteria play an etiologic role. Similarly, the identification of viruses as a cause of CNS infection permitted the separation of diseases in which the predominant involvement was in the subarachnoid space (viral meningitis) as opposed to diseases in which the brain parenchyma was predominantly involved (viral encephalitis). Technological developments in the modern era have included dramatic enhancements in neuroimaging, allowing improved intra vitam assessment of pathological changes in the meninges, ventricles, and brain

A HISTORY OF BACTERIAL MENINGITIS tissue. Similarly, molecular diagnostic techniques including use of polymerase chain reaction (PCR) amplification of genomic nucleic acid from viruses and bacteria from CSF have dramatically enhanced diagnostic capabilities for many CNS infections. Finally, the introduction of effective antibiotics to treat bacterial CNS infections in the middle part of the 20th century has paved the way in the modern era for the rapid development of an ever expanding array of antimicrobial agents with efficacy against neurotropic bacteria, fungi, parasites, and viruses.

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Merritt HH, Moore M (1935). Acute syphilitic meningitis. Medicine 14: 119–143. Mestrezat W (1912). Le liquide ce´phalo-rachidien, normal et pathologique, valeur clinique de l’examen chimique, syndromes humoraux dans les diverses affections. Maloine et Fils, Paris. Morse D (1961). Pre-historic tuberculosis in America. Am Rev Respir Dis 83: 489–504. Morse D, Brothwell DR, Ucko PJ (1964). Tuberculosis in ancient Egypt. Am Rev Respir Dis 90: 524–541. Morton CA (1891). The pathology of tuberculous meningitis with reference to its treatment by tapping the subarachnoid space of the spinal cord. BMJ 2: 840–841. Mullener E-R (1965). Six Geneva physicians on meningitis. J Hist Med 20: 1–26. Neelsen F (1883). Ein kasuistischer Beitrag zur Lehre von der Tuberkulose. Centrabl Med Wissenschaften 21: 497–501. Netter A (1898). Diagnostic de la me´ningite ce´re´brospinal (signe de Kernig, ponction lombaire). Sem Med (Paris) 18: 281–284. Neufeld F (1900). Eber eine spezifische Bacteriolytische Wirkung der Galle. Z Hyg Infektionskr 34: 454–464. ¨ ber die Agglutination der PneumokokNeufeld F (1902). U ken und u¨ber die Theorien der Agglutination. Z Hyg Infektionskr 40: 54–72. North E (1811). A Treatise on a Malignant Epidemic Commonly Called Spotted Fever. T. and F. Swords, New York. (See Rev Infect Dis [1980] 2: 811–816 for a partial reprinting.) Nyfeldt A (1929). E´tiologie de la mononucle´ose infectieuse. C R Se´ances Soc Biol Fil 101: 590–592. Odier L (1779). Me´moire sur l’hydroce´phale interna, ou hydropisie des ventricules du cerveau. Soc R Med Paris, Me´moires Med Phys Med 3: 194–323. Orenstein AJ (1931). Vaccine prophylaxis in pneumonia: a review of 14 years, experience with inoculation of native mine workers of the Witwatersrand against pneumonia. J Med Assoc S Afr 5: 339–346. Pasteur L (1881). Note sur la maladie nouvelle provoque´e par la salive d’enfant mort de la rage. Bull Acad Med Paris 10: 94–103. Paul JR (1971). A History of Poliomyelitis. Yale University Press, New Haven CT, p. 12. Pearce JMS (2003a). Lumbar puncture In: Fragments of Neurological History. Imperial College Press, London, pp. 201–208. Pearce JMS (2003b). Kernig and Brudzinski. In: Fragments of Neurological History. Imperial College Press, London, pp. 365–366. Peltola H, Kayhty H, Sivonen A, et al. (1977). Haemophilus influenza type B capsular polysaccharide vaccine in children: a double-blind field trial of 100,000 vaccines 3 months to 5 years of age in Finland. Pediatrics 60: 730–737. Pitman J (1991). The John Abercrombie collection. Proc R Coll Physicians Edin 21: 349–354. Pleadwell FL (1924). A new view of Elisha North and his treatise on spotted fever. Ann Med Hist 6: 245–257.

A HISTORY OF BACTERIAL MENINGITIS Quin CW (1779). Dissertatio de hydrocephalo interno. Balfour and Smellie, Edinburgh. Quincke HI (1891). Die Lumbalpunction des Hydrocephalus. Berl Klin Wochenschr 28: 929–933, 965–968. ¨ ber Meningitis serosa. Samml Klin Quincke H (1893). U Vortrage 67: 655. ¨ ber Lumbalpunction. Berl Klin Quincke H (1895). U Wochenschr 32: 861, 889–891. Rich AR, McCordock HA (1933). The pathogenesis of tuberculous meningitis. Bull Johns Hopkins Hosp 52: 5–37. Rivers TM (1922). Influenzal meningitis. Am J Dis Child 24: 102–124. Rolleston H (1919). Cerebro-spinal fever. Lancet 1: 541–549. Rosenberg DH, Arling PA (1944). Penicillin in the treatment of meningitis. J Am Med Assoc 125: 1011–1017. (Reprinted in JAMA 251: 1870–1876.) Scheld WM (2001). A brief history. In: AR Tunkel (Ed.), Meningitis. Lippincott, Philadelphia, PA, pp. 1–16. Scheld WM, Mandell GL (1984). Landmark perspective. Sulfonamides and meningitis. JAMA 251: 791–794. Schottmuller H (1903). Die Artunscheidung der fu¨r den Menschen Pathogenen Streptokokken Durch Blutagar. Munch Med Wochenschr 1: 849, 909. Schwentker FF, Gelman S, Long PH (1937). The treatment of meningococcic meningitis with sulfanilamide: a preliminary report. J Am Med Assoc 108: 1407–1408. (Reprinted in JAMA 251: 788–789, 1984.) Senn L (1825). Recherches anatomico-pathologiques sur la me´ningite aigue¨ des enfants, et ses principales complications (hydroce´phale aigue¨ des auteurs). Paris. Shane SJ, Clowater RA, Riley C (1952). Treatment of tuberculous meningitis with cortisone and streptomycin. Can Med Assoc J 67: 13. Slawyk E (1899). Ein Fall von Allgemeininfektion mit Influenzabacillen. Z Hyg Infektionskr 32: 443–448. Smith HV, Vollum RL, Cairns H (1948). Treatment of tuberculous meningitis with streptomycin (a report of the Medical Research Council). Lancet 1: 627. Steele JH (1975). History of rabies. In: GM Baer (Ed.), The Natural History of Rabies. Academic Press, New York, pp. 1–29. Sternberg GM (1881). A fatal form of septicemia in the rabbit produced by subcutaneous inoculation of human saliva. Natl Board Health Bull 2: 781–783. Strong N (1810). An Inaugural Dissertation on the Disease Termed Petechial or Spotted Fever. Gleason, Hartford.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 29

Historical aspects of the major neurological vitamin deficiency disorders: overview and fat-soluble vitamin A DOUGLAS J. LANSKA * Department of Neurology, Veterans Affairs Medical Center, Tomah, WI, USA

VITAMINS AND DIETARY DEFICIENCY DISEASES Introduction Vitamins are organic micronutrients that are essential to normal growth and metabolism, and are present in only minute amounts in natural foodstuffs. Historically, vitamin deficiency disorders have been major causes of neurological morbidity and mortality throughout the world, often affecting large segments of malnourished populations. The neurological presentations vary with the deficiencies involved, but include dementia, amnestic confabulatory states, delirium, acute psychosis, blindness, eye movement abnormalities, ataxia, myelopathy, polyneuropathy, and congenital neural tube defects. Although diseases that are now recognizable as vitamin deficiency disorders have been known for millennia, the “vitamin doctrine” was not developed until the early-20th century (Hopkins, 1929/1965). Prior to this development, vitamin deficiency disorders were generally attributed to toxic or infectious causes, the most powerful pathophysiological paradigms of the late 19th and early 20th centuries. Since the initial development of the vitamin doctrine, there has been an explosive growth in our understanding of cellular metabolism, including the coenzyme functions of many of the vitamins. In some cases we now possess a fairly complete pathophysiological understanding of the development of specific neurological vitamin deficiency disorders, are able to identify such disorders early, are able to treat and often cure people with such disorders when identified early using synthetic forms of the vitamins, and most

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importantly are able to prevent these disorders in the first place by targeted supplementation and food fortification. As a result, incidence, prevalence, case fatality, and mortality of neurological vitamin deficiency disorders have declined dramatically in developed countries since the middle of the 20th century. Endemic forms of these disorders have been either eliminated from or greatly curtailed in developed countries, and the relatively rare residual cases generally reflect individual predispositions because of altered intake (e.g., alcoholics, food faddists, total parenteral nutrition), malabsorption (e.g., pernicious anemia, chronic diarrhea, iatrogenic causes, alcoholism), and altered metabolism or abnormal utilization (e.g., medications, coincident disease). Unfortunately, high rates of many neurological vitamin deficiency disorders persist in developing countries and other populations beset with war, famine, and poverty. This chapter begins a historical review of vitamin deficiency disorders causing neurological illness, and includes a general overview of the historical origins of the vitamin doctrine and an historical review of fat-soluble vitamin A. Study of the history of neurological vitamin deficiency disorders can be rewarding from several vantage points, and can augment understanding of normal neurochemistry and neurophysiology, neuropathophysiology, the interrelationships between neurological and systemic illness, neurotherapeutics, neuroepidemiology, and neurologically oriented social medicine and public health. Seldom in the case of neurological disorders is such a breadth and depth of medical understanding available to help prevention and treatment efforts.

Correspondence to: Douglas J. Lanska MD, Staff Neurologist, VA Medical Center, 500 E Veterans St., Tomah, WI 54660, USA. E-mail: [email protected], Tel: +1-608-372-1772, Fax: +1-608-372-1240.

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Components of a physiologically complete diet and Hopkins’ “accessory food factors” In the late 19th century, a physiologically complete diet was believed to require only a sufficient amount of proteins, carbohydrates, fats, inorganic salts, and water. However, as early as 1880 and 1881, in studies for a doctoral thesis, Russian physician Nicolai I. Lunin (1853–1937) in Dorpat (now Tartu, Estonia) found that mice did not thrive or grow when fed on purified diets containing only these constituents, although he made no effort at identifying any missing essential factors in the inadequate diets (Hopkins, 1929/1965; Voss, 1956; Rosenfeld, 1997). In 1905, Cornelius Pekelharing (1848–1922) in Utrecht performed similar experiments and achieved similar results, but found that animals that received milk instead of water thrived. Pekelharing suggested that there was an unrecognized substance in milk, present in very small amounts, which was necessary for the animals to adequately utilize the other dietary components – a clear statement of what would later be called the “vitamin doctrine” (Hopkins, 1929/1965; Rosenfeld, 1997). Unfortunately, the early reports by Lunin, Pekelharing, and others attracted little attention until the work of British biochemist Frederick Hopkins (1861–1947) at Cambridge University was published in 1912. From 1906 to 1912 Hopkins conducted similar feeding experiments with young mice and rats (Hopkins, 1929/1965). Hopkins’ experiments were notable for providing careful observations under controlled laboratory conditions with “analytical control of materials, for the meticulous weighing and measurement of the quantities of food consumed, for the many days over which animals were studied . . . , for consistent recording of the weight and growth of the rats, and for . . . independence from current dogma” (Weatherall, 1990, p. 123). Hopkins found that rats fed purified mixtures of protein (casein) or amino acids, carbohydrates (sucrose, starch), fats (butter or lard), mineral salts, and water failed to grow or even lost weight and died, unless the diet was supplemented with small amounts of milk (Hopkins, 1906, 1912, 1929/1965). Hopkins concluded that milk contained “accessory food factors” that are required in trace amounts for normal growth (Hopkins, 1912, 1929/1965). Although there were clearly others who anticipated this work, and although other investigators had difficulty reproducing and confirming Hopkins’ results, Hopkins shared the 1929 Nobel Prize in Physiology or Medicine for his contributions to the “discovery of the growth-stimulating vitamins” (Hopkins, 1929/1965).

From Funk’s “vitamine” to vitamin In 1911 and 1912 Polish chemist Casimir Funk (1884– 1967), then working at the Lister Institute for Preventive Medicine in London, proposed that the active dietary factor that was effective in the treatment of animal models of beriberi was a specific organic substance present in trace amounts – one of several trace dietary factors that were essential for life and which, when deficient, resulted in such diseases as beriberi, scurvy, rickets, and pellagra (Funk, 1911, 1912, 1922; Harrow, 1955). Funk had isolated a concentrate from rice polishings that seemed to be curative for polyneuritis in pigeons, and that his chemical analyses suggested was probably an amine. Because this substance appeared to be vital for life, Funk named it “vitamine” for “vital amine” (Funk, 1912). Funk supposed that vitamines would all belong to the same chemical class, just as amino acids in proteins are chemically related. However, Funk’s concentrates were primarily nicotinic acid, which was contaminated with small amounts of the anti-beriberi factor (thiamin). Nevertheless, Funk’s term was widely adopted and applied to a series of food substances, regardless of their chemical structures. Indeed, the introduction of the term and its popularization led to further research efforts internationally, as these dietary substances became recognized as clinically important beyond the prevention of some distant tropical diseases. In 1920, Jack Drummond (1891–1952) proposed that the “e” be dropped from “vitamine,” because there was no evidence that the essential dietary factors are amines; the revised term “vitamin” would then conform to a standard nomenclature convention, one in which substances of undefined composition end with the suffix “-in” (Drummond, 1920; Rosenfeld, 1997).

VITAMIN A DEFICIENCY: NIGHT BLINDNESS AND KERATOMALACIA Introduction Vitamin A is integral to sensory transduction and specifically the transduction of light for visual perception. Vitamin A is the precursor of the visual pigments within the rods and cones of the retina. In particular, a derivative of vitamin A, 11-cis retinal, is the chromophore within the G-protein-coupled photoreceptor protein, rhodopsin, which is localized to the outer segments of rod cells in the retina. This transmembrane detector undergoes a conformational change in response to light, which activates an intracellular G-protein-coupled transduction cascade, and ultimately cellular responses that lead to visual perception. The

NEUROLOGICAL VITAMIN DEFICIENCY DISORDERS: OVERVIEW AND VITAMIN A 437 study of this physiological process has not only greatly evening at dusk, afflicted sailors became blind and had expanded knowledge of sensory transduction, visual to be led about the ship. Several affected sailors, perception, and dark adaptation, but has provided a after being kept below decks for 3–5 days, transiently prototypical model and tremendous insights into regained normal night vision, but became night blind the functions of a large class of structurally related again when exposed to sunlight (although mysterious G-protein-coupled cell receptors involved, for example, at the time, this no doubt resulted from marginal in detecting odorants, neurotransmitters, and horvitamin A reserves, which could be tenuously renewed mones (Hargrave and McDowell, 1992; Filmore, 2004). with minimal light exposure, but which were insuffiBecause rhodopsin is available in greater quantities cient for more rapid rates of depletion). Schwarz than any other G-protein-coupled receptor, it has been found that both boiled ox liver and pig liver were studied in much greater detail than its fellow Gcurative. protein-linked receptors (Hargrave and McDowell, Corneal epithelial defects were clearly recognized in 1992). Drugs targeting members of this integral memthe 19th century in those subsisting on diets now recogbrane protein family now represent nearly half of all nizable as deficient in vitamin A. Corneal ulceration prescription pharmaceuticals and are a major focus was reported in 1817 by Franc¸ois Magendie (1783–1855) of current drug development (Filmore, 2004). among vitamin A-deficient dogs fed for several weeks The neurological disorder associated with vitamin A on a diet limited to sugar and water, although he errodeficiency is night blindness, which has plagued malneously attributed this to a deficiency of dietary nitronourished populations for millennia, and remains a gen (i.e., protein) (Budd, 1842; Wolf, 1996). In 1842, major public health problem in many countries around English physician George Budd (1808–1882) described the world. similar corneal ulcers among East Indians during a sea voyage to England (Budd, 1842; Hughes, 1973; Wolf, 1996), and in 1857 African explorer David Livingstone Description of night blindness reported corneal lesions among African natives who and keratomalacia subsisted on coffee, manioc, and edible whole or coarNight blindness was recognized by the ancient Egyptians sely ground grains of a cereal grass (Wolf, 1996). In and the ancient Greeks (Dowling and Wald, 1958; Wolf, 1904, Masamichi Mori in Japan described widespread 1996). During the Roman Era, Galen (c. 129–199 AD) xerophthalmia (corneal dryness), often with keratomalaclearly described “nyktalopia” as night blindness and cia (ulceration and perforation of the cornea), among recommended eating raw beef liver (now known to conJapanese children subsisting mostly on rice and barley, tain high concentrations of vitamin A) to correct the and further reported that liver and cod-liver oil were condition (Wolf, 1996). Chinese medical texts also curative (Mori, 1904; Wolf, 1996). described night blindness: Sun-szu-mo (7th century The association between night blindness and corneal AD) recommended pig liver as a treatment (Wolf, epithelial defects was recognized in the late-19th and 1996). Later, during European colonial expansion, early-20th centuries. In 1860, V. von Hubbenet first several physicians – including Jacobus Bontius (1592– reported the association between night blindness and 1631), the first European physician in the Dutch East corneal epithelial defects (“silver scales on the corIndies, and Willem Piso (1611–1678) in Brazil – described nea”), attributed this to an inadequate diet, and found night blindness and its cure with shark liver (Wolf, it treatable with beef liver (Wolf, 1996). In 1862, Bitot 1996). In 1754, German physician C.A. von Bergen reported foamy white spots (“Bitot spots”) on the described epidemics of night blindness in rural Russia corneas of children with night blindness (Wolf, 1996), and postulated a nutritional cause (Wolf, 1996). English and by 1863 concluded that night blindness and physician William Heberden (1710–1801), often considxerophthalmia are both manifestations of the same ered the outstanding clinician of his era, also described disorder (Bitot, 1863; Wolf, 1996, 2001). Similarly, in a case of “nyctalopia, or night-blindness,” in a sailor 1913, Shinobu Ishihara (1879–1963) recognized the assowho developed blindness at night, with retained daytime ciation of night blindness and keratomalacia in malvision, which gradually abated within 3 days of going nourished children (Ishihara, 1913; Wolf, 1996). ashore (Heberden, 1818, pp. 269–270). In 1919, during World War I, Carl E. Bloch (1872–1952) The nutritional basis of night blindness was further studied malnourished Danish children with night blindelaborated by Austrian naval physician Eduard ness and keratomalacia, who had subsisted on fat-free Schwarz (1831–1862) during an around-the-world milk, oatmeal, and barley soup (Bloch, 1919; Wolf, scientific expedition (1857–1859) (Wolf, 1996). Night 1996). In a critical experiment, Bloch prospectively stublindness (“hemeralopia”) developed in 75 of the 352 died 32 institutionalized toddlers (aged 1–4 years), half men on board, often simultaneously with scurvy. Every of whom received animal fat (whole milk and butter),

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while the others received vegetable fat (margarine). The animal fat group remained healthy, whereas 50% of the vegetable fat group developed corneal xerosis (Bloch, 1919; Wolf, 1996, 2001). All of the xerosis cases were rapidly cured with cod-liver oil. Bloch concluded that whole milk, butter, and cod-liver oil contain a fat-soluble substance that protects against xerophthalmia.

Boll’s discovery of the visual pigment In 1876 and 1877, Franz Boll (c. 1849–1879) observed a relationship between retinal color and light exposure: (1) the frog retina is paler after light exposure and can become completely colorless in direct sunlight; and (2) excised animal retinas that had been exposed to light are colorless, but the purple color is restored if animals are kept in the dark for a period of time after exposure to light before they are killed (Boll, 1876, 1877, 1877/1977; Ku¨hne, 1879/1977; Baumann, 1977; Hubbard, 1977; Wolf, 2001). Boll concluded that light causes bleaching of the retinal pigment, and also suggested that the outer segments of the rods contain a substance that conveys an impression of light to the brain by a photochemical process.

Ku¨hne’s experiments with retinal preparations and rhodopsin Willy Ku¨hne (1837–1900), professor of physiology at the University of Heidelberg, stimulated by Boll’s observations, began experimental studies of the retina in 1877, and continued these over a productive 5-year period, resulting in a series of 22 important papers (Ku¨hne, 1878, 1879/1977; Ewald and Ku¨hne, 1877; Crescitelli, 1977). By the time he began his retinal studies, Ku¨hne was already a renowned physiologist who had previously isolated and named the digestive protease trypsin from the pancreas, coined the word “enzyme,” and contributed greatly to the biochemistry of protein digestion (Wolf, 2001). Ku¨hne pursued his retinal studies with similar zeal and with arguably even more important results. In frogs, Ku¨hne confirmed that visual purple (Sehpurpur) was bleached by light, but maintained its color in the dark, even after death. In a darkroom illuminated by red light, Ku¨hne perfected a technique for isolating frog retinas, which remained purple in the dark but became colorless when exposed to sunlight (Ku¨hne, 1879/1977; Wolf, 2001). In contrast to previous opinions (including Boll’s) that the retinal pigment is red, Ku¨hne was adamant that the rod pigment is in fact purple and named it visual purple. This bleaching process progressed through several different color stages (from purple to orange to yellow to buff and then to colorless), which Ku¨hne correctly interpreted as indicating chemical transformations, because

of the changing absorption spectra and the changing fluorescence of the different stages in ultraviolet light (Ku¨hne, 1879/1977; Wolf, 2001). It is now known that rhodopsin (11-cis retinal plus the protein opsin) is purple with blue fluorescence, an intermediate stage is orange with contributions of purple and yellow, all-trans-retinal-opsin is yellow, and the end-product of the light-bleaching process, free all-trans-retinol, is colorless with green fluorescence (Wolf, 2001). The rate of photo-bleaching is dependent on temperature, as well as on the intensity and wavelength of light. Ku¨hne correctly concluded that photo-bleaching is a photochemical process, and not a strictly thermal process, because infrared light is invisible and does not bleach the retinal preparations. The photo-bleaching process was also found to be reversible and dependent on the retinal pigment epithelium (Ku¨hne, 1879/1977; Wolf, 2001). An excised frog eyeball could be fully bleached after being kept in sunlight for 30 min, but the purple color still reappears in the dark, independent of the circulation of the blood. In contrast, an isolated, bleached retinal preparation separated from the retinal pigment epithelium is unable to regenerate the purple color. However, if the isolated bleached retinal preparation is placed onto an isolated retinal pigment epithelium, the purple color does regenerate, demonstrating unequivocally the essential role of the retinal pigment epithelium in pigment regeneration within the retina. The process of regeneration of the visual pigment was puzzling though, as it was “extraordinarily slow” (too slow by far to account for the rapidity of changing visual sensation), and because it seemed to occur by two processes: one slow process different than a simple reverse of the bleaching process (which Ku¨hne named neogenesis), and a relatively rapid process that could reverse the intermediaries (but not the final product) back to visual purple (which Ku¨hne named anagenesis). Ku¨hne localized visual purple (rhodopsin) to the outer segments of the rods within “platelets” (now called “disks”), and observed that bile or bile salts dissolve the rods, bringing rhodopsin into solution where it could be further studied chemically (Ku¨hne, 1879/ 1977; Wolf, 2001). Ku¨hne further surmised that rhodopsin included a protein moiety, because it was a large molecule that, when in solution, did not diffuse through a semipermeable membrane and that could be precipitated with ammonium sulfate (Ku¨hne, 1879/ 1977; Wolf, 2001). As early as 1877, Ku¨hne likened vision to a repetitive photographic process (Wald, 1950). Ku¨hne developed this idea further when he found he was able to see images bleached onto a retina. After having a

NEUROLOGICAL VITAMIN DEFICIENCY DISORDERS: OVERVIEW AND VITAMIN A frog stare into a flame for 14 h, he isolated its retina and observed a bleached area in the shape of an inverted flame. Ku¨hne found he could create other retinal images, which he called “optograms,” after having frogs or rabbits stare at a window for several minutes. Ku¨hne’s optograms stimulated widespread speculation that such images could be used forensically to determine the guilty party from the retinal image of someone just murdered. Ku¨hne initially dismissed such speculation; however, by 1880, when a young man was beheaded by guillotine in the nearby town of Bruschal, Ku¨hne apparently had a different viewpoint and immediately retrieved the corpse, extracted the eyes in a dimly lit room screened with red and yellow glass, and within 10 min of the decapitation viewed one of the few reported human optograms (Wald, 1950). Ku¨hne’s work concluded with his proposed “optochemical hypothesis,” which attributed vision to a photochemical change in visual purple (rhodopsin), such that the chemical products or some process related to the chemical change is responsible for stimulating the visual cells and thereby conveying a visual image. Ku¨hne’s prescient concept of photochemical transduction would later be shown to be largely correct, particularly with the important work of Wald and colleagues beginning in the 1930s.

McCollum, Osborne, and Mendel, and the discovery of fat-soluble vitamin A In 1913, Elmer Verner McCollum, PhD (1879–1967), at the University of Wisconsin in Madison, with his volunteer assistant Marguerite Davis (1887–1967), discovered a fat-soluble accessory food factor, present only in certain fats and distinct from the water-soluble anti-beriberi factor (McCollum and Davis, 1913, 1914; McCollum, 1964; Day, 1997; University of Wisconsin College of Agricultural and Life Sciences). Rats fed on a diet of presumably pure protein (casein), carbohydrates, and salt grew well for several months, but then stabilized or lost weight, unless the diet was supplemented with certain “lipins” that were extractable with ether from butter fat and eggs. McCollum felt that the lapse of growth after several months was due to the exhaustion of body stores of some unrecognized organic growth factor that was normally present in certain fats. Similar work was presented almost simultaneously by Lafayette Mendel (1872–1935) of the Sheffield Scientific School (affiliated with Yale University) and Thomas Osborne (1859–1929) of the Connecticut Agricultural Station in New Haven, who together also reported the high potency of codliver oil in supporting growth under these conditions (Osborne and Mendel, 1913, 1914).

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In 1913, Gowland Hopkins and A. Neville suggested that both American groups had been able to obtain growth with the diets of casein and lactose, because these substances had been incompletely purified and were contaminated with a water-soluble growth factor (Hopkins and Neville, 1913). In further studies, McCollum and Simmonds (1916) confirmed Hopkins’ suspicion and concluded that rats need both a watersoluble factor and a fat-soluble factor for growth. In 1916, McCollum and his graduate student Cornelia Kennedy labeled these “fat-soluble A” and “watersoluble B” (McCollum and Kennedy, 1916; Day, 1997). McCollum initially believed that “fat-soluble A” was a single vitamin capable of treating both xerophthalmia and rickets (McCollum and Kennedy, 1916); however, in 1922, McCollum and colleagues demonstrated that cod-liver oil could be treated (by aeration at 100 C for at least 12 h) so as to eliminate its efficacy against xerophthalmia, while maintaining its antirachitic activity in rats (McCollum et al., 1922). Ultimately the anti-xerophthalmia factor was named vitamin A and the anti-rachitic factor was named vitamin D.

Linking visual manifestations to vitamin A deficiency In 1913, Ishihara proposed that a “fatty substance” in blood is necessary for synthesis of both rhodopsin and the surface layer of the cornea, and that night blindness and keratomalacia develop when this substance is deficient. Shortly thereafter, Osborne and Mendel showed that, in the absence of dietary supplementation with certain fats, rats developed weight loss, night blindness, and corneal ulcers, thus illustrating the most important physiological functions of vitamin A (i.e., support of vision, epithelial differentiation, and growth), and also providing an experimental model of human night blindness and keratomalacia (Osborne and Mendel, 1914; Wolf, 1996). In 1925, Fridericia and Holm directly linked vitamin A to night blindness in animal experiments: vitamin A-deficient rats, when light adapted (i.e., with light-“bleached” retinas) and placed in the dark, formed rhodopsin at a slower rate than did normal rats (Fridericia and Holm, 1925; Wolf, 1996). In 1929, Holm demonstrated the presence of vitamin A in retinal tissue. In the late 1930s, Wald and colleagues began studies of experimentally induced human vitamin A deficiency and demonstrated a progressive rise in the visual threshold over a month-long period on a vitamin A-deficient diet, and subsequent rapid resolution of the deficit over 90 min upon ingestion of carotene (i.e., provitamin A) (Wald and Steven, 1939). A number of subsequent studies in animals and man further

440 D.J. LANSKA corroborated the association between vitamin A defiof a single Wanderjahre, Wald worked in three differciency and night blindness and keratomalacia (Dowling ent laboratories under the guidance of three internaand Wald, 1958; Wolf, 2002). tionally recognized mentors, all of whom ultimately received the Nobel Prize in Physiology or Medicine for different contributions (Wald, 1935a, b, 1967/1972; The isolation, chemical structure, and Dowling, 2000, 2002). chemical synthesis of vitamin A Wald began work in the laboratory of biochemist Otto Warburg (1883–1970) at the Kaiser-Wilhelm-Institut In attempts to isolate the active growth-promoting facfu r Biologie in Berlin, Germany (now the Max Planck ¨ tor in fats, Osborne and Mendel (1914) obtained an active Institute for Biology in Tu¨bingen, Germany), where he yellow oil from butter, egg yolks, and cod-liver oil, but dissected animal retinas to obtain the light-sensitive not from lard or olive oil. Steenbock (1919) subsequently compound rhodopsin (Dowling, 2002). Based on a chenoted that active growth-promoting extracts from butmical test and the absorption spectrum, Wald tentatively ter, egg yolk, or carrots are yellow, while active extracts concluded that the retina contains vitamin A, a finding from liver or kidney are white. In 1920, Steenbock and that he subsequently confirmed in the laboratory of Paul Gross suggested that fat-soluble factor A is associated Karrer at the University of Zurich (Warburg had sugwith a yellow pigment and is converted in vivo to an gested the transfer because Karrer had elucidated the active colorless form (Steenbock and Gross, 1920; Wolf, structure of vitamin A in 1931) (Karrer, 1937/1966). After 1996). However, around the same time, Palmer and this, Wald moved briefly to the cellular metabolism Kempster (1919) fed chickens a diet free of yellow piglaboratory of Otto Meyerhof (1884–1951) at the Kaiserments (i.e., white corn, skimmed milk, bone meal, and Wilhelm-Institut fu¨r medizinische Forschung (now the small amounts of pork liver) and discovered that the Max Plank Institute for Medical Research) in Heidelberg, chickens nevertheless grew normally and laid eggs that Germany, where Wald discovered the visual cycle of (despite colorless egg yolks) produced normal chicks. vitamin A (Wald, 1935a, b; Wolf, 2001). These confusing results were not resolved until 1930, Wald’s former mentor Hecht had proposed, based on when Moore, in experiments with rats, showed that the the relationship between photosensitivity and time during active yellow pigment extracted from plants, butter dark adaptation, that dark adaptation “follows the course fat, or egg yolks (b-carotene) is a precursor (i.e., proof a bimolecular reaction . . . [and that] visual reception in vitamin) that is converted to an active colorless factor dim light is conditioned by a reversible photochemical (vitamin A or retinol) in vivo and accumulates within reaction involving a photosensitive substance and its two the liver (Moore, 1930; Wolf, 1996). Later studies found products of decomposition” (Hecht, 1919, pp. 516–517). that the enzymatic conversion of b-carotene to retinol Wald confirmed Hecht’s prediction and showed that visual occurs in the intestinal mucosa (Wolf, 1996). purple (rhodopsin) is decomposed by light into a comIn the 1930s, Paul Karrer (1889–1971) and colleagues pound he called “retinene” and a protein (later called at the University of Zurich isolated b-carotene (the “opsin”) (Wald, 1935a, b; Karrer, 1937/1966; Wolf, 1996). main dietary precursor of vitamin A) and retinol, and Retinene was subsequently shown by R.A. Morton and determined their chemical structures (Karrer et al., T.W. Goodwin to be the aldehyde of vitamin A, “retinalde1931; Karrer, 1937/1966). Karrer shared the 1937 Nobel hyde,” now known as “retinal” (Morton and Goodwin, Prize in Chemistry “for his investigations on carot1944; Ball et al., 1946). Retinal could either recombine with enoids, flavins and vitamins A and B2” (Karrer, 1937/ opsin to reform rhodopsin, or could instead be converted 1966). In 1947, Isler and colleagues completed the full to retinol (vitamin A). Because “vitamin A is the precursor chemical synthesis of vitamin A (Isler et al., 1947). of visual purple [rhodopsin], as well as the product of its The availability of vitamin A through food fortification decomposition,” Wald proposed that the “visual processes and medicinal supplements virtually eliminated ocular therefore constitute a cycle” (Wald, 1935b, p. 368). vitamin A deficiency from developed countries by the During the 1930s, Wald also initiated studies of second half of the 20th century (Underwood, 2004). cone vision and was able to extract a red-sensitive pigment from chicken retinas that he called iodopsin Wald and the visual cycle of vitamin A (Dowling, 2000; Kresge et al., 2005). In the midAfter completing his graduate studies in zoology with 1950s, Wald and colleagues showed that iodopsin Selig Hecht (1892–1947) at Columbia University (Wald, bleaches to form retinal and a protein, which is differ1948a, 1967/1972; Dowling, 2000, 2002), American phyent from the protein opsin in rhodopsin. Hence, Wald siologist George Wald (1906–1997) obtained a National proposed the terms “scotopsin” for the opsin of rods, Research Council Fellowship in Biology (1932–1934) to and “photopsins” for the opsins of cones (Wald et al., pursue the photochemistry of vision. Within the space 1955a; Dowling, 2000).

NEUROLOGICAL VITAMIN DEFICIENCY DISORDERS: OVERVIEW AND VITAMIN A Wald’s group subsequently elaborated the enzymatic conversions of various elements in the rhodopsin system (Wald, 1948b; Wald and Hubbard, 1949, 1950; Wald and Brown, 1950; Hubbard and Wald, 1951; Hubbard, 1956; Dowling, 2000). By the mid-1950s, Wald, Ruth Hubbard (Wald’s second wife), and Paul Brown, with the assistance of several organic chemists, determined that the rhodopsin system is dependent upon an isomerization of retinal (a conformational change in the molecule), and specifically that the 11-cis isomer of retinal was the precursor of all visual pigments (Wald and Hubbard, 1950; Wald et al., 1955b; Hubbard and Wald, 1952; Hubbard et al., 1953; Brown and Wald, 1956; Hubbard, 1956, 1966; Oroshnik et al., 1956). 11-cis retinal is twisted and sterically hindered and stable only in the dark. Light causes isomerization to the all-trans form of retinal, which in turn must eventually be re-isomerized for the visual cycle to continue (Hubbard and Kropf, 1958; Hubbard, 1966). By slowing the chemical processes with liquid nitrogen, Wald’s group also demonstrated that rhodopsin goes through a series of very transient molecular transformations, and that one of these intermediaries (meta-rhodopsin II) triggers excitation of the photoreceptor before retinal is ultimately hydrolyzed from opsin (Matthews et al., 1963). In 1942, Hecht and colleagues had demonstrated that a single photon could trigger excitation in a rod (Hecht et al., 1942). In 1965, Wald suggested that a large chemical amplification must occur for a single photon to be able to trigger such excitation of the rod, and by analogy with the blood clotting system this amplification could potentially occur by a cascade of enzymatic reactions (Wald, 1965). Later studies showed that rhodopsin is a transmembrane protein consisting of seven membrane-spanning helices, that are interconnected by extracellular and intracellular loops, and that form a binding pocket for its ligand, 11cis retinal. Absorption of light by 11-cis retinal causes isomerization to all-trans retinal and propagation of a conformational change in the protein to the cytoplasmic surface. The meta-rhodopsin II intermediary then interacts with transducin, a G-protein, to activate phosphodiesterases that control cyclic GMP levels, which in turn modulate release of neurotransmitter from the rod cell (Stryer, 1986; Hargrave and McDowell, 1992). In 1967, Wald was recognized with a Nobel Prize in Physiology or Medicine for “discoveries concerning the primary physiological and chemical visual processes in the eye” (Wald, 1967/1972).

Hormone-like actions of vitamin A In 1960, Dowling and Wald showed that almost all of the non-visual roles of vitamin A are carried out by retinoic acid, and further that retinoic acid could not be metabolized to retinol (the form in which vitamin

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A is transported), or to retinyl esters (the form in which vitamin A is stored), or to retinal (the aldehyde needed for synthesis of visual pigments) (Dowling and Wald, 1960). As a result, rats maintained with retinoic acid (but not vitamin A or its various provitamins, i.e., dietary carotenoids) grew normally but became extremely night blind and eventually permanently blind. As rhodopsin concentrations declined, visual thresholds rose, followed by loss of opsin, disintegration of the outer segments of the rods, and severe dropout of visual cells. Because retinoic acid is not stored in the body and cannot be metabolized to a storage form, the animals stopped growing within a few days of deprivation of retinoic acid and developed severe systemic symptoms within 1–2 weeks. Subsequently retinoic acid was found to act in a hormone-like fashion to regulate gene expression (Ross and Ternus, 1993), a role for vitamin A that Wolf and De Luca had proposed as early as 1970 (Wolf and De Luca, 1970; Wolf, 1996). In 1987, P. Chambon and colleagues in Strasbourg, France, and R.M. Evans and colleagues in San Diego, simultaneously discovered retinoic acid receptors in cell nuclei, which bind with retinoic acid to modulate gene expression, thereby influencing embryonic development, cellular differentiation (including that of the cornea), and growth (Gigue`re et al., 1987; Chambon, 1996; Wolf, 1996).

Public health interventions to address vitamin A deficiency in developing countries The first global survey of xerophthalmia conducted by the World Health Organization in the early 1960s suggested a significant prevalence of the disorder in many countries (Ooman et al., 1964), but was later found to have seriously underestimated the global burden of vitamin A deficiency (Sommer et al., 1981; Reddy, 2002; Underwood, 2004). Subsequently, various intervention trials were conducted, including controlled trials in Jordan and India in the late 1960s, which demonstrated the feasibility of periodic vitamin A dosing to prevent vitamin A deficiency disorders (Reddy, 2002). In 1975, under the auspices of the US Agency for International Development (USAID) and the World Health Organization (WHO), the International Vitamin A Consultative Group was established at a meeting of the United Nations International Children’s Emergency Fund (UNICEF) in New York, to coordinate and facilitate activities to combat vitamin A deficiency disorders worldwide (Reddy, 2002; Underwood, 2004). By the 1980s, global estimates suggested 13 million children suffered from xerophthalmia and another

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40–80 million children were at risk (Sommer et al., 1981; Underwood, 2004). But within 20 years these estimates were again found to underestimate the burden of illness resulting from vitamin A deficiency, with recent estimates suggesting that 3 million preschool children have clinical signs of vitamin A deficiency annually, and that another 140–250 million preschool children are at risk based on serum vitamin A levels (Underwood, 2004). In the 1980s and 1990s, large randomized, doubleblind, placebo-controlled clinical trials were conducted in developing countries. They demonstrated that vitamin A supplementation could reduce childhood mortality by approximately one quarter to one third, even by giving concentrated vitamin A supplements at 6-month intervals (Sommer et al., 1986; Beaton et al., 1993; Semba, 1999; Underwood, 2004). Vitamin A supplementation of malnourished children is now considered one of the most cost-effective health interventions known (World Bank, 1993; Semba, 1999). Although consistent periodic distribution of vitamin A supplements can control vitamin A deficiency disorders, sustained control by this means is fragile, especially in countries with economic decline and civil unrest (Underwood, 1998, 2004). As was the case with eradication of endemic pellagra in the United States in the early-20th century (Lanska, 2002), other measures are also needed to ensure adequate diets and improve socio-economic conditions before vitamin A deficiency disorders can be truly controlled (Underwood, 1998, 2004; Underwood and Smitasiri, 1999).

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McCollum EV (1964). From Kansas Farm Boy to Scientist: The Autobiography of Elmer Verner McCollum. University of Kansas Press, Lawrence, KS. McCollum EV, Davis M (1913). The necessity of certain lipins in the diet during growth. J Biol Chem 15: 167–175. McCollum EV, Davis M (1914). Observations on the isolation of the substance in butter fat which exerts a stimulating effect on growth. J Biol Chem 19: 245–250. McCollum EV, Kennedy C (1916). The dietary factors operating in the production of polyneuritis. J Biol Chem 24: 491–502. McCollum EV, Simmonds N (1916). The relation of the unidentified dietary factors, the fat-soluble A, and watersoluble B, of the diet to the growth-promoting properties of milk. J Biol Chem 27: 33–43. McCollum EV, Simmonds N, Becker JE, et al. (1922). Studies on experimental rickets. XXI. An experimental demonstration of the existence of a vitamin which promotes calcium deposition. J Biol Chem 53: 293–312. Matthews RG, Hubbard R, Brown PK, et al. (1963). Tautomeric forms of metarhodopsin. J Gen Physiol 47: 215–240. Moore T (1930). Vitamin A and carotene. Biochem J 24: 692–702. ¨ ber den sog. Hikan (Xerosis conjunctivae Mori M (1904). U infantum, ev. Keratomalxie) II. Mitteil. Jahrbuch fu¨r Kinderheilkunde 51: 175–195. Morton RA, Goodwin TW (1944). Preparation of retinene in vitro. Nature 153: 405–406. Ooman HAPC, McLaren DS, Escopini H (1964). Epidemiology and public health aspects of hypovitaminosis A. A global survey on xerophthalmia. Trop Geogr Med 16: 271–315. Oroshnik W, Brown PK, Hubbard R, et al. (1956). Hindered cis isomers of vitamin A and retinene: the structure of the neo-b isomer. Proc Natl Acad Sci USA 42: 578–580. Osborne TB, Mendel LB (1913). The relation of growth to the chemical constituents of the diet. J Biol Chem 15: 311–326. Osborne TB, Mendel LB (1914). The influence of cod liver oil and some other fats on growth. J Biol Chem 17: 401–408. Palmer LS, Kempster HL (1919). Relation of plant carotenoid to growth, fecundity and reproduction of fowl. J Biol Chem 39: 299–337. Reddy V (2002). History of the International Vitamin A Consultative Group 1975–2000. J Nutr 132: 2852S–2856S. Rosenfeld L (1997). Vitamine–vitamin. The early years of discovery. Clin Chem 43: 680–685. Ross AC, Ternus ME (1993). Vitamin A as a hormone: recent advances in understanding the actions of retinol, retinoic acid, and beta carotene. J Am Diet Assoc 93: 1285–1290. Semba RD (1999). Vitamin A as “anti-infective” therapy, 1920–1940. J Nutr 129: 783–791. Sommer A, Tarwotjo I, Hussaini G, et al. (1981). Incidence, prevalence, and scale of blinding malnutrition. Lancet 1: 1407–1408.

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Sommer A, Tarwotjo I, Djanadi E, et al., the Aceh Study Group (1986). Impact of vitamin A supplementation on childhood mortality. A randomized controlled community trial. Lancet I: 1169–1173. Steenbock H (1919). White corn vs. yellow corn and a probable relation between the fat-soluble vitamine and yellow plant pigments. Science 50: 352–353. Steenbock H, Gross EG (1920). Fat-soluble vitamine. J Biol Chem 41: 149–162. Stryer L (1986). Cyclic GMP cascade of vision. Annu Rev Neurosci 9: 87–119. Underwood BA (1998). From research to global reality: the micronutrient story. J Nutr 128: 145–151. Underwood BA (2004). Vitamin A deficiency disorders: international efforts to control a preventable “pox.” J Nutr 134: 231S–236S. Underwood BA, Smitasiri S (1999). Micronutrient malnutrition: policies and programs for control and their implications. Annu Rev Nutr 19: 303–324. University of Wisconsin College of Agricultural and Life Sciences. Our Landmark Accomplishments: Historical Markers on the CALS Campus. http://www.cals.wisc. edu/media/history, accessed 13 April 2007. Voss HE (1956). Nicolai I Lunin – 1853–1937. J Am Diet Assoc 32: 317–320. Wald G (1935a). Vitamin A in eye tissues. J Gen Physiol 18: 905–915. Wald G (1935b). Carotenoids and the visual cycle. J Gen Physiol 19: 351–371. Wald G (1948a). Selig Hecht (1892–1947). J Gen Physiol 32: 1–16. Wald G (1948b). The synthesis from vitamin A of “retinene1” and of a new 545 mμ chromagen yielding lightsensitive products. J Gen Physiol 31: 489–504. Wald G (1950). Eye and camera. Sci Am 183: 32–41.

Wald G (1965). Visual excitation and blood clotting. Science 150: 1028–1030. Wald G (1967/1972). The molecular basis of visual excitation: Nobel lecture, December 12, 1967. In: Nobel Lectures, Physiology or Medicine 1962–1970. Elsevier, Amsterdam, pp. 292–315. http://nobelprize.org/nobel_prizes/medicine/ laureates/1967/wald-lecture.pdf [accessed 12-18-06] Wald G, Brown PK (1950). The synthesis of rhodopsin from retinene1. Proc Natl Acad Sci USA 36: 84–92. Wald G, Hubbard R (1949). The reduction of retinene1 to vitamin A1 in vitro. J Gen Physiol 32: 367–389. Wald G, Hubbard R (1950). The synthesis of rhodopsin from vitamin A1. Proc Natl Acad Sci USA 36: 92–102. Wald G, Steven D (1939). An experiment in human vitamin A-deficiency. Proc Natl Acad Sci USA 25: 344–349. Wald G, Brown PK, Smith PH (1955a). Iodopsin. J Gen Physiol 38: 623–681. Wald G, Brown PK, Hubbard R (1955b). Hindered cis isomers of vitamin A and retinene: the structure of the neo-b isomer. Proc Natl Acad Sci USA 41: 438–451. Weatherall M (1990). In Search of a Cure: A History of Pharmaceutical Discovery. Oxford University Press, Oxford. Wolf G (1996). A history of vitamin A and retinoids. FASEB J 10: 1102–1107. Wolf G (2001). The discovery of the visual function of vitamin A. J Nutr 131: 1647–1650. Wolf G (2002). The experimental induction of vitamin A deficiency in humans. J Nutr 132: 1805–1811. Wolf G, De Luca LM (1970). Recent studies on some metabolic functions of vitamin A. In: HF De Luca, JW Suttie (Eds.), Fat-soluble Vitamin Symposium. University of Wisconsin Press, Madison, pp. 257–265. World Bank (1993). World Development Report 1993: Investing in Health. Oxford University Press, New York.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 30

Historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins DOUGLAS J. LANSKA * Department of Neurology, Veterans Affairs Medical Center, Tomah, WI, USA

INTRODUCTION This chapter will review the major neurological disorders associated with deficiencies of the water-soluble B vitamins, including particularly beriberi, Wernicke– Korsakoff disease, pellagra, neural tube defects, and subacute combined degeneration of the spinal cord.

THIAMIN (VITAMIN B1) DEFICIENCY: BERIBERI ANDWERNICKE^KORSAKOFF DISEASE Peripheral nervous system manifestations of thiamin deficiency have been recognized for millennia in Asia in the form of a sensorimotor polyneuropathy called beriberi. People affected by beriberi first develop nonspecific constitutional symptoms including weakness, fatigue, irritability, anorexia, and abdominal discomfort. As the disease progresses, patients develop symptoms of peripheral polyneuropathy with paresthesias, neuropathic pain, and numbness (referred to as “dry beriberi”), often accompanied by congestive heart failure with pedal edema, pleural effusions, and pulmonary edema (“wet beriberi”). The prevalence of beriberi increased greatly in Asia with a change in the milling process for rice in the late 19th century, around the time that the central nervous system manifestations of thiamin deficiency – Wernicke’s encephalopathy and Korsakoff’s psychosis – were recognized in Europe. Only in the 20th century were these disorders all clearly linked to a deficiency of a specific dietary factor, which was ultimately determined to be the vitamin now called thiamin. The isolation and synthesis of thiamin in the 1930s greatly improved the acute treatment of these disorders, but more importantly made possible the prevention of large outbreaks of beriberi, as well as the prevention *

of many sporadic cases of all neurological forms of thiamin deficiency, through food fortification.

Brontius’s description of the sensorimotor neuropathy of beriberi Dutch physician Jacobus Brontius (1592–1631), frustrated by the meager earnings from his practice in Leyden, accepted a job in 1627 as physician for the Dutch East India Company in Batavia (now Jakarta), on the island of Java (in what is now southern Indonesia). In Batavia, Brontius observed and studied a wide range of novel tropical diseases, and gave the first European description of the sensorimotor polyneuropathy of beriberi in a book, De Medicina Indorum Libri IV, which was first published posthumously in 1642 (Brontius, 1745/1945). Brontius noted that the word beriberi, meaning sheep, was applied because afflicted individuals had a steppage gait that resembled the gait of sheep. Among the clinical features recognized by Brontius were generalized weakness, tremulousness, and paresthesias. The etymology of the word beriberi has been variously attributed, some claiming like Brontius that it derives “from the Hindustan beri, a sheep, in allusion to the peculiar gait in some instances of the disease . . . [while others have claimed that it derives] from the Sudanese beriberi, beribit, berebet, stiff walking, pottering walking; . . . from the Singhalese [Sinhalese, Sri Lankan] Bharyee, weak movement [or “a very bad sickness”]; . . . from the Hindustan in Bharbari, swelling, edema, and . . . from the Arabic buhr, asthma and bahri, a sailor, in allusion to the fact that it is a form of dyspnea frequently meet with among sailors in the Arabian seas . . .” [emphasis added] (Anonymous, 1916, p. 790).

Correspondence to: Douglas J. Lanska, MD, Staff Neurologist, VA Medical Center, 500 E Veterans St., Tomah, WI 54660, USA. E-mail: douglas. [email protected], Tel: +1-608-372-1772, Fax: +1-608-372-1240.

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D.J. LANSKA he met Dutch military physician Christiaan Eijkman Takaki and the dietary prevention of kakke´ (1858–1930), who had been studying with Koch since (beriberi) in the Japanese navy 1885 (only 3 years after Koch’s revolutionary discovery Although beriberi had been recognized in Asia for sevthat tuberculosis is caused by a specific bacterium). eral thousand years, its incidence increased dramatically Impressed with Eijkman, Pekelharing asked that he be in the 1870s, when it became one of the most common assigned as an assistant to the commission. diseases in Asia as an unrecognized consequence of a From late 1886 through the summer of 1887, the comchange in diet of the population. By this time, steammission focused on possible infectious causes of beriberi driven mills had been introduced to Asia from Europe at a laboratory established in the Military Hospital in Bataand were replacing the previous milling process (Verhoef via, Java. In late 1887, Pekelharing and Winkler were et al., 1999). The new steam-powered mills efficiently recalled to Holland (where Winkler was appointed as the removed the so-called polishings and with these went first professor of neurology in the Netherlands) and Eijkessential nutrients, including thiamin. The new polished man was appointed director of the laboratory (Verhoef rice was considered to be superior in taste and quality et al., 1999; Carpenter, 2000). Eijkman subsequently tried and became a dietary staple throughout Asia. unsuccessfully to infect rabbits and monkeys with the From 1878 to 1882, approximately one third of microorganisms that his colleagues had isolated from peoenlisted Japanese sailors reported ill with kakke (i.e., ple who had died of beriberi. Undaunted, Eijkman conberiberi) annually (Takaki, 1906a, b, c; Itokawa, 1976; cluded that the responsible infection must be slowly Hawk, 2006). Japanese military physician Kanehiro progressive, with considerable time needed to develop Takaki (1849–1915) noted that the diets of Japanese sailclinically evident manifestations. To make sure that extraors were relatively deficient in nitrogen content (i.e., neous factors were not responsible for the observed results protein) compared with the diets of British and German over a long time interval of disease development, many sailors, who were not susceptible to beriberi. As a control animals were needed. By late 1889, he had begun result, Takaki incorrectly attributed the beriberi among using chickens for these injection studies, presumably Japanese sailors to a dietary deficiency of protein. because the chickens were cheaper and easier to maintain. On a training cruise in 1883, 161 of the 278 Japanese At that point, Eijkman was fortunate to observe a sersailors (58%) developed beriberi and 25 died (9%), endipitous event, astute enough to understand its possible prompting Takaki to push for dietary reforms. After significance, and diligent enough to pursue the necessary receiving permission for a trial of a modified diet, studies to evaluate the possibilities: a “polyneuritis” broke Takaki arranged for a repetition of the training cruise out among the laboratory’s chickens, which was characthe following year, with all factors held constant terized by an unsteady gait with frequent falls and diffiexcept for the diet, which was modified by increased culty in perching, later an inability to stand or fly amounts of meat, barley, and fruit (thus increasing attributed to ascending weakness, and finally slowed the presumptively deficient nitrogen content). In conrespiration, cyanosis, hypothermia, progressive lethargy, trast to the heavy toll the previous year, there were and neck extension preceding death (Eijkman, 1929/ no deaths and only 14 cases of beriberi, all among sai1965, 1990). Histological examination of peripheral lors who refused to eat the full rations of meat and nerves stained by the Marchi method demonstrated milk. With these dramatic results, the diets of all Japaaxonal degeneration, most pronounced in the legs, which nese sailors were similarly modified, so that, by 1887, was thought to resemble the changes seen in the periphTakaki reported that there were only three cases with eral nerves of people who had died of beriberi (Eijkman, no deaths over the previous year, compared to more 1990; Carpenter, 2000). Curiously, both injected and than 1000 cases annually prior to 1884. control chickens were affected, but, because they had been kept together in large cages, Eijkman suspected that Eijkman and the polyneuritic the chickens he had injected with microorganisms had chickens of Java somehow contaminated the control chickens. However, In 1886, the Dutch government, hoping to find the cause in additional experiments he found that keeping the chickof beriberi that had become a tremendous problem for ens in separate cages made no difference, causing him to its colonies in the East Indies, sent a commission to wonder whether the entire institute had become infected. investigate under the direction of Cornelius Pekelharing, Further studies to elucidate the putative infection were Professor of Pathology at the University of Utrecht, with unrevealing, but a new possibility presented itself when Cornelius Winkler, a neurologist (Eijkman, 1929/1965; Eijkman learned that the onset of polyneuritis in chickens Carpenter, 2000). When Pekelharing went to Berlin to coincided with a change to polished rice, which only learn from Robert Koch (1843–1910) the latest microbioresolved when they were serendipitously switched back logical techniques for use in his investigations of beriberi, to brown rice (Eijkman, 1929/1965, 1990).

NEUROLOGICAL VITAMIN DEFICIENCY DISORDERS: B VITAMINS 447 Eijkman then began “deliberate feeding experihad different frequencies of beriberi, the two considered ments” with chickens. In 1889, Eijkman found that the possibility that the different prisons were using rice chickens fed on a diet restricted to cooked polished processed in different ways. Rations were highly standarrice developed polyneuritis generally after 3 or 4 dized in Java prisons (e.g., 750 g rice, 1 chili pepper, 150 g weeks, but recovered if returned to feed-grade of other mixed vegetables), but the type of rice was not unpolished rice (Eijkman, 1990). Despite his dietary specified and therefore open to the discretion of the prison experiments, Eijkman had trouble abandoning his governors, local market availability, prices, etc. (Carpeninitial microbiological framework: in keeping with the ter, 2000). Vorderman wrote a form letter to each prison late-19th-century concept of “ptomaines,” Eijkman governor asking for the incidence of beriberi and the type suggested that “cooked rice favored conditions for of rice in use (Carpenter, 2000; Vandenbrouke, 2003). By the development of micro-organisms of a still 1896, preliminary results from available replies suggested unknown nature in the intestinal tract, and hence for that beriberi was almost exclusively confined to prisons the formation of a poison causing nerve degeneration” using polished white rice. Based on these results, the gov(Eijkman, quoted in Carpenter, 2000, p. 39). ernment approved a larger and more in-depth study. Later experiments, from 1891 to 1895, demonstrated Unfortunately, Eijkman was ill with malaria and had to that the difference between polished and whole rice could return to Holland. not be attributed to inadequate preservation or contamiVorderman spent the next 5 months visiting all 101 nation of the polished rice (e.g., by a microbial toxin), prisons scattered across the large island (some 54 000 because: (1) freshly prepared polished rice could also square miles), taking samples of the rice used, recording cause beriberi; and (2) beriberi did not develop from the frequency of beriberi over the previous 18 months, brown or “rough rice” (i.e., with only the coarse husk and recording environmental information about each removed but still containing the “silver skin” or pericarpprison. When the rice samples were examined at the ium and the germ largely intact), even though this form of laboratory in Batavia, there was considerable variation rice deteriorates much more quickly (Eijkman, 1929/1965, in the completeness of deskinning, so that the rice had 1990). Disease development also did not depend on to be categorized as mostly polished (
75% of grains whether the polished rice was cooked or raw, on the water were deskinned), mostly unpolished (< 25% of grains used for cooking (as it even developed with artesian or were deskinned), or intermediate. Of the 96000 people distilled water), or on the presence of coarse rice husks imprisoned at institutions using unpolished rice, less as a source of dietary fiber. Importantly, Eijkman found than 1 in 10000 developed beriberi, whereas of the that the polyneuritis could be cured or prevented by feed150000 people at institutions using polished rice, 1 in ing the chickens either unpolished rice or the discarded 39 (2.8%) developed beriberi (Verhoef et al., 1999; Carrice polishings. penter, 2000). Although beriberi prevalence varied draFeeding the chickens other starchy plant foods (e.g., matically with the type of rice used, it did not vary sago and tapioca) produced identical results to those with with the source of the rice (imported or locally procooked rice, making Eijkman wonder whether beriberi is duced), the age of the buildings, floor permeability, adeat least in part due to lack of adequate food, as some of quacy of ventilation, or degree of overcrowding. On the the birds were considerably emaciated – a suspicion seebasis of these data, Vorderman persuaded governmental mingly confirmed when the birds recovered when fed authorities to modify the prison diets to include more only meat. However, birds fed on a combined diet of unpolished rice, and also more beans and other vegetastarch and meat ultimately developed beriberi, even bles. Any subsequent change in incidence was apparthough they did not become emaciated. Furthermore, ently never formally studied (Carpenter, 2000), simple starvation did not produce beriberi. Eijkman although it was reported that this public health measure (1929/1965) concluded that “inanition in itself could not rapidly eliminated beriberi from the prison populations be the main cause of the disease (any more than ‘protein’ (Verhoef et al., 1999; Vandenbrouke, 2003). or ‘salt’ deficiency), even though it promoted it.” Vorderman’s study was a valuable early effort at observational epidemiology, but not without limitations. For example, Vorderman relied on retrospective Vorderman’s observational studies clinical diagnoses (of variable validity), did not assess of beriberi in Java prisons each prisoner’s duration of exposure to polished rice In late 1895, Eijkman discussed the etiology of beriberi (especially when some sentences were as short as a with his friend Adolphe Vorderman (1844–1902), Inspecfew days and others were much longer), and did tor-General of Public Health, who was the government not address potential confounding factors (e.g., a difphysician responsible for the medical inspection of prisons ference in disease frequency for coastal and central across Java. Because it was known that different prisons prisons) (Carpenter, 2000).

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Grijns’ dietary deficiency explanation of beriberi presaged the “vitamin doctrine” Dutch physician Gerrit Grijns (1865–1944) from the University of Utrecht was assigned to continue the studies of beriberi in Java after Eijkman returned to Holland in 1896. Having no preconceived ideas concerning etiology, Grijns considered additional possibilities that had not been addressed by Eijkman. Eijkman’s work had already indicated that it was not the protein in the silverskin of the rice that was important for preventing beriberi, so Grijns systematically excluded potential deficiencies of minerals or fats in the polished rice associated with beriberi (Carpenter, 2000). Grijns tested other foods and discovered that both mung beans and “pigeon peas” had antineuritic properties (Eijkman, 1929/1965; Carpenter, 2000). Grijns also excluded a toxic effect specific to rice starch by demonstrating that polyneuritis also developed in chickens fed only on autoclaved meat or on potato flour plus a protein supplement (i.e., mung beans in which the antineuritic properties were destroyed by autoclaving) (Eijkman, 1929/1965; Carpenter, 2000). What dietary factor was left to consider, Grijns wondered, since the various components of a physiologically complete diet as then understood (i.e., sufficient proteins, carbohydrates, fats, inorganic salts, and water) had all apparently been excluded as possibilities? Grijns noted two well-known but insufficiently appreciated facts that suggested foods might contain previously unidentified nutrients: (1) sailors suffering from scurvy could be cured by fresh meat and fresh green vegetables (or by citrus fruits or their juices, as was well known from James Lind’s experiments in 1747); and (2) infant formulas were not a satisfactory substitute for breast milk even with the same concentrations of protein, sugar, fat, and salts. Grijns’ subsequent attempts at extracting the antineuritic factor from rice bran were unsuccessful, but he discovered that the antineuritic factor had been destroyed by the processing method he used. In 1901, Grijns considered two possibilities to explain the known facts concerning the etiology of beriberi: first, a “deficiency or partial starvation” of a substance that was necessary in small amounts for maintaining metabolic functions of the peripheral nervous system and the muscles; or second, the lack of a protective dietary factor that normally acts to maintain resistance of the peripheral nervous system to an environmental agent (e.g., a microorganism) that otherwise causes neural degeneration. In either case, Grijns supposed, beriberi was actually caused by a dietary deficiency of a specific natural substance found in certain foods (Carpenter, 2000). Unfortunately, Grijns’ important work presaging the “vitamin doctrine” was published in Dutch and not widely recognized at the time. In 1929, Eijkman shared

the Nobel Prize in Physiology or Medicine with Frederick Hopkins “for their discovery of the growth stimulating vitamins,” but Grijns’ important work was overlooked by the Nobel Prize Committee and Eijkman failed to give Grijns appropriate recognition in his Nobel Prize Lecture. Grijns’ research achieved wider recognition only after colleagues had his work translated and published in English in 1935 (Grijns, 1935). Grijns’ work did lead to a clinical trial after Vorderman visited a mental hospital in Buitenzorg and discussed the treatment of beriberi with Hulshoff Pol, the physician in charge (Carpenter, 2000). Pol set up a controlled trial of 300 patients to compare the value of mung beans, green vegetables (suggested by Vorderman, because these were a dietary staple in the surrounding villages), regular disinfection (to assess the proposal of another physician that beriberi was spread by cockroaches), and a control with no specific treatment. As the patients were housed in 12 separate pavilions, the different treatments were allocated to four different groups of three pavilions each. After 9 months, none of the patients in the mung bean group had developed beriberi, compared with 19% in the green vegetable group, 42% in the regular disinfection group, and 33% in the control group. The three pavilions receiving beans were protected from developing beriberi, and further tests demonstrated that beans could reverse the pedal edema and congestive heart failure, though they did not restore the function of severely damaged nerves.

Wernicke’s clinicopathological description of Wernicke’s encephalopathy Over a 1-year period in the late 1870s, German neuropsychiatrist Carl Wernicke (1848–1905), working at the Charite´ in Berlin, treated three patients with an unusual constellation of neurological findings including mental disturbances, ophthalmoparesis, nystagmus, and ataxia (Wernicke, 1881/1977). The first was a 20-year-old woman Wernicke treated in early 1877 after she had swallowed sulfuric acid and developed protracted vomiting. After some degree of recovery, she developed photophobia, impaired vision, drowsiness, and gait ataxia. Examination disclosed somnolence, disorientation, apathy, and later extreme anxiety, nocturnal agitation, convergent strabismus with asymmetric lateral rectus weakness, vertical nystagmus, impaired convergence, optic disc swelling, and multiple flame-shaped retinal hemorrhages. The symptoms progressively worsened and she died within 2 weeks of onset. Wernicke subsequently observed similar symptoms in two alcoholic men, both of whom were hospitalized with agitated delirium. Wernicke summarized the clinical features of his three cases, noting particularly the progressive ophthalmoparesis, ataxia, and encephalopathy with either

NEUROLOGICAL VITAMIN DEFICIENCY DISORDERS: B VITAMINS agitation or somnolence. In all three cases, pathological examination of the brain at autopsy demonstrated numerous punctate hemorrhages symmetrically arranged in the gray matter around the third and fourth ventricles and the aqueduct of Sylvius. Wernicke considered these pathological changes to have resulted from an acute, inflammatory disease of the rostral brainstem involving cranial motor nerve nuclei of the extraocular muscles, analogous to poliomyelitis and its involvement of the gray matter of the anterior horns of the spinal cord – hence his term, “acute hemorrhagic polioencephalitis superior.”

Korsakoff’s clinical description of Korsakoff’s psychosis From 1887 to 1889, in a series of three articles, Russian psychiatrist Sergei Sergeievich Korsakoff (sometimes spelled Korsakov, 1853–1900) gave a comprehensive description of a cognitive disorder now known as Korsakoff’s psychosis, occurring in conjunction with peripheral polyneuropathy (Korsakoff, 1889/1955; Victor and Yakovlev, 1955). As early as 1887, Korsakoff felt that the cognitive disorder and the polyneuropathy represented “two facets of the same disease . . . The pathologic cause provoking multiple neuritis may affect several parts of the nervous system, central as well as peripheral, and according to where this cause is localized there will be symptoms either of neuritis or of the brain” (quoted in Victor and Yakovlev, 1955, p. 395); hence his initial terms, “psychosis associated with polyneuritis” and “polyneuritic psychosis.” By 1889, Korsakoff recognized that, “At times . . . the symptoms may be so slight that the whole disease manifests itself exclusively by psychic symptoms” (quoted in Victor and Yakovlev, 1955, p. 395): therefore, as Korsakoff stated in his final publication, “One might also call it psychosis polyneurotica, but using this designation one must remember that an identical psychic disturbance may occur also in cases in which the symptoms of multiple degenerative neuritis may be very slight or even entirely wanting” (Korsakoff, 1889/1955, p. 402). The other term suggested by Korsakoff – “toxemic cerebropathy (cerebropathia psychica toxemica)” – was based on his concept that the diverse conditions associated with the disorder could all be “reduced to an incorrect constitution of the blood, developing under their influence and leading to an accumulation in the blood of toxic substances,” which could poison the central nervous system, the nerves, or both (Korsakoff, 1889/1955, p. 402). Although many modern authors consider only a restricted form of cognitive disorder under the eponym of Korsakoff’s psychosis – i.e., the combination of

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anterograde amnesia and confabulation – Korsakoff originally described a much wider range of mental states, often occurring sequentially, including an agitated delirium, an apathetic acute confusional state, and a confabulatory anterograde amnestic state. It was, however, the confabulatory amnestic state, typically following an agitated delirium, that most intrigued Korsakoff. Korsakoff based his conclusions on at least 46 patients – approximately two thirds of whom were alcoholics, with the remainder having a wide variety of conditions often associated with protracted vomiting, including postpartum infections, intestinal obstruction, abdominal tumor, typhoid fever, and jaundice. Korsakoff’s writings do not include a pathologic description of the disease. Also, he was apparently unaware of the important association of the cognitive and neuropathic features with the oculomotor findings and ataxia described by Wernicke in 1881: Korsakoff did mention that “sometimes there are ophthalmoplegia externa, nystagmus, and like manifestations,” but he attached no great significance to this, considered these symptoms among a range of other manifestations that indicated “a disturbance of the entire organism,” and did not pursue this further (Korsakoff, 1889/ 1955, p. 399).

Relationship between Wernicke’s encephalopathy and Korsakoff’s psychosis Neither Wernicke nor Korsakoff appreciated the close relationship between the disorders the two of them described. It was not until the early years of the 20th century that Bonho¨ffer recognized the close relationship between Korsakoff’s psychosis, delirium tremens, and Wernicke’s encephalopathy (Bonho¨ffer, 1901, 1904). Bonho¨ffer also recognized that the lesions in Wernicke’s encephalopathy are not inflammatory. By 1904, Bonho¨ffer concluded that neuritis (neuropathy) and a memory disorder can be found in all patients with Wernicke’s encephalopathy. During the subsequent decade, several authors noted the frequent co-occurrence of Wernicke’s encephalopathy and Korsakoff’s psychosis. Because Wernicke’s encephalopathy was often fulminant, autopsies were done on many of the cases, including Wernicke’s first three cases (Wernicke, 1881). In contrast, Korsakoff’s psychosis often required survival from Wernicke’s encephalopathy to be manifest, so that pathological material was less available. Consequently Korsakoff was unable to describe the pathology, despite having evaluated at least 46 patients. The clinico-pathologic overlap was nevertheless ultimately recognized between Wernicke’s encephalopathy and Korsakoff’s psychosis (Gamper, 1928; Kant, 1932–1933; Campbell and Biggart, 1939).

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For example, Kant (1932–1933) noted an amnestic disorder in all patients presenting with Wernicke’s encephalopathy, and also found the characteristic brainstem pathology of Wernicke’s encephalopathy in all fatal cases of Korsakoff psychosis. In the 1920s and 1930s, careful pathological studies noted the selective distribution of symmetric lesions affecting the mammillary bodies, the gray matter immediately surrounding the third ventricle and involving the hypothalamus and the medial portion of the thalamus, the periaqueductal gray matter (including the oculomotor nuclei), the posterior colliculi, and less frequently the floor of the fourth ventricle (involving the dorsal vagal nuclei and the median eminence) (Gamper, 1928; Campbell and Biggart, 1939). Specific histological changes in affected areas included hyperemia and sometimes small hemorrhages, vascular irregularities and proliferation of small blood vessels, relatively slight evidence of damage to nerve cells, variable microglial and astrocytic glial reaction, and absence of inflammatory infiltration. Although predominantly a polioencephalopathy, white matter was sometimes affected, including the columns of the fornix adjacent to the mammillary bodies and the optic nerves. Subsequent pathological studies have repeatedly documented a high frequency of cases of Wernicke– Korsakoff disease that went unrecognized during life, for example 86% in Harper’s (1979) series of 51 cases. Characteristic clinical findings of Wernicke’s encephalopathy (e.g., a triad of organic mental syndrome, ophthalmoparesis, and ataxia) were typically reported in clinical studies, but in only a minority of cases in pathological studies, suggesting various selection and reporting biases in both types of study, and also that cases with atypical clinical features were seldom being recognized during life (Cravioto et al., 1961).

Isolation and synthesis of thiamin In the late 1800s and early 1900s, several investigators tried unsuccessfully to isolate the antineuritic substance (Jansen, 1956; Williams, 1961; Carpenter, 2000). In 1926, Jansen and Donath, working in Batavia (where Eijkman had worked), finally crystallized the substance from rice polishings (Jansen and Donath, 1926; Jansen, 1956; Williams, 1961; Carpenter, 2000). Jansen and Donath had known that the protective factor was a relatively small molecule that was dialyzable and probably an organic base (Jansen, 1956). Work was frustratingly slow, however, until they were able to identify a small tropical bird (i.e., the bonbol) that was more susceptible than chickens and therefore developed manifestations of deficiency more quickly

and more reliably. Jansen and Donath ultimately isolated about 100 mg of a chemically pure substance that was extraordinarily potent in the prevention of polyneuritis in bonbols and also effective in the treatment of affected pigeons. The investigators sent 40 mg of these crystals to Eijkman in Utrecht where he was able to demonstrate their prophylactic and curative properties in the pigeon polyneuropathy model (Jansen, 1956; Carpenter, 2000). In 1931, A. Windaus and colleagues in Go¨ttingen isolated the pure, crystalline vitamin from yeast and demonstrated the presence of a sulfur atom in the molecule that had previously been overlooked by Jansen and Donath (Jansen, 1956; Williams, 1961; Carpenter, 2000). With knowledge of the empirical chemical formula, Robert Williams and colleagues proceeded to elaborate the chemical structure, and in 1936 Williams and J.K. Cline completed the chemical synthesis (Williams and Cline, 1936; Williams, 1961), followed nearly simultaneously by the same feat in two other laboratories (Jansen, 1956; Carpenter, 2000). The structure proved to include a pyrimidine ring linked by a methyl group to a thiazole ring. As a result of the chemical synthesis of thiamin, dietary supplementation became feasible, and by the 1950s synthetic forms of the vitamin were produced cheaply and used to enrich polished rice (Jansen, 1956). Vitamin B1 was initially named aneurin (for anti-neuritic vitamin), but was subsequently named thiamine (for thio = sulfur-containing vitamin), or more recently thiamin (Carpenter, 2000).

The metabolic role of thiamin In the 1930s, Rudolph Peters and colleagues in Oxford developed a biological assay of thiamin deficiency using acute opisthotonous in pigeons as the biomarker. They discovered that: (1) lactic acid was elevated in the brain of thiamin-deficient pigeons, particularly in the brainstem, even before clinical signs were evident (whereas exercise increased brain lactate levels fairly evenly across different brain areas); (2) elevated brain lactate levels were associated with decreased oxygen uptake, especially in the brainstem when pyruvate was the substrate; (3) elevated brain lactate was associated with a decreased rate of oxidation of pyruvate; (4) thiamin increased the respiration of brain tissue, with the essential biochemical step being the addition of thiamin pyrophosphate (cocarboxylase) as a cofactor for pyruvate dehydrogenase; and (5) ingested nonphosphorylated thiamin (i.e., from plant rather than animal sources) must be phosphorylated to be active as a cofactor (Kinnersley and Peters, 1930; Meiklejohn et al., 1932; Peters, 1936; Ochoa and Peters, 1938; Banga et al., 1939; Ochoa, 1939; Victor et al., 1989).

NEUROLOGICAL VITAMIN DEFICIENCY DISORDERS: B VITAMINS 451 Subsequent studies demonstrated the range of Wernicke’s encephalopathy responded to thiamin, but activity of thiamin in intermediary carbohydrate metathe entire syndrome was probably due to a “combination bolism, including acting as a coenzyme for pyruvate of several nutritional deficiencies” (Jolliffe et al., 1941). dehydrogenase (in the decarboxylation of pyruvate to In the late 1930s and early 1940s, similar pathologic acetyl-CoA), a-keto-glutarate dehydrogenase (in the decchanges were produced in various animal models by arboxylation of a-keto-glutarate in the Krebs cycle), and maintaining the animals (e.g., rats, foxes, fish, and transketolase (in the pentose phosphate pathway) (Platt pigeons) on thiamin-deficient diets (Prickett, 1934; and Lu, 1939; Horecker and Smyrniotis, 1953; Racker Alexander et al., 1938; Alexander, 1941). For example, et al., 1953). Although many of the biochemical pathways in 1934, C.O. Prickett of the Alabama Polytechnic Instiin which thiamin is utilized have been well studied, how tute demonstrated neuropathological changes in the thiamin deficiency actually produces the clinical and brainstem of rats maintained on a diet deficient in thiapathological manifestations of beriberi and Wernicke– min but supplemented with other vitamins: after 40 Korsakoff disease is less well understood, with condays the animals became ataxic and soon died with flicting evidence available concerning the roles of the bilateral petechial hemorrhages in the floor of the different thiamin-dependent enzymes (Victor et al., 1989). fourth ventricle and involving the vestibular nuclei and the nucleus solitarius (Prickett, 1934). Similarly, in 1938, Leo Alexander of Boston and colleagues Etiology of Wernicke–Korsakoff disease demonstrated that experimental beriberi in pigeons After the reports of Wernicke and Korsakoff in the produced lesions which appeared similar to those 1880s, alcoholism was recognized as the most fredescribed by Wernicke in 1881. quently associated underlying cause of the disorder. Even into the 1950s, the details of the clinical feaStill, a wide range of other associated conditions was tures associated with isolated thiamin deficiency were also recognized in which thiamin deficiency could be contested. In 1952, Phillips and colleagues reported attributed to inadequate intake, impaired absorption detailed studies of nine patients with classic Wer(e.g., protracted vomiting and gastrointestinal disturnicke’s encephalopathy (i.e., with ophthalmoparesis, bances), increased requirements (e.g., fever, carbohynystagmus, ataxia, and mental disturbances) who were drate loading), or some combination of these. given a diet composed solely of glucose and minerals, Wernicke’s encephalopathy was often associated with with specific vitamins added after periods of observaprotracted vomiting, particularly in pregnancy (hypertion (Phillips et al., 1952). None of the clinical features emesis gravidarum) (Wernicke, 1881; Henderson, 1914). improved before administration of thiamin, despite In the 1930s and early 1940s, a deficiency of B vitamins alcohol withdrawal, bed rest, and addition of other was proposed as the cause of Wernicke–Korsakoff vitamins (i.e., niacin, calcium pantothenate, pyridoxine, disease, and shortly thereafter the therapeutic effects of folic acid, ascorbic acid, riboflavin, or cyanocobalathiamin were demonstrated in this condition. In 1933, min). Instead, the ophthalmoparesis progressed and Bender and Schilder suggested that Wernicke’s encephathe nystagmus decreased only in association with the lopathy was due to a vitamin deficiency rather than to increasing oculomotor paresis. With administration of alcohol toxicity (Bender and Schilder, 1933). In 1937, thiamin, the ophthalmoparesis improved markedly in Wagoner and Weir reported clinical improvement with 1–6 h, confirming that ophthalmoparesis is due to a speB vitamins in Wernicke’s encephalopathy following procific lack of thiamin. The nystagmus and ataxia tracted vomiting during pregnancy (Wagoner and Weir, improved more slowly and less completely, while the 1937). In 1939, Bowman and colleagues reported the thermental changes improved only minimally with improved apeutic effects of thiamin in patients with Korsakoff’s attention but with some greater confabulation. The psychosis (Bowman et al., 1939). Campbell and Biggart authors felt that the evidence for a causal association (1939) implicated thiamin deficiency as the common etiobetween thiamin deficiency and the nystagmus and logic factor resulting from various conditions associated ataxia was “less conclusive,” and that no definite conwith Wernicke’s encephalopathy, including alcoholism, clusions were possible concerning the relationship hyperemesis gravidarum, and carcinoma. between mental disturbances and vitamin deficiency. In 1941, Jolliffe and colleagues at the Psychiatric Studies from the 1930s and thereafter tried to utilize Institute of Bellevue Hospital in New York documented assays of blood or urine thiamin, or assays of blood the rapid resolution of ocular palsies, and the slower pyruvate and lactate, for clinico-pathological correlaimprovement in ataxia and peripheral neuropathy with tion, clinical diagnosis, and treatment monitoring. thiamin treatment, whereas the cognitive changes – However, neither blood nor urinary thiamin levels especially Korsakoff’s psychosis – proved to be intractare sensitive indicators of tissue stores of thiamin, able. They concluded that the ophthalmoparesis of and elevated blood pyruvate and lactate levels are not

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sufficiently specific (Platt and Lu, 1939; Wortis et al., 1942; Sauberlich, 1967; Victor et al., 1989). In the early 1960s, the etiological relationship between thiamin deficiency and Wernicke’s encephalopathy was further supported by chemical analyses that demonstrated elevation of erythrocyte transketolase levels in the blood of patients with the disorder, consistent with thiamin deficiency (Brin et al., 1956, 1958; Dreyfus, 1962; Victor et al., 1989). Subsequently transketolase levels have been developed into a useful clinical test for Wernicke’s encephalopathy (Dreyfus, 1962; Dreyfus and Hauser, 1965; Sauberlich, 1984; Victor et al., 1989).

NIACIN DEFICIENCY: PELLAGRA Delirium, dementia, psychosis, and depression were common neuropsychiatric features of pellagra as it was seen in the 18th and 19th centuries in Europe and in the early portion of the 20th century in the United States (Lombroso, 1892, quoted in Marie, 1910; Lanska, 1996, 2004).

Recognition of pellagra Pellagra was apparently unknown prior to the introduction of maize into Europe from the New World. Gaspar Casa`l (1691?–1759), physician to King Ferdinand of Spain, described the signs and symptoms of pellagra in 1735, noted that the condition was known locally as mal de la rosa (disease of the rose), because of the erythematous rash on sun-exposed areas of the body, and linked it with poverty and a diet with little milk, meat, or other foods of animal origin (Marie, 1910; Etheridge, 1972; Bollet, 1992; Rajakumar, 2000). In 1771, the Italian Francesco Frapolli noted that, in Italy, the disease was associated with poverty and a diet largely restricted to maize-based polenta, exacerbated by sun exposure, and known locally as pellagra (pelle, skin, and agra, rough) (Frapolli, 1771/1945; Marie, 1910; Niles, 1916). In addition to the dermatitis recognized by Casa`l and Frapolli, other clinical manifestations included dementia (or depression), diarrhea, and death – the “4 Ds.” From the time of Casa`l’s description, endemic pellagra was recognized across large areas of Europe, particularly Spain and Italy, where peasants subsisted on nutritionally marginal corn-based diets, but also in France, Romania, Bulgaria, Yugoslavia, Austria, Hungary, Russia, as well as Egypt and North Africa. In the United States, endemic pellagra arose much later as a result of dietary deficiencies arising from the cotton monoculture of the South following the Civil War (Etheridge, 1972; Bollet, 1992; Lanska, 1996). A number of scattered cases of pellagra were reported from the

time of the Civil War up into the early-20th century, although not all reported cases were recognized as such at the time of the reports, and the diagnoses in the others were doubted. Beginning in 1907, outbreaks of pellagra were reported in various asylums, and by 1910 the disease was recognized throughout most of the southern states and in several other states (Searcy, 1907a, 1907b; Etheridge, 1972; Bollet, 1992; Lanska, 1996). Even if there were occasional (at that time unrecognized) cases in the United States prior to 1900, it was only after 1900 that pellagra became a significant public health problem, particularly in the South. As was the case with beriberi in Asia in the 19th century, the epidemic of pellagra in the South followed the introduction of a new grain processing method that effectively removed much of the vitamins from the processed grain. Specifically, in the case of pellagra there was a shift from use of coarsely ground corn meal produced in local, water-driven, grist mills before 1900 to use of finely bolted meal produced by large milling companies, which was degerminated to prevent development of rancidity during storage and shipment (Sydenstricker, 1958).

Pellagrous dementia From the earliest descriptions of pellagra in the United States around 1907, several investigators noted prominent neuropsychiatric manifestations including depression, delirium, and dementia. In 1907, Ray et al., (1907–1908) from the State Hospital for the Insane, in Columbia, South Carolina, reported to the South Carolina State Board of Health similarities between the neuropsychiatric features of pellagra and those of syphilitic general paresis and acute delirium. Similarly, in 1909, in a report for the 35th annual meeting of the American Neurological Association, neurologist Eugene Bondurant (?–1950) from Mobile, Alabama, noted that pellagra may begin with lassitude and dysthymia, with subsequent development of emotional lability, psychosis, depression, delirium, and dementia, typically with depression predominating (Bondurant, 1910). In 1915, psychiatrist H. Douglas Singer of the Illinois State Psychopathic Institute in Kankakee argued that previous statistics concerning the frequency of neuropsychiatric disturbance in pellagra were biased, among other things having been ascertained in psychiatric facilities without careful clinical evaluation and without reference to a population base in the community. Using data from Spartanburg County, South Carolina over the period from January 1912 to June 1913, obtained from community surveys conducted by the Thompson-McFaddin Pellagra Commission and from

NEUROLOGICAL VITAMIN DEFICIENCY DISORDERS: B VITAMINS 453 persons adjudged insane with and without pellagra in the by pellagrous countries; and (4) A change of food county, Singer provided data supporting an incidence rate generally resulted in a diminution or disappearance of insanity of approximately 520 cases per 10000 pellaof pellagra, especially if all corn or corn products were grins per year, 75 times the rate of diagnosed insanity in removed from the diet. Such evidence, while supporthe general population of that county (calculated from tive, was neither definitive nor universally accepted. Singer, 1915, p. 149). Singer also noted that there was an Opponents of the zeist theory (“anti-zeists”) coun“extraordinary frequency of pellagra arising de novo in tered that: (1) Although pellagra was first recognized hospitals for the care of the insane” and that patients with as a specific disease in the early-18th century, this did neuropsychiatric disorders were also somehow predisnot prove it was not present earlier; (2) Pellagra was posed to develop pellagra (Singer, 1915, p. 150). endemic only over a small part of the extensive area By the 1920s and 1930s, the triad of neuropsychiatric where corn was cultivated, and, indeed, it was absent dysfunction with skin and gastrointestinal manifestations from many places where maize was a staple food; was well known and thought to be specific, but insensi(3) Cases were reported among people who reportedly tive, for the diagnosis of pellagra, particularly in the early had not eaten corn or corn products, and from places stages (Stevens, 1922; Meakins, 1936). In 1943, Virgil where corn was not cultivated; and (4) In many places Sydenstricker (1889–1964), Chairman of the Department the apparent frequency of pellagra increased or of Medicine at the University of Georgia School of Meddecreased without any apparent change in dietary habits. icine (now the Medical College of Georgia), again noted One subset of zeist theories proposed that corn was that the neuropsychiatric manifestations of pellagra were associated with a pellagra-causing toxin: for example, toxvariable, not specific, and could be the presenting maniins could be a component of natural corn, could be elabofestation of pellagra (Sydenstricker, 1943). rated by microorganisms such as bacteria or fungi involved in corn spoilage (Reed, 1910; Bass, 1911), or might be produced in the alimentary canal (MacNeal, 1913). By Etiologic theories of pellagra the time pellagra was recognized as endemic in the United By the early-20th century, toxic, infectious, nutritional, States, world opinion was strongly against corn containing and hereditary theories of the etiology of pellagra found a toxic substance, unless the corn had been modified in limited empiric support (Roberts, 1913a; Niles, 1916; some way (e.g., by microorganisms), because corn was Lanska, 2006). Each new theory spawned various, often consumed in many places with apparent impunity. aggressive therapies, including cecostomy with colonic Some authorities, particularly the Italian physician irrigation, arsenical administration, and dietary manipuCesare Lombroso (1836–1909), suggested that a toxin lation. Initial therapeutic results were misleading and was produced in spoiled corn, which was not present in ultimately disappointing. Identification of effective good corn, and many investigators subsequently considtherapies was hampered by poorly controlled studies ered pellagra to be analogous to ergotism resulting from with small sample sizes, failure to consider placebo ingestion of toxic products of a fungus growing on rye effects or natural history, and inclusion of cases with used as a foodstuff (Lombroso, 1892; Marie, 1910; Reed, mistaken diagnoses or unrecognized concurrent condi1910; Bass, 1911; Voegtlin, 1914; Lanska, 2004); however, tions (Lanska, 2006). the distribution of pellagra did not coincide well with the The major etiologic theory of pellagra at the time of very irregular and variable distribution of spoiled corn. initial recognition in the United States was the “zeist” Another subset of the zeist theories considered corn theory (a term derived from Zea mays, the scientific to have inadequate nutritional value. The initial formuname for maize or Indian corn), which attributed pellalation of this theory was that a corn-based diet provides gra to the ingestion of corn. Although corn was widely insufficient protein, but chemical analyses of corn did held to be in some way responsible for pellagra, pronot substantiate this and many recognized authorities posed mechanisms varied widely. Support for the corn argued persuasively against this possibility (Lavinder, theory came mainly from ecologic observations in 1909; Niles, 1916). For example, in 1916, Niles stated which groups of individuals served as the unit of ana“this explanation is inadequate. If corn is lacking in lysis: (1) The appearance and certainly the recognition certain nutritive qualities – in gluten, in nitrogenous of pellagra followed historically the introduction of matter – so is rice, which, nevertheless, does not procorn as a staple food into Spain, France, Italy, and duce pellagra” (Niles, 1916, p. 62). More sophisticated other countries of southern Europe; (2) Endemic pellaanalyses later showed that corn is deficient in certain gra occurred only in countries where corn was grown amino acids, and this imbalanced protein became and used extensively among the rural poor; (3) Counviewed as the responsible factor. tries where corn was not grown or used as food were A number of infectious theories were also profree of pellagra, even if contiguous to or surrounded posed, and various investigators and authoritative

454 D.J. LANSKA groups (e.g., Sambon, 1905; Marie, 1910; Siler et al., Indeed, these experiments are not reported in a volume 1914a, b, 1917) supported an infectious etiology, although of Fraser and Stanton’s collected papers on beriberi no consistent organism was implicated (Sambon, (Fraser and Stanton, 1924). While Vedder viewed the 1905), affected individuals were not febrile, there was British government’s suppression of these unethical no evidence of inflammation, and attempts at transexperiments only as unfortunate, apparently lamenting mitting the condition with body secretions or skin the loss of information that he felt might clarify the scrapings failed (McCafferty, 1909; Anderson, 1911; etiology of the condition, clearly at least some who Lavinder, 1911; Singer et al., 1912; Lavinder et al., reviewed these experiments recognized them as 1914). Some considered that a microorganism was immoral, such that they had to be suppressed at a time eaten with corn and subsequently set up an intestinal prior to development of formal rules for protection of infection (which could of course explain some of the human experimental subjects. No such censorship or gastrointestinal manifestations of pellagra), while censure occurred in response to the similarly immoral others suggested that a filterable virus was responsible experiments by McCafferty. (Harris, 1913), and still others considered that a Joseph Goldberger and the “P-P factor” vector, such as a mosquito, common sand fly, or gnat, was responsible for transmitting a parasitic condition In 1914, with pellagra morbidity and mortality expanding similar to malaria, filariasis, or trypanosomiasis rapidly in the South, the US Public Health Service commis(Sambon, 1905; Lavinder, 1910; Marie, 1910; Roberts, sioned Dr. Joseph Goldberger (1874–1929) to study the dis1913a, b). ease. From 1914 to 1929, Goldberger completed wellBased on human-to-monkey transmission experidesigned epidemiologic investigations, tested theories with ments using a combination of subcutaneous, intravehuman experiments, and developed an animal model nous, and intracerebral injections of large quantities of (Parsons, 1943; Terris, 1964; Kraut, 2003; Lanska, 2006). material originating from two fatal human cases of pelGoldberger’s first paper was published in June 1914. He lagra, Harris (1913) claimed to have produced pellagra in emphasized three epidemiologic facts that had been two of three injected monkeys and therefore concluded repeatedly observed: (1) In various medical institutions, that pellagra was caused by a filterable virus (Harris, the inmates developed pellagra after varying periods of 1913, p. 1950). However, these results were not repliresidence, but ward personnel, attendants, and nurses were cated, and other studies attempting to transmit the disuniformly exempt despite prolonged and close contact ease from human cases to monkeys were “uniformly with affected patients; (2) Pellagra preferentially affected negative” (Anderson, 1911; Lavinder, 1911; Singer et al., rural areas; and (3) Pellagra is associated with poverty 1912, p. 175; Lavinder et al., 1914). Around 1909, at the (Goldberger, 1914a). Based on these considerations, GoldMt. Vernon Hospital “for the colored insane” in Tuscaberger boldly proposed a plan of prevention that emphaloosa, Alabama, Assistant Superintendant E.L. McCaffsized dietary changes with a reduction in cereals, erty, MD, also performed unethical human experiments vegetables, and canned foods, and an increase in fresh in unsuccessful attempts to transmit pellagra to unafmeats, eggs, and milk (Goldberger, 1914a; Terris, 1964). fected institutionalized patients: “We tried to infect Goldberger initiated a series of observational stusome patients by swabbing out the sick one’s mouth dies to clarify factors that might have etiologic signifiand rubbing it into the well one’s mouth; also swabbed cance, and that could be tested with more formal the sores on the hands and feet, and scarified well ones’ experiments or applied with presumptive preventive hands, but failed to get any results,” he wrote (McCafferty, approaches. In 1914, surveys of state institutions 1909, p. 229). Unfortunately, misuse of vulnerable showed that those developing pellagra ate an unbahuman subjects for experimental attempts at transmitlanced diet low in protein. In 1920, community surveys ting conditions later found to be deficiency diseases showed that pellagrous households had diets deficient was not isolated to this report. For example, as noted in animal protein (lean meat, milk, butter, cheese, by Vedder (1913, p. 144): eggs), recognized vitamins (particularly the “fat soluble A” factor), and minerals (Goldberger et al., Fraser and Stanton, in the course of their work 1920a, b, c, d; Sydenstricker, 1933; Kasius, 1974). on beriberi [in Malaya beginning in 1907], perNo differences were observed between pellagrous formed a large number of human experiments, and nonpellagrous households in terms of cereal supin which they tried by every conceivable method, plies (particularly maize), caloric content of the diets, including insect transmission, to infect healthy or the proportion of calories derived from carbohyindividuals from beriberi patients. These experidrate and fat combined (Goldberger et al., 1920a, b, ments were all negative, but were unfortunately c, d; Sydenstricker, 1933; Kasius, 1974). The incidence suppressed by the [British] Government for poliof pellagra varied by age, gender, family income, and tical reasons.

NEUROLOGICAL VITAMIN DEFICIENCY DISORDERS: B VITAMINS season, but there was no clear relation to sanitary conditions (Goldberger et al., 1920a, b, c, d; Goldberger and Sydenstricker, 1927; Sydenstricker, 1933; Kasius, 1974). Goldberger proceeded to test his theory and exclude alternatives with careful human experiments. From 1915 to 1923, he and his colleagues showed that initiation of a well-balanced diet at two Mississippi orphanages and the Georgia State Asylum eliminated pellagra from these institutions, places where it had previously been prevalent (Goldberger et al., 1915a, b, 1923). Those fed a diet of fresh meat, milk and vegetables, instead of a corn-based diet, did not develop pellagra, and those already affected rapidly recovered (Goldberger, 1914a, b; Goldberger et al., 1915a, b, 1923). A subsequent return to the institutional diet resulted in a return of pellagra, which again disappeared with resumption of the wellbalanced diet (Goldberger et al., 1923). In 1915, with the cooperation of Governor Earl Brewer, Goldberger experimented on 11 healthy volunteer prisoners at Rankin State Prison Farm near Jackson, Mississippi, with the prisoners offered pardons in return for their participation (Goldberger and Wheeler, 1915, 1920a, b; Bollet, 1992; Harkness, 1996; Kraut, 2003). The prisoners were fed a milk- and meat-free cornmeal diet, and six were felt to have developed cutaneous manifestations of pellagra within 6 months, although later studies suggested that some of the cutaneous manifestations (particularly the scrotal lesions) were those of riboflavin deficiency (Sebrell and Butler, 1938; Oden et al., 1939; Horwitt et al., 1949, 1956; Carpenter and Lewin, 1985). Proponents of competing theories, particularly those championing an infectious etiology, challenged Goldberger’s results (e.g., MacNeal, 1916). Intending to convert his critics, Goldberger performed a remarkable series of demonstrations. In 1916, he showed that pellagra could not be transmitted by injection of blood from pellagrous patients, by swabs of nasal and pharyngeal secretions swabbed onto healthy volunteers, by ingestion of capsules containing scabs of pellagrins’ rashes, or by ingestion of capsules containing pellagrins’ fecal material (Goldberger, 1916; Kraut, 2003). Goldberger used himself, his wife, and his colleagues as the subjects of these “filth parties.” None of them contracted pellagra, but they did not convert all of their critics either (MacNeal, 1916; Kraut, 2003). In the 1920s, Goldberger and colleagues determined that pellagra developed despite supplementation with minerals, known vitamins, and a liberal supply of protein of presumably good biological quality (Goldberger and Tanner, 1922, 1925; Goldberger et al., 1926; Goldberger, 1927). Goldberger and colleagues demonstrated that yeast extract, milk, and fresh lean beef are capable of preventing pellagra, whereas soy beans, cowpeas, butter, cod-liver oil, and canned tomatoes are not (Goldberger and Tanner, 1925; Terris, 1964). After raising

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the possibility that pellagra resulted from a deficiency or imbalance in dietary amino acids (Goldberger and Tanner, 1922), Goldberger ultimately concluded that pellagra is a dietary-deficiency disease that could be cured by a pellagra-preventive factor or “P-P factor” (later, “vitamin P-P”) that was lacking in corn, but that could be found in meat and milk. Goldberger and colleagues also began experiments with dogs, after learning in 1922 that the dog disease named “black tongue” (sometimes spelled blacktongue) was the canine equivalent of human pellagra (Chittenden and Underhill, 1917; Goldberger et al., 1922, 1926, 1928; Goldberger and Wheeler, 1928). From 1922 to 1928, Goldberger and colleagues demonstrated that black tongue could be produced experimentally with a diet containing mainly corn meal (Goldberger et al., 1926, 1928; Goldberger and Wheeler, 1928). Further studies evaluated the black tongue-preventive properties of a wide variety of foods and correlated these results with the pellagra-preventive properties of the same foods. By 1926 Goldberger and associates established that a small amount of dried brewer’s yeast could cure or prevent pellagra less expensively than fresh meat, milk, and vegetables (Goldberger and Tanner, 1925). A heat-stable component of yeast was shown to prevent the development of black tongue (Goldberger et al., 1928). Enterprising yeast manufacturers, in need of business during Prohibition, seized the opportunity and filled newspapers with propaganda: “only brewer’s yeast will cure and prevent pellagra.” A gullible populace of worried well “pellagraphobiacs” responded by buying more and more yeast. After 1928, yeast was provided free in endemic areas by state and county health departments and the American Red Cross (Davies, 1964). After Minot and Murphy showed that liver and liver extracts could cure pernicious anemia (1926–1928), Goldberger and Sebrell showed that liver extract could also prevent black tongue (Goldberger and Sebrell, 1930). In the early 1930s, many physicians tried liver extracts in the treatment of pellagra with equally positive results, but although liver extracts were more potent than yeast, they were prohibitively expensive and often ineffective parenterally in the dosages used (Sydenstricker, 1958; Davies, 1964). Goldberger never identified the elusive P-P factor, because his research was cut short by his death in 1929, but the year he died the Committee on Vitamin B Nomenclature of the American Society of Biological Chemists recommended naming the P-P factor vitamin G in his honor (Seidell et al., 1929).

Endemic pellagra was a manifestation of complex social issues Once the relationship between poverty, diet, and pellagra was established – primarily by Edgar Sydenstricker

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(1881–1936) and Goldberger – it became clear that pellagra was a manifestation of complex social issues and could not be easily eradicated even with the availability of a medicine that was curative (Sydenstricker, 1915, 1933; Goldberger et al., 1918, 1920a, b, c, d; Goldberger and Sydenstricker, 1927; Kasius, 1974; Lanska, 2002). Indeed, elimination of endemic pellagra would require improving the diet of a large portion of the rural Southern population, a behavioral and social change of tremendous magnitude and complexity. Nevertheless, with the impetus of further economic collapse of the Southern cotton monoculture and the manpower requirements of World War II, the needed political resolve developed and sufficient social reform occurred, so that eradication of endemic pellagra in the United States was accomplished by the 1950s. The antebellum cotton- and tobacco-based agriculture of the South had initially been compromised by the lack of slaves after the Civil War, but soon produced further economic servitude in the form of sharecropping, in which the landowners got a quarter to a half of the crop. Financially strapped sharecroppers devoted all available land to the cash crops (i.e., cotton and tobacco), and lived on inadequate unbalanced diets consisting largely of cheap corn meal. This entrenched sharecropping system would not be abandoned voluntarily by the powerful landowners or by some indebted sharecroppers, who had no ready alternatives. Unlike the elimination of slavery, which required political resolve and a civil war, the social change needed to eliminate sharecropping was initiated in large part by a tiny beetle. The boll weevil crossed the Rio Grande River from Mexico in the early 1890s and spread east and north to affect all the cotton growing regions of the United States by 1920. The boll weevil contributed greatly to the increasing economic woes of the Southern farmers during the 1920s, and consequently to a marked rise in pellagra incidence and mortality in the late 1920s. Boll weevil devastation of the cotton crops was a major reason for the subsequent development of crop diversification and crop rotation principles, including those developed and promoted by agricultural chemist George Washington Carver (1864–1943). During the depression, cotton was no longer an economically viable crop. The agricultural extension services encouraged farmers to reduce the acreage under cotton, keep livestock for personal food use, and diversify cultivated crops. Southern farmers learned to alternate soil-depleting cotton or tobacco crops with soil-enriching crops, such as peanuts, peas, soybeans, sweet potatoes, and pecans. From 1928 to 1933, total acreage under cotton or tobacco declined markedly and the production of vegetables and farm products for home use increased equally dramatically

(Davies, 1964). With these changes, pellagra mortality declined precipitously in the early 1930s, and subsequently plateaued until the advent of an effective treatment (i.e., niacin) was discovered in 1937.

Niacin In 1937, Conrad Arnold Elvehjem (1901–1962), an agricultural biochemist at the University of Wisconsin, finally isolated the P-P factor from active liver extracts, showed that the P-P factor is nicotinic acid (subsequently named niacin for nicotinic acid vitamin), and demonstrated that nicotinic acid and nicotinic acid amide cure black tongue in dogs (Elvehjem et al., 1937, p. 938). Soon after Elvehjem’s initial report in 1937, further animal trials demonstrated that niacin cured pellagra in pigs and monkeys (Harris, 1938), and human clinical trials confirmed that niacin had dramatic therapeutic effects and rapidly cured pellagra in people, including the cutaneous and cognitive manifestations (Fouts et al., 1937; Smith et al., 1937; Elvehjem et al., 1938; Matthews, 1938; Schmidt and Sydenstricker, 1938; Spies, 1938; Spies et al., 1938a, b, c, d, 1939; Sydenstricker et al., 1938). In 1937, Paul Fouts of the Lilly Laboratory for Clinical Research, Indianapolis City Hospital, Indiana University, along with colleagues, noted that, “All patients showed distinct improvement in general condition and mental attitude within 48 hours of onset of therapy” (Fouts et al., 1937, p. 406). Also in 1937, David Smith and colleagues from Duke University noted a dramatic recovery in a 42-year-old pellagrin treated with intravenous nicotinic acid (Smith et al., 1937). In 1938, Tom Spies of the University of Cincinnati College of Medicine and the Cincinnati General Hospital, along with colleagues, reported that treatment with nicotinic acid had dramatic results in 60 pellagrins with acute or subacute psychosis (Spies et al., 1938b). Spies subsequently lauded the beneficial effects of nicotinic acid in the treatment of pellagra, but nevertheless recognized that simply replacing the niacin deficiency was not a long-term solution; instead, maintenance of an adequate diet was necessary (Spies et al., 1939).

Dietary modification and food fortification Dietary modification was the first truly effective approach for the prevention of pellagra, but on a wide scale social reform was needed to ensure implementation. Initially dietary modification proved impractical because of economic conditions and dietary habits. Even with free distribution of yeast by the American Red Cross and by state and county health agencies, or with availability of inexpensive nicotinic acid, pellagra persisted in endemic areas, because of ignorance,

NEUROLOGICAL VITAMIN DEFICIENCY DISORDERS: B VITAMINS 457 inertia, poor food habits, and an “enormous backlog of corn diets where pellagra was common, and some chronic malnutrition” (Sydenstricker, 1958, p. 413). foods that were known to be effective in the prevenSubsequently, the fortification of foodstuffs by tion of pellagra (e.g., milk) were found to have a low vitamin supplementation was implemented largely to content of niacin (Goldsmith, 1958). Subsequent work ensure adequate numbers of fit soldiers for World showed that the amino acid tryptophan is converted War II (Lanska, 2002). Despite reasoned pleas for food to niacin in vivo and that this conversion is not depenfortification by academics in the late 1930s (e.g., Jolliffe, dent on intestinal bacteria as it occurs with parenterally 1938; Cowgill, 1939) and patriotic campaigns in the early administered tryptophan. Approximately 60 mg of 1940s, initial efforts to enrich bread and flour were not dietary tryptophan are needed to produce 1 mg of niavery effective because of limited public interest and lack cin (Goldsmith et al., 1961). of economic incentive for millers and bakers (Wilder, Corn-based diets were found to cause pellagra, lar1956; Park et al., 2000, 2001; Backstrand, 2002; Bishai gely because they had low concentrations of tryptoand Nalubola, 2002; Mensah et al., 2004). At the beginphan and because any endogenous niacin was bound ning of World War II, only 40% of the nation’s manufacin the form of nicotinyl esters which are not hydrotured flour was enriched, because small companies lyzed on digestion so that the nicotinic acid is not bioproduced cheaper unenriched flour to compete with the available. Pellagra was produced experimentally in larger manufacturers of enriched flour. In 1940, the human subjects given diets low in niacin and tryptoCouncil on National Defense requested that the National phan (Goldsmith, 1956) and tryptophan was found to Academy of Sciences establish a Food and Nutrition be effective in treating pellagra (Vilter et al., 1949). Board, which in 1941 established recommended intake Thus, in the 1940s and 1950s pellagra was reformulated levels for about a dozen nutrients, including niacin (Comas a deficiency disease due to inadequate niacin and its mittee on Food and Nutrition, 1943). amino acid precursor tryptophan (Goldsmith, 1956, Because a significant percentage of recruits were 1958; Goldsmith et al., 1956, 1961). Later studies ineligible for military service as a result of nutritional showed that both riboflavin and pyridoxine are necesdeficiency diseases (Jolliffe, 1938; Cowgill, 1939; sary for the metabolism of tryptophan, and that pyriKrupp, 1942), the US Army decided in 1942 to purchase doxine is specifically needed for the synthesis of only enriched flour, which encouraged many more niacin from tryptophan. manufacturers to produce enriched flour. Enrichment The general term “niacin” now includes nicotinic of bread with niacin, thiamin, riboflavin, and iron acid and its amide, i.e., nicotinamide, and any derivawas subsequently mandated by Food Distribution tives convertible in vivo to biologically active comOrder No. 1, issued on 29 December 1942 and effective pounds. Two derivatives in particular – nicotinamide as of 18 January 1943. This action, combined with adenine dinucleotide (NAD) and nicotinamide adenine improved economic conditions as a result of wartime dinucleotide phosphate (NADP) – are essential to all increases in employment, augmented the decline in pelcells, and are involved in multiple biochemical reaclagra morbidity and mortality that had begun by 1930 – tions, including glycolysis, pyruvate metabolism, and and finally resulted in eradication of endemic pellagra pentose, fatty acid, and sterol biosyntheses (Goldsmith, in the United States. 1965). Previous terminology (e.g., coenzyme I or diphosNearly all of sporadic cases in the United States phopyridine nucleotide for NAD, and coenzyme II or and other developed countries are now seen in alcotriphosphopyridine nucleotide for NADP) is no longer holics, although very rarely other patients can used. develop the disease, because of malabsorption, iatroThe basis for the cognitive manifestations of pellagra genic situations (e.g., total parenteral nutrition with has not been fully elucidated, but is probably related at inadequate supplemental niacin), or when they subsist least in part to disrupted brain serotonin metabolism on bizarre diets owing to mental illness or extraordin(Krishnaswamy and Ramanamurthy, 1970). Serotonin ary circumstances (Sydenstricker, 1958; Spivak and is synthesized from tryptophan by a simple pathway Jackson, 1977). involving sequential hydroxylation and decarboxylation. In pellagra, much of the limited available tryptophan is utilized to maintain nitrogen balance and most of the The niacin–tryptophan connection and remainder is metabolized in the liver to synthesize niconiacin neurochemistry tinamide, thus greatly limiting the tryptophan available By the 1940s, it became clear that the total niacin confor serotonin synthesis. The most important factor regtent of foods was not the only factor in the developulating synthesis of serotonin in the brain is the availment of pellagra. Diets in some areas where pellagra ability of tryptophan, which can be further limited was rare were found to contain less niacin than did by concentrations of other large neutral amino acids

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(e.g., leucine, isoleucine, valine, methionine, and phenylalanine) that compete for blood–brain barrier uptake through a single amino acid carrier mechanism. Low platelet levels of serotonin and low urinary excretion of 5-hydroxyindolacetic acid (i.e., the main metabolite of serotonin) have been documented in pellagrous dementia (Krishnaswamy and Ramanamurthy, 1970; Raghuram and Krishnaswamy, 1975).

additional single-carbon units attached to the nitrogen atoms, etc. (Hoffbrand and Weir, 2001). The term “folic acid” now refers to the synthetic compound, pteroylglutamic acid, which is not present in natural foods, while the term folate refers to the large family of natural or synthetic compounds with similar vitamin activity, including synthetic folic acid and the natural folates (Hoffbrand and Weir, 2001; Wald, 2001).

FOLATE DEFICIENCY: NEURAL TUBE DEFECTS

Risks of administering folic acid to patients with pernicious anemia

Folate deficiency was initially recognized clinically as a macrocytic anemia in the 1920s, which was only clearly separated from pernicious anemia by the mid-20th century. When folate was finally isolated in the mid-1940s, it was shown to correct the macrocytic anemia associated with pernicious anemia, while the neurological manifestations progressed. Beginning in the 1960s, folate deficiency was increasingly recognized as the major cause of preventable neural tube defects. In the early 1990s well-designed randomized trials established that folate supplementation could prevent neural tube defects. Subsequent studies have established genetic predispositions for neural tube defects in offspring in the form of gene polymorphisms for enzymes involved in folate-dependent homocysteine metabolism. These latter findings help to explain how the genotype of the mother, the genotype of the unborn child, and environmental factors (e.g., folate intake) can all impact on the risk of neural tube defects.

In 1939, M.M. Wintrobe had reported that yeast or yeast extracts could produce a hematological response in patients with pernicious anemia (Wintrobe, 1939), a finding confirmed by others in the early 1940s (Vilter et al., 1945). Although administration of folic acid was subsequently found to be safe in normal people and those with various neurological disorders, and to be temporarily effective in correcting the anemia of Addisonian pernicious anemia (Moore et al., 1945; Vilter et al., 1945; Harvey et al., 1950; Weissberg et al., 1950), beginning around 1946 a number of reports appeared indicating that folic acid would not prevent the progression of the central nervous system dysfunction in patients with pernicious anemia, and several anecdotal reports suggested that administration of folic acid might accelerate neurological dysfunction or even precipitate abrupt neurological worsening in some cases (Vilter et al., 1946; Heinle and Welch, 1947; Vilter et al., 1947; Berk et al., 1948a; Bethel and Sturgis, 1948; Haden, 1948; Wagley, 1948; Wills, 1948; Dickinson, 1995). Despite the concern at the time (and since), available data from historical cases and case series (although methodologically limited) do not support a difference in the rates of progression of neurological deterioration in patients with untreated pernicious anemia (i.e., without administration of vitamin B12) with and without administration of folic acid (Dickinson, 1995). The rate of progression of neurological manifestations in patients with untreated pernicious anemia is widely variable, and in some cases marked deterioration develops over periods of a few weeks (Dana, 1899a, b; Duckworth, 1900; Richmond and Williamson, 1905; Kennedy, 1913; Globus and Strauss, 1922; Dickinson, 1995).

Isolation and synthesis of folic acid Folate was identified as the active substance in brewer’s yeast in the late 1930s. In 1941, Mitchell and colleagues isolated this factor from spinach leaves and named it folic acid, a derivative of folium, the Latin word for leaf (Mitchell et al., 1941; Hoffbrand and Weir, 2001). In 1945, Angier and colleagues reported the successful synthesis of folic acid (Angier et al., 1945), several years before the synthesis of vitamin B12 (in 1948). Angier and colleagues showed that folic acid is composed of a pteridine ring, paraminobenzoic acid, and glutamic acid, and they called it pteroylglutamic acid (Angier et al., 1945; Stokstad, 1979). Soon after the synthesis of folic acid was achieved in 1945, it was demonstrated to be effective in the treatment of macrocytic anemias that are generally refractive to treatment with refined liver preparations, including the macrocytic anemias of malnutrition, pregnancy, sprue, and celiac disease. Naturally occurring folates were subsequently found to vary in composition from the synthetic pteroylglutamic acid, with, for example, multiple polyglutamate residues,

Folate metabolism and the expanding role of folates in pathogenesis of various diseases In the 1950s and 1960s, the biochemical reactions involving folates were elucidated, and folates were found to be essential for transfer of single carbon units in the conversion of the amino acid homocysteine to methionine

NEUROLOGICAL VITAMIN DEFICIENCY DISORDERS: B VITAMINS 459 (by the B12-dependent enzyme methionine synthase), in multifactorial causes, including a combination of both purine (adenine, guanine) and pyrimidine (thymine) biogenetic and environmental factors. synthesis (and thus in the biosynthesis of DNA and In 1964, British obstetrician Brian Hibbard sugRNA), in DNA methylation, and in numerous other gested an association between fetal neural tube defects cellular reactions. The need for folate was found to and maternal deficiency or defective metabolism of increase with rapid tissue growth and cell division folates (Hibbard, 1964). In 1976, Richard Smithells at (at least in part because of the need for folate in DNA the University of Leeds and colleagues demonstrated and RNA biosynthesis), as in hematopoiesis, epithelial that women with megaloblastic anemia during preggrowth and differentiation, spermatogenesis, pregnancy have a high frequency of neural tube defects nancy, and fetal development. Among the earliest in their offspring (Smithells et al., 1976). In 1980, clinical manifestations of folate deficiency are Smithells and colleagues reported a non-randomized hematological changes, including hypersegmentation trial of multivitamin supplementation among women of neutrophils, production of megaloblasts in the bone who had previously given birth to one or more infants marrow, and eventually development of macrocytic aneaffected with neural tube defects (Smithells et al., mia. The increased rate of folate-dependent tissue 1980): there was a 5% recurrence rate for the non-supgrowth and differentiation during pregnancy (McPartlin plemented group compared with a 0.6% recurrence et al., 1993) increases dietary folate needs by about rate for the supplemented group. 0.2–0.3 mg per day (Czeizel, 1995): as a result, pregnant Additional observational studies and non-randomized women with marginal folate levels, as in the cases clinical trials were published during the 1980s and 1990s studied by Wills in India in the 1930s (Wills and that documented protective effects of higher folic acid Mehta, 1930, 1931; Wills, 1931), were found to be intake or of vitamin supplements containing folic acid susceptible to potentially fatal macrocytic anemias and during the periconceptional period (i.e., from 1 month to fetal malformations, particularly neural tube defects before pregnancy through the first trimester) among (Hibbard, 1964). women who had not previously had a pregnancy affected From the 1950s to the 1990s, the range of folateby a neural tube defect (occurrence studies) and among responsive disorders has expanded. Recognition that women who had a previous pregnancy affected by a folic acid therapy enhances tumor growth led to develneural tube defect (recurrence studies). These studies opment of folate antagonists for anticancer therapy, showed a wide range of estimated efficacy in the occurincluding development of methotrexate. Studies of rence of neural tube defects with folic acid supplementachildren with inborn errors of metabolism identified tion, but the summary efficacy estimate across the forms of homocysteinuria with methylmalonic acidvarious studies indicated an overall 50% reduction in risk uria, impaired methionine synthase, and resulting of neural tube defects (Wald, 1993). defective remethylation of homocysteine; pathologic The strongest evidence in support of periconcepstudies in such cases demonstrated marked vascular tional folic acid supplementation came from two large pathology, suggesting an association between vascular randomized trials published in the early 1990s (MRC disease and hyperhomocysteinemia. Subsequent studies Vitamin Study Research Group, 1991; Czeizel and demonstrated abnormal methionine metabolism in sigDuda´s, 1992; Czeizel, 1993a, b, 1995; Wald, 1993; nificant proportions of patients with unexplained Czeizel et al., 1994). The Medical Research Council atherosclerotic cardiovascular disease, and later studies study under the direction of Nicholas Wald at demonstrated elevations of serum homocysteine in St. Bartholomew’s Hospital Medical College in London patients with cerebrovascular and peripheral vascular was a multi-center, multinational, randomized, doubledisease. blind, controlled, recurrence prevention trial conducted in 33 centers in seven countries (MRC Vitamin Study Research Group, 1991; Wald, 1993). The MRC study Prevention of neural tube defects found a 72% reduction in recurrence of neural tube with folic acid defects with 4 mg of folic acid daily over the period In c. 1 in 500 to 1 in 1000 pregnancies, the neural tube from before conception and during the first trimester fails to close properly 28 days after conception, produamong women with a previous neural tube defect-associng a neural tube defect – either with failure of clociated pregnancy (MRC Vitamin Study Research sure of the cranial end producing anencephaly or Group, 1991; Wald, 1993). The Hungarian study, conencephalocele, or with failure of closure of the ducted by Andrew Czeizel of the National Institute caudal end producing spina bifida or myelomeningoof Hygeine in Budapest, was a randomized, doublecele. Neural tube defects are the most common blind, controlled, occurrence prevention study with congenital malformations and are thought to have periconceptional supplementation with multivitamins,

460 D.J. LANSKA including 0.8 mg of folic acid (Czeizel and Duda´s, 1999). Folic acid supplementation can also be effective, 1992; Wald et al., 2001; Czeizel et al., 1994; Czeizel, but vitamins are used consistently by less than a third 1995). Among approximately 5000 women with of women of childbearing age, and the remainder do confirmed pregnancy and an “informative offspring,” not consider taking vitamin supplements until after maternal periconceptional folic acid supplementation they discover that they are pregnant (McNulty et al., produced a significant decrease in the first occurrence 2000). Unfortunately, neural tube defects develop in of neural tube defects compared to a placebo-like (i.e., the fourth week post-conception, i.e., before a pregtrace element) control group. nancy is confirmed. Furthermore, about half of pregA meta-analysis of data from these trials and a prenancies are unplanned (Grimes, 1986; Forrest, 1994), vious small (underpowered and not statistically signifibut even women who plan their pregnancies are poorly cant) trial by Laurence and colleagues collectively compliant with folate supplementation (Clark and Fisk, indicated that periconceptual folate administration 1994; Scott et al., 1994; Wild et al., 1997; McNulty et al., reduces both the occurrence and recurrence risks of 2000). Therefore, an approach relying on supplementaneural tube defects by at least 70% (Laurence et al., tion will not prevent most of the folate-preventable 1981; MRC Vitamin Study Research Group, 1991; cases of neural tube defects. Food fortification, in conWald, 1993). Subsequent studies have generally suptrast, can cost-effectively increase folate levels across ported these findings and suggest that periconceptional the population without requiring a change in behavior multivitamin supplementation can significantly reduce (Romano et al., 1995; Wald et al., 2001). the occurrence of other congenital abnormalities In 1996, the US Food and Drug Administration in addition to neural tube defects (Kirke et al., 1992; selected flour, corn meal, pasta, and rice for mandaCzeizel, 1993a, b; Czeizel et al., 2004). tory folic acid fortification beginning in January 1998 Data from the randomized controlled trials have at a level of 140 mg per 100 g of cereal grain product been used to establish governmental recommendations (Food and Drug Administration, 1993a, b, 1996a, b). concerning folic acid intake, and have also been used This was estimated to result in an average adult conto establish health policy concerning vitamin fortificasumption of approximately 100 mg of folic acid daily tion of foodstuffs (Honein et al., 2001). In 1991, the from fortified cereal grain products, effectively ensurUS Centers for Disease Control published a review of ing that about half of reproductive-age women will the evidence for the prevention of recurrent neural receive the recommended 0.4 mg daily from all sources tube defects and recommended 4 mg of folic acid for (Food and Drug Administration, 1993a, b; Romano women who had previously had an infant or fetus with et al., 1995). This level of fortification – deemed the a neural tube defect (Centers for Disease Control, best possible accommodation between concerns for 1991). In 1992, the US Public Health Service recomthe fortification of the target population of women mended that all women capable of becoming pregnant of child-bearing age and the safety of the much larger should consume 0.4 mg (4000 mg) of folic acid daily non-target population – was expected to prevent many (Centers for Disease Control and Prevention, 1992; but not all neural tube defects that might be prevented Cornel and Erickson, 1997). Because naturally occurby sufficient maternal folic acid intake. Folic acid forring folate is less readily absorbed than synthetic folic tification was limited to relatively low levels because of acid, in 1998 the Institute of Medicine recommended a fear that folic acid would correct the hematological that women of childbearing age consume 0.4 mg daily abnormality in patients with vitamin B12 deficiency, potentially delaying diagnosis, and allowing progresfrom dietary supplements or fortified foods for the sion of central and peripheral nervous system manifesprimary prevention of neural tube defects (Institute tations of vitamin B12 deficiency (e.g., Reynolds, of Medicine, 1998). 2002). Many have challenged the logic and ethics of Potential strategies for increasing folate levels this rationale and the resulting national fortification among women are dietary modification, folic acid decisions (e.g., Wald and Bower, 1994), but levels of supplementation, and food fortification (Centers for fortification remain modest. As a result, dietary modiDisease Control and Prevention, 1992; Wald and fication and folic acid supplementation continue to be Bower, 1995; Czeizel, 2000; McNulty et al., 2000). necessary and appropriate modes of intervention. Despite various education campaigns, the estimated Since 1996, folic acid fortification has produced a dietary folate intake for US women averages only 0.2 significant improvement in population folate status in mg daily and it was considered impractical to have the United States (Jacques et al., 1999; Lawrence women systematically increase their intake of folateet al., 1999; Honein et al., 2001; Wald et al., 2001; rich foods (e.g., fruits, leafy green vegetables, and Erickson, 2002; Mathews et al., 2002; Rader, 2002; grains) sufficiently to raise daily folate intake to 0.4 Centers for Disease Control and Prevention, 2004; mg daily (Centers for Disease Control and Prevention,

NEUROLOGICAL VITAMIN DEFICIENCY DISORDERS: B VITAMINS Pfeiffer et al., 2005), and similar improvements have been observed in other countries that have adopted this strategy (Ray et al., 2000; Wald et al., 2001). In 1999, data from the Framingham Offspring Cohort showed that fortification of enriched grain products with folic acid was associated with a substantial improvement in folate status of the population (Jacques et al., 1999; Rader, 2002). Similar results were demonstrated in populations enrolled in large managed care plans (Lawrence et al., 1999), and in representative samples of women participating in the National Health and Nutrition Examination Survey (NHANES) (Centers for Disease Control and Prevention, 2000; Pfeiffer et al., 2005). By 2001, findings using birth certificate data for live births in 45 states and the District of Columbia between 1990 and 1999 suggested that a decline of approximately 20% in the prevalence of neural tube defects at birth followed fortification of the US food supply with folic acid (Honein et al., 2001). A later analysis by the Centers for Disease Control and Prevention (2004) suggested a 27% decline in the average annual proportion of pregnancies affected by neural tube defects after fortification (i.e., 1999–2000 compared with 1995–1996).

Gene polymorphisms for enzymes involved in folate-dependent homocysteine metabolism In the 1990s, several studies demonstrated hyperhomocysteinemia in mothers of children with neural tube defects, despite the absence of folate or vitamin B12 deficiency in these mothers, while other studies identified hyperhomocysteinemia in children with spina bifida, despite the absence of folate or vitamin B12 deficiency in these children. Because of this, several groups examined enzymes involved in homocysteine metabolism for potential mutations or polymorphisms linked to an increased risk of neural tube defects, suspecting that disturbed homocysteine metabolism in either mothers or their offspring could cause neural tube defects. In 1995, Nathalie Van der Put and colleagues reported that a common thermolabile variant (i.e., 677C!T) in the 5,10-methylenetetrahydrofolate reductase gene among mothers is associated with decreased function of the enzyme and with increased risk of neural tube defects in their offspring (Van der Put et al., 1995, 1996, 1997, 2001). Methylenetetrahydrofolate reductase catalyzes the formation of 5-methyltetrahydrofolate, the biologically active form of folate needed for the remethylation of homocysteine to methionine, so either inadequate folate, a defective methylenetetrahydrofolate reductase, or a combination of these increases plasma homocysteine concentrations. Among folate-deficient people, homozygotes

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for the 677C!T mutation (i.e., the TT genotype with two mutant T alleles) have higher plasma homocysteine concentrations than those with the CC genotype. Other studies have noted the same polymorphism in children with hyperhomocysteinemia and spina bifida (Bjrke-Monsen et al., 1997; Shaw et al., 1998; Shields et al., 1999), and Denis Shields and colleagues found a much stronger relationship between the genotype and phenotype of the child than between the genotype of the mother and the phenotype of the child (Shields et al., 1999). When the genotypes of both the mother and the child were considered, the 677C!T mutation accounted for at most 25% of the observed protective effect of folate (Van der Put et al., 1995), suggesting that other defective enzymes either in folate metabolism or folate transport may also be involved (Van der Put et al., 1998; Brody et al., 2002). Subsequent studies have demonstrated that elevated maternal homocysteine concentrations in women with such polymorphisms can be lowered by supplemental folate intake, even in women with normal folate levels to begin with (Kang et al., 1988; Nelen et al., 1998; Brouwer et al., 1999; Fohr et al., 2002). Although methylenetetrahydrofolate reductase gene polymorphisms are only moderate risk factors for neural tube defects (Van der Put et al., 1997), at a population level they contribute to a significant portion of the observed burden of neural tube defects. They also help to explain how the genotype of the mother, the genotype of the unborn child, and environmental factors (e.g., folate intake) can all impact on the risk of neural tube defects.

CYANOCOBALAMIN DEFICIENCY: SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD Pernicious anemia was recognized clinically in the mid19th century, but the associated neurological manifestations – particularly the myelopathy now known as subacute combined degeneration of the spinal cord – was not recognized clinically and linked with pernicious anemia until the end of the 19th century. In the 1920s, Minot and Murphy (1926) showed that large quantities of ingested liver could be used to effectively treat pernicious anemia. Cyanocobalamin (vitamin B12) was finally isolated by the mid-20th century, and this greatly improved the treatment of pernicious anemia and the associated neurological manifestations.

Pernicious anemia Originally at a meeting of the South London Medical Society in 1849, and subsequently in a monograph in 1855, Thomas Addison (1793–1860) at Guy’s Hospital in London described several cases with “idiopathic”

462 D.J. LANSKA anemia characterized by pallor, weakness, and progres1898; Russell et al., 1900; Putnam and Taylor, 1901; sively worsening health leading to death (Addison, Billings, 1902; Bramwell, 1915; Woltman, 1918; Hurst 1855/1942). Later this condition was called Addisonian and Bell, 1922; Weil and Davison, 1929; Greenfield anemia, at least until Biermer of Zurich named it and O’Flynn, 1933). perniciöse Anämie (i.e., pernicious or fatal anemia) Clinicians of the period struggled to distinguish the when describing 15 cases of severe anemia (of mixed clinical and pathologic features of this condition from etiologies) in 1872 (Biermer, 1872; Haden, 1948). those of other recognized causes of progressive myeloIn 1870, Fenwick in London associated stomach pathy (Dana, 1891a, b), particularly those that could atrophy with this form of anemia and demonstrated affect multiple white matter tracts of the spinal cord, that stomach mucosa from an affected fresh cadaver i.e., what New York neurologist Charles Loomis Dana could not digest boiled egg white with prolonged incu(1852–1935) had referred to categorically as “combined bation, whereas mucosa from a control stomach could sclerosis or mixed-system myelitis” (Dana, 1887, p. 1). (Fenwick, 1870; Mackay and Whittingham, 1968; In the absence of a valid diagnostic test (i.e., before Florkin, 1973; Okuda, 1999). Subsequently, Cahn and recognition of vitamin B12 deficiency as the cause), early cases were particularly hard to distinguish from Mering showed that a patient with pernicious anemia other conditions, and many of the early reports had no hydrochloric acid in the stomach contents, a included cases with other etiologies (Pant et al., 1968). finding later demonstrated to be pervasive in this Nevertheless, subacute combined degeneration of the disorder (Cahn and Mering, 1886; Faber and Bloch, spinal cord was clearly linked with pernicious anemia 1900; Hurst and Bell, 1922; Levine and Ladd, 1924). by about 1900. Soon it was recognized that achlorhydria precedes the In 1891, Boston neurologist James J. Putnam development of anemia (Hurst and Bell, 1922). (1846–1918) of Harvard Medical School and the It was not until the 1850s – after Addison’s original Massachussetts General Hospital reported eight communication – that the first red cell counts were done cases, four with autopsy. The neurological presentaby Vierordt, and that hemoglobin was discovered by tion and course in these early cases typically included Funke (Funke, 1851; Vierordt, 1851; Haden, 1948). In progressive paresthesias, incoordination, impaired 1875, William Pepper (1843–1898) of Philadelphia noted sensation and position sense in the arms and legs, the extreme hyperplasia of the bone marrow in patients preserved and even exaggerated muscle stretch with pernicious anemia (Pepper, 1875). In 1880, Paul Ehrreflexes and ankle clonus, and weakness progressing lich (1854–1915), using aniline dyes developed by his couto terminal paraplegia (Putnam, 1891). sin Carl Weigert (1845–1904), identified large erythroid Early neuropathological studies by Dana and precursor cells that he called “megaloblasts” in stained Putnam along with later neuropathological studies, blood smears of patients with pernicious anemia demonstrated that the degeneration of white matter (Ehrlich, 1880). Subsequent hematologists noted charactracts was initially uneven and patchy, with small foci teristics of megaloblastic anemia in the peripheral blood enlarging and coalescing to involve entire white matter (i.e., macrocytes, poikilocytes, and hypersegmented columns and the most severe involvement generally neutrophils) and bone marrow (e.g., megaloblasts, metaaffecting the posterior columns of the lower cervical myelocytes, and megakaryocytes) (Billings, 1902). Later, and thoracic cord, extending in some cases to the Francis W. Peabody of the Thorndike Memorial Laboramedulla (Dana, 1891a, b; Putnam, 1891; Pant et al., tory in Boston hypothesized that this macrocytic anemia 1968). The degenerative process affects most dramatiwas due to maturational arrest of erythroblasts in the cally the myelin sheaths (although axons are also bone marrow (Peabody, 1927; Florkin, 1973; Kass, 1978). damaged), with marked swelling of myelin sheaths giving a vacuolated “sieve-like” appearance to stained Subacute combined degeneration spinal cord sections, evident even in some of the of the spinal cord earliest published pathological illustrations (Dana, In 1884, Lichtenstein described cases of pernicious 1891a, b; Putnam, 1891; Pant et al., 1968). anemia with neurologic manifestations felt to be sugSensory symptoms and signs are early and promigestive of tabes dorsalis (Lichtenstein, 1884; Haden, nent features of the disease. Although Putnam initially 1948). Following Lichtheim’s report in 1887 of progresremarked that “the nerve roots were more or less dissive myelopathy associated with pernicious anemia in eased” (Putnam, 1891, p. 72), by 1901 he and Taylor three cases, two with autopsy, similar cases were reported on a “common freedom from degeneration reported by a number of authors over the next several of nerve roots, both motor and sensory, and peripheral decades (Dana, 1891a, b, 1899a, b, 1908; Putnam, 1891; nerves” (Putnam and Taylor, 1901, p. 92). Even if Minnich, 1893; Taylor, 1895; Lloyd, 1896; Russell, in individual cases “somewhat imperfectly staining

NEUROLOGICAL VITAMIN DEFICIENCY DISORDERS: B VITAMINS 463 bundles [within the nerve roots] may be made out . . . Davison, 1929; Greenfield and O’Flynn, 1933; Weir [the] dorsal roots at no point show the changes which and Gatenby, 1963; Robertson et al., 1971). are an essential part of the pathological process in tabes [dorsalis]” (Putnam and Taylor, 1901, p. 76). Toxic and infectious theories for pernicious Severe cases showed some involvement of the posteranemia and subacute combined ior roots (Putnam, 1891), but not enough to explain degeneration the severe degeneration of the posterior columns as a At the beginning of the 20th century, pernicious anemia secondary phenomenon (Pant et al., 1968). and the associated subacute combined degeneration of Involvement of peripheral nerves was suggested the spinal cord were considered by many investigators clinically (Woltman, 1918), but initial pathological to result from infectious or toxic causes (Dana, 1899a, reports of peripheral nerve involvement with subacute b; Russell et al., 1900; Hunter, 1901; Billings, 1902; combined degeneration of the cord were scanty and Bramwell, 1915; Hurst and Bell, 1922; Weil and Davison, inconsistent (Putnam, 1891; Putnam and Taylor, 1901). 1929; Weiss, 1991; Lanska, 2008a). As early as 1901, Peripheral nerve involvement was recognized patholoHunter suggested that pernicious anemia is the result gically by the 1930s and 1940s (Greenfield and Carmiof infection and release of an exotoxin. He attributed chael, 1935; Van der Scheer and Kock, 1938; Foster, the glossitis to a specific microorganism, which when 1945; Ungley, 1949), with later studies also demonstratswallowed produced gastritis and ultimately gastric ing slowed peripheral nerve conduction velocities atrophy, and he further attributed the anemia to the (Mayer, 1965). release of a toxin in the intestinal tract, which when Clinical manifestations of optic atrophy were elaboabsorbed into the portal circulation caused hemolysis rated from the 1930s by a number of authors (Courville (Hunter, 1901; Haden, 1948). and Nielson, 1938; Kampmeier and Jones, 1938; Turner, In 1922, Hurst and Bell similarly proposed that per1940), with degeneration of the papillomacular bundle nicious anemia resulted from “oral sepsis, absence of previously demonstrated pathologically by Bickel free hydrochloric acid from the stomach contents, (1914) and more extensive degeneration of the optic and consequent intestinal infection and intoxication” nerves anterior to the optic chiasm demonstrated later (Hurst and Bell, 1922, p. 266). In support of this theby Adams and Kubic (1944). ory, they noted the constant association of pernicious The association of subacute combined degeneration anemia with gastric achlorhydria, evidence that the gasof the spinal cord with anemia was recognized by many tric achlorhydria precedes the development of anemia, of the early authors describing this form of myelopathy, the frequent presence of gastrointestinal symptoms although only some emphasized a strong or universal (e.g., diarrhea, “bilious attacks” with occasional vomitrelationship with pernicious anemia specifically ing, “flatulent dyspepsia”), the fact that gastroin(Lichtheim, 1887; Billings, 1902; Bramwell, 1915; testinal symptoms precede the development of Woltman, 1918; Hurst and Bell, 1922; Weil and Davison, neurological manifestations, the frequent finding of 1929). By the 1920s, subacute combined degeneration of bacteria in the sockets of infected teeth, and the the spinal cord was clearly associated with both finding of identical bacteria colonizing the atrophic pernicious anemia and gastric achlorhydria (Hurst and stomach. Hurst and Bell’s bacterial toxin theory led Bell, 1922; Greenfield and O’Flynn, 1933). to specific (albeit ineffective) treatments, in an attempt In 1900, Russell and colleagues suggested the name to rid the body of the causative infection and the sec“subacute combined degeneration of the spinal cord” ondary generation of the putative toxins, including (Russell et al., 1900, p. 40). Other names proposed extraction of all teeth; tonsillectomy; ingestion of large included Putnam’s earlier “system sclerosis, associated doses of hydrochloric acid and milk soured by active with diffuse collateral degeneration” and “primary lactic acid bacilli; administration of a vaccine prepared combined sclerosis” (Putnam, 1891), and later “diffuse from streptococci isolated from extracted teeth, duodegeneration of the spinal cord” (Putnam and Taylor, denal contents, or feces; administration of arsenic; 1901); Dana’s earlier “sub-acute combined sclerosis of blood transfusion, etc. (Hurst and Bell, 1922). the spinal cord” (Dana, 1899a) and “subacute ataxic In 1926, Minot and Murphy noted – at the time of paralysis and combined sclerosis” (Dana, 1899b); and their initial presentation of the first truly effective “combined sclerosis of Lichtheim-Putnam-Dana type,” therapy for pernicious anemia (i.e., oral liver) – that and “combined systems disease” (Pant et al., 1968). the bacterial toxin theory was widely held. As they preAlthough Putnam and Taylor (1901) objected to this terdicted, proponents of toxic or infectious theories were minology, after about 1910 the term most often used not easily swayed by studies demonstrating improvewas “subacute combined degeneration of the spinal ment with certain diets, even if others at the time felt cord” (Bramwell, 1915; Hurst and Bell, 1922; Weil and

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that “the prompt and regular beneficial effect of liver feeding on erythropoiesis seemed unlikely to be the result of elimination of bacterial infection in the bowel” (Castle, 1974, p. 25), and even if intestinal flora were unchanged after such patients were returned to (relative) health after regularly consuming a diet with large amounts of liver (Castle, 1929). Many investigators nevertheless continued to consider the presence of pathologic bacterial colonization as persuasive evidence in support of a bacterial toxin theory, without adequately considering that such colonization could be a non-causal association. Microbial exotoxin theories gained further support in the early 1930s with the discovery in Finland of a macrocytic anemia associated with infestation of the small bowel by a tapeworm, particularly when it was shown that the anemia promptly improved after elimination of the parasite (Birkeland, 1932; Castle, 1974). Even in the 1950s, after the identification of vitamin B12, toxic and infectious theories of the pathogenesis of pernicious anemia were still debated (Crosby, 1983). However, the postulates of Robert Koch (1843– 1910) for establishing an infectious cause for pernicious anemia were never fulfilled for any of the putative organisms, nor was a systematic experimental effort ever undertaken with that goal in mind: specifically, the investigators never showed that the putative organisms isolated from people would cause pernicious anemia in susceptible animals, nor did they demonstrate that the organisms could then be recovered from such animals and re-grown in pure culture.

Minot and Murphy and the liver therapy for pernicious anemia During the first quarter of the 20th century, a wide variety of therapies were employed in the treatment of pernicious anemia – hydrochloric acid, iron, arsenic, removal of sources of infection including all teeth, drainage of the intestinal tract, splenectomy, blood transfusion, and special diets (Haden, 1948). With the exception of transfusion, which could prolong life somewhat, these therapies were largely ineffective and life expectancy was less than 2 years (Lanska, 2008b). Beginning around 1917, George H. Whipple (1878–1976) and colleagues, first in San Francisco and later in Rochester, New York, established that certain supplemental foods, such as spinach, beef muscle, and particularly liver, “had a powerful effect upon hemoglobin regeneration” (Whipple, 1934/1965, p. 347; Weiss, 1991). Although Whipple did not test or apply his ideas in people, he did suggest in 1922 that pernicious anemia is a disease “in which all pigment factors were present in the body in large excess but with a

scarcity of stroma-building material or an abnormality of stroma-building cells” (Whipple, 1922, 1934/1965, p. 348). By 1925, Whipple with Freida Robscheit-Robbins (1893–1973) demonstrated that liver increased the amount of hemoglobin regenerated in dogs maintained on a basal diet and kept chronically anemic by weekly bleedings accomplished by aspiration from the jugular vein (Robscheit-Robbins and Whipple, 1925). Although not immediately recognized, the magnitude of assimilation of inorganic iron was the most important factor in hemoglobin production in this experimental paradigm. Prior to 1925, dietary supplementation with small amounts of liver had been tried in a small number of cases of pernicious anemia without marked or consistent results. But these early investigators had neither systematically nor persistently fed these often anorexic patients large quantities of liver (e.g., a half pound or more daily), nor had they carefully quantified the amounts consumed or the results (Weiss, 1991). In 1925, George R. Minot (1885–1950), at Peter Bent Brigham Hospital in Boston, and William P. Murphy (1892–1987), at the Collis P. Huntington Memorial Hospital of Harvard University, decided to hospitalize a group of patients with pernicious anemia to systematically assess liver as a treatment. By 1926, Minot and Murphy reported clinical and hematological improvement in 45 patients with pernicious anemia treated with a dietary regimen that incorporated large quantities of liver – “From 120 to 240 Gm., and even sometimes more” (Minot and Murphy, 1926, p. 472). Clinically the patients improved, often dramatically so, in conjunction with improvements in hematological indices. This clinical improvement could be sustained for many years, well beyond the previous life expectancy of such patients (Murphy, 1934/1965). A major component of the hematological response in such patients was, in retrospect, likely due to folate which the subjects could readily absorb, rather than to vitamin B12, which the subjects with pernicious anemia could at best only marginally absorb (Chanarin, 1991). Importantly, patients with (relatively mild) neurological dysfunction also improved, for example with significant improvements in gait, suggesting in retrospect that sufficient vitamin B12 was also absorbed with this regimen. However, patients with more severe neurological dysfunction showed at best slow and limited improvement (Minot and Murphy, 1926). Using the reticulocyte response as an index of erythropoiesis, Minot and Murphy were able to recognize liver as the essential component of the regimen. With Edwin J. Cohn, a physical chemist in the Laboratories of Physiology at Harvard Medical School (later recognized for his fractionation of plasma proteins), they then tried unsuccessfully “to isolate the active principle” (Minot, 1934/1965). Nevertheless, they did demonstrate

NEUROLOGICAL VITAMIN DEFICIENCY DISORDERS: B VITAMINS that potent extracts could be given parenterally in very small quantities (Minot, 1934/1965; Murphy, 1934/1965). Whipple, Minot, and Murphy were subsequently recognized jointly with the 1934 Nobel Prize in Physiology or Medicine “for their discoveries concerning liver therapy in cases of anemia” (Minot, 1934/1965; Murphy, 1934/1965; Whipple, 1934/1965).

Castle’s intrinsic and extrinsic factors – linking gastric and hematological abnormalities In 1926, after Minot and Murphy’s success with the liver therapy for pernicious anemia, William B. Castle (1897– 1990) – then an assistant resident at the Thorndike Memorial Laboratory of Boston City Hospital, which had recently come under the direction of Minot as successor to Francis Peabody – decided to pursue his belief that gastric achlorhydria (“achylia gastrica”) was etiologically linked to pernicious anemia (Castle, 1966, 1974; Kass, 1978; Crosby, 1983; Herbert, 1984; Jandl, 1995). Castle, in considering why normal individuals do not have to eat large amounts of liver every day to maintain a normal blood count, noted that: (1) gastric achlorhydria precedes the other clinical manifestations of pernicious anemia (including the hematological and neurological manifestations); and (2) even when the blood of a patient with pernicious anemia is returned to normal with liver feeding, there is “a total lack of any amelioration in the secretory incapacity of the stomach” (Castle, 1929, 1974, p. 5; Johansen, 1929). Based on these observations, Castle proposed that “a virtual dietary deficiency might be produced in the presence of a diet entirely adequate for a normal individual, by the notable defect in the process of gastric digestions necessarily imposed by the absence of functional gastric juice . . .” (Castle, 1929, 1974, p. 6). Castle suggested first that an essential step of gastric digestion was impaired, thereby disrupting absorption of an essential dietary factor, and second that this defective process might be circumvented by utilizing gastric juices or some other component of the gastric digestive process from individuals with normal stomachs. To test this idea and its subsequent elaborations, Castle devised and implemented an ingenious series of experiments (Castle, 1929; Castle and Townsend, 1929; Castle et al., 1930; Castle and Ham, 1936). Castle’s first patient was a 60-year-old woman with untreated pernicious anemia who was first given two rare beef patties (200 gm) daily for 10 days, without a reticulocyte response (Castle, 1929). Castle then fed himself raw beef patties daily instead of breakfast and an hour later regurgitated his semi-liquid stomach contents using pharyngeal stimulation (Castle, 1929; Kass, 1978; Weiss, 1988). This mixture was treated

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with hydrochloric acid and incubated for 6–30 h, then filtered and neutralized, and immediately introduced into the stomach of the patient using a Rehfuss tube. Within 5 days the subject’s reticulocyte began to increase, peaking at 10 days, with a subsequent increase in the red blood cell count of over 1 million red cells per cubic millimeter within 30 days (Castle, 1929). Similar responses were observed in seven of nine additional patients, but two patients remained refractory (apparently because they lived in another city and the predigested material had to be transported to them, necessitating a prolonged delay after neutralization with sodium hydroxide). Although not stated in the original paper, Castle later acknowledged being the source of the normal human gastric juice (Weiss, 1988, p. 157). Castle concluded “that in contrast to the conditions within the stomach of the pernicious anemia patient, there is found within the normal stomach during the digestion of beef muscle some substance capable of promptly and markedly relieving the anemia of these patients” (Castle, 1929, 1974, p. 13). He and his coworkers further demonstrated that this response is not due to gastric juice alone (Castle and Townsend, 1929), and that contact between normal gastric intrinsic factor and dietary extrinsic factor is necessary for an erythropoietic response (Castle and Ham, 1936). Castle subsequently labeled the essential substance secreted by a normal stomach as “intrinsic factor,” and the substance present in food as “extrinsic factor” (Castle et al., 1930). Castle and colleagues showed that intrinsic factor is a thermolabile substance present in gastric juice, but not present in saliva or duodenal contents free of gastric juice (Castle et al., 1930). Although Castle did not clearly identify the role of intrinsic factor as an intestinal transport vehicle for extrinsic factor (later identified as vitamin B12), he did establish that: (1) the intrinsic and extrinsic factors have to interact for effective erythropoiesis in patients with pernicious anemia; and (2) nutritional deficiencies could result from malabsorption or impaired metabolism in addition to inadequate intake. Around this time, desiccated, defatted whole hog stomach as a replacement source of intrinsic factor was shown to be modestly successful in clinical trials. Later studies demonstrated that intrinsic factor is a glycoprotein with a molecular weight of 60 kD secreted by gastric parietal cells (Hoedemacher et al., 1964).

Isolation, structure, synthesis, and biochemical reactions of vitamin B12 Over two decades, from the late 1920s until the late 1940s, increasingly potent liver extracts were manufactured that could be given either intramuscularly or

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intravenously (Castle, 1966). Progress was slow in isolating the active substance in these factors, in part because of the initial need for bioassays using untreated cases of pernicious anemia, and in part because of inadequate separation methods (Castle, 1966; Okuda, 1999). In 1947, following the development of microbiological assay techniques (Shorb, 1947) and improved chromatographic techniques, vitamin B12 was finally isolated as pink crystals of cyanocobalamin – containing cobalt, nitrogen, and phosphorus – by Karl Folkers and colleagues at Merck and Company in the United States, and nearly simultaneously by E. Lester Smith at Glaxo Laboratories in England (Rickes et al., 1948; Smith, 1948; Smith and Parker, 1948; Okuda, 1999). Shortly thereafter, Castle and colleagues identified vitamin B12 as extrinsic factor, but found that oral vitamin B12 even with a source of intrinsic factor was still not as potent as parenteral vitamin B12 (Berk et al., 1948b). By 1955, Dorothy Crowfoot Hodgkin (1910–1994) of Cambridge University determined the molecular structure of cyanocobalamin using computer-assisted X-ray crystallography, work for which she received the 1964 Nobel Prize in Chemistry (Hodgkin et al., 1955; Hodgkin, 1964/1972). The complex structure of vitamin B12 included a single cobalt atom at the center of a tetrapyrrole or “corrin” macro-ring structure. A complete chemical synthesis of vitamin B12 was finally achieved in 1960 by an international consortium of chemists. Subsequent biochemical work demonstrated that only two enzyme systems require forms of vitamin B12 in man: adenosylcobalamin in the conversion of methylmalonyl coenzyme A to succinyl coenzyme A by methylmalonyl-coenzyme A mutase, and methylcobalamin in the conversion of homocysteine to methionine by methionine synthase (Sakami and Welsh, 1950; Flavin and Ochoa, 1957).

Selected clinically important studies after isolation of vitamin B12 Shortly after the isolation of vitamin B12, Randolph West (1948) demonstrated the efficacy of injected vitamin B12 in pernicious anemia, and West and Reisner (1949) were among the first to assess the response to parenteral vitamin B12 of the neurologic manifestations of subacute combined degeneration of the cord in patients with pernicious anemia. In five patients with spinal cord lesions, West and Reisner observed “varying degrees of improvement” and noted that “none has become worse,” and that “All of these patients with spinal cord lesions are walking readily” after treatment. Changes noted included improvements in ambulation, improvements in position sense with improvement or

normalization of a previously positive Romberg sign, and in some cases resolution of abnormal muscle stretch reflexes or cutaneous reflexes, but generally no evident improvement in vibratory sense abnormalities. In 1957, Dorscherholmen and Hagen subsequently demonstrated that there are two mechanisms involved in B12 absorption (Dorscherholmen and Hogen, 1957; also see Schilling, 1958). With physiologic (i.e., 1–2 mg) doses of oral radioactive vitamin B12, radioactivity appeared in plasma within several hours and reached a peak at 8–12 h, a process dependent upon intrinsic factor, but if much larger oral doses were administered the radioactivity appeared in plasma much sooner as a result of passive diffusion, independent of the presence or absence of intrinsic factor. The passive diffusion mechanism has subsequently been utilized clinically for the treatment of pernicious anemia with large (1000 mg) daily oral doses of vitamin B12. In 1957, Booth and Mollin showed that patients in whom the ileum had been resected did not absorb vitamin B12 well, and that radioactive vitamin B12 administered orally prior to laparotomy was localized to the terminal ileum several hours later using an intraoperative Geiger counter (Booth and Mollin, 1957, 1959). Additional studies showed that when vitamin B12 is released from foods by peptic digestion it is bound to intrinsic factor, affording partial protection against gut microorganisms and parasites during transport through the gut to the terminal ileum, where the complex binds to microvilli of the intestinal epithelial cells. The vitamin B12 is released into the interior of these cells, and then enters the blood stream, where it is transported by specific serum proteins (particularly transcobalamin II) to target cells. In 1957 and 1958, Michael Schwartz and colleagues in Copenhagen observed that the therapeutic efficacy of hog intrinsic factor preparations declined with use in pernicious anemia patients (Schwartz et al., 1957, 1958). Shortly thereafter, and through the 1960s, several lines of evidence converged in support of an autoimmune basis for pernicious anemia: (1) corticosteroids improved B12 absorption and reduced anemia; (2) gastric and serum autoantibodies to intrinsic factor and gastric parietal cells are present in the majority of patients; and (3) other autoimmune diseases (e.g., Hashimoto’s thyroiditis, insulin-dependent diabetes mellitus, Addison’s disease, and vitiligo) are common in such patients (Mackay and Whittingham, 1968; Okuda, 1999; Whittingham and Mackay, 2005). Pernicious anemia is now understood to begin with an autoimmune gastritis in which parietal cell antibodies produce atrophic gastritis with resultant decline in intrinsic factor production over decades. Although the recognition of antibodies to hog intrinsic factor

NEUROLOGICAL VITAMIN DEFICIENCY DISORDERS: B VITAMINS led to discovery of the autoimmune nature of pernicious anemia, these antibodies apparently do not decrease the effectiveness of hog intrinsic factor in promoting the absorption of vitamin B12, and the waning of efficacy of hog intrinsic factor was therefore attributed to “local effects in the intestinal tract” (Castle, 1966). In 1988, the principal target of these antibodies was identified by Karlsson and colleagues as the acid-producing H+/ K+-adenosine triphosphatase (ATPase) in the cell membrane of gastric parietal cells (Karlsson et al., 1988).

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 31

Muscular dystrophy CORRADO ANGELINI * Department of Neurosciences, University of Padova, Padova, Italy

INTRODUCTION The historical development of inherited muscle disorders dates back to the 16th century anatomical descriptions of Andreas Vesalius (1514–1564), who taught anatomy at the University of Padua. His most famous work, De Humani Corporis Fabrica, published in 1543, was based on human dissections and included beautiful woodblock plates prepared by Titian’s pupil Jan von Calcar illustrating whole human bodies with all the muscles displayed (“muscle men”) as well as studies of individual muscle groups (Fig. 31.1). Although Vesalius accurately illustrated most of the major muscle groups of the human body he did not specifically discuss diseases of muscle. The oldest printed text devoted exclusively to myology was written by G.B. Canani (1515–1579) in 1541 (Angelini and Armani, 1983) and entitled Musculorum Humani Corporis Picturata Dissectio (Fig. 31.2). Unfortunately only a few copies have survived including one originally in the library of the pathologist Giovanni Battista Morgagni (1682–1771). Morgagni in De Sedibus et Causis Morborum per Anatomen Indagatis, issued in 1761, showed several heart and brain disorders, but not specific muscle disease, although in an epistola he observed muscles of a “yellow” color. Another prominent 18th century scientist, Luigi Galvani (1737–1798), published De Viribus Electricitatis in Motu Musculari in 1792, and was the first to demonstrate the excitability of muscle and to illustrate the electrical neuromuscular junction. The identification of a primary disease of muscles, i.e., muscular dystrophy, occurred in the 19th century, and the distinction of these primary muscle diseases from illnesses in which muscle weakness was secondary to disease of motor neurons and their roots was a seminal event in neurology. There is still controversy as to who

*

should be given priority for the first description of muscular dystrophy. The problem is confounded by the fact that it is now recognized that muscular dystrophy is not a single disease but rather a heterogeneous set of diseases with different clinical phenotypes, pathological substrates, and both molecular and genetic determinants. In considering early descriptions of muscular dystrophy it is helpful to begin with an early “descriptive period” including the contributions of Giovanni Semmola (1793–1866), Gaetano Conte (1798–1858), Edward Meryon (1807–1880), and Guillaume B.A. Duchenne (1806–1875) and then to consider the later contributions leading to the modern classification of these diseases by William Erb (1840–1921), H. Hoffmann (1819–1891), and Joseph Dejerine (1849–1917). Descriptive period Semmola Conte Meryon Duchenne Nosographic period Erb Hoffman Leyden–Mobius Landouzy and Dejerine Charcot Becker Walton and Natrass Molecular period Unlimited

EARLY DESCRIPTIONS OF X-LINKED MUSCULAR DYSTROPHY We owe the first clinical description of muscular dystrophy to Giovanni Semmola (1793–1866) (Table 31.1). In a lecture to the Academia Pontaniana in Naples,

Correspondence to: Corrado Angelini, Professor of Neurology, Dept. of Neurosciences, University of Padova, Via Giustiniani 5, 35128 Padova, Italy. Tel: +39-049-8213625, Fax: +39-049-8751770. V.I.M.M. Venetian Institute of Molecular Medicine, Via Orus 2,35129 Padova, Italy. E-mail: [email protected], Tel: +39-049-7923202, Fax: +39-049-7923250.

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Fig. 31.1. Anatomical description of muscle groups by Vesalius.

Fig. 31.2. Anatomic description of upper arm and forearm muscles by Camanio in Musculorum Humani Corporis Picturata Dissectio, 1541.

MUSCULAR DYSTROPHY Table 31.1 Contributors to the first recognition of Duchenne muscular dystrophy (DMD) 1829: 1836: 1846: 1851: 1868:

Giovanni Semmola (1793–1866) Gaetano Conte (1798–1858) with L. Gioja Richard Partridge (1805–1873) Edward Meryon (1807–1880) Guillaume Benjamin Armand Duchenne de Boulogne (1806–1870)

Italy, he reported on two boys affected by a previously undescribed disorder (1829) which he referred to as “Ipertrofia muscolare” (muscular hypertrophy), in which muscular hypertrophy was considered to be the most noticeable clinical sign (Semmola, 1834). Semmola was a physician at the Hospital of Incurables in Naples, Italy, and a member of the Italian Royal Academy of Sciences. Some of his work has been collected in Opere Minori (Semmola, 1845) (Fig. 31.3). The same two cases were subsequently reported in the Annali Clinici dell’Ospedale degli Incurabili, by two other Italian physicians, Gaetano Conte (1798–1858) and L. Gioja, under the title of Scrofola del Sistema Muscolare (1836). Gaetano Conte was born in Naples in 1798 and showed exceptional talent from an early age. As a student in 1813 he received an award which would later allow him free access to the Collegio Medico Chirurgico. He was then conferred the Chair of Pathology in Salerno, which he occupied at age 23. He became professor at the Hospital for Incurables in Naples and wrote on epilepsy and on the therapeutic value of thermal baths in Ischia. While head of the hospital he was particularly interested in patients with scrofula, which at that time was related mainly to tuberculosis, but probably included other chronic diseases with profound muscle wasting, such as muscular dystrophy. The pathogenesis of “Scrofula of the muscular system” according to Conte had to do with the nutrition of muscle and atrophy of bone and possibly calcium deposition in muscle fibers. This pathogenesis, although not documented at the pathological level, is not too far from that established by Mokri and Engel (1975). The two children described by Semmola and Conte came to the Surgical Clinic of the University of Naples from Pescolamazza, a small village in the south of Naples. Both boys remained in the Surgical Clinic under Conte’s care for about 6 months. They were reported as having benefited from treatment with “iodine,” which, similar to mercury, was felt to stimulate blood flow. Following their stay at the Surgical Clinic the siblings were sent for further treatment in the hot thermo-mineral baths on the island of Ischia, and then returned to their native village. The elder boy “departed his life with signs of hypertrophy

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of the heart.” Two years later the younger brother, then aged 17, was re-admitted to hospital. He was found to have widespread muscle contractures and an enlarged tongue. Flexion contractures of the hips and knees were also present. According to Conte’s description Niccola was 17–18 years old, at that time, he was so underdeveloped that he appeared to be between 10 and 12 years old. There were no signs of puberty. Although his head was the regular size of an adult, it appeared out of proportion to the rest of his body. His tongue which was of normal colour, was swollen preventing clear speech, chewing or swallowing. The masseter muscles were over-developed. A short chest and thin ribs were further signs. He had a tense abdomen due to the rigidity of these muscles. Groups of muscles were hypertrophied, such as the deltoids, thigh muscles, and straight muscles of the abdomen [recti abdomini]. The tendons of these muscles seemed hard and thin. The patient also showed multiple flexion contractures. In particular, the thighs were flexed towards the pelvis, the legs towards the thighs – to the extent that the heels could touch the buttocks. His feet were so distorted that the backs were in line with the lateral malleolus and the tips with the medial malleolus. The inner muscles of the arms were rigid. The patient also seemed to have delayed cognitive development and function. (Conte and Gioja, 1863) The distinguished English neurologist William Gowers (1845–1915) referred to Conte’s report in his book Pseudo-hypertrophic Muscular Paralysis, published in 1879 as one of the first published examples of pseudo-hypertrophic paralysis (later to be called Duchenne muscular dystrophy; see below). The two brothers that Conte described were certainly affected by muscular dystrophy since they manifested hypertrophy of the calf and deltoid muscles. Weakness first became apparent around age 8, subsequently becoming progressive and affecting in particular the lower limbs. A similar early description of muscular dystrophy was reported in 1851 by an English physician Edward Meryon (1807–1880), who not only recognized nine cases in three different families but was also able to carry out what was likely the first pathological description of the fibro-fatty infiltration that took place in the muscles. His report has justifiably been considered the first complete clinico-pathological description of muscular dystrophy. Meryon was a founding member of the microscopical society of London in 1839 and was assisted in his studies by the Reverend Sidney Osborne, an accomplished microscopist who had for many years taken a deep interest in cases of granular degeneration

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C. ANGELINI Fig. 31.3. Opere Minori by Semmola (1845).

of the voluntary muscles (Tyler, 2003). The activity of Meryon and his description of muscular dystrophy were carefully documented by Alan and Marcia Emery (1995), who promoted the foundation of the “Meryon Society,” with descendants of the Meryon family, which gathers annually in Oxford and deals with the history of muscle disorders. Edward Meryon, born in Rye, was the son of John Meryon, an active participant in public and political

life. He enrolled as a medical student in 1829 at London University, at the present University College. In his curriculum Meryon indicated that he had studied medicine at the E´cole de Medicine de Paris. He joined the Royal College of Surgeons and Physicians in 1831. Meryon’s interest in the nervous and muscle system was stimulated by Charles Bell (1774–1842), and his first contribution on muscular dystrophy was a paper presented in 1851 at the Royal Medical

MUSCULAR DYSTROPHY and Chirurgical [Surgical] Society of London. The minutes of the meeting were reported in The Lancet and more complete details appeared in the Transactions of the Royal Medical and Chirurgical Society of London during the following year (Meryon, 1852). Meryon described nine boys (one of whom had died) in three different families affected by progressive muscular wasting and weakness. The clinical description was detailed and enlargement of the calf muscles was noted. Two brothers in the first family became chair-bound at ages 10 and 11. However, in one family the disease was milder with onset at around age 12 and ability to walk up to the age of 20. Therefore the siblings in this latter family are likely to have represented the first description of what would later be called the Becker variant of dystrophinopathy (Tyler, 2003). In fact all three brothers were affected, though their sister was asymptomatic. In the discussion of the paper in The Lancet (Meryon, 1851) he stated that the disease was of muscle and not of spinal cord. The lithographic illustrations of muscle tissue accompanying his 1852 article illustrated the disappearance of transverse striae and granular degeneration. It is interesting that the boy with enlarged calves who belonged to the family H. described by Meryon had a post-mortem examination by Partridge (1847). Although both Italian and English physicians had described early cases that are unequivocally examples of muscle dystrophy, the first eponym to be widely associated with this group of disorders was that of Guillaume B.A. Duchenne (de Boulogne). Duchenne (1806–1875) was the son of a fisherman and received his baccalaureate in 1825. Against his father’s will, he went to medical school in Paris. He was among the first to use electrical stimulation to study neurological diseases and their physiology. In 1842, using a modified Voltaic electrical machine, he was able to demonstrate localized muscular contracture during electrical stimulation, and subsequently continued this approach to study both normal and pathological reactions in muscles (Duchenne, 1849, 1850, 1855a). Duchenne saw his first case (Fig. 31.4) of what would later be called Duchenne muscular dystrophy (DMD) in his private clinic and he hypothesized that the disease resulted from a primary pathology in muscle. He recognized earlier cases but felt erroneously that in distinction from his own that these were of primary neuronal rather than muscular origin. In 1858 Duchenne observed the first case of a boy who he believed to be affected by what he called “progressive muscular atrophy with degeneration” and reported the case briefly in 1861 in the 2nd edition of his textbook. He was subsequently able to carry out a complete study of this patient

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Fig. 31.4. Duchenne’s original patient (Case I, Joseph Sarrazin) as reproduced in drawings.

including a muscle biopsy, and published an expanded description of the case in 1868. In this report Duchenne describes his first use of a “histological harpoon” for performing muscle biopsy during life (Fig. 31.5). The evolution of Duchenne’s ideas on muscular dystrophy as he obtained additional pathological specimens and extended his studies on this disease can be traced in his names for the disease process. His initial cases were lumped into the general category of “progressive muscular atrophy,” a broad group that included cases that today would be recognized as including both motor neuron diseases and muscular dystrophies. When he reported his initial case of DMD he called it “hypertrophic paraplegia of infancy of cerebral cause.” In 1868, with the benefit of additional pathological studies, he changed the name to “pseudo-hypertrophic muscular paralysis” or “myosclerotic paralysis.”

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C. ANGELINI friend M. Charcot to be good enough to assist me in it” (see Charcot). As Charcot himself noted: With respect to the state of the spinal cord, our observations were made on transverse sections, coloured with carmine. . . These sections have, besides, been very numerous, and were taken from different parts of the cervical and dorsal regions of the cord. I should here notice that the muscles which receive their nerves from the cervical enlargement were, for the most part, affected to a high degree, and that the deltoids, among others, exhibited most markedly the characteristics of hypertrophy by fatty substitution. If, in this case, the muscular lesions had been connected with spinal lesions the latter should not have failed to show themselves well marked in the cervical enlargement of the spinal cord. Now, the result was absolutely negative . . . the grey substance, which was the subject of a very special investigation, presented no trace of alteration. The anterior cornua were neither atrophied nor deformed . . . and the motor cells, normal in number, did not present, in the several parts which go to constitute them, any deviation from the normal type. Let us remember that the spinal roots, both anterior and posterior appeared also perfectly sound. (Charcot, 1872, pp. 228–239)

Fig. 31.5. Duchenne’s histological harpoon (emporte pie`ce histologique), the first instrument designed specifically for performing muscle biopsy. The cavity for collecting the muscle specimen is clearly seen in the two right-hand illustrations.

Duchenne was not able to obtain an autopsy on a case until 1871, when the second child he had biopsied (Case XII, Fig. 31.6) died. After fixing some muscle specimens in chromic acid, “Being desirous of giving additional value to their histological examination, I requested my

There can be no question of the magnitude of Duchenne’s contribution. In his books and monographs, he managed to outline virtually all the cardinal clinical features of DMD, save only his hereditary component. He identified the key pathological finding, and clearly recognized that DMD represented a primary disease of muscle rather than the secondary effects of disease within the spinal cord or brain. Although Duchenne was not the first to recognize the uniqueness of muscular dystrophy as a separate clinical species, the clarity and quality of his observations justify his eponymous recognition. It would remain for Duchenne’s contemporary, the great British neurologist, Sir William Richard Gowers, to put the final touches on the clinical picture based on a large series of both personal and reported cases, and to clearly identify DMD as an inherited disorder with a striking predilection for males. Clinical semiology of muscle disorders was further refined by William Gowers (1815–1915), the English physician who was the first to report the clinical sign characteristic of muscular dystrophy, related to the way in which patients rise from the floor to the standing position, that is still called Gowers’ sign (1879). This maneuver is a consequence of proximal leg weakness

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483 Fig. 31.6. Duchenne case XII: (F.11), “showing atrophy of the pectorals. Almost all the other muscles have a hypertrophic appearance.” The surrounding images are muscle specimens “from subjects affected with pseudohypertrophic paralysis of differing severity; showing the considerable quality of connective and fibrous interstitial tissue.” Muscle biopsy specimens from patients with Duchenne muscular dystrophy (DMD) at 45 magnification illustrate the “considerable quantity of connective and fibrous interstitial tissue” (F.12–F.14). The same specimens at 200 magnification (F.15–F.18). A normal muscle specimen (F.19). “Different degrees of fatty degeneration of the muscle fiber” (F.20–F.22). “Necrosis of the muscle fiber” (F.23a) and “proliferation of elements of fibrous tissue” (F.23b).

and so was by him described “He helps himself in a very peculiar way – by putting his hands upon his knees, and grasping his thighs higher and higher, and so by . . . climbing up his thighs he pushes his trunk up.” Gowers publicly presented early cases of this disorder to an audience at the National Hospital in 1879. For several years, he had followed a family with six

afflicted members in two generations. In the second generation, four of the six brothers were afflicted, including a 12-year-old (Arthur S., Case 5), a 7-yearold (William S., Case 4), a 4-year-old (Harvey S., Case 3), and a 3-year-old (name not specified, no case number) (Fig. 31.7). Two brothers aged 4 and 10 were apparently healthy. Gowers was intrigued by the fact that

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C. ANGELINI himself up.” William was more seriously affected. He had distinct enlargement of his calves (Fig. 31.7), small, thin thighs and back, an obvious lumbar lordosis, and prominent angled scapulae. His arms were also thin, except for the deltoids, which seemed enlarged. He also had wasting of his sternocleidomastoid muscles. In addition to presenting members of the S. family, Gowers also presented a 9-year-old boy (David W., Case 1) to his audience, and described his similarly affected brother. Noting again: He helps himself up in a very peculiar way – by putting his hands upon his knees, and then grasping his thighs higher, and so by climbing up his thighs he apparently pushes his trunk up. I wish to call your special attention to this peculiar action, because it is probably pathognomonic of the disease. Attention was called to it by Duchenne, and I have never seen it absent in a case so long as the patient possessed the necessary muscular power. I have never seen it in any other disease, and every doubtful case in which it was present ultimately proved to be an example of the affection. Its diagnostic importance is thus very great. (Gowers, 1879)

Fig. 31.7. Two brothers aged 4 (Harvey S., Case 3) and 7 (William S., Case 4) from Gowers. “The youngest . . . would not suggest to you the idea of disease. There is no obvious muscular wasting or enlargement, and yet . . . his movements were greatly impaired. He could only just succeed in rising from the floor . . . The other boy . . . as his photograph indicates, [has] very distinct enlargement of the calves. His thighs are small, the back thin, hollow in the lumbar region, the angles of the scapulae prominent, the muscles of the upper limbs thin, except the deltoids, which are rather large.”

one of the apparently normal brothers was the twin of Harvey S., who was clearly severely afflicted. Neither of their parents appeared affected, although the mother’s only brother and one of her four sisters had both died of an apparently similar illness, each at the age of 15. This latter case, in a girl, represented one of only three females afflicted with the disease in his personal series of 21 cases. None of the children of the unaffected sisters had shown evidence of the disease. Harvey S. did not have obvious muscular wasting or enlargement, but was already experiencing difficulty in rising from the floor. Gowers noted that “He could only just succeed in rising from the floor, getting first his toes upon the ground, then placing first one hand upon his knee, then the other, and so working

This peculiar method of arising from the floor (Fig. 31.8) would subsequently be referred to as “Gowers’ sign,” although as Gowers himself acknowledged, Duchenne had described the phenomena previously. The contributions to X-linked muscular dystrophy were further extended in 1955 by Peter Becker (1908–1989) who first clearly identified an allelic benign form of X-linked muscular dystrophy. Prof. Peter E. Becker trained at the Universities of Marburg, Berlin, Vienna, and Hamburg. He did his doctoral thesis on the “drawings of schizophrenics.” At age 26 he was a resident in neurology at the University of Hamburg and at ages 28–30 he attended the Kaiser Wilhelm Institute of Anthropology, Human Genetics and Eugenics, Berlin. At age 43 he became a clinical professor of neurology at the University of Freiburg and at age 49 he was appointed professor and chairman of Human Genetics, University of Gottingen.

THE NOSOGRAPHIC ERA The recognition of limb-girdle dystrophies Limb girdle muscular dystrophies (LGMD) were first recognized chiefly by a group of German physicians working in Heidelberg, i.e., Wilhelm Erb (1840–1921), Nicolaus Friedreich (1825–1885) and Johann Hoffman (1855–1919). The “Heidelberg myological trio” was

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Fig. 31.8. Gowers’ sign. “He helps himself up in a very peculiar way – by putting his hands upon his knees, and grasping his thighs higher and higher, and so by . . . ”

founded by Friedreich; he was born in Wu¨rzburg, Westphalia, and became acting chairman of Pathology and Internal Medicine, in Heidelberg. In 1863 Friedreich discovered spinocerebellar ataxia and in 1872 wrote Über Progressive Muskel Atrophie. He taught Erb, who attended medical school at the early age of 17, and received his Abilitatur at age 25.

Erb was the first to develop the concept of progressive muscular dystrophy and also provided classic descriptions of other neurological disorders including tabes dorsalis and myasthenia gravis. He was also interested in electrophysiology and described the Erb phenomenon, i.e., increased electrical irritability of motor nerves in tetany.

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C. ANGELINI Medical terms related to Erb Erb phenomenon: increased electrical instability of motor nerves in tetany Erb (electrodiagnostic) point: upper brachial plexus Erb (cardiologic) point: punctum quantum (aortic valve) Erb sign: degeneration reaction Erb–Westphal sign: absence of knee jerk in tabes dorsalis Erb syndrome: juvenile type of muscular dystrophy Erb–Charcot disease: spastic spinal paralysis Erber–Duchenne paralysis: upper arm plexus paralysis C5 + C6 Erb–Goldflam disease: myasthenia gravis

Another electrophysiological concept was Erb’s sign, i.e., a degenerative reaction of muscle. In 1884 he described the juvenile form of progressive muscular atrophy in six males (one boy in whom a maternal uncle was affected). At that time progressive muscular atrophy (Fig. 31.9) was divided into two groups: Aran– Duchenne spinal-muscular atrophy and Erb-type juvenile muscular dystrophy due to progressive muscle dystrophy (PMD). Erb also provided a myopathological description, outlining the histopathological criteria in one patient with a muscle fiber pathology, increased connective and adipose tissue, nuclear changes and chains, and fiber degeneration. Erb’s juvenile form of muscular dystrophy is quite similar to the clinical pictures now classified as LGMD 2A (calpainopathy), i.e., patients who present the following signs in the second decade of life: – weakness of the upper limb-girdle, progressing to the lower girdle – scapular winging – progressive course. Erb writes:

Fig. 31.9. Muscular weakness and wasting (1884).

The concept of the manifold and interesting forms of disorders that before long were subsumed under the name of “progressive muscular atrophy” has been revised several times over the last years, without a conclusive decision about all relevant questions. A few lines later the author states, not without selfconfidence: I believe I may claim the merit of being the first to have shown with full determination that in this apparently homogeneous group of disorders which remains after the successful exclusion of other things, such as forms of poliomyelitis and neuritis, sphingomyelopathy, secondary amyotrophies, etc. as “progressive muscular atrophy,” that in this group we have to discern at least two forms which are distinguished by a row of characteristic signs. I did this in my lecture at the Congress of Natural Scientists in Freiburg in 1883 and in my following paper in the Deutsches Archiv der Klinischen Medizin. Thus I have postulated my “juvenile muscular atrophy” and have already underlined its close relationship with the “pseudohypertrophy of the muscles” and with the “hereditary muscular atrophy” of Leyden; on the basis of evident clinical coincidence I have bundled these three forms of disorders to a probable nosological entity for which I propose the name “dystrophia muscularis progressiva.” (This work appeared in the first issue of the Zeitschrift fu¨r Nevenhelkunde, of which he was one of the founders; Erb, 1891.) The atrophic pelvic variety of LGMD was further described by Leyden and Mobius and as a nosographic entity finally identified by Walton and Natrass (1954). Nowadays a noticeable genetic and clinical heterogeneity

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of LGMD has been established (Angelini, 2004) and both autosomal dominant and recessively inherited forms of disease have been identified (Norwood et al., 2006).

by Landouzy and Dejerine in 1885. One of the most striking clinical features of the disease, i.e., the occurrence of partially abortive cases, was only later described by Tyler and Wintrobe (1950).

The recognition of facio-scapulo humeral dystrophy (FSHD)

THE MOLECULAR ERA

There is a difference of opinion on the priority in describing FSHD (Kazakov, 2001). Landouzy and Dejerine are widely recognized to have distinguished FSHD as a nosographic form in 1884–1885 and to have proved its myopathic nature. However, some authors pointed out that a similar disease might have been described by Duchenne under the name of “progressive muscular atrophy of childhood” (Table 31.2) and probably also by Johann Hoffmann, the third member of the Heidelberg myological trio, who with Oppenheim was first able to recognize spinal muscular atrophy. The autosomal dominant mode of inheritance of this special muscular dystrophy was, however, established

A new molecular era began in 1987 with the discovery of the dystrophin gene and its product by Kunkel and Hoffmann and was followed by the modern molecular classification of LGMDs. The genetic revolution and its impact could of course not have been anticipated nor appreciated by any of the early clinicians: rather, the individual entities they described were based predominantly on the clinical features of relatively small groups of cases supplemented by variable amounts of pathological data. The hereditary nature of many disorders was recognized, but it was not possible to identify specific molecular or genetic defects or to utilize this information to classify the various disorders. In the modern era molecular and genetic discoveries have

Table 31.2 List of names under which muscular dystrophy was described for the period 1829–1885 1. Ipertrofia del sistema muscolare volontario (hypertrophy of the voluntary systemic muscles) 2. Scrofula del sistema muscolare (wasting of the muscular system) 3. Atrophie musculaire avec transformation graisseuse (progressive muscular atrophy with fatty degeneration) 4. Granular and fatty degeneration of voluntary muscles 5. Atrophie musculaire progressive avec transformation graisseuse de´butant de la face des adultes ou` adolescence ou` enfance, he´re´ditaire (progressive muscular atrophy with fatty degeneration beginning with the face in adults or in youth or in childhood) 6. Hypertrophic paraplegia of infancy of cerebral cause 7. Atrophie musculaire graisseuse progressive sie´geant dans quelques muscles de la face, du tronc et des members des adultes, enfants et coge´nitale, he´re´ditaire (progressive hereditary fatty muscular atrophy with the affection of some muscles of the face, trunk and limbs in adults, children and congenital period) 8. Pseudohypertrophic muscular paralysis or myosclerotic paralysis 9. Atrophie musculaire graisseuse progressive de l’enfance (progressive fatty muscular atrophy of childhood) 10. Atrophie musculaire progressive de l’enfance (ou de l’adolescence et de l’adulte), he´re´ditaire (progressive hereditary muscular atrophy of childhood or youth and adult) 11. Atrophie musculaire progressive de l’enfance 12. Pseudohypertrophic muscular paralysis 13. Myopathie atrophique progressive (progressive atrophic myopathy; the same as Duchenne progressive muscular atrophy of childhood, in the opinion of Landouzy and Dejerine) 14. Atrophie musculaire progressive de l’enfance de Duchenne (de Boulogne) (the same as the facio-scapulohumeral type of Landouzy and Dejerine) 15. Myopathie atrophique progressive: Atrophie musculaire progressive de l’enfance (de Duchenne) facio-scapulohumeral type (de Landouzy and Dejerine)

Semmola, 1829 Conte and Gioja, 1836 Duchenne, 1864 Meryon, 1851, 1852 Duchenne, 1855b

Duchenne, 1861 Duchenne, 1861, 1862

Duchenne, 1868a Duchenne, 1868b Duchenne, 1868

Landouzy, 1884 Gowers, 1879 Landouzy and Dejerine, 1884

Landouzy and Dejerine, 1885 Landouzy and Dejerine, 1885

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dramatically changed our view on nosography and pathogenesis of muscular dystrophy. The molecular basis of many conditions is already being unraveled and it seems quite possible that, as we learn more about any type of “muscular dystrophy,” this will benefit our understanding of other forms.

REFERENCES Angelini C (2004). Limb-girdle muscular dystrophies: heterogeneity of clinical phenotypes and pathogenetic mechanisms. Acta Myol 23: 130–136. Angelini C, Armani M (1983). Features of modern myology: G.B. Morgagni and A. Vesalius. Neurology 33: 229. Camanio GB (1541). Musculorum humani corporis picturata dissectio terrena. Conte G, Gioja L (1836). Scrofola del sistema muscolare. Ann Clin dell’Ospedale degli incurabili di Napoli 2: 66–79. Duchenne (de Boulogne) fils (1864). De la paralysie atrophiquegraisseuse de l’enfance. Archives generales de Medecine 2 (6th Ser., tome 4): 28–50; 184–209; 441–455. Duchenne GB (1849). Recherches faites a` l’aide du galvanisme sur l’e´tat de la contractilite´ et de la sensibilite´ e´lectro-musculaires dans les paralysies du membre supe´rieur. C R Acad Sci Paris 29: 667–670. Duchenne GB (1850). Recherches sur l’e´tat de la contractilite´ et de la sensibilite´ e´lectro-musculaires dans les paralysies du membre supe´rieur, etudie´es a` l’aide de l’e´lectrisation localise´e. Arch Ge´n Me´d 22: 1–40. Duchenne GB (1855a). De l’E´lectrisation localise´e et de son application a` la physiologie, a` la pathologie et a` la the´rapeutique. 1st edn. Baillie`re, Paris. Duchenne GB (1855b). De l’atrophie musculaire avec transformation graisseuse et des paralysies atrophiques de cause traumatique et saturnine. In: Recherches e´lectrophysiologiques, pathologiques et the´rapeutiques. Se´rie de memoires adresse´es a` l’Acade´mie des sciences le 21 mai 1849, pour le concours du prix de me´dicine. Selections published in Duchenne de Boulogne: De l’E´lectrisation Localise´e. 1st edn. Baillie`re, Paris, pp. 622–624. Duchenne GB (1861). De l’E´lectrisation Localise´e. 2nd edn. Baillie`re, Paris. Duchenne GB (1862). Album de Photographies Pathologiques Complementaire du Livre Intitule´ de l’E´lectrisation Localise´e. Baillie`re, Paris. Duchenne GB (1868a). Recherches sur la paralysie musculaire pseudo-hypertrophique ou paralysie myoscle´rosique. Arch Ge´n Me´d 11: 5–25, 179–209, 305–321, 421–443, 552–588. Duchenne GB (1868b). De la paralysie musculaire pseudohypertrophique ou paralysie myo-scle´rosique. Gaz Hop Paris 41: 138–139, 141–142. Duchenne GBA (1868). Reserches sur la paralysie musculaire pseudohypertrophique ou paralysie myo-sclerosique. Archives Generales de Medecine 11: 25.

Emery AEH, Emery MHL (1995). The History of a Genetic Disease: Duchenne Muscular Dystrophy or Meryon Disease. Royal Society of Medicine, London, New York. Erb W (1884). Muskelbefund bei der juvenilen Form der Dystrophia muscularis progressiva. Neurol Zbl 13: 286–295. Erb W (1891). Dystrophia muscularis progressiva. Dtsch Z Nervenheilkd 1: 13. Gowers WR (1879). Pseudohypertrophic Muscular Paralysis. J & A Churchill, London. Kazakov V (2001). Why did the heated discussion arise between Erb and Landouzy-Dejerine concerning the priority in describing the facio-scapulo-humeral muscular dystrophy and what is the main reason for this famous discussion? Neuromuscul Disord 11: 421. Landouzy L, Dejerine J (1884). De la myopathie atrophique progressive myopathie he´re´ditaire de´butant dans l’enfance pour la face sans l’alte´ration du syste´me neurologique. C R Acad Sci Paris 98: 53–55. Landouzy L, Dejerine J (1885). De la myopathie atrophique progressive. Myopathie sans neuropathie, debutant d’ordinaire dans l’enfance, par la face. Revue de Medecine 5: 81–117, 253–366. Meryon E (1851). On fatty degeneration of the voluntary muscles. Lancet 2: 588–589. Meryon E (1852). On granular and fatty degeneration of the voluntary muscles. Trans R Med Chirurg Soc Lond 35: 73–84. Mokri B, Engel AG (1975). Duchenne dystrophy: electron microscopic findings pointing to a basic or early abnormality in the plasma membrane of the muscle fiber. Neurology 25: 1111–1120. Norwood F, De Visser M, Eymard B, et al. (2006). Limb girdle muscular dystrophies. Chapter 26. In: R Hughes, M Brainin, NE Gilhus (Eds.), European Handbook of Neurological Management. Blackwell, Maiden, Oxford, pp. 376–389. Partridge R (1847). Fatty degeneration of muscle (report of Proceedings of the Pathology Society of London, November 15, 1847). London Med Gaz 5: 944. Semmola G (1829). Memoria su due malattie non ancora descritte. Napoli 1829 (quoted by Conte and Gioja). Semmola G (1834). Sopra due malattie. Notizie dell’altra infermita`. Accademia Pontaniana 164–165. Semmola G (1845). Opere Minori. Tipografia C. Bartelli e Co., Napoli. Tyler FH, Wintrobe MM (1950). Studies in disorders of muscle: the problem of progressive muscular dystrophy. Ann Intern Med 32: 72–79. Tyler KL (2003). Origins and early descriptions of “Duchenne muscular dystrophy.” Muscle Nerve 28: 402–422. Vesalius A (1543). De Humani corporis fabrica. Tabulae anatomica sex- Basel. Walton JN, Natrass FJ (1954). On the classification, natural history and treatment of the myopathies. Brain 77: 169–231.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 32

Sensory and perceptual disorders NICHOLAS J. WADE * Department of Visual Psychology, School of Psychology, University of Dundee, Dundee, UK

INTRODUCTION The senses have always occupied a seat of significance in the theater of neurology, the term introduced by Thomas Willis (1621–1675; Fig. 32.1). Indeed, Willis (1672) himself wrote astutely on the sensory accompaniments to vertigo. However, the precise location of that seat has proved more difficult to determine. While the senses have provided signs of neural dysfunction, perception has not been subjected to the same cerebral scrutiny. There are several reasons for this, some of which reside in the ancient and attractive ways in which the senses were separated and others relate to the manner in which particular senses have been investigated historically. Disorders of the senses can be examined appropriately only after their orders have been established. That is, the normal operation of the senses and perception are required to be appreciated, at least implicitly, before departures from this scheme can be assessed and analyzed. In the case of perception there was a long descriptive history before theories were formed and experiments were performed. Thus it is possible to chart the phases through which phenomena pass in progressing from description to dissection. It is only after an adequate taxonomy of phenomena is established that departures from normality can be suitably assessed and treated. The first phase is a description of the phenomenon. In antiquity, many phenomena did not pass beyond this phase or indeed reach it. Description is followed by attempts to incorporate phenomena into the body of extant theory. Finally, the phenomena are accepted and utilized to gain more insight into the functioning of the senses and of the brain. In many cases, the phenomena have been described in the distant past, and no clear origin can be determined. An example is the

*

double vision that follows pressing one eye with the finger, and the single vision that normally occurs (Wade, 1998). In others, there is an obvious break with the past and a phenomenon is described and investigated for the first time. A good example is stereoscopic vision based on slight disparities in the images projected to each eye: Wheatstone (1838) described this on the basis of a chance observation. In order to examine it experimentally he invented the stereoscope, he named the depth so perceived stereoscopic vision, and he interpreted it within an empiricist theory of perception. Many perceptual phenomena are named after the first person considered to have described them. The Purkinje shift is such an instance; it is named after Purkinje’s (1825) description of the apparent brightness of colors before and after sunrise, although earlier accounts of it do exist (Wade and Brozˇek, 2001). The clarity of a succinct label frequently blurs the detailed natural history of phenomena, and such is certainly the case for the senses, where the problems of classification have tended to hinder rather than help the studies of disorders occurring in their functioning. The phenomena, once described, are typically placed within some theoretical framework. This often involves their classification as illusory or not. For most of the history of perceptual phenomena, interest was usually restricted to illusions or oddities of experience: the commonplace characteristics of constant perception were ignored (Wade, 2005).

CLASSIFICATION OF SENSES The five senses of sight, hearing, smell, taste, and touch were enumerated by Aristotle (c. 384–322 BC), and they are rooted in our culture. No matter what neurology might divine, they are so defined in the popular imagination. The prominence of eyes, ears, nose, and tongue on the head, and the specific experiences

Correspondence to: Nicholas J. Wade, Professor of Visual Psychology, School of Psychology, University of Dundee, Dundee DD1 4HN, UK. E-mail: [email protected], Tel: +44-1382-384616, Fax: +44-1382-229993.

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Fig. 32.1. “Circle of Willis” by Nicholas Wade. This “perceptual portrait” combines a portrait of Willis (after Birch, 1743) within a representation of the base of the brain by Christopher Wren (after Willis, 1664).

associated with them, have acted in the past, as well as in the present, to fix these four senses. Touch has presented more problems because its sensitivity is not localized to a particular sense organ, and the experiences derived from the skin are diverse. Pain, the sense most salient to neurology, was missing altogether. Touch and pain both presented problems for classifying the senses, although the ways they were treated differed radically. Touch was taken as the exemplar of all senses whereas pain was given less prominence; it was not included in the list of Aristotle’s “common sensibles,” which were defined by properties of the stimulus rather than of sensation. For Aristotle, no obvious stimulus could be assigned to pain, other than over-stimulation or damage to the other senses, and so it was placed in opposition to pleasure rather than associated with sense (Dallenbach, 1939). Neither touch nor pain could be localized in a particular sense organ.

Aristotle confronted the particular problems in the context of touch but not of pain. The other encumbrance to advance was ignorance of both the anatomy and physiology of the senses, let alone of the brain. Indeed, for Aristotle sensation was housed in the heart, although he was later taken to task for this by Galen (c. 130–200) who argued that all the senses have connections with the brain. Particularly large strides in understanding the senses and nervous function were made in the 19th century (Finger, 1994). The gross anatomy of the brain was clarified, and its microanatomy was subjected to achromatic scrutiny; the cell and neuron doctrines were advanced; function was related to structure, initially fancifully (and phrenologically) and later with surgical precision; and a wide range of cognitive dysfunctions were linked with abnormalities in brain structures. It is the period between these two states that will be examined in the context of sensory and perceptual disorders.

SENSORY AND PERCEPTUAL DISORDERS 491 Touch, requiring contact in order to experience it, which take the source of their sensation from the encewas often taken as the most important sense, and the phalon” (May, 1968, p. 400). one relative to which others could be related. It is perThe situation remained relatively unchanged haps for this reason that Aristotle maintained that throughout the medieval period (Kemp, 1990). Attentouch is a single sense, that the number of senses is tion was directed principally at interpretations of restricted to five, and that: “there cannot be a special vision, with much less heed paid to the other senses. sense-organ for the common sensibles either” (Ross, Developments did occur in fusing Aristotle’s account 1931, p. 425a). Boring’s conclusion about this dogma of the senses with Galen’s pneumatic physiology, and was clear: “It was certainly Aristotle who so long the medical tradition of describing diseases of the delayed the recognition of a sixth sense by his doctrine senses became more refined. that there are but five senses” (1942, p. 525). For Boring, as for most other historians of the senses, the Criteria for classifying the senses additional one that emerged in the early-19th century The sources of evidence available to Aristotle (and to was the muscle sense, although many subdivisions of those who followed him over the next 2000 years) for touch had been proposed in previous centuries (Wade, distinguishing between the senses were phenomenology 2003a). and gross anatomy. They could report on their experiAristotle’s survey of the senses was more extensive ences when stimulated, and they could relate them to than those of his predecessors (Beare, 1906). Most of their body parts. For example, sight ceased when the the knowledge we have of the earlier Greek commentaeyes were closed. Additional inferences could be tors derives from the writing of his pupil, Theophrasdrawn from disease or injury, as well as from developtus (c. 370–286 BC). Without his work On the Senses mental disorders. Blindness and deafness would have (Stratton, 1917) our understanding of early theories of been commonplace. Recourse was made to philosophy, the senses would be even more meager. Theophrastus usually linking the senses to the elements – fire, earth, categorized writers on the senses into two groups: water, and air – which permeated perception (Beare, those who considered that the senses were stimulated 1906). The classical accounts of the senses drew princiby similarities or by opposites. Thus, taste and touch pally upon psychological (or behavioral) evidence for could be treated as similar, since both involve contact. their independence. In contrast, developments in the The means of sensing by sight, hearing, smell, and last few centuries have relied increasingly on anatomitaste was speculated upon by most writers, but less cal and physiological indications of separate senses, was said about touch. and the behavioral dimension has been given less promAlcmaeon (fl. 500 BC) located the center of sensainence. tion in the brain, he described the optic nerve leaving While emphasizing the veridicality of sensing in the eye, and he described the experience of light that general, Aristotle did entertain the possibility of errors follows applying external pressure to the eye. In the con(illusions) entering into a particular sense. The examtext of touch, Anaxagoras (c. 500–438 BC) discussed ples he mentioned were those of color or sound confusensing warmth and cold, and Democritus (c. 460–370 sion and errors in spatial localization of colors or BC) contrasted heavy with light, and hard with soft. sounds. Illusions are often considered to be a modern Plato (427–347 BC) wrote that touch distinguished preoccupation, based on specific theories of percepbetween hot and cold, hard and soft, heavy and light, tion, but their origins are ancient and illusions can be as well as rough and smooth. Theophrastus himself said investigated with little in the way of theory (Wade, relatively little about touch. His theory of the senses in 2005). If there is an assumption of object permanence, general involved some intermediary between the object then an illusion occurs when the same object appears to and the sense organ; for vision, hearing, and smell this have different properties (of color, position, size, could be more readily maintained than for touch. shape, motion, etc.) under different circumstances. The approach by Galen to the senses displayed the Aristotle’s description of the motion aftereffect (in advantages of anatomical dissection (May, 1968). De somniis; Ross, 1931) was presumably considered Galen’s theory of the senses was physiological, and it worthy of note because the stones at the side of the was based on the concept of pneuma advocated by river appeared stationary prior to peering at the flowEmpedocles (c. 493–433 BC): “Unless the alteration in ing water but not afterward (Wade and Verstraten, each sense instrument comes from the encephalon 1998). Thus, the existence of an illusion might provide and returns to it, the animal will still remain without evidence of a sensory system. For example, we norsense perception” (May, 1968, p. 403). Galen restricted mally feel stable and still when we stand upright; howhis discussion to the “four sense instruments in the ever, an illusion of body motion can occur when we are head, namely, the eyes, ears, nose, and tongue, all of

492 N.J. WADE standing upright – if we have previously rotated the For it is more than probable, that what may be body rapidly. called organs of sense, have particular nerves, The situation regarding the senses was radically whose mode of action is different from that of revised in the 19th century, with developments in physics, nerves producing common sensation; and also anatomy, and physiology. Sources of stimulation could be different from one another; and that the nerves specified and controlled more precisely. This had already on which the particular functions of each of the occurred in the context of color, with Isaac Newton’s organs of sense depend, are not supplied from (1642–1727) methods of spectral separation of white light different parts of the brain . . . it is more proband mixing components of it (Newton, 1704). Thomas able, that every nerve so affected as to communiYoung (1773–1829) applied the method in 1802 and found cate sensation, in whatever part of the nerve the that all colors could be produced by appropriately comimpression is made, always gives the same senpounding three primaries; he suggested that the eye was sation as if affected at the common seat of the selectively sensitive to each. Young (1807) also introduced sensation of that particular nerve. (Hunter, the term “energy” in the context of weight, and this con1786, pp. 215–216) cept was related by others to different dimensions of senExamples Hunter gave to support this contention were sitivity, including light and sound. referred sensations arising after damage or amputaThe link between energy and sense organs was tion. The seeds of this idea can be found in antiquity, forged soon thereafter. Charles Bell (1774–1842) is although it was based on philosophical rather than phynoted for discovering that the anterior spinal nerve siological speculation. The doctrine of specific nerve roots are motor (Cranefield, 1974). His principal conenergies, as it became called, was given further supcern, however, was in specifying the senses and their port by Johannes Mu¨ller (1801–1858), in a monograph nerve pathways to the brain. His experiments were on comparative physiology and on eye movements described in a privately published pamphlet, which also (Mu¨ller, 1826), and it was amplified in his influential related stimulation to specific senses: handbook of human physiology (Mu¨ller, 1840, 1843, In this inquiry it is most essential to observe, that 2003). Although the doctrine was framed in terms of while each organ of sense is provided with a capadifferences between the senses, it was used increascity for receiving certain changes to be played ingly to determine qualitative distinctions within them upon it, as it were, yet each is utterly incapable (Finger and Wade, 2002). of receiving the impression destined for another The manner in which the nerves themselves work organ of sensation. It is also very remarkable that was hinted at by Luigi Galvani (1737–1798) when he an impression made on two different nerves of made a case for “animal electricity” (Galvani, 1791). sense, though with the same instrument, will proHe applied a discharge from a Leyden jar to the duce two distinct sensations; and the ideas resultexposed crural nerve or muscle of an isolated frog’s ing will only have relation to the organ leg, and it twitched. Galvani suggested that this was affected. (Bell, 1811; reprinted in 2000, pp. 8–9) due to a special type of electrical fluid that accumulates in the muscles of animals (Piccolino, 1997, 2003; In the context of vision, the demonstration of this fact Bresadola, 1998; Piccolino and Bresadola, 2003). had been known to Alcmaeon: pressure to the eye, even Alessandro Volta (1745–1827) maintained that aniin darkness, produced the experience of light (Gru¨sser mal tissue was not necessary for a current to pass, and Hagner, 1990). Bell was able to bolster this observaand that Galvani’s experiments were flawed. Volta tion with the application of electricity to the eye: had interests in the effects of electrical discharges on If light, pressure, galvanism, or electricity prothe senses; he carried out studies of galvanic light figduce vision, we must conclude that the idea in ures in the 1790s, and also found that intermittent stithe mind is the result of an action excited in mulation produced longer lasting effects than the eye or in the brain, not any thing received, constant stimulation. In his letter describing the pile though caused by an impression from without. or battery, Volta (1800) described how he applied elecThe operations of the mind are confined not by trical stimulation to the eyes, ears, nose, and tongue. the limited nature of things created, but by the He connected the wires from a battery between limited number of our organs of sense. (Bell, the mouth and conjunctiva of the eye, which resulted 1811; reprinted in 2000, p. 12) in the experience of light, even in a dark room. MoreA similar sentiment, voiced with primary reference over, he noted that the visual sensation was associated to the nerves and their pathways, was written a few with the onset and offset of the current, and a contindecades earlier by John Hunter (1728–1793): uous impression of light could be produced by rapid

SENSORY AND PERCEPTUAL DISORDERS 493 alternation of polarity (Piccolino, 2000). When he (1829–1914) gave them that name in 1871 (Price and applied a current to the two ears he reported: “At the Twombly, 1978). The experience of sensations in lost moment the circuit was completed I felt a shaking in limbs provides an example of the ways in which novel the head” (Volta, 1800, p. 427). This shaking did not perceptual phenomena can be interpreted. The first last long; when the current was continued he experiphase of description was due to the surgeon Ambroise enced sound and then noise. The sensations were so Pare´ (1510–1590; 1575, 1649); he initiated medical interdisagreeable that he thought them potentially dangerest in this intriguing aspect of perception, partly ous, and he did not wish to repeat them. Volta had because more of his patients survived the trauma of applied a current to his tongue and noted an acidic surgery (Finger and Hustwit, 2003). This was followed taste a few years earlier (Piccolino, 1997). by attempts to incorporate the experiences from missVolta’s pile did much to hasten experimental studies ing limbs into the body of extant theory. Rene´ of the senses. Electricity was a common stimulus that Descartes (1596–1650; 1637/1902, 1984, 1991) integrated could be applied to different sensory organs, inducing sensations in amputated limbs into his dualist theory of different sensations. Mu¨ller used the effects to support mind, and used the phenomenon to support the unity his doctrine: “The stimulus of electricity may serve as a of the mind in comparison to the fragmented nature second example, of a uniform cause giving rise in difof the body. Finally, the phenomenon was accepted ferent nerves of sense to different sensations” (1843, p. and utilized to gain more insights into the function1063). The first example was mechanical stimulation. ing of the senses. This was achieved in the 18th The action of nerves on muscles led first Carlo Matcentury by many physicians, but particularly by teucci (1811–1862) and later Emil du Bois Reymond William Porterfield (c. 1696–1771; 1759), who described (1818–1896) to propose the ways in which nerves propaand interpreted the feelings in his own missing leg; he gate impulses (Brazier, 1959, 1988). Experimental eviconsidered that sensations projected to the missing leg dence of action potentials was to await technological were no more remarkable than colors projected to advances in recording and amplifying small electrical sigexternal objects (Wade and Finger, 2003). nals; this was provided by Adrian (1928), who was able to Pare´ speculated that the lingering sensations from the record action potentials (Finger, 2000). When recordings lost limb were a consequence of stimulating the nerves in of nerve impulses could be made from individual cells the severed stump. Much more was known about the perin the visual pathway their adequate stimuli could be ipheral nervous system than about the brain, as was evidetermined. Adrian coined the term “receptive field” to dent from Pare´’s diagrams. It was still the belief that the refer to this, and it was applied to other senses, too. animal spirit flowed through the hollow nerves from the Thus, the criteria that emerged from these new technisenses to the ventricles in the brain. Once attention had ques for separating the senses are the quality of the been drawn to the phenomenon, then its phenomenology experience, the nature of the stimulus, the gross and was examined in more detail; it could also be integrated microanatomy of the receptor system, and the pathways into prevailing theories. This second phase is found in the to and representation of the cortex. The psychological speculations of Descartes (1637/1902) in his book on optics dimension is the oldest, and yet less attention has been where he argued that all sensation is located in the brain. paid to behavioral evidence for distinguishing and adding Objections to this view were expressed by some of Desto the senses than to that derived from anatomy and phycartes’ correspondents, and he responded by commenting siology. On the basis of these criteria there are many more on reports of sensations in amputated limbs (Descartes, than five senses but, as Dallenbach remarked, “The testi1984, 1991); they were used as evidence that all sensations mony of the ages proved ineffectual in refuting the Aristake place in the brain. In subsequent letters concerning totelian doctrine of the senses” (1939, p. 335). such sensations, Descartes attributed them to activity in the brain normally associated with the missing limb. Since the sensations were principally of pain, and Descartes had PHANTOM LIMBS developed a theory of pain, then the possibility that it was a Pain entered the theater of the senses via an illusory sensation was entertained. Nonetheless, Descartes used route. Pains from limb regions that had been amputhe phenomenon to cast doubt on the reliability of the tated were also associated with sensations of touch. senses in general. Evidence of loss of limbs, through disease, accident, Eighteenth-century reports by Porterfield (1759), warfare, or ritual, has been commented upon since Fordyce (1771), Hunter (1786), Erasmus Darwin (1794) records began. With this legacy, it is remarkable that and Marshal (1815) all involved sensations of touch as reports of phantom limbs entered so late into medical well as pain. The account by Porterfield is noteworthy, records. Indeed, the principal features of phantom as he was a surgeon who reported on his own phantom limbs were well known long before Silas Weir Mitchell leg (Wade, 2003b, 2005; Wade and Finger, 2003):

494 N.J. WADE Having had this Misfortune myself, I can the betVERTIGO ter vouch the Truth of this Fact from my own Vertigo refers to feelings of disequilibrium and dizziExperience; for I sometimes still feel Pains and ness; it accompanies many neurological disorders, Itchings, as if in my Toes, Heel or Ancle, &c. and its perceptual dimensions were reported upon in tho’ it be several Years since my Leg was taken antiquity. A good definition was provided in the 18th off. Nay, these Itchings have sometimes been so century by David Hartley (1705–1757): strong and lively, that, in spite of all my Reason and Philosophy, I could scarce forbear attemptGiddiness, or an apparent irregular Motion in ing to scratch the Part, tho’ I well knew there the Objects of Sight, almost always goes before was nothing there in the Place where I felt the any general Confusion or Privation of Sense Itching. (Porterfield, 1759, p. 364) and Motion; which is very agreeable to the Doctrine of Vibrations. For the general Disorder in Unlike Descartes, Porterfield did not consider the senthe Vibrations in the medullary Substance may sations as illusory, but as a normal consequence of perbe expected to be perceived in the Optic Nerve, ception. He displayed considerable sophistication in the and corresponding Part of the Brain, first and analysis of his phantom limb, by associating the projecchiefly, on account of the Acuteness and Precitive features of the experience with other aspects of sion of the Sense of Sight. Upon the same Principerception. He was well versed in Newtonian color theples it is easy to see, how great and unusual ory and cited Newton many times. Porterfield was Agitations of the Body, Impressions on the extending the subjectivity of sensation to phantom Stomach, on the olfactory Nerves, on the Eye, limbs, and incorporating the sensations into the body by the quick Transition of Objects, on the of perceptual theory. Eye and Fancy together, by looking down a In the 19th century both Charles Bell (1811) and Precipice, &c. should occasion a temporary Johannes Mu¨ller (1843, 2003) employed phantom limb Giddiness. (Hartley, 1749, p. 200) phenomena as supports for the doctrine of specific nerve energies. Mu¨ller provided descriptions of 13 Vertigo provides a clear example of the sequence cases of sensations following amputation. His sumthrough which phenomena pass, and the order that mary of the effects of amputation was astute: is rendered by a better understanding of its causes. Aristotle described the vertiginous effects of alcohol These sensations are not of an undefined charac(Ross, 1927). Theophrastus described the conditions ter; the pains and tingling are distinctly referred which can induce vertigo, like wine, moving the head to single toes, to the sole of the foot, to the dorin a circle, and looking at moving objects (see Sharples, sum of the foot, to the skin, &c. These important 2003). The Roman poet Lucretius (c. 95–55 BC) comphenomena have been absurdly attributed to the mented on the visual consequences of body rotation. action of the imagination, &c. They have been Ptolemy (c. 150) indicated that vertigo could be caused treated merely as a curiosity; but I have conby visual stimulation and Galen (c. 175) also made vinced myself of their constancy, and of their reference to vertigo caused by observing whirling patcontinuance throughout life, – although patients terns as well as body rotation. These were described become so accustomed to the sensations that in the context of diseases that lead to dizziness. All they cease to remark them. (Mu¨ller, 1840, these effects have been reported repeatedly since anpp. 745–746) tiquity (Wade, 2000, 2002), and occasionally novel The pain associated with phantom limbs lent support to sources of inducing vertigo have been described. theories that restricted pain to peripheral stimulation. Felix Platter (1536–1614) in 1614 and Willis (1672) While the phenomena continue to intrigue and excite heralded the early modern era by suggesting mechanisstudents of the senses (Ramachandran and Blakeslee, tic interpretations for vertigo in terms of motion of the 1998), they have provided the basis for transforming animal spirit in the brain. Willis described the visual theories of pain from peripheral to central sites (Melmotion that continues after body rotation ceases, and zack and Wall, 1965; Melzack, 1992, 2001). The disorthis was attributed to the continued motions of the aniders of sensation can be related to the orderly mal spirit relative to the stationary head. So little was function that has been disrupted. Nonetheless, phanthen known about the functions of the brain that this tom sensations have been reported in individuals with interpretation was long held. Even when the attraction limbs missing from birth, and these provide perplexof the animal spirit was waning, the logic of the explaities for theories based on developmental dimensions nation was retained. In his medical text on vertigo, of perception (Brugger et al., 2000). Herz (1786) modified the interpretation slightly by

SENSORY AND PERCEPTUAL DISORDERS referring to movement of nervous humors in the brain rather than animal spirits, but how these humors moved remained mysterious. Slightly earlier in the 18th century, Boissier de Sauvages (1772) discussed vertigo in his classification of diseases, and described it as an hallucination. He drew parallels with visual persistence when rapidly moving lights are presented, and suggested that the sensitivity of the retina was changed by the retrograde movements of blood in the vessels supplying it. He did discuss the effects of body rotation, and the possibility of unconscious eye movements during and after rotation was entertained. An alternative to speculating on processes in the retina or brain was to study the phenomenon of vertigo itself. Eighteenth-century interest in vertigo was principally medical, and most observations upon it were made in that context. For example, Whytt (1765) included giddiness amongst the symptoms for nervous diseases. The analysis of vertigo can be considered to have entered its modern phase following the experiments of William Charles Wells (1757–1817) in which the nature of post-rotary eye movements was described. He conducted his experiments before the introduction of the rotating chair (Wells, 1792, 1794); it was proposed by Erasmus Darwin (1801) and constructed by Cox (1804) as a treatment of mental disorders (Wade et al., 2005). As in other studies, Wells’ experiments on vertigo were conducted by actively spinning the body about a vertical axis. When body rotation stopped, the visual world appeared to rotate in the opposite direction. His experiments on visual vertigo involved generating afterimages before rotating his body, and then noting how they moved with respect to real images when rotation ceased. He appreciated that afterimages (which he called spectra) could be used as stabilized retinal images, and that they afforded a less subjective index of eye movements. Using afterimages, Wells related the direction of visual vertigo to the orientation of the head during rotation and demonstrated how the eyes moved following rotation: he described fast and slow phases of nystagmus, and provided the first account of discontinuous eye movements in vertigo; he showed that nystagmus could be suppressed by attending to targets, and he described torsional nystagmus. This was achieved by rotating the body with the head tilted backwards, and then stopping the body and observing rotation of a line afterimage when the head was upright (see Wade, 2000, 2002). Erasmus Darwin (1794, 1801) had examined vertigo following body rotation, produced by actively spinning about a vertical axis, but he did not see the significance of his rotating couch to such investigations. Jan Evangelista Purkinje or Purkyne¨ (1787–1869), on the other

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hand, produced vertigo by rotating the body voluntarily, on a roundabout, and in a rotating chair (Purkinje, 1820). He described rotary and post-rotary eye movements, and suggested “visual vertigo is a consequence of the conflict between unconscious involuntary muscular actions and voluntary conscious ones in the opposite direction” (1820, p. 95). In one characteristically heroic experiment, he was rotated for 1 h and then described the visual and somatosensory aftereffects that ensued! Purkinje’s experiments with a rotating chair fueled the interests of others to study visual motion using similar devices. Ernst Mach (1838–1916; 1875; Young et al., 2001) developed his own model of a rotating device for examining the perception of motion. With this device he was able to investigate both visual orientation during tilt and the effects of rotation and he demonstrated that vertigo can be induced by visual stimulation alone. Mach made the explicit connection between Purkinje’s experiments on vertigo and the function of the semicircular canals. On the basis of his spinning experiments, Mach advanced a hydrodynamic theory of vestibular function, as did Joseph Breuer (1842–1925) and Alexander Crum Brown (1838–1922) independently in 1874. Both examined body rotation, but with less sophisticated machinery than Mach’s: Breuer rotated the body actively, and Crum Brown used a revolving stool. Unlike many other independent discoveries these were not a source of dispute regarding priority. The three authors were scrupulous in acknowledging the research of the others. One of the most readily observable consequences of rotation is nystagmus, and it is now used as a clinical index of vestibular function. Robert Ba´ra´ny (1876– 1936) modified the rotating chair, and it is now called the Ba´ra´ny chair. In addition to examining nystagmus following rotation in the chair, Ba´ra´ny induced spinning sensations by irrigating the ear with warm and cold water. The procedure was known about and had been applied for many years; Friedrich Goltz (1834–1902; 1870) referred to it as common knowledge. This is now called caloric stimulation and it is a standard clinical test for vestibular function. Ba´ra´ny’s major contribution was to integrate the experiments of Goltz, Mach, Breuer and Crum Brown with clinical studies of Prosper Me´nie`re (1799–1862). Me´nie`re (1861) had linked experiments involving lesions to the semicircular canals with clinical cases of disorientation and dizziness, and the condition became known as Me´nie`re’s disease. The human centrifuge, in the form similar to that described by Erasmus Darwin, has provided the foundation on which much vestibular research has progressed, particularly with regard to space flight (White, 1964). Problems associated with spatial disorientation during flight remain a major concern, and both

496 N.J. WADE the centrifuge and the Ba´ra´ny chair continue to be DEVELOPMENTAL DISORDERS employed in efforts to reduce sensitivity to vestibular Descriptions at the phenomenological level have resulted stimulation. in the appreciation of some perceptual disorders. The movement set in train by Darwin and Cox has Whereas binocular vision was accepted as natural and taken some unexpected turns and some of the consenot subjected to theoretical scrutiny until the 19th cenquences of the original “spin doctors” are truly spinetury, its absence was reported upon in antiquity. It was chilling. As early as 1810, William Hallaran (c. 1765– initially based on the binocular double vision (diplopia) 1825) observed that the rotating chair could provide that accompanies passively pressing on one eye and also amusement as well as treatment. The legacy of these in the deviations in alignment of the eyes in some indispinning machines can be found in funfairs and theme viduals. Aristotle described the former and also parks throughout the world, and sensations of spinning remarked on the latter, which was called strabismus. are now sought rather than prescribed. Many fairMany of the statements about diplopia are reflecground attractions involve abnormal patterns of tions of the breakdown of binocular single vision. This motion, both vestibular and visual. Some devices prowas the case for Aristotle’s description of one of the duce complex paths of body motion, so that the vestibmost common ways of inducing double vision – by ular system is exposed to patterns of accelerations and gently pushing one eye with the finger: “if a finger decelerations that would never occur with self-motion. be inserted beneath the eyeball without being observed, Swings and roundabouts have provided sources of one object will not only present two visual images, but pleasure for children for centuries. will create an opinion of its being two objects” (see We associate disorders of perception with mental Ross, 1931, pp. 461b–462a). The involvement of eye disturbances, but we do not often think of stimulation movements was stressed by Ptolemy, who suggested of the senses as a treatment for insanity. Physicians in a functional advantage of double vision, namely to mental institutions used spinning chairs after Cox bring the two eyes into register with regard to the introduced one in 1804 (Wade et al., 2005). The one objects under inspection (Lejeune, 1956; Smith, 1996). employed by Hallaran (1818) is shown in Fig. 32.2. InitiScheiner (1619) noted that double vision often accompaally modest and later extravagant claims for the theranied drunkenness, but that it was restricted to horizontal peutic benefits of spinning were made by some rather than vertical misalignments, assuming an upright physicians. It was widely adopted in Europe in the first head: “Why do drunkards, and sober persons if they decades of the 19th century, but lost favor thereafter. have unusually enlarged eyes, see single things double, Its benefits have proved to be scientific rather than but only in breadth and not in height?” (Scheiner, medical, because it was used by students of the senses 1619, p. 241). Double vision had been examined with to investigate vertigo and led to a better understanding horizontal board by both Ptolemy and Alhazen (Sabra, of vestibular function. A century later it re-emerged as 1989), but it was given theoretical significance by the Ba´ra´ny chair for the clinical assessment of labyrAguilonius (1613) who defined the horopter as the froninthine function. Another legacy of spinning chairs is toparallel plane in which objects appear single, for a to be found in funfairs throughout the world. Two given convergence of the eyes. hundred years after the invention of Cox’s chair as a One way of examining binocular function is to comform of treatment for mental patients it can be thought pare vision with one eye or two. Despite the fact that of as a precursor of the numerous complex devices perceptual experience changes little when one eye is which can be found in theme parks around the world. closed, it does change, and the study of the differences Vertigo provides a good example of the develophas a long history. Contrary to the evidence accumument of a reasonably good phenomenology in the lated since the late-17th century, it was long believed absence of an adequate link to its physiological underthat vision with one eye was superior to that with pinnings. Although the anatomical structure of the vestwo. Aristotle took this to be self-evident, interpreting tibular system had been known since at least the 16th it in terms of eye movement control. The source of century, its function remained mysterious. Because of much subsequent comparison was driven by the Galeits proximity to the cochlear, it was thought to be nic theory of visual spirits: it was transmitted to one involved in hearing, serving to assist in auditory localior two eyes, and thus was more concentrated in mozation. It was only after the lesion studies of Pierre nocular viewing. Many statements were made about Flourens (1794–1867) in 1824, the clinical investigations tasks that were more difficult to perform with one of Me´nie`re, and the experimental studies of Mach, eye rather than two, or stimuli that were more difficult Breuer and Crum Brown that its sensory function in to see. Leonardo’s often quoted comparison between terms of detecting linear and angular accelerations viewing a painting of a scene and the scene itself was was appreciated (Wade and Tatler, 2005).

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Fig. 32.2. A rotating chair and bed for the treatment of mania (derived from Hallaran, 1818).

an implicit contrast between vision with one eye or two (Wade et al., 2001). It is most instructive because the concept of relief or depth is taken to be the distinguishing characteristic of binocular vision. Many investigators directed attention to tasks that could be performed better with two eyes (Wade, 1987), although they seemed reluctant to speculate on the reasons for this. Porterfield (1759) was more forthcoming: apparent size was determined by retinal size and appar-

ent distance, and judgments of the latter were degraded with monocular observation. Wheatstone (1838), with his knowledge of binocular depth perception, enquired why more errors are not made in monocular viewing. His answer was that many cues for depth and distance exist, and that alternatives are used when one source is not available. Most particularly, he proposed that motion of the head (motion parallax) was a potent substitute for retinal disparity (Ono and Wade, 2005).

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Fig. 32.3. Masks for correcting for strabismus as illustrated in Bartisch (1583).

Distortion of the eyes (strabismus) was recorded in the Ebers Papyrus, but its reported association with problems of binocular vision is more recent (Duke-Elder and Wybar, 1973; von Noorden, 1996). Aristotle described the ensuing diplopia, and Galen noted that the deviations of the eyes were always nasal or temporal; however, he did also state that strabismics rarely make errors in object recognition. Corrections for the deviation were advocated by several physicians, including Pare´ (1575). The most elaborate masks were prescribed by Bartisch (1583; Fig. 32.3), who appreciated that strabismus was more amenable to correction in children than in adults. Others sought to strengthen the weak eye by exercise or suggested patching the stronger eye. From the 18th century, attention was directed to the manner in which strabismics saw objects singly (Wade, 1998). There were those who believed that the nondeviating eye suppressed the signals from the deviating one. This was so despite the opposite being maintained by the strabismics themselves. The suppression could be a consequence of muscular misalignment or a refractive difference between the eyes. Others considered that the new pattern of stimulation could be learned (by association) to yield singleness of vision. Accordingly, nature and nurture could vie to determine why the eyes were awry. There were also descriptions of cases of alternating dominance, and the distinction between converging and diverging strabismus was made explicit. Studies of strabismus epitomize the emphasis that has been placed on binocular single vision; the many comparisons that were made between strabismic and binocular individuals dwelt on this to the exclusion of other aspects of binocular vision, like stereoscopic depth perception.

CONCLUSIONS Imposing some order on the senses was a long but necessary precursor to examining their disorders. Once the order was established then a range of fascinating phenomena came to light (particularly in vision) like blindsight, agnosias, optic ataxia, spatial neglect and migraine auras. Others that had long been known, like abnormalities of binocular and color vision, became open to more detailed scrutiny.

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Piccolino M (2000). The bicentennial of the Voltaic battery (1800–2000): the artificial electric organ. Trends Neurosci 23: 147–151. Piccolino M (2003). The Taming of the Ray. Electric Fish Research in the Enlightenment from John Walsh to Alessandro Volta. Olschki, Florence. Piccolino M, Bresadola M (2003). Rane, Torpedini e Scintille. Galvani, Volta e l’Elettricita` Animale. Bollati Boringhieri, Turin. Platter F (1614). Observationum. Waldkirch, Basel. Porterfield W (1759). A Treatise on the Eye, the Manner and Phænomena of Vision. Vol. 1. Hamilton and Balfour, Edinburgh. Price DB, Twombly SJ (1978). The Phantom Limb Phenomenon: A Medical, Folkloric, and Historical Study. Texts and Translations. Georgetown University Press, Washington, DC. Purkinje J (1820). Beitra¨ge zur na¨heren Kenntniss des Schwindels aus hautognostischen Daten. Medicinische ¨ esterreichischen Jahrbu¨cher des Kaiserlich-Ko¨niglichen O Staates 6: 79–125. Purkinje J (1825). Beobachtungen und Versuche zur Physiologie der Sinne. Neue Beitra¨ge zur Kenntniss des Sehens in subjectiver Hinsicht. Reimer, Berlin. Ramachandran VS, Blakeslee S (1998). Phantoms in the Brain. Fourth Estate, London. Ross WD (Ed.) (1927). The Works of Aristotle. Vol. 7. Clarendon Press, Oxford. Ross WD (Ed.) (1931). The Works of Aristotle. Vol. 3. Clarendon Press, Oxford. Sabra AI (Trans./Ed.) (1989). The Optics of Ibn Al-Haytham. Books I–III. On Direct Vision. The Warburg Institute, London. Scheiner C (1619). Oculus, Hoc Est Fundamentum Opticum. Agricola, Innsbruck. Sharples RW (2003). On dizziness. In: WW Fortenbaugh, RW Sharples, MG Sollenberger (Eds.) Theophrastus of Eresus on Sweat, on Dizziness, and on Fatigue. Brill, Leiden, pp. 169–250. Smith AM (1996). Ptolemy’s Theory of Visual Perception: An English Translation of the Optics with Introduction and Commentary. The American Philosophical Society, Philadelphia, PA. Stratton GM (1917). Theophrastus and the Greek Physiological Psychology before Aristotle. Macmillan, New York. Volta A (1800). On the electricity excited by the mere contact of conducting substances of different species. Philos Trans R Soc 90: 403–431. von Noorden GK (1996). Binocular Vision and Ocular Motility. 5th edn. Mosby, St. Louis, MO. Wade NJ (1987). On the late invention of the stereoscope. Perception 16: 785–818. Wade NJ (1998). A Natural History of Vision. MIT Press, Cambridge, MA. Wade NJ (2000). William Charles Wells (1757–1817) and vestibular research before Purkinje and Flourens. J Vestib Res 10: 127–137.

Wade NJ (2002). Destined for Distinguished Oblivion: The Scientific Vision of William Charles Wells (1757– 1817). Kluwer/Plenum, New York. Wade NJ (2003a). The search for a sixth sense: the cases for vestibular, muscle, and temperature senses. J Hist Neurosci 12: 175–202. Wade NJ (2003b). The legacy of phantom limbs. Perception 32: 517–524. Wade NJ (2005). Perception and Illusion: Historical Perspectives. Springer, New York. Wade NJ, Brozˇek J (2001). Purkinje’s Vision. The Dawning of Neuroscience. Lawrence Erlbaum Associates, Mahwah, NJ. Wade NJ, Finger S (2003). William Porterfield (ca. 1696– 1771) and his phantom limb: an overlooked first selfreport by a man of medicine. Neurosurg 52: 1196–1199. Wade NJ, Tatler BW (2005). The Moving Tablet of the Eye: The Origins of Modern Eye Movement Research. Oxford University Press, Oxford. Wade NJ, Verstraten FAJ (1998). Introduction and historical overview. In: G Mather, F Verstraten, S Anstis (Eds.), The Motion After-Effect: A Modern Perspective. MIT Press, Cambridge, MA, pp. 1–23. Wade NJ, Ono H, Lillakas L (2001). Leonardo da Vinci’s struggles with representations of reality. Leonardo 34: 231–235. Wade NJ, Norrsell U, Presly A (2005). Cox’s chair: “A moral and a medical mean in the treatment of maniacs.” Hist Psychiatry 16: 73–88. Wells WC (1792). An Essay upon Single Vision with Two Eyes: Together with Experiments and Observations on Several Other Subjects in Optics. Cadell, London. Wells WC (1794). Reply to Dr. Darwin on vision. The Gentleman’s Magazine and Historical Chronicle 64: 794–797, 905–907. Wheatstone C (1838). Contributions to the physiology of vision – Part the first. On some remarkable, and hitherto unobserved, phenomena of binocular vision. Philos Trans R Soc 128: 371–394. White WJ (1964). A History of the Centrifuge in Aerospace Medicine. Douglas Aircraft Company, Santa Monica, CA. Whytt R (1765). Observations on the Nature, Causes, and Cure of those Disorders which have Commonly been called Nervous Hypochondriac, or Hysteric. Becket, Du Hondt, and Balfour, Edinburgh. Willis T (1664). Cerebri Anatome: Cui accessit Nervorum Descriptio et Usus. Martyn and Allestry, London. Willis T (1672). De Anima Brutorum. Wells & Scott, London. Young LR, Henn V, Scherberger H (2001). Fundamentals of the Theory of Movement Perception by Dr. Ernst Mach. Kluwer/Plenum, New York. Young T (1802). On the theory of lights and colours. Philos Trans R Soc 92: 12–48. Young T (1807). A Course of Lectures on Natural Philosophy and the Mechanical Arts. Johnson, London. (Reprinted by Thoemmes Press, Bristol, 2002.)

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 33

The history of movement disorders DOUGLAS J. LANSKA * Department of Neurology, Veterans Affairs Medical Center, Tomah, WI, USA

THE BASAL GANGLIA AND DISORDERS OF MOVEMENT Distinction between cortex, white matter, and subcortical nuclei The distinction between cortex, white matter, and subcortical nuclei was appreciated by Andreas Vesalius (1514–1564) and Francesco Piccolomini (1520–1604) in the 16th century (Vesalius, 1542; Piccolomini, 1630; Goetz et al., 2001a), and a century later British physician Thomas Willis (1621–1675) implicated the corpus striatum in motor function: “When I opened a number of cadavers of patients who had died from a long paralysis . . . I always found the striate bodies more softened than any other part; also discolored like the dregs in an olive press, and the striae much obliterated” (Willis, 1664, as cited in Schiller, 1967, p. 526). Later Willis elaborated: “[When] the Animal Spirits . . . direct themselves thence into the Corpora Striata, and origins of the Nerves, they actuate all the moving parts, and as often as there is occasion, convey to them the Instincts of setting upon motions” (Willis, 1685, p. 413). Willis’ concept that the corpus striatum is the seat of motor power was pre-eminent for approximately 200 years, and this misconception later formed the basis of mid-19th-century localizations of several movement disorders to the striatum. Thus, for example, striatal dysfunction was implicated in chorea by British physician William Broadbent (1835–1907) (Broadbent, 1869) and British neurologist John Hughlings Jackson (1835–1911) (Jackson, 1868/1996, p. 238), and in athetosis by American neurologist William Hammond (1828–1900) (Hammond, 1871) – localizations that would prove essentially correct, though somewhat serendipitously. It was only with electrophysiologic stimulation studies by German physiologists Gustav Fritsch (1838–1927)

*

and Eduard Hitzig (1838–1907) on the cerebral cortex of dogs (Fritsch and Hitzig, 1870/1960), the stimulation and ablation experiments on rabbits, cats, dogs and primates by British physiologist David Ferrier (1843–1928) beginning in 1873 (Ferrier, 1876), and the careful clinical and clinical-pathologic studies in people by Jackson in the late 1860s and early 1870s, that the role of the motor cortex was appreciated, so that by 1876 Jackson could consider the “motor centers in Hitzig and Ferrier’s region . . . higher in degree of evolution than the corpus striatum” (Jackson, 1876/1996, vol. 1, pp. 150–151). By the late 19th century a number of movement disorders were fairly well described clinically, including several forms of tremor, Parkinson’s disease, Sydenham’s chorea, Huntington’s chorea, post-hemiplegic choreoathetosis, several forms of dystonia (including writer’s cramp, torticollis, and dystonia musculorum deformans), and Gilles de la Tourette’s syndrome. These disorders were puzzling, though, because in most cases pathologic studies had yet to identify a clear pathologic correlate of the clinical disease. In 1888, in his classic text, A Manual of Diseases of the Nervous System, British neurologist William Gowers (1845–1915) was not sure how to classify such movement disorders and lumped them under “general and functional diseases of the nervous system,” noting that in general there were no constant changes to be seen [in the brain] with the naked eye . . . but microscopical changes have been discovered in some of them with sufficient frequency to make it certain that there is far more than a mere disturbance of function, and it cannot be doubted that most of these maladies depend upon alteration in the nutrition of the nerve-elements, although these may not yet have been

Correspondence to: Douglas J. Lanska MD, Staff Neurologist, VA Medical Center, 500 E Veterans St., Tomah, WI 54660, USA. E-mail: [email protected], Tel: +1-608-372-1772, Fax: +1-608-372-1240.

502 D.J. LANSKA found, and perhaps cannot be detected without felt to represent “a re-entrant pathway through which more means of investigation than we at present influences emanating from specific areas of cortex are possess. (Gowers, 1888, p. 546) returned to certain of those same areas after intermediate processing within the basal ganglia and thalamus” Seventy years later, Canadian neurologist Andre´ (DeLong, 1990, p. 281). Cortical and nigral projections Barbeau (1931–1986) noted progress and offered hope, (i.e., input) to the basal ganglia motor circuit terminate but was frustrated with the limited understanding of primarily in the putamen, whereas motor output from etiology and pathophysiology as well as the inadequathe basal ganglia is directed primarily from the internal cies of available treatments for movement disorders: segment of the globus pallidus to the thalamus (ventral But what of the results? Many are improved that tier and mediodorsal nuclei) and to the substantia nigra a few years ago would have been miserable, pars reticulata in the brainstem. Within the basal ganglia many are permitted a more active life and are are two important projection systems: a “direct pathway” forever grateful . . . but none are cured! The from the putamen directly to the motor portions of the cause and exact pathology of the various disinternal segment of the globus pallidus and the pars retieases grouped under the extra pyramidal system culata of the substantia nigra; and an “indirect pathway” remain mysteries almost as deep as in the passing from the putamen through intermediate nuclei days of Sydenham and Parkinson. Many clinical (i.e., sequentially the external segment of the globus pallivarieties have been observed, many pathological dus and then the subthalamic nucleus) before being direcstudies carried out, but the suffering humanity ted to the basal ganglia output nuclei (i.e., the internal still goes on twisting, shaking, writhing, jumping segment of the globus pallidus). and jerking when it does not want to. (Barbeau, DeLong (1990, p. 281) and others proposed that “the 1958, pp. 486–487) direct pathway effectively provides positive feedback to the precentral motor fields, . . . [whereas] activity conducted along the indirect pathway appears to provide Models of basal ganglia function negative feedback to the precentral motor fields . . . Dramatic and rapid progress is now being made in Thus, in general it appears that enhanced conduction understanding how the basal ganglia function to through the indirect pathway leads to hypokinesia (by influence movement; how various structural, neuroincreasing pallidothalamic inhibition), whereas reduced chemical, and other derangements of basal ganglia conduction through the direct pathway results in hypercircuits produce different movement disorders; and kinesias (by reduction of pallidothalamic inhibition).” In how pharmacological and surgical treatments act to a later synthesis, Wichmann and DeLong (1998, p. 225) correct or improve some of the features of movement concluded that, “In general, hypokinetic disorders such disorders. In particular, since the late 1980s a series of as Parkinson’s disease are associated with increased increasingly sophisticated conceptual models of basal basal ganglia output, whereas hyperkinetic movement ganglia function (e.g., Alexander and DeLong, 1986; disorders such as Huntington’s disease are associated Albin et al., 1989a; Bergman et al., 1990; DeLong, with decreased output.” 1990; Wichmann and DeLong, 1998; Mink, 2003), Even the modelers themselves soon recognized that, supported and guided by experiments with animal models while helpful, “these models are only a first draft of of disease and by clinical experience with human patients basal ganglia function under normal and diseased con(e.g., Smith and Parent, 1988; Albin et al., 1989a; Bergman ditions” (Wichmann and DeLong, 1998, p. 232), with et al., 1990, 1994), have provided sufficient insight into significant residual discrepancies and inadequacies that disease mechanisms to guide the development of novel await resolution (Wichmann and DeLong, 1998; Obeso pharmacological and surgical therapies, particularly et al., 2000). For example, these models essentially pallidotomy and deep brain stimulation for Parkinson’s considered all hyperkinetic movement disorders to disease, but also somewhat for other forms of movement result from a reduction of inhibitory basal ganglia outdisorders. They have also served to guide research efforts put, particularly to the thalamus, and as such were with animal models or with human subjects (with sophistiunable to explain adequately how different forms of cated neuroimaging or during surgery) that have helped hyperkinetic movements occur (Mink, 2003). These to elaborate or correct portions of these models. models also left many other observations unexplained, These models of basal ganglia function initially including the lack of dyskinesias after pallidotomy, focused particularly on the balance of firing rates (rather lack of parkinsonism after thalamotomy, failure of than temporal or spatial pattern of firing) in various basal lesions of the external segment of the globus pallidus ganglia nuclei or projection systems. By 1990, the motor to abolish drug-induced dyskinesias (Wichmann and portion of the basal ganglia-thalamocortical circuits was DeLong, 1998), and failure to explain why different

THE HISTORY OF MOVEMENT DISORDERS clinical features of movement disorders (e.g., tremor, rigidity, bradykinesia, gait dysfunction, and postural instability in Parkinson’s disease) present to different degrees in some patients or respond differently to pharmacological or surgical procedures (Obeso et al., 2000). More complex models that address some of the earlier model deficiencies have subsequently been proposed (Mink, 2003), but remain largely untested and have had limited application to treatment.

TREMOR Distinction of rest and action tremors In the 2nd century, Galen (c. 130–200 AD) used the term tremor to refer to “involuntary alternating up-and-down motion of the limbs,” occurring during action and resulting from partial “weakness of the force that supports and moves the body” (Sider and McVaugh, 1979; Koehler and Keyser, 1997). Galen distinguished tremor from palpitation, an “unnatural expansion and collapse” occurring at rest (Sider and McVaugh, 1979; Koehler and Keyser, 1997). Later, in the 17th and 18th centuries, Franciscus de la Boe¨ (Sylvius; 1614–1672), Gerard van Swieten (1700– 1772), and others further distinguished involuntary movements during action and at rest (de la Boe¨, 1663; MolinaNegro and Hardy, 1975; Koehler and Keyser, 1997).

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British physician James Parkinson (1755–1824) provided the first clear clinical description of a specific rest tremor in his treatise on the “shaking palsy” in 1817 (Parkinson, 1817). His report received some, albeit limited, recognition (Schiller, 1986; Keppel Hesselink, 1996; Louis, 1997) until later in the 19th century, when French neurologist Jean-Martin Charcot (1825–1893) labeled the condition “Parkinson’s disease,” and distinguished the tremor of Parkinson’s disease from the kinetic “intentional” (intention) tremor seen in multiple sclerosis (Charcot and Vulpian, 1861; Charcot, 1877, 1887/1987, 1889; Goetz, 1986; Schiller, 1986; Goetz et al., 1995, 2001b, c; Keppel Hesselink, 1996; Lanska, 2000a). Charcot noted that in patients with multiple sclerosis tremor is not present at rest, but only with activity, and that the tremor amplitude increases with effort. In contrast, the tremor of Parkinson’s disease is present both at rest and during activity, and the amplitude does not increase with action (Fig. 33.1). The characteristics of different rest and action tremors were more fully elaborated in the late-19th and 20th centuries by a number of authors using more sophisticated recording devices and other technologies (Fig. 33.2) (Lanska, 2000a). Although overlapping tremor frequencies for different types of tremor precluded tremor recording devices from becoming a definitive

Fig. 33.1. Charcot’s semi-diagrammatic graphic representations of tremor based on tracings (Charcot, 1887, 1889): “No. 1 [top curve] represents the intentional tremor of disseminated sclerosis (i.e., multiple sclerosis). The line AB indicates the state of repose. The point B represents the moment of commencing the voluntary movement; BC represents the duration of the movement, and the trembling is represented by the wavy line xyz, of which each oscillation is larger the farther we get from B . . . No. 2 in the figure represents the tremors of paralysis agitans (i.e., Parkinson’s disease). You see at once on looking at this diagram how the two tracings differ in the portion BC. The segment under the line AB represents the time of repose. It is cut up by little waves corresponding to the continuous trembling. At point B voluntary movement commences. From this point the components of the wavy line xyz are a little longer and more irregular than in the period of repose, but they are never so much so as in disseminated sclerosis” (Charcot, 1889). Charcot’s graphical recording method, upon which this diagram was based, is not described, but in other circumstances he relied on various pneumatic tambour-like mechanisms (Charcot, 1889).

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B

A

C

Fig. 33.2. American physician Augustus Eschner used a tambour recording apparatus for some studies, including those requiring “simultaneous observations of the two sides of the body or of two or more different parts” (A) (Eschner, 1897). For example (B), the use of two tambours allowed simultaneous recording from both hands in a patient with Parkinson’s disease (upper curve is the left hand, lower curve is the right hand, and middle line marks time in seconds); the tracings demonstrate a synchronous tremor in the two hands at about 5.5 hertz. Eschner was also able to demonstrate (C) suppression of a rest tremor with action (i.e., finger extension) in a patient with Parkinson’s disease (left portion of the tracing shows a tremor at rest and the far right portion without tremor is during action). Prior to action, the tremor had a frequency of approximately 4.7 hertz. The tracings in B and C are the negatives of the originals made on smoked paper.

diagnostic tool, graphical recordings did allow 19thcentury investigators to demonstrate: (1) tremor frequency varies as a function of weight and elastic properties in different body parts; (2) tremor amplitude and frequency are inversely related; and (3) the tremor of Parkinson’s disease is a relatively low frequency rest tremor, suppressed by action, and generally synchronous in symmetric body parts, but varying in amplitude and frequency over time (Eschner, 1897; Lanska, 2000a; Lanska et al., 2001a).

Physiologic tremor As early as 1610, Italian physicist and astronomer Galileo Galilei (1564–1642) recognized that cardioballistic and respiratory movements contributed to the shaking of the magnified image in a hand-held telescope: “. . . the instrument must be held firm, and hence it is good, to escape the shaking of the hand that arises from motion in the arteries and from breathing, to fix the tube in some stable place . . .” (Galilei, 1610/1978, p. 147). In 1897, American physician Augustus Eschner (1862–1949) offered several ways of demonstrating physiologic tremor in healthy individuals, including holding a glass of water and viewing the surface, or using a mechanical recording apparatus. Eschner (1897, p. 306) noted that: “[Small amplitude

physiologic tremors should be expected] . . . as every muscular movement is made up of a series of alternate contractions and relaxations, occurring ordinarily with such frequency as to escape detection with the unaided eye.” Eschner considered uneven integration of individual muscle twitches to be the basis of physiologic tremor, but he ignored other possible components, including rhythmic bursts of discharges from central generators, oscillatory feedback systems, resonant properties of the moving parts, postural adjustments, and cardioballistic and respiratory movements (Lanska, 2000a).

Essential tremor In the late-19th century, physicians began to recognize familial forms of postural action tremors. In 1887, American neurologist Charles Dana (1852–1935) described a familial postural tremor: The affection in question consists of a fine tremor, constantly present in typical cases during waking hours, voluntarily controlled for a brief time, affecting nearly all the voluntary muscles, chronic, beginning at very early life, not progressive, not shortening life, not accompanied with paralysis or any other disturbances of

THE HISTORY OF MOVEMENT DISORDERS nervous function . . . It begins in infancy or childhood, sometimes being brought out by an infectious fever . . . The upper extremities are most noticeably affected, but it may involve the head, neck, eye, laryngeal, or, in fine, any of the voluntary muscles. It ceases during sleep, and can be inhibited temporarily by the will. Everything that produces excitement or nervousness increases the tremor. It may be barely noticeable, except under some excitement, or the influence of alcohol or tobacco. It does not interfere with delicate coordination. It neither stops nor increases on ordinary voluntary movements. (Dana, 1887, pp. 386–387, 392) Although Dana’s description of familial tremor has generally been accepted as an early description of hereditary essential tremor, the condition (1) reportedly increased under the influence of alcohol; (2) did not interfere with fine manual tasks; and (3) was not likely hereditary given the large reported pedigree, with almost all individuals affected (e.g., with 41 of 42 individuals in two successive generations affected, and with the sole exception an obligate carrier under an autosomal dominant mode of hereditary transmission) (Lanska, 2002a). There was considerable interest in hereditary neurologic disorders in the late-19th century, especially following Friedreich’s (1863) work on hereditary ataxia, and Huntington’s (1872) report of hereditary chorea. Yet there was no understanding at this time of Mendelian genetics, and most investigators considered any familial disorder as “hereditary.” Hereditary conditions were not understood in anything resembling the modern sense until Mendel’s laws were simultaneously rediscovered and made known by De Vries, Correns, and Tschermak von Seyenegg in 1900 (Mendel, 1865; Correns, 1900; De Vries, 1900; Tschermak von Seysenegg, 1900). Multigenerational familial tremors having characteristics of autosomal dominant transmission were recognized in the early-20th century (e.g., Mitchell, 1903; Critchley, 1949), but clear recognition of autosomal dominant transmission of essential tremor did not occur until the middle of the 20th century (Critchley, 1949; Davis and Kunkle, 1951; Jager and King, 1955; Larsson and Sjo¨gren, 1960). Since the late 1990s, essential tremor loci have been identified on several chromosomes: 3q13 (familial essential tremor 1), 2p24.1 (familial essential tremor 2), and 6p23. However, some pedigrees consistent with autosomal dominant essential tremor have excluded known genetic loci as a cause, supporting genetic heterogeneity (Ma et al., 2006). Twin studies and segregation analysis have further suggested that essential tremor may require interaction

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of environmental and genetic factors (Louis, 2001; Ma et al., 2006). British neurologist MacDonald Critchley (1900–1997) noted that “Some patients find that a heavy dose of spirits will temporarily check the tremor and this factor has appeared only too often to have served as an excuse for habits of intemperance” (Critchley, 1949, pp. 117–118). Davis and Kunkle (1951, p. 815) similarly reported, “Treatment with Phenobarbital apparently offers some symptomatic benefit, but this may be largely nonspecific, i.e., without altering the basic mechanism of the tremor. Although alcohol has been found beneficial by some patients, its prescribed use is unwarranted, for this may lead to excessive drinking.” Beneficial effects of propranolol were documented in the 1970s (Dupont et al., 1973; Winkler and Young, 1974) and the utility of primidone was documented in the 1980s (O’Brien et al., 1981; Findley et al., 1985). These two medications remain the best available drugs (Zesiewicz et al., 2005), but surgery is increasingly recognized as efficacious for tremor refractory to drug therapy (Hassler and Riechert, 1954). Thalamotomy is associated with significant potential complications, particularly if performed bilaterally (Goldman et al., 1992; Shahzadi et al., 1995; Jankovic et al., 1995), so thalamic stimulation has been increasingly used (Limousin et al., 1999; Pahwa et al., 1999; Schuurman et al., 2000).

PARKINSON’S DISEASE Parkinson’s disease is of fundamental importance to the history of movement disorders, because of its common occurrence, the dramatic progress that has been made in understanding and treating the condition, and the insights this progress has provided for understanding the anatomy and function of the basal ganglia.

Clinical description The first clear clinical description of Parkinson’s disease was the monograph titled An Essay on the Shaking Palsy by British general practitioner James Parkinson in 1817 (Parkinson, 1817). Parkinson gave a short account of six subjects, some of whom he had never examined, but only saw on the neighborhood streets or when making his medical rounds. He noted the tremulous involuntary shaking at rest, the asymmetric onset, the slowed movements, the flexed posture, and the festinating gait: Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace: the senses and intellects being unimpaired . . . The

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first symptoms perceived are, a slight sense of weakness, with a proneness to trembling in some particular part; sometimes in the head, but most commonly in one of the hands and arms . . . [As] the malady proceeds . . . [the] propensity to lean forward becomes invincible, and the patient is thereby forced to step on the toes and fore part of the feet, whilst the upper part of the body is thrown so far forward as to render it difficult to avoid falling on the face. In some cases, when this state of the malady is attained, the patient . . . [is] irresistibly impelled to take much quicker and shorter steps, and thereby to adopt unwillingly a running pace . . . The power of conveying the food to the mouth is at length so much impeded that he is obliged to consent to be fed by others . . . As the disease proceeds towards its last stage, the trunk is almost permanently bowed, the muscular power is more decidedly diminished, and the tremulous agitation becomes violent. The patient walks now with great difficulty, and unable any longer to support himself with his stick, he dares not venture on this exercise, unless assisted by an attendant . . . His words are now scarcely intelligible; and he is not only no longer able to feed himself, . . . the food is with difficulty retained in the mouth until masticated; and then as difficultly swallowed. Now also . . . another very unpleasant circumstance occurs: the saliva fails of being directed to the back part of the fauces, and hence is continually draining from the mouth . . . As the debility increases and the influence of the will over the muscles fades away, the tremulous agitation becomes more vehement . . . The chin is almost immoveably bent down upon the sternum. The slops with which he is attempted to be fed, with the saliva, are continually trickling from the mouth. The power of articulation is lost . . . [At] the last, constant sleepiness, with slight delirium, and other marks of extreme exhaustion, announce the wished-for release. (Parkinson, 1817, pp. 1–9) In his classroom lectures at the Salp^etriere over 50 years later, Jean-Martin Charcot lauded Parkinson’s clear and succinct clinical descriptions and suggested the eponym of “Parkinson’s disease.” Charcot rejected the earlier designation of “paralysis agitans,” correctly noting that Parkinson’s disease patients are not particularly weak and do not necessarily have tremor (Charcot and Vulpian, 1861; Charcot, 1877; Goetz, 1986; Schiller, 1986; Goetz et al., 1995, 2001b; Keppel Hesselink, 1996). Charcot distinguished bradykinesia as

a cardinal feature of the illness, separate from rigidity. Charcot and his students described the clinical spectrum of this disease, noting both tremorous and rigid/akinetic forms. Charcot believed strongly that Parkinson’s disease patients have no head tremor, and that any apparent tremor is a secondary oscillation resulting from trunk or extremity tremors. He demonstrated this with the use of a simple device: a head band to which was attached a long rod with a feather at the end; when patients with Parkinson’s disease sat or stood, the feather oscillated prominently, but if the trunk or arm was supported or moved, the head tremor immediately ceased. One of the best 19th-century descriptions of Parkinson’s disease was given by Gowers (1888) (Fig. 33.3), although he incorrectly reported weakness as a feature of the disease: The aspect of the patient is very characteristic. The head is bent forward, and the expression of the face is anxious and fixed, unchanged by any play of emotion. The arms are slightly flexed at all joints from muscular rigidity, and (the hands especially) are in constant rhythmical movement, which continues when the limbs are at rest so far as the will is concerned. The tremor is usually more marked on one side than the other. Voluntary movements are performed

Fig. 33.3. In 1888, British neurologist William Gowers published one of the best neurology textbooks of the 19th century, a two-volume textbook titled A Manual of Diseases of the Nervous System. Among the many excellent illustrations and meticulous and vivid descriptions were those concerning the clinical features of paralysis agitans (Parkinson’s disease).

THE HISTORY OF MOVEMENT DISORDERS slowly and with little power. The patient often walks with short quick steps, leaning forward as if about to run . . . The tremor is an alternating contraction in opposing muscles, causing a rhythmical movement of the parts to which they are attached. It is usually greatest in the hands and fingers, partly from the contraction of the forearm-muscles, partly from that in the interossei; the latter causes a movement of the fingers at the metacarpo-phalangeal joints similar to that by which Orientals beat their small drums. This movement may be chiefly in the thumb and forefinger, which may move as in the act of rolling a small object between their tips . . . Usually the head is free from tremor except such as may be communicated to it from the distant oscillation. It does not, however, always escape, as some [e.g., Charcot] have asserted . . . The great characteristic of the tremor of paralysis agitans is, as Parkinson pointed out, that it continues during rest. The hands go on moving when they are resting on the patient’s knee, and the legs when he is sitting. A voluntary movement may stop the tremor for a few seconds, sometimes for many, but it recommences and accompanies the movement . . . The loss of power varies much in degree. At first slight, it gradually increases, and is usually greatest in the part in which the tremor developed first and most. The patient may ultimately be unable even to move the index of the dynamometer, or to rise from his seat. But the paralysis is never absolute, – some power always persists. Voluntary movement is not only feeble; it is also slow . . . This seems to be, in part at least, the result of muscular rigidity, which causes a resistance to passive movement. Another effect of the rigidity is to impress certain characteristic postures on the limbs. These are determined by the fact that the rigidity preponderates in certain muscles, chiefly the flexors. The arms are flexed at the elbow-joints, sometimes slightly, sometimes almost at a right angle. The wrists are usually slightly extended. The position of the fingers varies . . . often they are flexed at the metacarpo-phalangeal joints and extended at the others, from preponderant contraction of the interossei . . . (Gowers, 1888, pp. 591–597)

Pathology In 1893, Blocq and Marinescu reported a 38-year-old woman with hemiparetic parkinsonism who was found at autopsy to have a tuberculoma of the right cerebral

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peduncle that had destroyed the substantia nigra (Blocq and Marinescu, 1893). Brissaud (1895) relied heavily on this case when suggesting that the substantia nigra might be the site of the lesion in Parkinson’s disease. In 1912 and 1913, Freiderich (or Fritz or later Frederic) Lewy (later spelled Lewey; 1885–1950) described serpentine or elongated eosinophilic intracytoplasmic Kugeln (i.e., “balls”) in the dorsal motor nucleus of the vagus nerve and in the substantia innominata of patients with Parkinson’s disease (Lewy, 1913; Sweeney et al., 1997; Schiller, 2000; Holdorff, 2002). In 1919, Tre´tiakoff first described the presence of these corps de Lewy (i.e., “Lewy bodies”), as he referred to them, in the substantia nigra, and proposed that they represented a pathology specific to Parkinson’s disease (Tre´tiakoff, 1919, 1921). Tre´tiakoff studied the substantia nigra in nine cases of Parkinson’s disease, one case of hemiparkinsonism, and three cases of postencephalitic parkinsonism, and found pathologic changes (i.e., depigmentation, neuronal loss, and gliosis) in the substantia nigra in all of them. Subsequently some investigators confirmed nigral pathology in Parkinson’s disease, while the Vogts and other authorities instead emphasized pathological changes in the striatum (Vogt and Vogt, 1920). In 1938, Hassler found that some cell groups within the zona compacta of the substantia nigra were severely affected (Hassler, 1938). In 1953, Greenfield and Bosanquet at the National Hospital, Queen Square, London, provided the most complete pathologic analysis of Parkinson’s disease, confirmed the selective loss of the ventrolateral cell groups within the zona compacta of the substantia nigra, and emphasized the nigral lesion and the Lewy body as features of Parkinson’s disease (Greenfield and Bosanquet, 1953; Goetz et al., 2001b).

Empiric pharmacotherapy with anticholinergic alkaloids Belladona alkaloids were empirically identified as helpful in Parkinson’s disease in the latter half of the 19th century. Charcot noted that the anticholinergic alkaloid hyoscyamine (the levorotatory form of atropine) was modestly beneficial for the tremor of Parkinson’s disease, as reported in the doctoral thesis of his German student Ordenstein in 1867 (Foley, 2003). In 1887, Wilhelm Erb successfully introduced scopolamine (initially somewhat confusingly called “hyoscine”) (Foley, 2003). Similar preparations were used for generations with at best modest success. Synthetic centrally acting anticholinergic medications were introduced in the 1950s and were soon adopted because they were associated with fewer systemic side effects (Corbin, 1949; Dorshay and Constable, 1949).

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Surgical treatment Because of the inadequacies of available pharmacotherapies, various neurosurgical approaches were also tried to address Parkinson’s disease and other movement disorders, beginning very crudely at the end of the 19th century and expanding into a more modern approach in the 1930s through the 1960s. Initially neurosurgeons focused on lesioning the corticospinal pathways, but such efforts merely traded tremor and bradykinesia for paralysis. Beginning around 1939, Meyers examined the effects of lesions in the caudate nucleus, globus pallidus, and ansa lenticularis, demonstrating that parkinsonian tremor and rigidity could be improved surgically without impairing consciousness or producing weakness or spasticity, although the surgical morbidity and mortality were prohibitively high (Meyers, 1940). Stereotactic techniques were introduced into human neurosurgery in 1947 (Spiegel et al., 1947), and beginning in the 1950s stereotactic lesions to treat the symptoms of Parkinson’s disease were made variously in the ventrolateral thalamus, globus pallidus, and the emerging ansa lenticular fibers, although by the early 1960s most surgeons were lesioning only the thalamus (Gildenberg, 1998). However, by the end of the 1960s, neurosurgical approaches to the treatment of Parkinson’s disease were suddenly eclipsed and largely abandoned with the general availability of L-DOPA. With the general availability of computed tomography in the 1980s, and with growing recognition of the limitations of medical treatments, earlier stereotactic neurosurgical ablation procedures were revisited and improved, particularly stereotactic pallidotomy (Laitinen et al., 1992a, b; Gildenberg, 1998; Speelman and Bosch, 1998). Since the late 1980s, an important role of the subthalamic nucleus in Parkinson’s disease has been identified, allowing targeted therapies that modulate subthalamic nucleus activity to be effectively used for Parkinson’s disease (Smith and Parent, 1988; Guridi and Obeso, 2001; Hamani et al., 2003; Hame´leers et al., 2006); initial beneficial results in animal models (Bergman et al., 1990; Aziz et al., 1991; Benazzouz et al., 1993) were subsequently confirmed in humans with Parkinson’s disease (Limousin et al., 1995, 1998; Krack et al., 2003). In 1987, Alim Louis Benabid, Pierre Pollak, and colleagues at the University of Grenoble in France pioneered the use of non-destructive and reversible high-frequency electrical stimulation of deep brain nuclei with implanted electrodes (Benabid et al., 1987). This deep brain stimulation approach was applied first to the Vim (ventralis intermedius) nucleus of the thalamus and was found to be effective in controlling disabling tremor (Benabid et al., 1991, 1994; Siegfried,

1994; Siegfried and Lippitz, 1994). Deep brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus has fewer reported adverse effects than ablative procedures, and has been found to be more globally effective than thalamotomy or thalamic stimulation in addressing rigidity, tremor, bradykinesia, motor fluctuations, and dyskinesias in patients with Parkinson’s disease; nevertheless, deep brain stimulation cannot prevent the progression of Parkinson’s disease, nor does it alleviate associated problems with cognition, speech, or balance.

Neurochemistry and the L-DOPA story Important biochemical developments began in the 1950s that paved the way for rational therapeutics, including the recognition by Montagu (1957) that dopamine is present in the mammalian brain, the report by Arvid Carlsson and colleagues that racemic DOPA (D,L 3-4 dihydroxyphenylalanine), a dopamine precursor, antagonizes the sedative and bradykinetic effects of reserpine in rabbits and mice (Carlsson et al., 1957), and the demonstration that dopamine is localized primarily within the neostriatum (Bertler and Rosengren, 1959; Carlsson, 1959; Sano et al., 1959; Foley, 2000). Based on the distribution of dopamine in the brain with concentration in the basal ganglia, the production of parkinsonism and brain catecholamine depletion by reserpine, and restoration of normal function by administration of the dopamine precursor DOPA, Carlsson and colleagues proposed that depletion of dopamine will induce parkinsonism and that treatment with L-DOPA will reverse the syndrome by restoring brain dopamine levels (Carlsson et al., 1957; Carlsson, 1959, 2003), work for which Carlsson was later awarded the Nobel Prize in Physiology or Medicine in 2000 (Carlsson, 2003). In 1960, Degwitz and colleagues demonstrated that L-DOPA reversed the sedation of reserpine in humans (Degwitz et al., 1960), confirming Carlsson and colleagues’ earlier report in animals. In 1961, Ehringer and Hornykiewicz documented the dramatic loss of dopamine in the striatum of brains from patients dying with post-encephalitic and idiopathic Parkinson’s disease (Ehringer and Hornykiewicz, 1960). In 1962, following this series of neurochemical discoveries and especially with the understanding that dopamine is depleted in the striatum, Birkmayer and Hornykiewicz (1961) reported dramatic reduction of akinesia and improvement in speech and gait in Parkinson’s disease patients using intravenous L-DOPA, and Barbeau et al. (1962) reported similar results with small oral doses of racemic DOPA. Birkmayer and Hornykiewicz’s description of what they called the

THE HISTORY OF MOVEMENT DISORDERS “L-DOPA-Effekt” still vividly conveys the dramatic improvement observed: The effect of a single i.v. administration of L-DOPA was, in short, a complete abolition or substantial relief of akinesia. Bed-ridden patients who were unable to sit up; patients who could not stand up when seated; and patients who when standing could not start walking, performed after L-DOPA all these activities with ease. They walked around with normal associated movements and they even could run and jump. The voiceless, aphonic speech, blurred by pallilalia and unclear articulation, became forceful and clear as in a normal person. For short periods of time the patients were able to perform motor activities which could not be prompted to any comparable degree by any other drug. (Birkmayer and Hornykiewicz, 1961; Hornykiewicz, 2001, p. 859) Unfortunately, subsequent reports of the efficacy of L-DOPA were at best inconsistent – a small placebocontrolled trial demonstrated no convincing benefit for L-DOPA treatment (McGeer and Zeldowitz, 1964), and a double-blind trial found no significant difference between L-DOPA and placebo (Fehling, 1966) – so in short order the initially reported beneficial effects of L-DOPA were largely discounted. With hindsight these negative results reflected a combination of small doses of medication and problems of study design (including very small sample sizes and inadequate controls). Cotzias and colleagues nevertheless persevered with DOPA as a treatment for Parkinson’s disease and, in 1967, reported the successful use of high-dose oral racemic DOPA in an open trial (Cotzias et al., 1967). Using doses from 4 to 16 grams of racemic DOPA daily, Cotzias et al. (1967, p. 375) noted “complete sustained disappearance or marked amelioration” of symptoms in half of their 16 patients, with a clear dose–response relationship, and with manageable side effects (transient nausea, faintness, occasional vomiting, and dyskinesias). Cotzias et al. (1969) later showed that the benefits of L-DOPA are sustainable for extended periods, and side effects could be managed or prevented by slow dose escalation or with co-administration of a peripheral dopa-decarboxylase inhibitor. These findings were later confirmed in double-blind trials with L-DOPA alone (Yahr et al., 1969) or in combination with a dopa-decarboxylase inhibitor (Calne et al. 1971). In 1975, Lloyd and colleagues showed that dopamine levels in the striatum are an order of magnitude higher in the striatum of Parkinson’s disease patients treated with L-DOPA than in untreated patients, are greater in good responders than poor responders, and are related to the time before death of the last dose (Lloyd et al., 1975).

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Subsequent progress has included development of longacting levodopa preparations and inhibitors of catecholO-methyltransferase (COMT), the enzyme responsible for most of the peripheral degradation of L-DOPA. Beginning in the mid-1960s, a previously unsuspected nigrostriatal dopaminergic neuronal projection was demonstrated first in the rat (Anden et al., 1964, 1965), and shortly thereafter unilateral lesions of the substantia nigra were shown to deplete striatal dopamine ipsilaterally in monkeys (Poirer and Sourkes, 1965; Goldstein et al., 1966). The nigrostriatal projection had escaped previous notice because the fibers were too small and thinly myelinated to be shown by classic histologic techniques. Degeneration of neurons in the pars compacta of the substantia nigra in Parkinson’s disease was then understood to cause depletion of striatal dopamine as a result of degeneration of the nigrostriatal projections, neatly explaining various pathologic and neurochemical observations, and finally settling the lingering controversy of whether it is the substantia nigra or the striatum that is affected in Parkinson’s disease (they both were!).

Dopamine agonists Shortly after the advent of L-DOPA therapy for Parkinson’s disease, it became apparent that chronic therapy was associated with development of motor fluctuations, dyskinesias, and loss of efficacy in some patients. These changes were thought to be due in part to loss of the presynaptic pigmented neurons in the substantia nigra, which normally function to convert L-DOPA to dopamine, which is then transported and released onto post-synaptic receptors in the striatum. It was hoped that the limitations of L-DOPA might be overcome by development of dopamine agonists that could directly stimulate striatal neurons. Apomorphine was the first dopamine agonist, synthesized from morphine in the 19th century. In 1951, Schwab and colleagues noted that apomorphine injection could cause a marked temporary improvement in Parkinson’s disease patients (Schwab et al., 1951), and in 1965 Ernst recognized the structural similarity of apomorphine and dopamine (Ernst, 1965). In 1970, in light of the side effects increasingly recognized with L-DOPA, Cotzias and colleagues re-evaluated apomorphine in Parkinson’s disease and reported significant anti-parkinsonian effects (Cotzias et al., 1970), but toxicity and the need for parenteral administration limited its usefulness. Later attempts with oral apomorphine (Cotzias et al., 1976) were also abandoned, because of the development of dose-dependent azotemia with long-term therapy. Only recently has apomorphine been revisited in the treatment of Parkinson’s disease.

510 D.J. LANSKA Most subsequent dopamine agonists were synthetic factors could be important to the pathogenesis of at least derivatives of ergot, the first of which was bromocripsome forms of Parkinson’s disease (Johnson et al., 1990). tine. In the late 1960s, bromocriptine was originally In 1990, Lawrence Golbe, Roger Duvoisin, and tested in humans as a potential prolactin inhibitor. Subcolleagues reported an autosomal dominant form of sequently, dopamine was found to be an inhibitor of Parkinson’s disease in two large kindreds originating prolactin release, and bromocriptine was found to have in the village of Contursi in the Salerno province of dopaminergic properties in rats (Corrodi et al., 1973). Italy (Golbe et al., 1990); the disease in this kindred In 1974, Calne and colleagues reported the beneficial was characterized by often early onset and rapid proeffects of bromocriptine in Parkinson’s disease in a gression, a lower frequency of tremor, responsiveness double-blind trial (Calne et al., 1974). Patients with severe to L-DOPA, and pathologic findings typical of Parkindyskinesia or motor fluctuations benefited from adding son’s disease with Lewy bodies. In 1996, Mihael Polybromocriptine while reducing the dose of L-DOPA. meropoulos and colleagues at the US National Kebabian and Calne (1979) later used the pharmacoloInstitutes of Health established linkage of Parkinson’s gic properties of bromocriptine to propose that there are disease in the Contursi kindred to chromosome 4q21-23 at least two kinds of dopamine receptors, termed D1 (Polymeropoulos et al., 1996), an area to which the alphaand D2, and that parkinsonism results at least in part from synuclein gene had been mapped (Chen et al., 1995). inadequate transmission at D2 receptors. These two types Shortly thereafter, Polymeropoulos et al. (1997) showed of receptors are now known to exert their biological that disease in this family and several Greek kindreds actions by coupling to and activating different molecular resulted from a mutation in the alpha-synuclein gene switches called G-protein complexes, so named because (PARK1). Alpha-synuclein – a small protein only 144 they react with GTP in order to transduce extracellular amino acids long – had been recognized in human “first messenger” signals identified by a specific extracelbrains in the mid-1990s (Ueda et al., 1993; Campion lular receptor to amplified intracellular “second messenet al., 1995), and was known to be concentrated in preger” signals (Gilman, 1997; Rodbell, 1997): specifically synaptic nerve terminals (Jakes et al., 1994). extracellular dopamine (the first messenger) acts on D1 Following recognition that familial Parkinson’s disreceptors (the discriminator) through a G-protein complex ease could result from mutations in the alpha-synuclein (the transducer) to activate adenylyl cyclase (the ampligene, synuclein was rapidly shown to be the major fibrilfier) and increase production of intracellular cAMP (the lar component of Lewy bodies and Lewy neurites in both second messenger), whereas extracellular dopamine acts sporadic Parkinson’s disease and dementia with Lewy on D2 receptors through a G-protein complex to inhibit bodies (Spillantini et al., 1997; Giasson et al., 2000). adenylyl cyclase and decrease cAMP production. Subsequent studies have shown that mutated alphaFive types of dopamine receptors are now recogsynuclein does not fold properly, resists proteasome nized: D1 and D5 receptors are members of the D1-like degradation, and tends to form insoluble aggregates. family of receptors, whereas D2, D3, and D4 receptors Although mutations in the alpha-synuclein gene are very are members of the D2-like family. These receptor rare and represent less than 1% of the worldwide burden types have overlapping but distinct localizations within of Parkinson’s disease, these developments triggered the central nervous system, but the D1 and D2 recepintense interest and rapid progress in understanding tors are the predominant receptor types within the the pathogenesis of Parkinson’s disease. nigrostriatal system, and both are highly expressed in In 1998, only a year after the discovery of the alphathe striatum (Lahti et al., 1995). The human genes for synuclein mutation, Japanese researchers reported all of these receptor types have been cloned. mutations in a separate gene (PARK2) on chromosome 6q25.2-q27, whose protein product was designated Genetics and molecular biology “parkin” (Kitada et al., 1998), in Japanese families with Throughout much of the 20th century, Parkinson’s disearly-onset parkinsonism segregating as an autosomal ease was suspected to be a “non-genetic” disorder, in part recessive trait (Matsumine et al., 1997). Other prebecause extended pedigrees of familial Parkinson’s viously reported families with juvenile-onset parkindisease were not available, in part because exogenous sonism (Ishikawa and Miyatake, 1995) were also then factors (e.g., neuroleptic medications and later MPTP) reported to have mutations in the PARK2 gene (Hayawere identified that produced forms of parkinsonism shi et al., 2000). Patients affected by mutations in clinically similar to that of Parkinson’s disease, and in part PARK2 were found to have a wide range in age of on the basis of twin studies that were interpreted as onset, with slow progression, generally symmetric excluding a significant genetic etiology for Parkinson’s involvement, dystonia at onset, hyperreflexia, a good disease. However, by 1990 a re-evaluation, including a response to L-DOPA, and dyskinesias during treatment meta-analysis of twin studies, suggested that genetic (Lucking et al., 2000; Kann et al., 2002; Pramstaller

THE HISTORY OF MOVEMENT DISORDERS 511 et al., 2005). Some patients were later found to present profound lethargy or stupor, that had occurred during at an older age with clinical features indistinguishable the winter of 1916–1917 (von Economo, 1917, 1918, 1931): from idiopathic Parkinson’s disease (Pramstaller et al., It seems strange when sleep appears as a symp2005). Although initially reported to lack Lewy bodies, tom of an illness. “Sleeping sickness” where the subsequent studies have shown that alpha-synuclein phenomenon of people falling asleep while eatpositive Lewy bodies can be present in the substantia ing or working was first described in two cases nigra and locus ceruleus of patients dying with parkinin our clinic in Vienna in 1916. Usually headassociated parkinsonism (Pramstaller et al., 2005). ache, nausea, and fever were followed, often Mutations in the PARK2 gene are now the most the next day, by sleeping, frequently in a most frequent known genetic cause of parkinsonism. uncomfortable position. One can wake them, In 1998, Kitada and colleagues suggested that parbut in severe cases, coma can rapidly lead to kin may interfere with ubiquitin-mediated protein death. Malfunction of eye muscles, especially degradation and cause the death of nigral neurons oculomotor dysfunction, and ptosis, was com(Kitada et al., 1998). mon. (von Economo, 1918, as translated by The ubiquitin-proteasome proteolytic system had been Dickman, 2001, p. 1696) elucidated, beginning in the late 1970s, largely through the He named the condition “encephalitis lethargica” and efforts of Aaron Ciechanover and Avram Hershko of identified three overlapping clinical subsets of the acute Technion-Israel Institute of Technology and Irwin Rose illness: somnolent-ophthalmoplegic, hyperkinetic, and of the University of California-Irvine, work for which amyostatic-akinetic. He documented the highly variable the three received the 2004 Nobel Prize in Chemistry (Cieacute manifestations, which included sleep disturbanchanover, 2005; Hershko, 2005; Rose, 2005). In this “garces, lethargy, neuropsychiatric disorders (e.g., catatonia, bage disposal” system, a very small (76 amino acids long), obsessive-compulsive disorder), oculomotor abnormalhighly evolutionarily conserved protein called ubiquitin is ities, and various associated hypo- and hyperkinetic activated by the ubiquitin-activating enzyme (E1), then movement disorders, including rigidity, akinesia, generaltransferred to a ubiquitin-carrier protein called ubiquiized and hemi-chorea, myoclonus, dystonia, opisthototin-conjugating enzyme (E2), which transfers the actinus, akathisia, and variably superimposed oculogyric vated ubiquitin to a ubiquitin-protein ligase (E3), which crises. Von Economo subsequently studied the evolution, in turn attaches the ubiquitin to a protein to be degraded. natural history, and sequelae of encephalitis lethargica Repetitive conjugation of ubiquitin moieties produces a over several years. He noted that post-encephalitic parkinpoly-ubiquitin chain, a tagging process dramatically sonism could develop early with the amyostatic form, or termed “the kiss of death,” which marks the protein for up to several years after apparently complete recovery recognition by the proteasome, a molecular complex that from other forms of acute encephalitis lethargica (von digests proteins into short peptides and finally into amino Economo, 1931). In addition, he emphasized the neuroacids that are recycled for further protein synthesis. pathological features, including microscopic inflammaIn 2000, Shimura and colleagues reported that parkin tory changes, particularly in the gray matter of the is indeed involved in protein degradation as a ubiquitinmidbrain tegmentum and the basal ganglia. protein ligase (E3), a function lost in autosomal recessive Encephalitis lethargica became a global pandemic juvenile-onset parkinsonism (Shimura et al., 2000). affecting more than one million people between apThe following year, Shimura et al. (2001) reported that proximately 1916 and 1925. As the epidemic of acute a particular form of alpha-synuclein is a protein substrate encephalitis waned in the mid-1920s, numerous cases for parkin, an important finding linking these two Parkinof post-encephalitic parkinsonism were identified, son’s disease genes by the ubiquitin-proteasome proteolytypically with bradyphrenia, generalized rigidity, bent tic system. Mutant parkin fails to attach ubiquitin to posture, and unsteady gait, but usually without a pillmisfolded proteins, which then accumulate and cause cell rolling tremor. Post-encephalitic parkinsonism cases death. Subsequent identification of other genetic forms were identified even into the 1930s, but by that time of parkinsonism have reinforced the importance of this the nosologic distinction between idiopathic Parkinpathway in the pathogenesis of Parkinson’s disease. son’s disease and post-encephalitic parkinsonism had become confused. There have been no further epiENCEPHALITIS LETHARGICA: demics of encephalitis lethargica, although rare sporaVON ECONOMO’S ENCEPHALITIS dic cases continue to be reported. In 1917 and 1918, Constantin von Economo (1876–1931) The etiology of encephalitis lethargica remains described the clinical and pathological findings of 13 unknown. Although encephalitis lethargica and influcases with an unusual encephalitic condition, often with enza both occurred in epidemics between 1918 and

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1923, the timing and extent of the outbreaks were dissimilar (Reid et al., 2001). Furthermore, recent studies failed to identify influenza RNA in archived encephalitis lethargica brain specimens, and suggested that the 1918 influenza virus was genetically incapable of neurotropic disease (McCall et al., 2001; Reid et al., 2001). Despite considerable effort, no neurotropic virus has yet been implicated, and some have suggested that encephalitis lethargica was a post-infectious autoimmune disorder similar to Sydenham’s chorea (Dale et al., 2004).

DRUG-INDUCED PARKINSONISM Neuroleptic-induced parkinsonism and associated movement disorders In the 1950s and 1960s, shortly after the introduction of chlorpromazine and other related tranquilizers (“neuroleptics”) (Delay et al., 1952; Hamon et al., 1952; Lehmann and Hanrahan, 1954), a variety of immediate and late (tardive) drug effects were recognized that included various abnormal involuntary movements, including akathisia, tremor, akinesia, parkinsonism, choreoathetosis, dystonia, and dyskinesias (Hall et al., 1956; Schonecker, 1957; Ayd, 1961; Faurbye et al., 1964). Acute dystonia, akathisia, and drug-induced parkinsonism – with prominent bradykinesia, and also rigidity, postural instability, and tremor – were recognized in as many as 10–20% of patients (Freyhan, 1957; Ayd, 1961). Akathisia – a term coined by Hasˇkovec (1901) to refer to individuals unable to remain seated as a result of hysteria or neurasthenia – was adopted to label features of motor restlessness occurring as a side effect of antipsychotic drugs (Steck, 1954; Kruse, 1960; Ayd, 1961); although early descriptions described motor restlessness, later accounts emphasized a subjective internal discomfort and a need to move to relieve this uncomfortable sensation (Chien et al., 1967; Van Putten, 1975). Tardive dyskinesia – a term introduced by Faurbye and colleagues in 1964 – was recognized as an involuntary, repetitive, and choreic or stereotypic movement disorder that persisted even after the offending drug was stopped (Schonecker, 1957; Uhrbrand and Faurbye, 1960; Faurbye et al., 1964); most prominent were involuntary patterned buccolingual masticatory movements with lip smacking, puckering, chewing, tongue movements, grimacing, and other facial movements.

MPTP In 1982, Langston and colleagues identified a group of drug addicts who had developed parkinsonism after mistakenly self-injecting a toxin called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a reaction product of the illicit synthesis of a meperidine analogue

(Langston et al., 1983; Langston and Palfreman, 1995). The addicts rapidly developed permanent parkinsonian signs, including tremor, bradykinesia, rigidity, and postural instability. A similar case had been reported in 1979, but the role of MPTP was not clarified at that time, in part because administration of MPTP to rats, rabbits, and guinea pigs failed to produce a motor deficit (Davis et al., 1979). In 1983, Burns and colleagues demonstrated that MPTP could induce parkinsonism in monkeys (Burns et al., 1983), with stooped posture, tremor, rigidity, and bradykinesia; these symptoms were reversed temporarily by administration of L-DOPA. When the brains of these monkeys were examined they were found to have histologic similarity to Parkinson’s disease, with destruction of neurons in the pars compacta of the substantia nigra and marked depletion of dopamine in the striatum (Mitchell et al., 1985; Forno et al., 1986). It was soon discovered that MPTP is converted in vivo to MPP+ (1-methyl-4-phenylpyridium) by monoamine oxidase type B (Markey et al., 1984), a conversion that is necessary (although not sufficient) for manifestation of the toxic effects of MPTP in animals. Pretreatment with monoamine oxidase inhibitors prevented both the accumulation of MPP+ and the toxic effects of MPTP (Heikkila et al., 1984; Langston et al., 1984; Markey et al., 1984). The discovery of the selective neurotoxic properties of MPTP established a useful animal model, greatly accelerated basic research, and supported theories that an environmental toxin could contribute to the multifactorial causes of Parkinson’s disease.

ATYPICAL PARKINSONISM In addition to Parkinson’s disease, a number of other neurodegenerative conditions have hypokinesia as a major clinical feature. Separation of these conditions from Parkinson’s disease ultimately led to important anatomical and physiological discoveries concerning basal ganglia function (Goetz et al., 2001d).

Wilson’s disease In 1911, British neurologist Kinnier Wilson (1878–1937) of the National Hospital, Queen Square, London, presented a thesis entitled “Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver” (Wilson, 1911). Wilson reviewed the clinical and pathologic features of 12 cases, including four he had seen and studied himself, two from the records of the National Hospital, and six previously published. Wilson concluded: Progressive lenticular degeneration may be defined as a disease which occurs apparently

THE HISTORY OF MOVEMENT DISORDERS only in young people, which is often familial, but not congenital or hereditary; it is essentially and chiefly a disease of the extra-pyramidal motor system, and is characterized by involuntary movements, usually of the nature of tremor, dysarthria or anarthria, dysphagia, muscular weakness, spasticity or hypertonicity, and contractures, with progressive emaciation; with these may be associated emotionalism and certain symptoms of a mental nature. It is progressive and, after a longer or shorter period, fatal. Pathologically it is characterized predominantly by bilateral degeneration of the lenticular nucleus, and in addition cirrhosis of the liver is constantly found, the latter morbid condition not giving rise to symptoms during the lifetime of the patient. (Wilson, 1912a, p. 1116) Wilson’s thesis was awarded a gold medal by the University of Edinburgh in 1911 (Wilson, 1911), and his definitive publication of 213 pages in Brain in 1912 occupied the entire issue (Wilson, 1912a). His findings were also published in shorter accounts in several languages (Wilson, 1912b, c, 1914). Though the first to describe the condition in detail, Wilson acknowledged earlier works by Westphal (1883) and von Stru¨mpel (1898) on “pseudosclerosis” (a 19th-century label for a clinical condition with tremor resembling that seen in multiple sclerosis but distinguished by the lack of ocular signs), and Gowers on familial “tetanoid chorea” (Gowers, 1888), associated ultimately with cirrhosis of the liver (Gowers, 1906). The full clinical spectrum of Wilson’s disease was not appreciated for many years. Unappreciated by Wilson, in 1902 Bernard Kayser (1869–1954) had described ring-like corneal deposition of greenish pigment in a patient suffering from pseudosclerosis (Kayser, 1902), a finding reinforced by Bruno Fleischer (1874–1965) in 1903, who recognized the ring as a marker for a neuropsychiatric disorder associated with cirrhosis (Fleischer, 1903; Dening and Berrios, 1990). 1n 1916, Bramwell suggested that Wilson’s disease could present with liver pathology (Bramwell, 1916), a finding ultimately confirmed by Uzman et al. (1956). By the early 1960s, it was clear that while other tissues, including kidney and bone, could also be affected (Bearn, 1957), before puberty Wilson’s disease generally presents with liver disease, whereas after puberty neurological presentations are typical (Walshe, 1962). Understanding that Wilson’s disease involved deposition of copper in tissues developed over several decades in the early-20th century. In 1913, Rumpel reported excess hepatic copper in a patient dying of Wilson’s disease (Rumpel, 1913), and, in 1922, Siemerling and Oloff described the association of corneal pigmentation (“Kayser–Fleischer rings”) with sunflower cataracts and

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noted the similarity of the cataracts to those developing with a copper-containing foreign body in the eye (Siemerling and Oloff, 1922), but unfortunately these findings were apparently overlooked (Walshe, 2006). Later, Vogt (1929), Haurowitz (1930), Glazebrook (1945), and others reported excess copper in the brain or liver of patients dying of Wilson’s disease. In 1948, in an influential paper, Cumings (1948) demonstrated excess copper in both the brain and the liver of patients with Wilson’s disease. In the late 1940s, Holmberg and Laurell (1947, 1948) purified and characterized a blue copper-containing plasma glycoprotein they called “caeruloplasmin” (from the Latin caeruleus, dark blue), which was demonstrated to have reduced plasma concentrations in patients with Wilson’s disease in the early 1950s (Bearn and Kunkel, 1952; Scheinberg and Gitlin, 1952). A genetic basis for Wilson’s disease was suggested by Bramwell (1916) and by Hall (1921) (who also coined the term “hepatolenticular degeneration”), but the autosomal recessive mode of transmission was not established unequivocally until 1960 by Bearn (1960). The gene responsible for Wilson’s disease was mapped to chromosome 13 in 1985 (Frydman et al., 1985), and in the early 1990s Wilson’s disease was found to be due to mutations in the ATP7B gene on the long arm of chromosome 13 (13q14.3), which codes for a 140-kD coppertransporting P-type ATPase (Bull et al., 1993; Petrukhin et al., 1993; Tanzi et al., 1993). The Wilson’s disease gene has close homology with the Menke’s disease gene ATP7A, and is distinct from the loci for ceruloplasmin on chromosome 3 and the metallothionein cluster on chromosome 16. Loss of function of the Wilson’s disease gene product results in excessive intracellular deposition of copper in hepatocytes, hepatic cellular necrosis, and leakage of copper into the plasma, from whence it is transported to and deposited in other tissues, including brain. In 1948, Cumings suggested that British anti-lewisite (BAL) might be of value in removing copper from the body and thereby in improving the prognosis of Wilson’s disease (Cumings, 1948). BAL is a chelating agent designed during World War II as an antidote to the arsenical vesicant gas “lewisite,” which had been developed during World War I (Vilensky et al., 2002; Walshe, 2006). By 1951, Cumings (1951) and Denny Brown and Porter (1951) reported clinical benefit from BAL in patients with Wilson’s disease, even though the treatment required repeated painful intramuscular injections and was highly toxic. Several therapies have superseded BAL in the treatment of Wilson’s disease. In 1956, Walshe suggested that penicillamine could be an effective orally administered chelator for copper (Walshe, 1956), a suggestion confirmed by 1960 (Scheinberg and Sternlieb, 1960;

514 D.J. LANSKA Walshe, 1960). Penicillamine rapidly replaced BAL, but of four cases, two of whom had severe parkinsonism within a decade penicillamine was also found to produce masking cerebellar signs, and two of whom had predoseveral significant immunologically induced side effects minant cerebellar ataxia (Scherer, 1933a, b; Berciano (Walshe, 1968), which led to continued efforts to find et al., 1999); in these cases, the severity of parkinsonism safer alternatives (Walshe, 1982, 2003, 2006). In 1961, correlated with degenerative changes in the substantia Schouwink demonstrated that orally administered zinc nigra and striatum, rather than with the degree of cerecould significantly reduce the absorption of copper bellar degeneration, as had been previously thought from the gut (Schouwink, 1961), a finding which was (Berciano et al., 1999). In 1964, American neurologist unpublished and initially largely unknown. Zinc was Raymond Adams (1911–2008) and Belgian neuropathollater shown to be helpful in the long-term management ogist Ludo van Bogaert (1897–1989) introduced the term of Wilson’s disease patients (Hoogenraad et al., 1979, “striatonigral degeneration” for a sporadic neurodegen1987; Brewer et al., 1983, 1998), although it may not be erative disorder characterized by parkinsonism plus adequate for initial therapy (Walshe, 2006). Zinc induces other neurological findings (e.g., cerebellar dysfunction, the synthesis of intestinal metallothionein, a metalchoreoathetosis, dystonia, pyramidal or pseudobulbar binding protein in the intestinal mucosa, which effecsigns) (Adams and van Bogaert, 1964). tively binds copper in a complex that cannot be systemiIn 1960, Shy and Drager described a primary neurodecally absorbed, and is ultimately excreted in the stool generative condition in which autonomic failure occurred with desquamated intestinal epithelial cells. In 1982, in association with other neurological manifestations: Walshe introduced triethylene tetramine (Trientine) as a The full syndrome comprises the following feasubstitute chelator for patients intolerant of penicillatures: orthostatic hypotension, urinary and recmine (Walshe, 1982); triethylene tetramine is much safer tal incontinence, loss of sweating, iris atrophy, than penicillamine and does not exhibit the frequent external ocular palsies, rigidity, tremor, loss of hypersensitivity reactions seen with penicillamine. In the associated movements, impotence, the findings 1970s and 1980s, liver transplantation was introduced of an atonic bladder and loss of the rectal and increasingly used for patients with hepatic failure sphincter tone, fasciculations, wasting of distal (Groth et al., 1973; Sokol et al., 1985; Rothfus et al., 1988). muscles, evidence of a neuropathic lesion in Multisystem atrophy the electromyogram that suggests involvement (olivo-ponto-cerebellar degeneration) of the anterior horn cells, and the finding of a neuropathic lesion in the muscle biopsy. The For decades, the overlapping clinical features and patholoage of onset is usually in the fifth to the seventh gies in individual cases with sporadic olivo-pontodecade of life. The disorder appears to be more cerebellar atrophy, striatonigral degeneration, and Shy– frequent in the male. Any of the above signs or Drager syndrome have been sources of confusion, bursymptoms may be the presenting ones, and the geoning terminology, and competing nosologies. These hypotension may be a relatively late finding. disorders are now recognized as forms of multiple system The duration of the illness . . . shows the disorder atrophy, an adult-onset sporadic neurodegenerative disto be of relatively slow progression. (Shy and ease characterized clinically by varying degrees of parkinDrager, 1960, pp. 511–512) sonism, cerebellar ataxia, pyramidal signs, and autonomic dysfunction, and characterized pathologically by degeneration in the substantia nigra, putamen, olivary nucleus, pontine nuclei, and cerebellum. The term “olivo-ponto-cerebellar atrophy” was coined by French neurologists Joseph Jules Dejerine (1849–1917) and Andre´ Thomas in 1900, in their report of a 53-year-old patient who developed progressive cerebellar ataxia, a masked face, dysarthria, hypertonia, hyperreflexia, and urinary incontinence (Dejerine and Thomas, 1900, 1900/1977). Autopsy at age 55 showed severe degeneration of the basis pontis, inferior olivary nuclei, middle cerebellar peduncles, and less so the inferior cerebellar peduncles, with loss of Purkinje cells particularly in the cerebellar hemispheres. In 1933, Scherer gave the first clear description of striatonigral degeneration in clinicopathologic studies

Variability in presentation, with components of autonomic, extrapyramidal, and cerebellar features, led Graham and Oppenheimer to introduce the term “multiple system atrophy,” which was intended to “cover this collection of overlapping progressive, presenile multisystem degenerations” (Graham and Oppenheimer, 1969): There is a group of progressive neurological conditions, most often arising during middle life, with symptoms and signs of lesions affecting several central nervous structures, more or less symmetrically. These cases are usually sporadic, but sometimes familial. The pathological findings are of cell loss and gliosis in a selection of well-defined structures (including both anatomical “nuclei” such as the putamen, and extensive cellular

THE HISTORY OF MOVEMENT DISORDERS 515 layers, such as the Purkinje cells of the cerebel1963 and 1964 with neurologist John C. Steele (1934–) lum). In different cases, different selections of and neuropathologist Jerzy Olszewski (1913–1964) structures are affected. Some combinations of (Richardson et al., 1963; Olszewski et al., 1964; Steele lesions are commoner than others: thus, familiar et al., 1964; Steele, 1994). names, such as OPCA, have come into use. NeverAs reported by Steele and colleagues, their theless combinations are encountered which do patients had not correspond with any familiar syndrome. In . . . an unusual progressive neurological disorder such cases, unnecessary confusion is caused by with ocular, motor, and mental features. The inventing new names, of the type “pallido-subthaclinical picture was characterized by supranuclamico-vestibular atrophy,” for unusual syndrolear ophthalmoplegia, particularly of downward mes . . . What is needed is a general term to gaze, pseudobulbar palsy, dysarthria, dystonic cover this collection of overlapping progressive rigidity of the neck and upper trunk, and presenile multisystem degenerations. As the dementia . . . Commonly the disease started in causes of this group of conditions are still the sixth decade and led to death within several unknown, such a general term would merely be a years . . . Pathological investigation showed the temporary practical convenience . . . What we presence of cell loss, gliosis, neurofibrillary wish to avoid is the multiplication of names for tangles, granulovacuolar degeneration and “disease entities” which in fact are merely the demyelination in various regions of the basal gangexpressions of neuronal atrophy in a variety of lia, brain stem, and cerebellum . . . (Steele et al., overlapping combinations. We therefore propose 1964, p. 357) to use the term multiple system atrophy to cover The original appellation “heterogeneous system degenthe whole group. Among the structures at risk in eration” (Richardson et al., 1963; Olszewski et al., 1964) this disease we must include the preganglionic was soon abandoned because the authors were not certain cells of the autonomic system. These may be that it was a primary degenerative disease (Steele, 1994). attacked apparently in isolation . . . or in combiThe eponymic designation of “Steele–Richardson– nation with other structures . . . (Graham and Olszewski syndrome” was first used by Andre´ Barbeau Oppenheimer, 1969, pp. 32–33) in 1965 (Barbeau, 1965). In 1989, Papp and colleagues reported that oligodenThe initial speculation that progressive supranucdroglia in multiple system atrophy contain argyrophilic, lear palsy might be a post-infectious disease (based tubulofilamentous inclusions in the cytoplasm, which on similarities with postencephalitic parkinsonism) were called “glial cytoplasmic inclusions” (Papp et al., (Steele et al., 1964) has been discounted (Kristensen, 1989). Glial cytoplasmic inclusions are not membrane 1985). Likely cases of progressive supranuclear palsy bound and are composed ultrastructurally of filaments have been retrospectively identified from the era and granular material. This important discovery helped before the occurrence of encephalitis lethargica to define multiple system atrophy as a clinicopathological (Brusa et al., 2004), although one early suspected case entity and drew attention to the prominent role of the (Steele, 1994), reported in 1904 by Posey and in 1905 oligodendrocyte in the pathogenesis of the disorder by Spiller, has since been shown to have had a mid(Papp and Lantos, 1992; Lantos, 1998). Glial cytoplasmic brain neoplasm (Posey, 1904; Spiller, 1905; Siderowf inclusions were subsequently shown to be highly immuet al., 1998). Attempts to transmit progressive supranoreactive for ubiquitin and alpha-synuclein (Arima nuclear palsy to animals by intracerebral inoculation et al., 1998; Spillantini et al., 1998; Tu et al., 1998; Wakahave been unsuccessful (Steele, 1972). bayashi et al., 1998). The recognition that multiple system Progressive supranuclear palsy is characterized atrophy has inclusions composed of alpha-synuclein pathologically by predominant brain stem, diencephaprovided an unexpected molecular link between multiple lon, and basal ganglia pathology, with neuronal loss, system atrophy and Lewy body diseases, such as Parkingliosis, and the presence of globose neurofibrillary tanson’s disease and Lewy body dementia. Collectively these gles (i.e., filamentous neuronal inclusions composed of disorders are now considered “synucleinopathies.” dense aggregates of neurofilaments and associated proteins). The neurofibrillary tangles are composed Progressive supranuclear palsy predominantly of 15-nm straight filaments (Tomonaga, “Progressive supranuclear palsy” is the descriptive 1977), which have strong immunoreactivity to the name applied by neurologist J. Clifford Richardson microtubular-associated protein tau. The recognition (1909–1986) for an unusual condition he first encounthat progressive supranuclear palsy has inclusions tered in the 1950s and later reported in detail in composed of tau provided a molecular link between

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various neurodegenerative disorders with predominant parkinsonism (including cortico-basal ganglionic degeneration and frontotemporal dementia and parkinsonism linked to chromosome 17), which are collectively considered among the “tauopathies.”

Cortico-basal ganglionic degeneration In 1967, Rebeiz and colleagues described three cases of what is now called cortico-basal ganglionic degeneration under the appellation of “corticodentatonigral degeneration with neuronal achromasia” – a label which summarized the distribution of neuropathological changes and highlighted one of the microscopic features (Rebeiz et al., 1967). The patients demonstrated progressive neurological deficits in middle age, with manifestations including unilateral or markedly asymmetric motor impairment, with dystonic arm postures, tremulous or jerking movements, dyspraxia, and gait dysfunction. What were later labeled as “alien limb” phenomena were recognized in the initial cases, including “uncontrollable elevation and abduction of the limbs that came on during attempted motor activity. Thus, when the patient attempted to walk, the leg hovered in the air instead of being placed on the ground, causing the patient to fall. Alternatively, when the unaffected right arm was being used in purposive activity, the left arm rose up in its way, greatly hampering the right arm’s performance” (Rebeiz et al., 1967, p. 23). Further cases were subsequently described under various labels including corticobasal degeneration (Gibb et al., 1989) and cortico-basal ganglionic degeneration (Riley et al., 1990). It is now recognized that a variety of movement disorders occur commonly in association with corticobasal ganglionic degeneration, including parkinsonism (with akinesia, rigidity, postural instability, and falls), limb dystonia, action tremor, and focal reflex myoclonus. Other common clinical features include apraxia, alien limb phenomenon, eyelid and oculomotor abnormalities, dysarthria, and dysphagia, so-called frontal lobe reflexes (e.g., grasp), pyramidal tract signs, and cortical sensory loss. Pathologically, there is asymmetrical cortical atrophy most pronounced in the medial fronto-temporal cortex contralateral to the side of the body most severely affected, with associated marked neuronal loss, extensive fibrillary gliosis, and achromatic ballooned neurons (Rebeiz et al., 1967, 1968; Gibb et al., 1989; Riley et al., 1990). Many surviving neurons are “ballooned” with cytoplasmic swelling, displacement of the nucleus to an eccentric location, cytoplasmic vacuoles of varying sizes, and loss of typical staining of the cytoplasm (“neuronal achromasia”). The substantia nigra pars compacta shows a marked loss of

neurons with pigmentary incontinence, melanin-containing macrophages, marked gliosis, and occasional ballooned neurons. Ultrastructurally the ballooned neurons are filled with cytoplasmic aggregates of 10-nm filaments that stain immunohistochemically with phosphorylated neurofilament proteins. Although Rebeitz et al. (1968) emphasized involvement of cerebellar nuclei, these nuclei have not been prominently affected in subsequent cases.

CHOREOATHETOSIS Since the Middle Ages, the term chorea (from the Greek word woreia for “dance”) has been used to describe both organic and psychological disorders of motor control. In the Middle Ages, epidemics of a psychosomatic “dancing mania” erupted in central Europe coincident with the Black Plague, with St. Vitus among the various saints called upon to intercede, leading to the term “chorea Sancti Viti” (Krack, 1999; Goetz et al., 2001e). Paracelcus (1493–1541) introduced the concept of chorea as an organic medical condition with his tri-part categorization: chorea imaginativa (arising from the imagination), chorea lasciva (arising from sexual desires), and chorea naturalis (organic chorea) (Goetz et al., 2001d).

Sydenham’s chorea In 1686, British physician Thomas Sydenham (1624– 1689) applied the term Saint Vitus’ dance to his description of childhood chorea (Sydenham, 1686; Goetz et al., 2001c). However, in so doing he also added confusion, because after Sydenham the term St. Vitus’ dance could mean either organic chorea (aka Sydenham’s chorea, chorea minor, or chorea anglorum) or psychogenic chorea (aka chorea major or chorea germanorum). There is a kind of convulsion, which attacks boys and girls from the tenth year to the time of puberty. It first shows itself by limping or unsteadiness in one of the legs, which the patient drags. The hand cannot be steady for a moment. It passes from one position to another by a convulsive movement, however much the patient may strive to the contrary. Before he can raise a cup to his lips, he makes as many gesticulations as a mountebank; since he does not move it in a straight line, but has his hand drawn aside by spasms, until by some good fortune he brings it at last to his mouth. He then gulps it off at once, so suddenly and so greedily as to look as if he were trying to amuse the lookers-on. (Sydenham, 1686, 1848/1979, vol. 2, pp. 257–258) Subsequently, a number of observers suggested a relationship between childhood chorea, rheumatic arthritis, and valvular heart disease (e.g., Bouteille, 1810;

THE HISTORY OF MOVEMENT DISORDERS 517 Bright, 1831; Se´e, 1850; Roger, 1866; reviewed by JumJackson) is caused typically by embolism but which in mani and Okun, 2001). some cases may be caused by “a morbid condition of the In 1887, William Osler (1849–1919) reviewed and blood” (Broadbent, 1869; Greenfield and Wolfsohn, 1922). reported clinical and pathologic data on 410 cases of In the early 20th century the embolic theory was disSydenham’s chorea treated at the Infirmary for Nercarded because of the “diffuse nature of the encephalivous Diseases in Philadelphia since 1876 (Osler, 1887). tis,” the absence of pathology of the cardiac valves in In 1894, while at Johns Hopkins, Osler published a many cases of childhood chorea, and the relative absence monograph based largely on his earlier studies in Philaof chorea in cases of adult bacterial endocarditis (Greendelphia, titled On Chorea and Choreiform Affections field and Wolfsohn, 1922). Instead, several authorities (Osler, 1894), which continues to be among the most proposed that Sydenham’s chorea was a bacterial meninwidely cited 19th-century American contributions to goencephalitis (Poynton and Paine, 1913; Greenfield and neurology (Lanska, 2001). Wolfsohn, 1922). However, bacteria were not consistently The bulk of Osler’s treatise focused on Sydenham’s cultured from brain tissue or cerebrospinal fluid of chorea, which he described as “an acute disease of childaffected cases, and the process by which an infection hood . . . characterized by irregular, involuntary movewould selectively target the corpus striatum was never ments, a variable amount of psychical disturbance, and satisfactorily explained. Sydenham’s chorea is now associated very often with arthritis and endocarditis” understood to result from an antibody cross-reaction to (Osler, 1894, p. 2). Osler carefully reviewed both the litbasal ganglia epitopes following infection with group A erature and the Philadelphia experience to marshal b-hemolytic streptococci (Husby et al., 1976). evidence that Sydenham’s chorea is an infectious disorHuntington’s disease der, which is frequently associated with endocarditis, particularly affecting the mitral valve. George Huntington’s (1850–1916) classic description of By 1899, a diplococcus had been isolated from the adult-onset hereditary chorea in 1872 was preceded by cerebrospinal and pericardial fluids of a child who died earlier clinical descriptions by Waters in 1841, Lund in with chorea and carditis, and from 1901 to 1903 Poynton the 1860s, and Lyon in 1863 (Waters, 1842; Lyon, 1863; and Paine produced irregular movements, arthritis, and Browning, 1908a, b; rbeck, 1959; reviewed in Lanska, carditis in rabbits intravenously injected with diplococci 2000b). Huntington first encountered victims of heredifrom affected patients (Poynton and Paine, 1913). Develtary chorea at age 8, while accompanying his physician opment of the antistreptolysin O titer as a marker of father around East Hampton at the extreme eastern end antecedent streptococcal pharyngitis in the early 1930s of Long Island, New York. After his own medical school allowed definite proof that all manifestations of rheugraduation in 1871, George Huntington incorporated the matic fever, including Sydenham’s chorea, are a sequel clinical notes of cases treated previously by his father to group A streptococcal pharyngitis (Coburn, 1931; and grandfather in an essay titled “On chorea,” which Todd, 1932; Taranta and Stollerman, 1956). was edited by his father. Huntington noted the hereditary By the late 1930s, sulfonamides were demonstrated transmission, the gradual onset of chorea in adulthood, to prevent recurrences of rheumatic fever (Coburn the progressive course, a tendency to insanity and suicide, and Moore, 1939), and in the 1940s prompt administraand lack of response to treatment: tion of penicillin for group A streptococcal pharyngitis The hereditary chorea . . . is confined to certain was shown to prevent primary (initial) attacks of rheuand fortunately a few families, and has been matic fever (Rammelkamp et al., 1952; Stollerman, transmitted to them, an heirloom from genera1997). The use of antibiotic prophylaxis for prevention tions away back in the dim past. It is spoken of of rheumatic fever led to a marked drop in the inciby those in whose veins the seeds of the disease dence of rheumatic fever and its major manifestations, are known to exist, with a kind of horror, and including Sydenham’s chorea (Nausieda et al., 1980; not at all alluded to except through dire necesSpecial Writing Group . . ., 1992; Stollerman, 1997). sity, when it is mentioned as “that disorder.” It As early as the 1860s, striatal dysfunction was impliis attended generally by all the symptoms of cated in childhood chorea by British physicians common chorea, only in an aggravated degree, John Hughlings Jackson and W.H. Broadbent. Jackson hardly ever manifesting itself until adult or midconcluded that: “It has long seemed to me that embodle life, and then coming on gradually but lism . . . of parts in the region of the corpus striatum gives surely, increasing by degrees, and often occupya most satisfactory explanation of the physiology and ing years in its development, until the hapless pathology of cases of chorea” (Jackson, 1868/1996, sufferer is but a quivering wreck of his former p. 238). Broadbent claimed that chorea is “a delirium of self . . . There are three marked peculiarities in the sensori-motor ganglia,” which (in agreement with

518 D.J. LANSKA this disease: 1. Its hereditary nature. 2. A tenThe gross pathology of Huntington’s disease with marked dency to insanity and suicide. 3. Its manifestatrophy of the striatum (particularly the head of the cauing itself as a grave disease only in adult date and putamen with accompanying dilatation of the life . . . When either or both the parents have frontal horns of the lateral ventricles) was recognized by shown manifestations of the disease, and more Alzheimer (Alzheimer, 1911). Later studies demonstrated especially when these manifestations have been selective loss of GABA-ergic medium-sized spiny projecof a serious nature, one or more of the offspring tion neurons in the striatum (Vonsattel et al., 1985) with almost invariably suffer from the disease, if relative sparing of the much smaller population of striatal they live to adult age. But if by any chance these interneurons, including medium and large aspiny neurons children go through life without it, the thread is (Dawbarn et al., 1985; Ferrante et al., 1985, 1987). Indirect broken and the grandchildren and great-grandprojections to the external globus pallidus are the first to children of the original shakers may rest assured degenerate (Reiner et al., 1988; Albin et al., 1990, 1992). that they are free from the disease . . . The tenThe degree of clinical disability generally reflects the dency to insanity, and sometimes that form of degree of loss of striatal neurons (Myers et al., 1982). insanity which leads to suicide, is marked . . . The distinct clinical profile, midlife onset, and autoAs the disease progresses the mind becomes somal dominant inheritance pattern made Huntington’s more or less impaired, in many amounting to disease ideal for investigation by genetic linkage analyinsanity, while in others mind and body both sis a century after Huntington’s description. The initial gradually fail until death relieves them of their approach used by Gusella and colleagues was based sufferings . . . Its third peculiarity is its coming on the detection of variations (polymorphisms) in the on, at least as a grave disease, only in adult length of DNA fragments resulting from digestion with life . . . It begins as an ordinary chorea might restriction endonucleases which recognize specific begin, by the irregular and spasmodic action of nucleotide base sequences (Gusella et al., 1983); the certain muscles, as of the face, arms, etc. These resulting “restriction-fragment length polymorphisms” movements gradually increase, when muscles (RFLPs) from individuals in large Huntington’s disease hitherto unaffected take on the spasmodic kindreds were hybridized with arbitrary segments of action, until every muscle in the body becomes labeled DNA derived from normal genomic DNA. In affected (excepting the involuntary ones), and the decade from 1983 to 1993, Huntington’s disease the poor patient presents a spectacle which is was sequentially linked to an anonymous polymorphic anything but pleasing to witness. I have never DNA marker, associated with a mutation in the IT15 known a recovery or even an amelioration of (“interesting transcript 15”) gene on the tip of the short symptoms in this form of chorea; when once it arm of chromosome 4 (in 4p16.3), and with the combegins it clings to the bitter end. No treatment bined effort of a consortium of researchers from seems to be of any avail, and indeed nowadays laboratories around the world it was ultimately attribuits end is so well known to the sufferer and his ted to an unstable expanded CAG trinucleotide repeat friends, that medical advice is seldom sought. in a gene coding for a large (350-kilodalton) multiIt seems at least to be one of the incurables . . . domain protein with multiple functions labeled hunting(Huntington, 1872, pp. 320–321) tin (Gusella et al., 1983, 1985; Zabel et al., 1986; Gilliam et al., 1987; Wasmuth et al., 1988; Hoogeveen et al., Huntington’s description of hereditary chorea was 1993; Huntington’s Disease Collaborative Research considered particularly important, because of his clear Group, 1993). and concise wording, and because it demonstrated that As a result of these developments, Huntington’s dishereditary conditions could have their clinical onset in ease was found to be the most common member of a adulthood (Lanska, 2000b). William Osler noted that family of neurodegenerative diseases caused by muta“In the history of medicine there are few instances in tions in which a CAG trinucleotide repeat expansion in which a disease has been more accurately, more grathe protein coding region of a gene produces long segphically, or more briefly described” (Osler, 1908, ments of polyglutamine (or “polyQ,” where “Q” is the p. 115). By the late 1880s, authors began referring to single letter code for glutamine) in the encoded protein. hereditary chorea as “Huntington’s chorea,” as did PolyQ diseases – including Huntington’s disease, dentaHuntington himself after about 1895 (Lanska, 2000b). torubral-pallidoluysian atrophy (DRPLA), spinal and bulEarly neuropathological studies, particularly in the bar muscular atrophy (Kennedy’s disease), and several early-20th century, revealed atrophy, neuronal loss, and spinocerebellar ataxias – are all dominantly transmitted, fibrillary astrocytosis, particularly in the basal ganglia typically adult-onset neurodegenerative disorders affectand less consistently in adjacent areas and the neocortex. ing selected neuronal populations.

THE HISTORY OF MOVEMENT DISORDERS 519 Identification of the Huntington’s disease gene and tendency for early-onset cases to be associated with paterthe huntingtin protein product triggered a remarkable nal transmission were understood to result from meiotic surge in research and numerous important discoveries instability of the Huntington’s disease trinucleotide repeat of cell function and disease pathogenesis. Within several expansion, particularly during spermatogenesis. Indeed, years, disease course and degree of pathological severity by the 1990s it was recognized that anticipation was a were clearly associated with the magnitude of the trinucommon phenomenon of trinucleotide repeat diseases. cleotide repeat expansion (Furtado et al., 1996; Penny The trinucleotide repeat number was found to change in et al., 1997). The CAG triplet is normally repeated about more than 70% of transmissions from parent to offspring, 20 times (with non-expanded alleles considered to with a tendency toward expansion (Andrew et al., 1993), include less than 27 CAG repeats). Alleles with 27–35 apparently because the CAG repeats form stable, hairCAG repeats are considered “mutable normal alleles,” pin-like structures, which produce mistakes with replicabecause they are not associated with clinical disease tion and consequently further expansion of the but have potential meiotic instability and so could possitrinucleotide repeat. This instability of the CAG repeats bly transmit disease in some offspring (American Colduring meiosis was found more often to result in expanlege of Medical Genetics/American Society of Human sions (and sometimes quite large expansions) during Genetics statement, 1998). Pathological effects occur paternal transmission, so that juvenile-onset cases typiwhen the length of polyQ exceeds a threshold of 36–40 cally inherit the disease from their fathers (Duyao et al., glutamines (Duyao et al., 1993; Snell et al., 1993; 1993; Snell et al., 1993; Telenius et al., 1993; Zuhlke et al., Rubinsztein et al., 1996; American College of Medical 1993; Ranen et al., 1995). Thus, anticipation was found Genetics/American Society of Human Genetics stateto result from a novel mutation process and not from ment, 1998). A single copy of the mutant gene invariably selective gene activation or suppression mechanisms. causes disease when the number of repeats is 40 or more The molecular mechanisms responsible for the (complete penetrance), while some but not all indivitrinucleotide repeat expansion mutation have not been duals develop disease when the number of repeats is fully clarified: DNA replication slippage, homolygous between 36 and 39 (reduced penetrance) (Rubinsztein recombination, and slippage during dysfunctional DNA et al., 1996; American College of Medical Genetics/ damage repair are among the mechanisms proposed. American Society of Human Genetics statement, 1998). Initial studies suggested that trinucleotide repeat expanThe length of the CAG trinucleotide repeat (and hence sion mutations occurred during meiosis, particularly of polyQ) is inversely related to the age of onset and during spermatogenesis (Duyao et al., 1993), but both directly related to the severity of symptoms: disease somatic tissues and gametes were subsequently found onset typically occurs in the fourth or fifth decade of life to experience trinucleotide repeat mosaicism (Telenius for CAG repeat expansions of 40–50, but juvenile-onset et al., 1994, 1995; Furtado et al., 1996), with the greatest cases occur in those with more than 60 repeats, and juvelevels of repeat mosaicism detected in brain and sperm nile onset is invariably present in those with more than (Telenius et al., 1994, 1995). Analysis of sperm from 100 repeats (Duyao et al., 1993; Stine et al., 1993; Trottier affected patients showed that both the mutation freet al., 1994; Brandt et al., 1996; Penny et al., 1997). quency and the mean change in allele size increase with Huntington’s disease had long been reported to have increasing somatic repeat number (Leeflang et al., 1999); progressively earlier onset in successive generations, but the extraordinarily high mutation frequency (82%) was the cause of this “anticipation” phenomenon was felt consistent with a mutation process occurring throughunclear and was suspected by some authors to represent out germline mitotic divisions, rather than occurring dura form of observation or selection bias (e.g., because ing just a single point in meiosis (Leeflang et al., 1999). persons of early onset in previous generations could be Analysis of testicular germ cells subsequently demon“selectively nonreproductive” because of manifestation strated that human germline trinucleotide repeat expanof the disorder; see Myers et al., 1982), although a varisions could occur before meiosis begins, but some ety of genetic mechanisms including imprinting with expansions continue to occur during meiosis (Yoon DNA methylation were also considered (Reik, 1988; et al., 2003). The expansion mechanism may be augmenRidley et al., 1988, 1991; Farrer et al., 1992). It was also ted in the male germline because of continuous cell recognized by the late 1960s that a disproportionate division of spermatogonia throughout adult life, which number of cases with early onset (before age 21 years) could explain the tendency of trinucleotide repeat length had inherited the Huntington’s disease gene from their in offspring to increase as a function of the age of the parfathers (Merritt et al., 1969; Barbeau, 1970). ent (Farrer et al., 1992). It is now believed that germline These curious observations were inexplicable by tradiexpansion accounts for the phenomenon of anticipation, tional mechanisms, but after the Huntington’s disease and that tissue-specific somatic expansion may contribute gene was identified, both genetic anticipation and the to the tissue specificity of pathologic involvement.

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Most efforts to understand the pathophysiology of Huntington’s disease have been driven by the “gainof-function” hypothesis in which a novel toxic property of mutated huntingtin is assumed to cause dominantly transmitted neurodegeneration. By 1997 it was recognized that mutant huntingtin with its expanded polyglutamine segment misfolds and aggregates, possibly as self-associating antiparallel b strands (“polar zippers”) (Perutz et al., 1994), to form insoluble intranuclear inclusions (Davies et al., 1997; DiFiglia et al., 1997). The discovery of intracellular aggregates of mutant huntingtin supported the concept that neurodegenerative diseases are generally associated with protein misfolding, and suggested further that polyglutamine toxicity might result from its ability to form aggregates (Davies et al., 1997; DiFiglia et al., 1997). It was subsequently demonstrated that nuclear localization is necessary for toxicity (Yang et al., 2002), but it is still not clear (and is indeed contentious) whether nuclear aggregates are themselves toxic, are benign biomarkers, or are effectively neuroprotective (e.g., perhaps representing the cell’s attempts to inactivate the toxic expanded protein) (Zoghbi and Orr, 2000). Several studies using animal models now suggest that soluble protein fragments, rather than insoluble aggregates, are the toxic factors involved. One problem for the gain-of-function hypothesis had been that rare disease homozygotes (i.e., with two mutant alleles) had been identified prior to identification of the Huntington’s disease gene, and were found to have a similar age of onset to disease heterozygotes, suggesting that Huntington’s disease is a rare “pure dominant” disorder (Wexler et al., 1987); however, because patients homozygous for Huntington’s disease receive a “double dose” of any gain-of-function mutation, a greater toxic effect would be anticipated for homozygotes – an expectation ultimately confirmed in 2003 with a preliminary demonstration that homozygotes have a more severe clinical course (Squitieri et al., 2003). The pathophysiology of neurodegeneration in Huntington’s disease is still not fully understood, but several possible mechanisms have been implicated, including the following: (1) apoptosis (i.e., inappropriate activation of programmed cell death, for example from direct activation of an apoptotic enzymatic cascade, or through loss or lack of transport of anti-apoptotic neurotropic factors); (2) transcriptional dysregulation (e.g., due to sequestration of polyglutamine-containing nuclear transcription factors); (3) excitotoxicity (i.e., death of neurons resulting from excess glutamate neurotransmission); and (4) mitochondrial dysfunction (possibly linked to excitotoxicity) (Coyle and Schwarcz., 1976; McGeer and McGeer, 1976; Olney and de Gubareff, 1978; Beal et al., 1986). Indeed, these putative

neurodegenerative processes were either initially investigated or elaborated substantially in models of Huntington’s disease, and have since been applied to a range of neurologic disorders. The recent developments of transgenic mouse, fly, worm, and cellular models of Huntington’s disease have contributed greatly to understanding of cellular processes and potential pathogenic mechanisms. Because of such models, there is now increasing evidence that multiple possibly overlapping pathologic mechanisms are involved in Huntington’s disease, and in particular both toxic gain-of-function properties of mutated huntingtin and loss of function of wild-type huntingtin are now thought to contribute to neural degeneration. More than a century after Huntington recognized the futility of treatment for hereditary chorea (Huntington, 1872), there are still no effective therapies to delay onset or slow progression in Huntington’s disease.

Athetosis and post-hemiplegic hemichorea In the first American textbook of neurology, published in 1871, neurologist William Hammond described a condition that he called “athetosis” (from the Greek term for “without fixed position”), “characterized by an inability to retain the fingers and toes in any position in which they may be placed, and by their continual motion” (Hammond, 1871; Lanska et al., 2001b). There were associated “pains in the spasmodically affected muscles, and especially complex movements of the fingers and toes, with a tendency to distortion,” with a slower, sinuous quality compared with chorea, and without any associated weakness (Fig. 33.4). Hammond speculated that “one probable seat of the morbid process is the corpus striatum,” a supposition ultimately supported by the autopsy on the original case that was reported by his son Graeme Hammond in 1890 (Hammond, 1890). There was a lesion involving the posterior thalamus, part of the internal capsule, and the lenticular nucleus (Fig. 33.4). Hammond “called attention to the fact that the motor tract was not implicated in the lesion, and claimed that this case was further evidence of his theory that athetosis was caused by irritation of the thalamus, the striatum, or the cortex, and not by a lesion of the motor tract” (Hammond, 1890, p. 555). Despite the confirmation of a proposed clinicopathological association, athetosis was, and remains, controversial, being considered by many late-19th- and 20th-century neurologists as a form of post-hemiplegic chorea or part of a continuum between chorea and dystonia. Silas Weir Mitchell described similar cases under the term “post-paralytic chorea,” noting “as there is a postchoreal paralysis, so, also, is there a post-paralytic chorea . . . [In] adults who have had hemiplegia and have

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Fig. 33.4. Athetosis. Woodcut of athetosis taken from a photograph as illustrated in William Hammond’s Text-book of Nervous Diseases in 1871. Hammond proposed that the responsible lesion would be found in the basal ganglia. The autopsy in 1890 confirmed Hammond’s prediction. Hammond’s prediction and the subsequent confirmation are often regarded as a landmark in the clinicopathologic correlation of movement disorders, and specifically in the linkage of abnormal movements to pathology of the basal ganglia. However, at the time of Hammond’s prediction, the motor centers were thought to be located in the corpus striatum.

entirely recovered power, there is often to be found a choreal disorder, sometimes of the leg and the arm, usually of the hand alone” (Mitchell, 1874, p. 343). Gowers felt there was considerable clinical overlap between Hammond’s athetosis and “post-hemiplegic disorders of movement,” and described similar patients in whom the movement disorder followed a sudden hemiplegia with some degree of recovery (Fig. 33.5) (Gowers, 1876, 1888). He argued for athetosis to be placed in a spectrum of “post-hemiplegic disorders of movement,” between the irregular “quick, clonic spasm” of chorea and the “slow, cramp-like incoordination” and tonic spasms associated with “spastic contracture” (Gowers, 1876, p. 291). As a result, Gowers was willing to accept athetosis with the proviso that

hemiparesis could be associated, depending on the extent of the lesion. Charcot, on the other hand, dismissed Hammond’s athetosis as “simply choreiform movements” (Charcot, 1881, p. 390) or as “only a variety of post-hemiplegic hemichorea” (Charcot, 1881, p. 394), to which Hammond retorted, “I have only to say that the distinction between the two conditions is as well marked as between chorea and disseminated cerebro-spinal sclerosis. In athetosis the movements are slow, apparently determinate, systematic, and uniform; in post-hemiplegic chorea they are irregular, jerking, variable, and quick. Moreover, athetosis is not by any means necessarily post-hemiplegic” (Hammond and Hammond, 1893, p. 324).

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Fig. 33.5. Post-paralytic choreoathetosis was recognized by many eminent late-19th-century neurologists, including Charcot, Gowers, and Mitchell. The left-most column of illustrations from Gowers’ textbook shows “continuous mobile spasm (athetosis) after slight hemiparesis” in a 24-year-old syphilitic patient who developed left hemiparesis at age 23 and abnormal involuntary movements 4 months later; “The hand was in continuous movement between the two positions shown” (Gowers, 1888, p. 80). The center column of illustrations, also from Gowers’ textbook, shows some of the postures of the left hand of a 23-year-old man with “post-hemiplegic mobile spasm”; the abnormal movements began 1 year after onset at the time of some improvement in volitional movement (Gowers, 1876, Plate 12; 1888, p. 80). The right-most column of illustrations shows other “examples of the position of the fingers in the movements of athetosis (Stru¨mpel)” as found in the late-19th-century multiauthored American textbook of neurology edited by Francis Dercum (Sinkler, 1895, p. 265).

Even modern authors have erroneously indicated that Hammond’s original cases were examples of a posthemiplegic movement disorder (Dooling and Adams, 1975; Sharp et al., 1994), but, as emphasized by Hammond, “In the original case there had never been hemiplegia, nor was there such a state in the second case, on which [Hammond’s] description of the disease was based” (Hammond and Hammond, 1893, p. 324). Hammond’s cases both occurred after convulsions and loss of consciousness, and both were associated with some sensory loss. Hammond accepted that hemiplegia could be an antecedent in some cases, but “Where the motor tract is implicated there will be hemiplegia, spastic spasm, and exaggerated reflexes in addition to the athetosis” (Hammond and Hammond, 1893, p. 324). Many preferred to incorporate athetosis into a broader conceptualization of chorea, noting that some cases included features of both types of abnormal movement, and that both could occur after hemiparesis (Wilson, 1925). However, in 1950, Malcolm Carpenter reviewed the literature and concluded that:

Athetosis is a pattern of involuntary dyskinesia which can be distinguished from chorea and is characterized by increases and decreases of tone in irregular sequence in antagonistic muscle groups and slow involuntary movements involving chiefly, but not exclusively, the distal appendicular musculature such that vermicular activity results . . . Hemiathetosis usually develops after hemiparesis, or in association with it, as a consequence of necrotizing cerebrovascular lesions which destroy part of the internal capsule and striatum on the side opposite that of the activity. (Carpenter, 1950, p. 900)

Ballism and the subthalamic nucleus (nucleus luysii) In 1865, Jules Luys (1828–1897) named the subthalamic nucleus the “accessory band of the superior olives” (bandelette accessoire des olives supe´rieures), terminology that was anatomically incorrect, as noted by

THE HISTORY OF MOVEMENT DISORDERS 523 Auguste Forel (1848–1931), who instead proposed to modulate the output of the pallidum (Whittier and rename it Luys’ body (or corpus Luysii) (Luys, 1865; Mettler, 1949a). Whittier and Mettler (1949b) found Forel, 1877; Parent, 2002; Hame´leers et al., 2006). that at least 20% of the subthalamic nucleus had to Several authors in the late-19th century and early-20th be damaged to produce hemichorea-hemiballismus, century reported cases of hemiballismus – characterized although smaller lesions could produce hyperkinetic by continuous, non-patterned, vigorous, or even violent, movements if the efferent fibers in the subthalamic large amplitude, proximally generated involuntary limb fasciculus were also involved. Subsequent lesions of movements – but none of these early authors clearly the internal segment of the globus pallidus abolished or established the subthalamic nucleus as the locus of patholameliorated the hemichorea-hemiballismus, a finding ogy in hemiballismus. In 1884, Ralph Canfield and James which was interpreted (erroneously) as suggesting that J. Putnam presented one of the earliest such reports in the subthalamus normally exerts an inhibitory influence their case of a 59-year-old man with “acute hemiplegic on the pallidum (Whittier and Mettler, 1949b), and which chorea”: “The right arm and leg were found to be in vioin any case provided an experimental basis for what lent and constant motion of a distinctly choreic type, but would later be a useful surgical therapy (Suarez et al., involving the muscles of the larger joints – hip, shoulder, 1997; Slavin et al., 2004). etc. – even more than those of the smaller” (Canfield and Throughout the first half of the 20th century, hemiPutnam, 1884, p. 220). In describing the location of areas ballismus was generally thought to have a poor progof infarcted brain at autopsy, Canfield and Putnam (1884, nosis, often with progression to death within weeks p. 222) noted that “The only ganglionic matter involved or months (Whittier and Mettler, 1949b), but more besides the substantia nigra was (probably) the so-called recent studies have shown that hemiballismus can have ganglion of Luys,” but other brain areas were also a relatively benign course with spontaneous recovery, involved, and no supportive body of evidence or theoretior can respond to various pharmacological or surgical cal framework were available to make a clear clinicaltherapies (Klawans et al., 1976; Dewey and Jankovic, pathologic correlation. 1989; Ristic et al., 2002). In addition, with the advent The relationship between a lesion of the subthalamic of computed tomography and magnetic resonance imanucleus and contralateral hemiballismus was first conging, the recognition of both non-stroke causes (partivincingly demonstrated by J.P. Martin in 1927 (Martin, cularly for patients under age 55 years) and cases 1927): Martin reviewed the world’s literature and noted with lesions outside of the subthalamic nucleus has that 11 of 12 previously reported patients with hemibalexpanded markedly (Dewey and Jankovic, 1989). lismus and available pathology had lesions in the area As late as the 1980s, the subthalamic nucleus was of the contralateral subthalamic nucleus, including thought to modulate basal ganglia output via primarily two with lesions restricted to the subthalamic nucleus, inhibitory (and presumably GABA-ergic) efferents to plus an additional case reported by Martin had a small the pallidum, a seemingly straightforward conclusion hemorrhage nearly limited to the subthalamic nucleus. generally consistent with previous experimental findIn 1947, Whittier noted that lesions of the connections ings and with the clinical observation that lesions of of the subthalamic nucleus could also produce contrathe subthalamic nucleus seem to release the dramatic lateral hemichorea or hemiballismus in man, a finding movements of hemichorea-hemiballismus. However, reinforced by Martin a decade later when he reported since the late 1980s, the neurochemistry and neurophya patient with post-hemiplegic hemichorea-hemiballissiology of the subthalamic nucleus have been substanmus associated with degeneration of efferent connectially revised (Smith and Parent, 1988; Albin et al., tions of the subthalamic nucleus as they passed 1989b; Guridi and Obeso, 2001; Hamani et al., 2003; across the internal capsule in the subthalamic fascicuHame´leers et al., 2006). lus en route to the internal segment of the globus In 1988, using immunohistochemical methods, pallidus (Whittier, 1947; Martin, 1957). Smith and Parent (1988) found that virtually all cell In 1949, Whittier and Mettler produced experimenbodies in the subthalamic nucleus of monkeys are, in tal hemichorea-hemiballismus in monkeys by lesioning fact, intensely immunoreactive to glutamate, but not the contralateral subthalamic nucleus (Whittier and to gamma-aminobutyric acid as had been expected. Mettler, 1949a, b), an animal model subsequently utiThis finding, which implied an excitatory rather than lized extensively by Carpenter (Carpenter et al., 1950; inhibitory function for subthalamic nucleus efferents, Carpenter and Carpenter, 1951; Carpenter, 1955). These was soon independently confirmed in cats (Albin studies demonstrated profuse interconnections between et al., 1989b). Subsequently, in 1992, Hamada and the subthalamic nucleus and the pallidum, but no clear DeLong demonstrated directly that discharge rates of descending connections from the subthalamic nucleus, neurons in both segments of the globus pallidus suggesting that the subthalamic nucleus served to of monkeys decreased substantially following lesions

524 D.J. LANSKA of the subthalamic nucleus, confirming that the tonia, although he labeled it “athetosis” (Barraquersubthalamic nucleus provides excitatory input to both Roviralta, 1897; Barraquer-Bordas and Gime´nez-Rolsegments of the globus pallidus (Hamada and DeLong, da´n, 1988). In 1908, Gustav Schwalbe (1844–1911), 1992). Since then, the subthalamic nucleus has been under the tutelage of Theodore Ziehen (1862–1950), increasingly recognized to play an important role in presented his thesis on dystonic spasms in three sibthe pathophysiology of both hyperkinetic and hypokilings with onset between ages 12 and 14 years, which netic movement disorders (Crossman, 1989). he attributed to a combination of hysteria and a variety of tics – hence his label “tonic cramps with hysDYSTONIAS terical symptoms” (Schwalbe, 1908; Truong and Fahn, 1988), a designation apparently influenced by In 1944, Herz provided detailed cinematographic and Ziehen (1911), who later called this “torsion neurosis.” electromyographic analyses of 15 personal cases of Schwalbe noted the “chronic course, characterized generalized dystonia, as well as an extensive review predominantly with tonic, not painful, asymmetrical of more than 100 literature cases, and concluded that cramps of variable intensity and duration spreading dystonic movements are best described as slow, over the muscles of the whole body” (Schwalbe, sustained, powerful, and non-patterned contortions of 1908, as translated by Truong and Fahn, 1988, p. 657). the axial and appendicular muscles, with simultaneous In his 1911 treatise, Hermann Oppenheim (1858–1919) contractions of agonist and antagonist muscles (Herz, described four Jewish children with a progressive form 1944a, b, c). Dystonia is now defined as “a syndrome of generalized dystonia, which he termed “dystonia musof sustained muscle contractions, frequently causing culorum deformans” (Oppenheim, 1911; Goetz et al., twisting and repetitive movements, or abnormal pos2001f). Oppenheim insisted that dystonia is an organic tures” (Fahn, 1988). Current classification schemes disease and therefore rejected Ziehen’s term “torsion neucategorize dystonias by age of onset, parts of the body rosis.” Oppenheim introduced the term “dystonia” to affected (focal, segmental, multifocal, or generalized), reflect his conclusion that the disorder is associated with and etiology (primary or secondary) (Fahn, 1988). a generalized abnormality of tone with coexistent hypoSince the original descriptions in the 19th and earlyand hypertonia: “in addition to an increased tonus of 20th centuries, dystonias have repeatedly been insome muscles, one finds hypotonia of most of the others” terpreted in psychological or psychiatric terms, because (Oppenheim, 1911, as translated by Grundmann, 2005, p. of the bizarre contortions exacerbated by voluntary 682). Oppenheim also suggested an alternative name, movement, the relief by certain movements or gestures “dysbasia lordotica progressiva,” emphasizing postural (gestes antagonistes), and failure to identify a neurodeformity and the bizarre gait, which he termed “monkey pathological substrate, particularly for generalized gait” or “dromedary gait.” dystonias (Zeman and Dyken, 1967; Zeman, 1970). Only Flatau and Sterling (1911) instead emphasized torin the late-20th century was an organic framework sion spasms as the major clinical feature: “Since the established with identification of genetic mutations in nature of the disease is still unknown to us we should some families with dystonia (Ozelius et al., 1989, retain its most outstanding characteristic in the desig1997a, b) and with demonstration that the putamen, nation. In our opinion this consists in the drawing, caudate, and posterior ventral thalamus were often twisting spasm which is progressive in these affected damaged contralateral to hemidystonia (Narbona et al., children, so we select the designation ‘progressive tor1984; Marsden et al., 1985; Pettigrew and Jankovic, 1985). sion spasm’ ” (Flatau and Sterling, 1911, as translated Therapies for dystonia have focused on both central by Grundmann, 2005, p. 683). Because this is not a priand peripheral pharmacology, with anti-cholinergic mary disease of muscles, and because not all patients agents long employed with variable and at best modest develop fixed postural deformities, “dystonia” or “torbenefit for neuroleptic-induced dystonia (Winslow sion dystonia” is now generally preferred over preet al., 1986; Goff et al., 1991), cranial dystonia (Lang vious designations (Fahn, 1988). et al., 1982; Nutt et al., 1984), and generalized dystonia In the late 1950s and 1960s, Wolfgang Zeman and (Fahn, 1983), and, since the 1980s, with botulinum toxin colleagues demonstrated that primary torsion dystonia increasingly used as a treatment for focal dystonia is a heritable disease (Zeman et al., 1959), and recog(Elston and Russell, 1985; Mauriello, 1985; Tsui et al., nized formes frustes in families with autosomal domi1985, 1986, 1987; Brin et al., 1987). nant transmission (Zeman et al., 1960; Zeman and Dyken, 1967). Roswell Eldridge at the US National Generalized primary tortion dystonia Institutes of Health subsequently emphasized autosoIn 1897, Spanish neurologist Lluis Barraquer-Roviralta mal recessive patterns among Ashkenazi Jews (1855–1928) described a patient with generalized dys(Eldridge, 1970). In the 1980s and 1990s, it became

THE HISTORY OF MOVEMENT DISORDERS clear that the disorder, though genetically heterogeneous, is usually transmitted as an autosomal dominant trait with reduced penetrance. The first primary dystonia locus, DTY1, was localized to chromosome 9q32-34 in 1989, and in 1997 the genetic mutation was identified as a three-base pair (GAG) deletion in the coding region of the Torsin A gene (Ozelius et al., 1989, 1997a, b). This mutation is responsible for most patients with early-onset primary torsion dystonia. Many other loci have now been identified with different modes of inheritance. Treatment of primary generalized dystonia is still limited. Some benefits have been demonstrated with high doses of anticholinergic drugs (Burke et al., 1986), sometimes combined with baclofen or other drugs, and with bilateral deep-brain stimulation of the globus pallidus (Vidailhet et al., 2005).

Writer’s cramp and other occupational dystonias Several authors described writer’s cramp in the 1830s, including Scottish neuroanatomist and surgeon Charles Bell (1774–1842) and J.H. Kopp (Bell, 1830; Kopp, 1836; Goetz et al., 2001g), and these are often cited as the earliest reports, although reports as early as the mid18th century have also been recognized (Lewis 1885– 1886). In 1864 and 1865, British surgeon Samuel Solly (1805–1871) presented a series of clinical lectures on “scrivener’s palsy, or the paralysis of writers” that has been credited with increasing medical recognition of this condition (Solly, 1864, 1865a, b): The disease, as the name implies, shows itself outwardly in a palsy of the writing powers. The muscles cease to obey the mandates of the will. It comes on very insidiously, the first indication often being only a painful feeling in the thumb or forefinger of the writing hand, accompanied with some stiffness; these unnatural sensations subsiding during the hours of rest and sleep, to return with the writer’s work on the next day. The loss of power is not sudden, as in a paralytic stroke nor is it a complete paralysis of any group of muscles. The paralysed [sic] scrivener, though he cannot write, can amuse himself in his garden, can shoot, and cut his meat like a Christian at the dinner-table; indeed he can do almost anything he likes, except earn his daily bread as a scribbler . . . When scriveners’ palsy first commences, the victim of it only feels its direful influence after a hard day’s work. He regards it only as a sign of fatigue, and, as he starts fresh the next morning, attaches no importance to it as the first attack of a serious enemy; but in a short time he is obliged

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to rest earlier in the day, and hails his early dinner hour with joy, as giving him some respite from the fangs of his tormentor. He tries to overcome his difficulty by holding the pen firmer, but this really only increases the evil. Suddenly he finds his pen dash off at a tangent, and the work that he intended to write in the proper line is, to his horror, commenced in the left-hand corner of the page. Not unfrequently [sic] the act of writing is arrested, not by such sudden diversion, but by trembling, and a shaking palsy limited to the right hand. (Solly, 1864, p. 709) Writer’s cramp became a fairly common disabling problem in the 19th century, in part because of the large amount of writing performed, and in part because the available writing instruments required greater force to move across the page (Fig. 33.6) (Gowers, 1888). Case series of writer’s cramp in the 19th century were often very large, including many dozens or even hundreds of patients (Poore, 1878). In 1864, Solly noted that “the greatest part of the middle classes of London get their bread by the use of the pen, either as the exponent of their own thoughts or the thoughts of others, or in recording the sum gained, lost, or spent in this great emporium of commerce – this vast Babylon [i.e., London]” (Solly, 1864). As noted by Sheehy and Marsden (1982, p. 462): “The frequency of the disorder in [the] late Victorian era must stand as a tribute to the success of the British Empire, the enormous office staff required to run it, and the difficulties of manipulating the quill pen.” There was a general recognition in the late-19th century that writer’s cramp was analogous to other conditions that would later be recognized as forms of focal dystonia, including other occupational dystonias

Fig. 33.6. Writer’s cramp or “scrivener’s palsy” was prevalent in the 19th century, before the advent of typewriters or writing instruments (e.g., ballpoint pens) that moved smoothly across the paper. The figure illustrates the “cramped method of holding pen, habitual to a patient who suffered from writer’s cramp” (Gowers, 1888, p. 662).

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and torticollis (Solly, 1864; Beard and Rockwell, 1871; Lewis, 1885–1886; Burr, 1895). For example, Solly noted that “Scriveners’ palsy is not the only instance of a set of muscles being cramped and paralyzed [sic] by longcontinued exertion. There is, as has been observed by Virchow, shoemakers’ cramp, milking cramp, the musicians’ cramp, compositors’ and the sempstresses cramp” (Solly, 1864, p. 709). Similarly, George Beard and Alphonso Rockwell noted in 1871 that writer’s cramp “seems to differ but little from certain other spasmodic conditions, such as wry neck [torticollis] and histrionic spasm” (Beard and Rockwell, 1871). In 1888, William Gowers, while noting that writer’s cramp was the most common of the “occupational neuroses” (a term he derived from the German “Beschaftigungs-neurosen”), nevertheless acknowledged several other less common forms, including “pianoforte player’s cramp” (occurring particularly among women professionals) and “telegraphist’s cramp,” as well as similar conditions among violin players, zither players, harpists, sempstresses, tailors, knitters, engravers, milkers, painters, cigarette makers, money counters, and rarely blacksmiths (Gowers, 1888). German pianist Robert Schumann (1810–1856) was a prominent musician who had a task-specific dystonia (“pianist’s cramp”) that influenced both his playing and his composition, and that ultimately ruined his performance career; Schumann’s Toccata, Op. 7, written around 1830, was a virtuoso piano work that Schumann wrote to avoid using his dystonic right middle finger (Altenmu¨ller, 2005). Instruments used in the treatment of writer’s cramp evolved over time, and most were largely abandoned when the development of better writing instruments and alternative means of written communications (e.g., the typewriter) decreased the frequency of and disability associated with writer’s cramp (Lanska and Goetz, 2002). Patients initially devised a number of simple but cumbersome methods of minimizing the muscle contractions associated with writing, including enlarging the dimensions of their pens (e.g., with a piece of cork, potato, or apple). A large number of simple mechanical writing aids were subsequently devised and reported in the 19th-century medical literature. Most of these instruments limited thumb and finger flexion, and instead utilized unaffected finger extensors or more proximal muscles moving the wrist, elbow, or shoulder (Fig. 33.7). Nevertheless, many authorities considered any benefit of such aids to be limited, temporary, and in no way curative (Lewis, 1885–1886; Robins, 1885a; Burr, 1895), and some argued that use of such instruments ultimately resulted in clinical involvement of the entire arm and even greater disability. With improvements in writing instruments, there was “no temptation to exert pressure” while writing (Putnam, 1879); these changes followed replacement of quills and dip pens

upon the development of workable stylographic pens in the 1870s and fountain pens c. 1883 and after. After the development of the typewriter in the late-19th century, the use of such mechanical aids decreased markedly (Gowers, 1888; Blackwood, 1889). Nineteenth-century authorities on writer’s cramp also frequently advocated varying degrees of rest (Gowers, 1888; Lanska, 2002b), and sometimes applied splints or slings to ensure that the limb would not be used: e.g., some physicians enforced rest by fastening the hand upon a splint (Buzzard, 1872), while others similarly ordered the “arm to be carried in a sling for a week or so, to remind the patient that all writing is to be shunned” (Robins, 1885b). In the 1970s Alan Scott, a US ophthalmologist, introduced the use of botulinum toxin type A as a chemodenervating agent in the treatment of strabismus, and in the 1980s Scott extended the use of this agent to focal dystonias, including blepharospasm and torticollis (Scott et al., 1973; Tsui et al., 1985). Botulinum toxin type A was subsequently approved for clinical use in 1989, and botulinum toxin type B was approved for clinical use in 2000, particularly for cervical dystonia. Based on one well-designed, randomized, controlled clinical trial in writer’s cramp (Kruisdijk et al., 2007), and several other studies, botulinum toxin is now considered a “probably effective” treatment option for treatment of upper limb dystonias, including writer’s cramp (Simpson et al., 2008). It is also considered safe and effective for treatment of cervical dystonia, and probably effective for blepharospasm and adductor spasmodic dyphonia (Simpson et al., 2008).

MYOCLONUS Myoclonus is a sudden, non-suppressible, shock-like muscular contraction triggered within the central nervous system. Myoclonic movements can be “positive” or “negative”: positive myoclonus results in the contraction of a muscle or muscles, whereas negative myoclonus (e.g., asterixis) is instead associated with a brief loss of muscle tone (Shahani and Young, 1976; Young and Shahani, 1986). By 1903, Lundborg proposed a classification system that remains largely in use today, with primary (essential), secondary, and epilepsy-associated categories (Lundborg, 1903; Goetz et al., 2001h).

Essential myoclonus In 1881, Nikolaus Friedreich (1825–1882) reported a 50year-old man with a 5-year history of multifocal muscle jerking, occurring at a rate of 10–50 per minute, and affecting both sides of the body symmetrically but asynchronously. The rapid muscle jerks affected the

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Fig. 33.7. In the 19th century, numerous writing aids were invented to facilitate writing for those with writer’s cramp. Shown are a range of aids distributed by George Tiemann and Company of New York (Tiemann, 1899). All of the instruments serve to redirect the type of hand and finger muscle contractions used to grip or move the writing instrument. The top row shows various loop attachments for the fingers (to minimize the need to pinch the writing instrument), the second row shows grip devices (with a similar intent), and the bottom rows show devices that allow a sliding motion along the writing surface (in some cases resembling a modern “mouse” for a personal computer). With permission.

528 D.J. LANSKA bulk of a full muscle, without marked limb or joint with associated brief lapses of posture, causing bilatmovement, except in the most powerful contractions. eral asynchronous flapping movements associated with Friedreich called the syndrome “paramyoclonus multiintermittent pauses of electrical activity of from 50 plex” to indicate quick movements, distinct from epito 200 milliseconds on EMG tracings (Adams and lepsy, symmetrically affecting multiple sites of the Foley, 1949, 1953; Leavitt and Tyler, 1964; Young and body (Friedreich, 1881; Goetz et al., 2001h). Although Shahani, 1986). Friedreich suspected the problem was caused by a In 1949, Raymond Adams and Joseph Foley(1916–) spinal cord disorder, no pathology of the spinal cord first noted an “almost rhythmical” tremor during mainwas later identified at autopsy (Hallett, 1986). tenance of posture in patients with advanced hepatic Friedreich’s term was adopted in shortened form as encephalopathy (Adams and Foley, 1949). In 1953, “myoclonus” and in modern terminology his case Adams and Foley expanded on their clinical descripwould be classified as essential or idiopathic myoclotion, correctly recognized that the flapping tremor is nus. Lindemulder (1933) later reported a family with due to pauses in electromyographic activity and not essential myoclonus, which helped demonstrate that to intermittent increases in electrical activity as had such generalized myoclonus could occur in the absence been supposed, and proposed the term “asterixis” for of neurodegenerative disorders, epilepsy, or obvious the “intermittency of the sustained contraction of metabolic derangement. groups of mucles” that characterized the abnormal movements:

Myoclonic epilepsy Throughout the 19th century, myoclonic jerks in association with epilepsy were recognized by various authors, as part of what would now be called infantile spasms (West, 1861). In 1891, Unverricht reviewed the literature on myoclonus, dismissed the majority of cases reported to that point as incorrectly designated, and also described patients with progressive multifocal myoclonus and epilepsy (Unverricht, 1891). In 1903, Lundborg described additional patients with familial progressive myoclonic epilepsy, distinct from “paramyoclonus multiplex” or essential myoclonus. In the 1990s, progressive myoclonic epilepsy of Unverricht–Lundborg was linked to mutations in the cystatin B gene on chromosome 21q.22, which codes for a small protein in the superfamily of cysteine protease inhibitors. Other forms of progressive myoclonic epilepsy were also recognized, including lysosomal storage diseases (e.g., neuronal ceroid lipofuscinosis), mitochondrial disorders (e.g., myoclonic epilepsy with ragged red fibers or MERRF), and glycogen storage diseases (e.g., Lafora’s disease).

Secondary or symptomatic myoclonus In the 1920s and 1930s, multifocal myoclonus was recognized as a feature of encephalitis lethargica (Walshe, 1920; von Economo, 1929), Creutzfeldt-Jakob disease (Creutzfeldt, 1920; Jakob, 1921), and subacute sclerosing panencephalitis (Dawson, 1934). Secondary myoclonus is now recognized in a wide variety of disorders, including infections, metabolic derangements, hypoxia, and neurodegenerative diseases (Goetz et al., 2001h).

Asterixis and metabolic tremor Asterixis is characterized by brief, arrhythmic interruptions of sustained (tonic) voluntary muscle contraction

A practical clinical test by which it may be elicited is having the patient hold the arms outstretched with wrists and fingers dorsiflexed. With the extremities in this position there occurs, in addition to a fine tremor of the fingers, a sudden lapse of the assumed posture, lasting a fraction of a second, in the fingers, wrist, and sometimes the elbow and shoulder. It is irregular in frequency and variable in amplitude; usually the rate is about once every one to five seconds. When the limb is in repose it disappears and during strong muscle contraction it is temporarily suppressed . . . Inasmuch as this movement disorder is essentially an inability to maintain a fixed posture the term asterixis (a – privative, sterixis – maintenance of posture) is suggested. Electromyographic analysis of the disorder reveals that the tremor has a frequency of 6–8 per second and that with the lapse of posture there is a reduction or cessation of electrical activity in both the muscles sustaining the posture and in their antagonists . . . Although present in the majority of cases of hepatic coma, we have seen it in three cases of polycythemia with mental confusion and in three cases of uremia. Therefore, it may be regarded as a characteristic but not specific clinical sign of hepatic coma. (Adams and Foley, 1953, p. 51) Others soon recognized that asterixis occurred with various metabolic encephalopathies, including uremia, respiratory failure, drug intoxications, and electrolyte imbalances (Conn, 1960; Leavitt and Tyler, 1964), or unilaterally with various focal brain lesions located in the cerebral hemisphere contralateral to the asterixis (Leavitt and Tyler, 1964; Young et al., 1976).

THE HISTORY OF MOVEMENT DISORDERS In 1964, Leavitt and Tyler added several important clinical observations concerning asterixis and the associated tremor: The characteristic tremulousness and asterixis occurred only after a latent period of 2–30 seconds, tremulousness appearing first . . . [In] the context of increasing tremulousness, yet clearly interrupting the pattern of tremulousness, the hand, almost as a unit, but with fingers leading, lapsed forward anywhere from 2 to 5 cm only to be jerked back to its original position. The backward movement was often more violent than the lapse forward. The patients had no control over the lapse and no warning of its occurrence. Positional lapses were unassociated with any lapse in attention or consciousness . . . No patient was able to prevent himself from jerking his hand back once the lapse had occurred. The lapse occurred at similar rates in both hands, but asynchronously. Although commonly evoked with the dorsiflexed hand in pronation, asterixis against gravity occurred when the dorsiflexed hand was supinated. (Leavitt and Tyler, 1964, p. 361) Leavitt and Tyler found that the average duration of electrically silent periods associated with asterixis on electromyography was 50–70 milliseconds. Although lapses in electrical activity were initiated simultaneously in different muscles within the same limb, the degree of electrical silence varied between muscles and even across locations within the same muscle. The EMG correlate of a flapping movement was found to be “a triple pattern of silence, discharge, and silence,” with the initial period of electrical silence occurring approximately 70 milliseconds before the movement artifact, followed by an “asymmetrical burst of electrical activity” corresponding to “a braking and withdrawal of the forward loss of position,” and then terminating with a 20–30 millisecond period of electrical silence which represented a “terminal pause inhibition of the ‘braking-withdrawal’ discharge to prevent an overshoot” (Leavitt and Tyler, 1964, p. 364). Leavitt and Tyler’s electrophysiological studies also showed that much of the tremulousness seen with asterixis was in fact due to shorter pauses or sudden brief decrements in voluntary electromyographic activity occurring asynchronously in different muscle groups of the same limb (Leavitt and Tyler, 1964). They labeled this tremulousness “metabolic tremble” or “metabolic tremor,” and felt this was “a manifestation of the same phenomena that underlie asterixis” (Leavitt and Tyler, 1964). Shahani and Young later labeled as “negative myoclonus” the postural lapses associated with reductions

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in EMG activity: “Because these synchronous brief pauses, which occur at irregular intervals in the ongoing voluntary EMG activity, produce movements that appear clinically to be myoclonic, one may characterize this as ‘negative myoclonus’” (Shahani and Young, 1976, p. 780). Young and Shahani considered negative myoclonus to be “a more inclusive term encompassing asterixis and tremor in patients with metabolic encephalopathy and other circumstances in which brief periods of EMG silence produce an abnormal movement” (Young and Shahani, 1986, p. 154).

Lance–Adams syndrome (posthypoxic action myoclonus) Acute posthypoxic myoclonus is characterized by generalized, often massive, muscle jerks, associated with generalized spike and polyspike activity on electroencephalography. In 1963, James Lance (1926–) and Raymond Adams described intention or action myoclonus in patients who had posthypoxic encephalopathy (Lance and Adams, 1963). Chronic posthypoxic myoclonus was often restricted to the limbs, increased markedly in frequency and intensity with attempts to move a limb, particularly for precise motor tasks, and was also triggered by sensory stimulation, startle, or strong emotions. In addition to the “positive” spontaneous, action, and stimulussensitive forms of myoclonus, affected patients also had “negative myoclonus,” with postural lapses in their legs while standing or walking, causing leg buckling and falls, with associated periods of electrical silence in the leg muscles (Frucht and Fahn, 2000; Lance and Adams, 2001). “Positive myoclonus” often followed spike discharges on EEG with a latency of from 7 to 32 msec, whereas “negative myoclonus” was associated with post-spike slow waves or occurred in isolation. Additional associated neurologic findings included dysarthria, cerebellar dysfunction (i.e., dysmetria, intention tremor, and ataxia), gait disturbance, and grand mal seizures.

PATHOLOGIC STARTLE SYNDROMES Startle is a universal and phylogenetically ancient stereotyped reflex response to sudden, intense stimulation, which can be exaggerated in a wide variety of neuropsychiatric disorders, including various culture-bound syndromes (e.g., jumping, miryachit, and latah), hyperekplexia, startle epilepsy, benzodiazepine and alcohol withdrawal syndromes, post-traumatic stress disorder, and general anxiety disorder (Howard and Ford, 1992).

Jumping In 1878, American neurologist George Beard (1839–1883) described the “Jumpers, or jumping Frenchmen,” found

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among the French Canadians of northern Maine (Beard, 1878, 1880a, b). His initial report was based on conversations and correspondence (Beard, 1878), but he subsequently investigated the cases personally (Beard, 1880a, b). He noted excessive reactivity to sounds, automatic obedience, and echolalia. The term “jumping” encompassed all of the associated abnormal startle manifestations, including “lifting the shoulders, raising the hands, striking, throwing, crying, and tumbling” (Beard, 1880b, p. 174). Jumpers were physically healthy and active, and clearly distinguishable from the state of nervous exhaustion which he had previously described and labeled as “neurasthenia” (Beard, 1869). Symptoms persist throughout life, or in Beard’s (1880b, p. 176) words: “once a jumper, always a jumper.” Beard felt jumping could only be practically studied by psychological means: Far out of the range of the aided senses, far beyond the reach of the microscope, or perhaps the spectroscope, there may be molecular changes or disturbances which manifest themselves in these jumpings and strikings and throwings as a result and correlative. But for the present, possibly for all time, we can only study this subject psychologically . . . (Beard, 1880b, p. 175) The cause of jumping remains unknown. Beard noted that jumping was familial, and believed that jumping was therefore necessarily “hereditary”; however, jumping is rarely seen in women and no detailed pedigrees supporting Mendelian inheritance have been published. Clinical authorities who have examined jumpers have most commonly interpreted jumping to be a culturally standardized startle response or an operant-conditioned response (Saint-Hilaire et al., 1986). Jumping was largely forgotten until further cases were described in the mid-1960s and afterwards (Kunkle, 1965, 1967; Rabinovitch, 1965). These later descriptions include a somewhat expanded clinical spectrum, which includes pathologic startle reaction, automatic obedience, echolalia, and rarely echopraxia and coprolalia.

Miryachit In 1884, New York neurologist and former Surgeon General William Hammond (1828–1900) noted similarities between Beard’s description of “jumping” and a recently published description of Siberian “miryachit” (meaning “to act foolishly”) (Hammond, 1884). Several US Navy officers had observed an affected Siberian ship’s steward while on the Ussuri River in southeastern Siberia in 1882. The steward was afflicted by echopraxia, echolalia, and excessive startle, but without reported automatic obedience or actual jumping; he was unable to resist imitating

the grunts, shouts, or pounding on the bulkhead intentionally produced by the crew and passengers to provoke his behavior. Unlike Beard, who had personally examined jumpers, Hammond did not make his own personal observations of miryachit.

Hyperekplexia Hyperekplexia or “startle disease” was described in the late 1950s and early 1960s, and is characterized by generalized hypertonia and hypokinesia in infancy, followed by an exaggerated startle response to unexpected stimuli, gait difficulties, frequent falls without loss of consciousness, nocturnal myoclonus, and increased frequency of hip dislocations and inguinal hernias (Suhren et al., 1966; Andermann et al., 1980; Kurczynski, 1983). An autosomal dominant pattern of transmission was recognized in a pedigree spanning five generations by Suhren et al., (1966). In the 1990s, mutations in the a1 subunit of the glycine receptor were identified (Shiang et al., 1993). Subsequently, both autosomal dominant and autosomal recessive forms were recognized, with mutations affecting the presynaptic glycine transporter-2, the a1 and b subunits of the glycine receptor, and other postsynaptic glycinergic proteins including gephyrin and RhoGEF collybistin.

TICS Tics are involuntary, rapid, non-rhythmic, stereotyped movements that are episodically present and occur on a background of normal movements. Tics can be categorized as motor (e.g., brief movements) or vocal (e.g., abnormal sounds produced by moving air through the nose, mouth, or throat) (The Tourette Syndrome Classification Study Group, 1993). French physician Jean Itard (1775–1838) offered the first clear description of tic disorders in 1825 (Itard, 1825), a report later cited by Gilles de la Tourette (1885), who included Itard’s case in his larger series of nine cases. Tics were also recognized by French physician Armand Trousseau (1801–1867), who wrote: Non-dolorous tic consists of abrupt momentary muscular contractions more or less limited as a general rule, involving preferably the face, but affecting also neck, trunk, and limbs. Their exhibition is a matter of everyday experience. In one case it may be blinking of the eyelids, a spasmodic twitch of cheek, nose, or lip; in another, it is a toss of the head, a sudden, transient, yet everrecurring contortion of the neck; in a third, it is a shrug of the shoulder, a convulsive movement of diaphragm or abdominal muscles, – in fine, the term embodies an infinite variety of bizarre

THE HISTORY OF MOVEMENT DISORDERS 531 actions that defy analysis. These tics are not least surprise will exaggerate the tics, as will infrequently associated with a highly characterstrong emotional encounters . . . On the other istic cry or ejaculation – a sort of laryngeal or hand, tics may be diminished and in fact complediaphragmatic chorea – which may of itself contely suppressed by various factors . . . The movestitute the condition; or there may be a more ments completely cease during sleep . . . Patients elaborate symptom in the form of a curious impulse can experience spontaneous periods of remission to repeat the same word or the same exclamation. where incoordination becomes minimal, although Sometimes the patient is driven to utter aloud what never disappearing completely . . . These patients’ he would fain conceal. (Trousseau, 1873, p. 267; mental state is perfectly normal . . . During a perquoted by Meige and Feindel, 1907, p. 27) iod of excitement, when the patient has an incoordinated movement, he will begin to shout an Tics gained wider recognition late in the 19th century, inarticulated sound – usually when the movement after Charcot presented cases before his classroom audiis at its height. It is often difficult to translate this ence (Charcot, 1887/1987). Tics occur as a required diagsound – “hem,” “ouh,” “ouah,” or “ah” . . . Our nostic feature of Gilles de la Tourette syndrome (see patients are echolalics, and this marks one of below), but can also occur in a wide variety of neurologic their major symptomes . . . Echolalia should not disorders. be considered in its most restricted sense, since these people also will imitate a gesture or an Gilles de la Tourette syndrome act . . . Not only do these patients say obscene words, but it seems that there can be a combinaIn 1881, French neurologist Georges Gilles de la Tourtion of echolalia and coprolalia . . . The progresette (1857–1904), house physician at the Salp^etriere sion of this condition, as much as we can tell, is under Jean-Martin Charcot (1825–1893), translated slow and insidious . . . Could a patient eventually Beard’s report of “jumping Frenchmen” (Gilles de la overcome the problem altogether, after many Tourette, 1881). In 1884, Gilles de la Tourette conepisodes of remission? We cannot be absolutely trasted American jumping, Siberian miryachit, and a certain, but from our case histories, we would similar Malaysian condition called latah (Gilles de la conclude that the condition never completely Tourette, 1884; Lajonchere et al., 1996). He concluded disappears . . . Let us recall first some of the funthat the three disorders were identical, and reported damental symptomes: (1) this illness is herediseeing similar cases on Charcot’s service with hyperextary; it is characterized by motor incoordination citability, motor tics, echolalia, and coprolalia. in the form of abrupt muscular jerks that are often Gilles de la Tourette’s classic description of what severe enough to make the patient jump; (2) the Charcot later called maladie des tics de Gilles de la incoordination can be accompanied by articuTourette was written “with the help of Professor lated or inarticulated sounds. When articulated, Charcot” and based upon a series of nine patients: the words are often repetitions of words which The condition which we will describe generally the patient may have just heard. Such vocal imitastarts at a young age . . . Although the movetion (echolalia) may have a physical corollary ments can vary in their form from one individual whereby the subject imitates an act or gesture to another, they still maintain general characterthat he has just seen; (3) among the expressions istics which are the same in all subjects. One of which the patient may repeatedly utter during these characteristics is the abruptness with one of his convulsions, some have the special which the movements appear and another is character of being obscene (coprolalia); (4) the their rapidity. Suddenly, and without warning, physical and mental health of these patients is a grimace or contortion appears once, twice or otherwise basically normal. The condition seems several times. Then all is quiet. But soon afterincurable and life long, with onset in childwards (for generally the intervals between movehood. (Gilles de la Tourette, 1885; as translated ments are quite close) new jerks appear. by Goetz and Klawans, 1982, pp. 4–10) Importantly, most of these movements are limited either to the face, an extremity, or a combiDespite clinical overlap between “jumping” and Gilles nation of these two . . . Emotional upset caused de la Tourette syndrome, these entities are now recogby internal conflict or physical discomfort will nized as distinct. In “jumping,” the key feature is an aggravate both the frequency and the intensity abnormal startle response, the abnormal reaction is of the abnormal movements. These patients are always provoked, and tics are absent; whereas, in Gilles particularly sensitive to external stimuli: the de la Tourette syndrome, the key feature is spontaneous

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motor and vocal tics, although patients with Gilles de la Tourette syndrome may also have an exaggerated startle response. Gilles de la Tourette did not emphasize spontaneous tics as the essential feature of this syndrome, in part because of his attempt to establish a close relationship between the patients he reported and those with jumping, miryachit, and latah. Echolalia is no longer considered a major clinical feature, and a strict concordance between vocal tics and simultaneous motor tics is no longer accepted. Nevertheless, the modern definition of Gilles de la Tourette syndrome incorporates all the original diagnostic criteria proposed by Gilles de la Tourette (1885) with Charcot’s input (Kushner et al., 1999): childhood onset, motor and vocal tics, natural waxing and waning, and chronicity. Freudian psychodynamic and psychological theories of the etiology of Gilles de la Tourette syndrome were dominant in the early 20th century. In the 1960s, the discovery that neuroleptic medications, particularly haloperidol, were useful in treating tic disorders provided support for a biological origin, and further supported an important role for dopamine in the pathophysiology (Seignot, 1961; Shapiro et al., 1973). A pathophysiologic role for dopamine has been further suggested by later findings in the 1970s and 1980s that (1) levodopa and dopamine agonists can induce or exacerbate tic disorders; (2) tardive tic disorders can occur after long-term neuroleptic treatment (suggesting facilitation by dopamine receptor hypersensitivity); (3) cerebrospinal fluid metabolites of dopamine (i.e., homovanillic acid) are selectively reduced (suggesting decreased dopamine turnover); and (4) clinical improvement with haloperidol is associated with an increase in cerebrospinal fluid metabolites of dopamine (Klempel, 1974; Klawans et al., 1978; Butler et al., 1979; Cohen et al., 1979; Mitchell and Matthews, 1980; Singer et al., 1982). Gilles de la Tourette syndrome has been recognized as familial since Gilles de la Tourette’s original report (Gilles de la Tourette, 1885). However, no clear pattern of inheritance and no specific gene defect have been documented, although an autosomal dominant pattern with incomplete penetrance and variable expression is most widely accepted. Modern genetic studies of Gilles de la Tourette syndrome have been frustrating because of difficulties in defining phenotypes, and in determining whether subjects with obsessive-compulsive symptoms or elements of attention deficit disorder should be considered as affected cases (Goetz et al., 2001i).

CONCLUSION At the beginning of the 21st century, clinicians and neuroscientists can look with some satisfaction at the progress made in the field of movement disorders, par-

ticularly in the half century since Barbeau’s historical review in 1958 (Barbeau, 1958) – for example, improved understanding of how the basal ganglia modulate cortical motor function, improved understanding of the pathophysiology of several diseases (e.g., parkinsonism, Wilson’s disease, and Huntington’s disease), development of effective therapies (e.g., for Parkinson’s disease and Wilson’s disease), and effective prevention (e.g., for rheumatic fever and its effects, including Sydenham’s chorea), development of useful animal models (e.g., the MPTP model of Parkinson’s disease, and transgenic mouse, fly, worm, and cellular models of Huntington’s disease), and identification of genes for several disorders (e.g., Huntington’s disease, Wilson’s disease, some familial forms of torsion dystonia, essential tremor, and Parkinson’s disease). Still, much more work remains to be done to understand these disorders and treat them effectively. The rapid pace of increasing knowledge in this area, and the recent development of powerful new technologies (e.g., in the fields of neuroimaging, genetics, molecular biology, among others), suggest strongly that further significant progress can be anticipated.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 34

The history of sleep medicine RAFAEL PELAYO *, NICKISSA HODGSON AND CHRISTIAN GUILLEMINAULT Sleep Medicine Center, Stanford University School of Medicine, Stanford, CA, USA

INTRODUCTION Sleep has fascinated humans throughout recorded history. Aristotle (384–347 BC) and Hippocrates (460–370 BC) attempted to explain sleep and dreams. Sleep was often used as a term synonymous with death. A belief in a spirit world or afterlife may have originated from a need to explain dream imagery of the deceased. Most, if not all, major religions have accounts of dreams as a means of communication between man and God(s). The study of sleep thus began very early and was clearly of interest to early physicians. However, the modern history of sleep studies begins with the development of the ability to continuously record the electrical activity of the brain. Hans Berger (1873–1941), in 1924, recorded brain electrical activity and demonstrated differences between the activity observed in sleep and wakefulness. In his publications, which started appearing in 1930, he called the signals that he recorded the “electroencephalogram.” From these initial efforts came an understanding of the complexity of the electrical brain activity during sleep. In a series of papers published between 1935 and 1939, Alfred Lee Loomis and colleagues at Harvard characterized electroencephalograph (EEG) patterns correlated with five discrete stages of sleep. These descriptions of specific sleep EEG rhythms introduced a new era of sleep research. This chapter will review the fundamental events that have established the modern field of sleep medicine.

UNDERSTANDING THE NEUROANATOMY OF SLEEP Constantin Von Economo (1876–1931) Von Economo in Vienna made landmark observations of patients suffering from encephalitis lethargica. He correlated the clinical symptoms of insomnia and of continuous lethargy with two different inflammatory lesions.

*

Lesions in the pre-optic area and anterior hypothalamus led to insomnia and hyperkinetic movements whereas lesions of the posterior hypothalamus led to sleepiness, continuous lethargy and eye-movement abnormalities. Von Economo found that the anterior hypothalamic lesions often extended to the diencephalon (basal ganglia) while the posterior hypothalamic lesions were associated with lesions in the periaqueductal gray matter with frequent extension to the oculomotor nuclei, explaining the frequent co-occurrence of oculomotor symptoms. This led Von Economo to speculate that the anterior hypothalamus contained a sleep promoting area and that an area spanning from the posterior wall of the third ventricle to the third cranial nerve nucleus was involved in activity promoting wakefulness. He also speculated that the syndrome of narcolepsy involved the latter area, an area also suspected to be involved in narcolepsy by Charles P. Symonds (1926). Von Economo’s theory was supported by the work of Walter Rudolph Hess (1881–1973) who in 1929 performed stimulation of the central gray matter in the regions of the thalamus and showed that it induced sleep. Walter Ranson (1880–1942) in collaboration with Ingram in 1932 induced sleepiness with lesions at the top of the brain stem, which also supported Von Economo’s theory. Later Wally J.H. Nauta (1946) showed that posterior hypothalamic lesions produced sleepiness whereas anterior hypothalamus lesions induced insomnia. Nauta described a “sleep center” in the anterior hypothalamus, which had an active influence on the occurrence of sleep. He confirmed Von Economo’s clinical pathology conclusions by experimental stimulation.

Moruzzi and Magoun Moruzzi and Magoun in 1949 described “the ascending reticular activating system.” They found that lesions of

Correspondence to: Rafael Pelayo MD, Sleep Medicine Center, Stanford University School of Medicine, 450, Broadway Street, Pavilion C, 2nd Floor, Redwood City, CA 94305, USA. E-mail: [email protected], Tel: +1-650-723-6601, Fax: +1-650-725-8910.

548 R. PELAYO ET AL. the reticular formation, but not of adjacent sensory The identification of REM as a distinct state was the pathways, produced a loss of cortical activation. The work of Michel Jouvet in Lyon (France) (see also Ch. 40). lesions with the most marked effect were located in Jouvet trained in neurosurgery. After reading of the pontis oralis nucleus, mid-brain reticular formation Dement and Kleitman’s research, Jouvet studied sleep and the posterior hypothalamic-subthalamic regions. in cats. He found (Jouvet and Michel, 1959) that the cat Lesions in the mid-brain tegmentum and caudal diencehad muscle atonia in association with rapid eye movephalons showed that dissociation between cortical actiments and a desynchronized EEG pattern. In 1962, vation and behavioral arousal of wakefulness could be Jouvet called this state “paradoxical sleep.” The “paraobtained. dox” was that the cats had an EEG that resembled Following these initial studies, lesions at different wakefulness while remaining asleep. Together with levels were performed to reveal the neuroanatomy Michel and Courjon, Jouvet (Jouvet et al., 1959) also responsible for cortical activation. This neuroanatomy reported that this new “state” was associated with the included not only the reticular formation but also the presence of large electrical potentials that were first seen posterior hypothalamus-subthalamus and basal forein the pons, but appeared a few milliseconds later and brain systems (nucleus basalis of Meynert). Transecwere able to be recorded most easily in the lateral genicution of the brain stem behind the pontis oralis late nucleus and with further but limited delay, in the tegmentum by Batini and other collaborators of Moroccipital cortex, leading to the characterization of uzzi (1958, 1959) resulted in complete insomnia. This Ponto-geniculo-occipital (PGO) spikes. These events were indicated that important sleep-generating structures phasic and along with twitches and irregular breathing led were located in the lower brain stem. Further studies to the subdivision of REM sleep into phasic and tonic showed that neurons in the medullary dorsalis reticular REM sleep. formation and nucleus of tractus solitarius could genAs advances in understanding the neuroanatomy and erate sleep. These studies identified a sleep generating neurophysiology of animal sleep developed, a need was system in the brain stem in association with a sleep recognized to standardize the terminology of human generating system involving the pre-optic area, the sleep across different research and clinical settings. This anterior hypothalamus and the basal forebrain. led to a landmark event under the leadership of William Dement, the formation of the first professional sleep society: the Association of Psychophysiological Study of REM and Development of Sleep Medicine Sleep (APSS). This group published a human sleep stage Our understanding of sleep was greatly changed by the scoring manual in 1968, edited by Allan Rechtschaffen discovery of rapid eye movement (REM) sleep, which and Anthony Kales. This publication (Rechtschaffen has also been called paradoxical sleep (PS) and desynand Kales, 1968) has served as an international reference chronized sleep. The discovery is based on the pioneerthat has unified has the sleep research community. ing work of Nathaniel Kleitman (1895–1999) on basic With the recognition of sleep stages the question rest and activity cycles (1939; revised 1963). Kleitman arose as to what the cellular basis was for these differand Richardson were the first to conduct time isolation ent stages of sleep. Mircea Steriade (1924–2006) led the experiments in humans. Kleitman questioned whether research on the cellular basis of the sleep stage oscillathe activity cycle shown by infants after birth could be tions (2003). He emphasized the concept that the cerean integral multiple of a basic rest–activity cycle bral cortex and the thalamus constitute a unified (1939). Kleitman also studied the “depth of sleep.” His system that generates the coalescence of different brain interest in eye motility led the way for the discovery rhythms into complex wave sequences, which include of REM. In 1953, Aserinsky and Kleitman reported regvarious low frequency oscillations but also fast rhythms. ularly occurring periods of eye motility during sleep. The history of normal sleep research is not limited In 1957, Dement and Kleitman reported the cyclical to electrophysiology. Neuropharmacological research variation of EEG sleep and its relation to eye movecontributed to an understanding of the neuro-transmitments, body movements and dreaming. They found ters and peptides involved in sleep (Jouvet, 1972). that the cyclical variation from a period of eye moveBiochemistry and cellular imaging techniques were ment to the successive one was between 90 min and applied to unravel the intracellular mechanism of nor100 min. At that time sleep was still considered a single mal sleep. With the emerging knowledge of normal state, so the authors characterized the EEG corresleep mechanisms a parallel need for understanding sponding to REM as “emergent stage 1” as opposed abnormal sleep was necessary. Together this led to to “descending stage 1,” which was seen at sleep onset. the development of the new field of sleep medicine. REM sleep was discovered but not yet identified as a The remainder of this chapter will review the history completely different state. of specific sleep disorders.

THE HISTORY OF SLEEP MEDICINE

PATHOLOGY AND SLEEP ^ THE PRELIMINARY PHASE: SLEEP AS PART OF NEURON ELECTROPHYSIOLOGY Sleep disorders have been observed throughout history. However, only recently has the systematic study of sleep disorders been attempted.

Henri Gastaut and the birth of modern sleep medicine Henri Gastaut’s (1915–1995) continuous search for abnormal behavior of epileptic origin led him to monitor many subjects’ wakefulness and sleep (see also Ch. 40). His focus on epilepsy was also his limitation. If the abnormal behavior he observed was not of an epileptic nature, his interest would fade. However, many of the young researchers that worked with him, such as Roger Broughton, Carlo Tassinari, and Jean-Paul Spire, reported their findings on abnormal sleep behaviors (Gastaut et al., 1965a; Broughton, 1968). Tassinari also collaborated with Elio Lugaresi and Giorgio Coccagna. An important early meeting was hosted by Herman Fischgold in 1963 for the European EEG Society in Paris. The proceedings were published as Le sommeil de nuit normal et pathologique (1965). At this meeting the Gastaut group led discussions on sleepwalking, night terrors, and sleep-related epileptic behavior (Gastaut et al., 1965a). Another landmark meeting was the 15th European electrophysiology meeting, whose proceedings were published in English as The Abnormality of Sleep in Man (Gastaut et al., 1968). The findings of Jackobson and Kales on somnambulism in children, and those of Y. Hishikawa, Bedrich Roth, P. Passouant, A. Rechtschaffen, and W.C. Dement, were presented at this meeting. The first study of sleep EEGs of pregnant women by O. Petre-Quadens (1968) and the first attempt to digitally quantify/score sleep by Itil and Shapiro (1968; see also Itil et al., 1968) were also included. In 1970, Guilleminault with support of the Socie´te´ Me´dicale des Hoˆpitaux de Paris outlined a new view on pathology during sleep based on the findings of differences in neuronal firing patterns during sleep compared to wakefulness (Guilleminault, 1970). He suggested that as a result of these different patterns of neuronal activity between wakefulness and sleep, brain control of vital functions might also differ and this could result in specific sleep-related pathologies. The focus on “sleep medicine” allowed the creation of a small clinical unit to monitor patients with different cardiac, respiratory and metabolic diseases during sleep. It was the first unit entirely devoted to the field of sleep medicine with a focus that extended beyond EEG monitoring.

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The understanding of the Pickwickian syndrome It was William Osler in the 8th edition of his textbook in 1918 who suggested the term Pickwickian syndrome. However, William Henry Broadbent in 1877 published, in the Lancet, a case of obstructive sleep apnea (OSA). The best early description of OSA is by Richard Caton (1842–1926) of a 37-year-old poultry dealer with excessive sleepiness: The moment he sat down on his chair sleep came on and even when standing and walking he would sink into sleep constantly while serving customers in his shop, sleep would come as he stood by the counter, he would wake and find himself holding in his hand the duck or chicken which he had been selling to a customer a quarter of an hour before, the customer having in the meantime departed . . . when in sound sleep a very peculiar state of the glottis is observed, a spasmodic closure entirely suspending respiration. The thorax and abdomen are seen to heave from fruitless contractions of the inspiratory and expiratory muscles; their efforts increase in violence for about a minute or a minute and a half, the skin mean time becoming more and more cyanosed, until at last, when the condition to an on-looker is most alarming, the glottic obstruction yields, a series of long inspirations and expirations follows and cyanosis disappears. This acute dyspneic attack does not awaken the patient. The night nurses stated that these attacks go on throughout the night. (Caton, 1889) Caton called his patient a “narcoleptic.” Other cases published at the end of the 19th century were found by Peretz Lavie in his exhaustive search for the “first Pickwick” (2003). The relationship between sleep and breathing and the fact that there may be a difference between the control of breathing during wakefulness and sleep was noted by Silas Weir Mitchell, who published an article in 1850 “On sleep disorders,” and he stated that there are breathing disorders that “occur solely during sleep.” He added: Where for some reason, the respiratory centers are diseased or disordered, a man may possess enough ganglionic energy to carry on breathing well while the will can supplement the automatic activity of the lower centers. But in sleep these being not quite competent, and the volition off guard, there ensues a gradual failure of respiration, and the man awakes with a sense

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of impending suffocation. This is not to be confounded with the hysterical sleep symptoms of sense of suffocation, which is close to the phenomena of nightmares, and is followed by or associated with fear and is soon lost on awakening. This write-up preceded by many years the description of Ondine’s curse by Severinghaus and Mitchell (1962) and the understanding of the role of sleep in abnormal breathing. The identification of obstructive sleep apnea as an independent syndrome was not immediately accepted. One of the problems was the association of obesity with cataplexy. Many patients were thus called “narcoleptic” (Sieker et al., 1955). The existence of cases with clear cataplexy, sleepiness and obesity led to the labeling of many sleepy patients as “narcoleptics,” with or without obesity. The usage of polygraphic recording during sleep led to a new understanding of syndromes during sleep. Werner Gerardy in Heidelberg (1960) described a polygraphic recording of an obese patient during the day. During the test, the patient fell asleep and had episodes of “periodic breathing” with intermittent absence of airflow and associated changes in heart rate. Gerardy et al. (1960), as many others before, later attributed the observed sleepiness to CO2 retention. Drachman and Gumnit (1962), aware of the work of Gerardy et al., studied a Pickwickian patient during daytime naps with simultaneous monitoring of oxygen saturation and CO2 tension, thoraco-abdominal monitoring, pulse rate and EEG. This was the first “polysomnogram” recorded during a daytime nap. These authors found that their patient “fell asleep repetitively” with a drop in oxygen saturation (SaO2) and a change in heart rate. They attributed the sleepiness of their Pickwickian patients to carbon dioxide “poisoning” with periodic alterations of consciousness. The first nocturnal “polysomnogram” was probably performed by Bulow and Ingvar (1961) who studied breathing during sleep in normal subjects and demonstrated a clear change of breathing pattern during sleep onset. These authors insisted on the “close linkage between respiration and regulation of wakefulness under physiological conditions.” Jung and Kuhlo (1965) monitored Pickwickian patients during sleep and presented their results in 1964. Kuhlo indicated that the sleepiness seen in Pickwickian patients may be related to the continuous interruptions of sleep or to a central defect and not to CO2 poisoning; however, this point was subject to debate (Gastaut et al., 1965b, 1966). Three theories were considered to explain the “diurnal hypersomnia” of

Pickwickian patients: first the role of CO2 retention, a view supported by American researchers; second was the role of a primary sleep disturbance of central origin (Jung and Kuhlo, 1965); and the third theory involved respiratory-related arousals secondary to abnormal breathing events supported by the Gastaut group (1965a). During the following 5 years Pickwickian patients were studied during sleep throughout the world. A prevalent finding was “central apneas,” which raised the question of a “central” factor in the pathogenesis of these patients. The pathogenesis was clarified in 1969 when Kuhlo et al. reported the complete relief of sleepiness following tracheostomies in Pickwickian patients. This confirmed the conclusions of Gastaut et al. (1965b) of the importance of respiratoryrelated arousals. Lugaresi and his group wanted to unify Pickwick, alveolar hypoventilation during sleep (Ondine’s curse), and related syndromes under one term; they grouped these breathing syndromes under the category of “hypersomnia with periodic breathing” (Sadoul and Lugaresi, 1972).

OBSTRUCTIVE

SLEEP APNEA SYNDROME

Following the 1972 Rimini conference the term obstructive sleep apnea syndrome (OSAS) was introduced and defined (Guilleminault et al., 1972, 1973, 1975, 1976a), with the goal of indicating the existence of a more distinct condition than what was considered under the rubric “Pickwickian syndrome” or “hypersomnia with periodic breathing” (Sadoul and Lugaresi, 1972). A second international meeting was held in the USA with the support of the Kroc foundation focusing on sleep apnea syndrome (Guilleminault and Dement, 1978).

Treatments of OSAS Sullivan developed equipment to apply continuous air pressure to avoid the collapse of the upper airway. Combining an air compressor with an air-tight mask, Sullivan and colleagues succeeded in eliminating the sleep-related obstruction in a severely affected patient. This provided an effective non-surgical treatment of OSAS using continuous positive airway pressure (CPAP) (Sullivan et al., 1981). The search for new treatments for obstructive sleep apnea was not limited to CPAP. In Japan a surgical procedure on the soft palate was developed for snoring and OSAS (Fujita et al., 1981). Although this was initially successful, followup studies found a large number of patients ultimately relapsed (Silvestri et al., 1983; Powell et al., 1996). It was suggested that earlier interventions might be more fruitful in curing OSAS. If abnormal breathing during sleep was not corrected promptly, progressive local

THE HISTORY OF SLEEP MEDICINE neuropathies related to chronic snoring and dysregulation of upper airway controls during sleep might occur (Friberg et al., 1998; Friberg, 1999; Kimoff et al., 2001; Afifi et al., 2003; Nguyen et al., 2005). The development of the “Stanford surgical protocol” began in 1981 with N. Powell and R. Riley (Powell et al., 1983), establishing the benefits of a multi-step surgical approach (Riley et al., 1986, 1990). In addition to surgery, oral appliances were developed as an alternative treatment for OSAS (Cartwright, 2001).

PREVENTION: SLEEP DISORDERED BREATHING IN CHILDREN Catlin in the 19th century insisted that children should breathe through their nose and that mouth breathing was abnormal (Catlin, 1861). The routine evaluation of children for obstructive sleep apnea did not begin until the mid-1970s (Guilleminault et al., 1976b, 1982). Guilleminault described how an increase in respiratory effort during sleep could lead to frequent arousals impacting cognition and behavior, including hyperactivity, inattention, sleep walking, sleep terror, morning headaches, and enuresis. Guilleminault and colleagues showed a persistence of obstruction after traditional adeno-tonsillectomy (Guilleminault et al., 1989a). This resulted in the more recent introduction of orthodontic techniques to improve OSAS in adults (Cistulli, 1996) and in children (Guilleminault and Li, 2004; Pirelli et al., 2004).

RESTLESS LEGS SYNDROME Willis in 1685 described a patient with restless legs syndrome (RLS): “when being in bed, they betake themselves to sleep, presently in the arms and legs, leaping and contractions of the tendons and so great the restlessness and tossing of their members ensue, that the diseased are no more able to sleep, than if they were in place of greatest torture.” This syndrome was called restless legs syndrome by Karl-Axel Ekbom in 1945. RLS was noted to be associated with small movements of the big toe that occurred at regular short intervals during sleep. This motor manifestation was suspected to have an epileptic origin. Charles Symonds called this movement “nocturnal myoclonus” (1953) and concluded that it was an epileptic equivalent. Lugaresi et al. (1968) demonstrated that Symonds was incorrect and that “nocturnal myoclonus” (now called “periodic limb movement”) was not an epileptic disorder and was seen in association with RLS. Akpinar (1982) successfully tried levodopa/carbidopa treatment to eliminate the paresthesia of RLS. Further therapeutic advances occurred with the development of selective dopamine agonists. Further progress was made with description of

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familial cases of RLS in Quebec associated with specific genetic mutations (Desautels et al., 2001).

PARASOMNIAS: ABNORMAL BEHAVIOR DURING SLEEP Initially it was Gastaut and colleagues who coined the term “disorders of arousal” (Gastaut and Broughton, 1965; Broughton, 1968) and showed that non-REM (NREM) parasomnias were not typically due to seizures with the important exception of a frontal lobe focus with a familial presentation (Pedley and Guilleminault, 1977). The delta sleep origin of many parasomnias was described (Jacobson et al., 1965; Fisher et al., 1973). The concept of sleep instability to account for parasomnias was developed (Gaudreau et al., 2000; Guilleminault et al., 2003a, 2005), and was refined with the description of the Cyclic Alternating Pattern (CAP) (Terzano and Parrino, 2000). A parasomnia of both historic and clinical importance is REM behavior disorder (RBD). Jouvet and Delorme (1965) and Hendricks et al. (1982) performed experimental brain-stem lesions leading to an “active daytime behavior” during REM sleep. Similar behavior was noted in humans during delirium (Hishikawa and Kaneko, 1965; Sugano et al., 1980; Hishikawa et al., 1981) and in patients with brain-stem neurodegenerative disease (Quera-Salva and Guilleminault, 1986). Finally Schenck et al. (1986) reported a series of “idiopathic cases” and called the disorder “REM behavior disorder.” Initially thought to be “idiopathic,” it is associated with other neurological disorders, in particular with Parkinson’s disease, multiple system atrophy and Lewy body dementia (Schenck et al., 1996; Schenck and Mahowald, 2002). Progressively the notion emerged that RBD was more commonly associated with synucleinopathy (Turner et al., 2000; Boeve et al., 2001; Schenck and Mahowald, 2002).

THE THALAMUS AND ASSOCIATED SLEEP DISORDERS Fatal Familial Insomnia Discovery of Fatal Familial Insomnia (FFI) and characterization of its inexorable clinical evolution toward complete disappearance of sleep, and ultimately death, was followed by the discovery that it was a prion disease associated with mutations in the gene encoding the prion protein (Lugaresi et al., 1986; Medori et al., 1992). The studies of FFI led to a unified concept of several neurodegenerative disorders such as FFI and Creutzfelt-Jakob disease; they also emphasized the role of specific nuclei of the thalamus in the regulation of sleep and wakefulness. This ties into the associated severe thalamic dementia identified since the 1930s (Stern, 1939; Schulman, 1957; Oda, 1976).

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Other abnormal sleep disorders were associated with thalamic lesions following cat studies with bilateral thalamectomy (Villablanca and Marcus, 1972; Villablanca and Salinas-Zeballos, 1972). Isolated bilateral thalamic stroke was reported to lead to abnormal sleep behavior (Guilleminault et al., 1993). Kleine–Levin syndrome may also be associated with thalamic pathology (Huang et al., 2005).

NARCOLEPSY AND THE HYPOCRETIN CONTROL OF SLEEP/WAKEFULNESS Caffe´ in 1862, and Westphal in 1877, published reports on patients with sleeping attacks associated with episodes of loss of motor and language abilities without recognition of a specific new entity. In 1880 Jean-Baptiste Ge´lineau coined the term “narcolepsy.” Lowenfeld (1902) required the presence of both sleepiness and “falls” for the diagnosis of narcolepsy. Henneberg (1916) called the falls “cataplectic inhibition.” Adie, in 1926, changed the term to “cataplexy.” Wilson (1927) described sleep paralysis. But it was Luman Daniels (1934) who published a complete description of the syndrome, with the classic “tetrad,” re-emphasized later by Yoss and Daly (1957), of narcolepsy, cataplexy, hypnagogic hallucinations and sleep paralysis. They described cataplexy as “a state of helplessness into which a narcoleptic patient may be precipitated by emotional stress; he is not unconscious but a mass of toneless muscles; and he promptly recovers, none the worse for his experience.” In 1931, Janota, and Doyle and Daniels, suggested the use of ephedrine to treat narcolepsy and in 1935 Prinzmetal and Bloomberg introduced benzedrine. Voegel in 1960 first reported abnormal REM sleep while monitoring sleep in narcolepsy. This was also shown by others (Rechtschaffen et al., 1963; Takahashi and Jimbo, 1963; Passouant et al., 1964; Hishikawa and Kaneko, 1965). This discovery led to the creation of the Multiple Sleep Latency Test (MSLT) (Mitler et al., 1979; Carskadon and Dement, 1985), for the diagnosis of the syndrome. The first international definition of narcolepsy was adopted in 1975 (Guilleminault et al., 1976a). In 1983 Juji and Honda reported an association of HLA (DR2) with narcolepsy in Japan (Honda et al., 1983; Juji et al., 1984). A different HLA marker was found by Neely et al. (1987) studying AfricanAmericans. An association between narcolepsy and HLA marker DQB1-0602 was present in most but not all cases of narcolepsy (Guilleminault and Grumet, 1986; Guilleminault et al., 1989b). A dog model for cataplexy was found in 1973 (Mitler et al., 1974; Foutz et al., 1979). This model allowed

research into the cause of narcolepsy (Delashaw et al., 1979; Foutz et al., 1981; Mignot et al., 1993). The role of the neuropeptide hypocretin/orexin (de Lecea et al., 1998) in narcolepsy–cataplexy was nearly simultaneously described by two different teams, one led by Mignot (Lin et al., 1999) and one by Yanagisawa (Chemelli et al., 1999). It was found in 1999 that narcoleptic dogs had a genetic abnormality of a hypocretin/orexin receptor while genetic knock out of mice also led to narcolepsy–cataplexy. In 2000 Nishino et al. showed that human narcoleptics were found to have decreased or absent hypocretin/orexin levels in the cerebrospinal fluid. Peyron et al. (2000) and Thannickal et al. (2000) identified a specific destruction of hypocretin cells in the posterolateral region of the hypothalamus (the same region as identified by Von Economo in his patients with encephalitis lethargica) in the brains of human narcoleptics. This neuronal destruction may account for secondary narcolepsy (Aldrich and Naylor, 1989; D’Cruz et al., 1994; Malik et al., 2001).

IATROGENIC SLEEP DISORDERS: THE SLEEP DEPRIVATION OF INDUSTRIAL CIVILIZATION A discussion of the history of sleep would not be complete without reviewing what is perhaps the most common sleep disorder of all, societal sleep deprivation. Inadequate sleep is a problem of modern life. Major world catastrophes from the “Exxon-Valdez” oil spill to the Chernobyl nuclear disaster have been linked to sleep deprivation. The impact of sleep deprivation and shift work on industrial and traffic accidents has been well documented (Czeisler et al., 1982; Akerstedt et al., 1987; Dinges et al., 1997; Powell et al., 2001; Connor et al., 2002; Liu and Tanaka, 2002). The impact of these sleep schedules and chronic sleep restriction on metabolic variables and immune function has been emphasized only recently. The deadly effect of continuous sleep deprivation on rodents was first demonstrated (Rechtschaffen et al., 1983, 1989). More recently limited sleep restriction in young normal humans has shown changes in secretion patterns of specific peptides such as leptin and ghrelin (Guilleminault et al., 2003b; Spiegel et al., 2004) as well as an increase in food intake, development of insulin resistance during sleep, increase in weight and abnormal adipocytic stimulation (Leproult et al., 1997; Spiegel et al., 2004). Simultaneously, changes in secretion of cytokines, particularly interleukin 1 and 6 and TNF alpha, were observed (Redwine et al., 2000) and raised the question of the role of chronic sleep restriction in obesity, atherosclerosis, cardiovascular disease, metabolic syndrome and premature invalidism or death.

THE HISTORY OF SLEEP MEDICINE

CONCLUSION Sleep medicine has become a well-recognized subspecialty and has now joined the mainstream of medicine. We all should look forward to a future in which healthy sleep is recognized as a pillar of good health. This narrative of the history of sleep medicine is limited, and many research avenues are not presented, but these omissions only demonstrate further the living history and vitality of this new field.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 35

The frontal lobes CHRISTOPHER M. FILLEY * Behavioral Neurology Section, Departments of Neurology and Psychiatry, University of Colorado Denver School of Medicine and the Denver Veterans Affairs Medical Center, Denver, CO, USA

INTRODUCTION One of the foremost goals of neuroscience is the explanation of uniquely human characteristics. This motive has inspired thinking about the brain for several millennia. Contemporary neuroscientists widely believe that distinctly human capacities implicate the frontal lobes – the largest of the cerebrum, occupying about a third of the cortical surface – and studies of these regions are burgeoning today. Yet it has been just 200 years that the frontal lobes have been anatomically delineated, and knowledge of their function is still far from complete. In this chapter, the history of the frontal lobes will be reviewed by exploring the historical antecedents of modern investigations, the early attempts at determining functional affiliations, the more detailed studies of the 20th century, and the present understanding of frontal lobe structure and function. Progress has been substantial, and the information acquired so far sets the stage for more sophisticated research into the operations by which the brain mediates cognitive and emotional function. Given the apparent role of the frontal lobes in a host of behaviors with far-reaching implications, not only for medicine but also the understanding of human achievement and destructiveness, what remains to be discovered will impact society as a whole as well as neuroscience.

FROM ANTIQUITY TO THE RENAISSANCE The origin of neurological science can be traced to the Edwin Smith Papyrus of the 17th century BC, which bore hieroglyphics from Egyptian civilization of about 3500 BC and made reference to the brain, its convolutions, the cerebrospinal fluid, and individuals with neurological disorders (Breasted, 1930). Despite these remarkable observations, the Egyptians considered the

heart, not the brain, as the seat of the soul, and the understanding of the brain and its afflictions was heavily influenced in antiquity by spiritual and theological thinking in which intervention by celestial gods and possession by spirits figured prominently (McHenry, 1969). The Golden Age of classical Greece fostered important advances in the understanding of the brain. The writings of Hippocrates (460–377 BC) and his contemporaries, known collectively as the Corpus Hippocraticum, emphasized the brain as the source of intelligence, dreams, and thought, and included many astute observations of individuals with clinical syndromes reflecting brain lesions (Sigerist, 1961). Knowledge of brain structure and function was extremely limited, but the Hippocratic writings include the strikingly contemporary concept that the brain is the organ of the mind. Following Hippocrates’ death, human dissections were undertaken in the Hellenistic era by Herophilus and Erasistratus, anatomists who worked in Alexandria in the years after Alexander’s conquest of Egypt in 332 BC. In addition to examining cranial nerves, cerebral blood vessels, and ventricles, these early dissectors made pioneering attempts to understand the brain parenchyma: Herophilus described the anatomy of the two most obvious parts of the brain, the cerebrum and cerebellum, and Erasistratus theorized that humans were more intelligent than other animals because of their more extensively convoluted cerebral hemispheres (Finger, 2002). The Greeks recognized no specific lobes of the brain, but intriguing aspects of classical art beginning in Grecian times imply the preliminary notion that frontal brain regions might be associated with higher mental function. Depictions of gods, demigods, and revered poets and artists from Greek and Roman art sometimes showed overdeveloped or projecting foreheads, in contrast to laborers, athletes, gladiators, and women, who tended to have short, broad heads with retreating foreheads (Finger, 1994).

*Correspondence to: Christopher M. Filley MD, Behavioral Neurology Section, 12631 East 17th Avenue, MS B185, PO Box 6511, Aurora, Colorado, 80045, USA. E-mail: [email protected], Tel: +1-303 724-2187, Fax: +1-303 724-2202.

558 C.M. FILLEY The major figure of antiquity after the Greeks was was not pursued. Still, Vesalius’ work remains a monuGalen of Pergamon (130–200 AD), whose work domimental work of anatomy, and one of the most impornated medicine for more than a millennium. Galen tant books ever published in medical science. was proscribed from performing human dissections THE 17TH AND 18TH CENTURIES by religious sentiment and Roman law, but he did carry out vivisection of monkeys, horses, oxen, sheep, and An early appreciation of the frontal regions of the swine, and also examined human skeletons. Despite brain was evident in the work of the English physician these limitations, he made impressive advances in Thomas Willis (1621–1675). A major figure in neudescribing many neuroanatomical structures, including roscience, Willis is known for the arterial circle at the the dura mater, the four ventricles, and the pineal base of the brain named after him, and for adding gland (Galen, 1956). Moreover, despite the views of the word “neurology” to the scientific vocabulary, but many in antiquity who believed that the soul was to he is also considered one of the greatest neuroanatobe found in the fluid of the ventricles, Galen took a mists (Molna´r, 2004). In his textbook of 1664, Cerebri more empirical view – based largely on his admiration Anatome, which remained the most influential contrifor Hippocrates – and believed that the substance of bution to neuroanatomy for nearly 200 years, Willis the brain accounted for mentation (Galen, 1968). He named many regions of the brain and proposed that did not, however, venture any speculation about the the higher cognitive functions of the brain could be localization of mental functions in any particular parts attributed to the convolutions of the cerebral cortex of the brain, and study of this question would need to (Willis, 1664). He also attempted to parcellate the wait many hundreds of years until human anatomy cerebral hemispheres, but concluded that each had just could be directly investigated. two lobes – anterior and posterior – that were sepaThe Renaissance in Europe had as profound effect rated by the middle cerebral artery in the Sylvian fison the world of science as it did on the humanities. sure (Willis, 1664). Comments on a specific definition The spirit of scientific investigation of natural pheor function of the frontal lobes were not included in nomena, newly liberated from centuries of religious his work. Indeed, the cerebral cortical convolutions suppression, enabled detailed and systematic dissection were generally regarded as chaotic and random, and of the human body and thus major advances in neurono specific correlations between structure and function anatomy. One of the most notable figures of the era of the cerebrum were established in Willis’ era. was Leonardo da Vinci (1452–1519), whose prodigious In the 18th century, one unusual figure deserves accomplishments included masterful drawings of the credit for developing a remarkably modern view of skull and central nervous system based on direct obserthe frontal lobes. Emanuel Swedenborg (1688–1772) vation (Pevsner, 2002). Exploiting the opportunity to was a Swedish scientist, philosopher, and theologian dissect the human body, he advanced knowledge of who studied the brain, among his many interests, in the ventricles, cranial nerves, and spinal cord. The cerhopes of understanding the relationship of body and ebrum, however, remained largely unexplored, and litsoul (Ramstro¨m, 1910). Neither a clinician nor an tle progress was made in delineating the details of experimentalist, he was nevertheless able to synthesize cortical structure or lobar organization. existing knowledge of the 1740s into a surprisingly The seminal event in the neuroanatomy of the accurate view of the motor and higher functions of Renaissance occurred in 1543 with the publication of the frontal lobes. He recognized that posterior frontal De Humani Corporis Fabrica by Andreas Vesalius regions now identified as motor cortices controlled (1514–1564). With this extraordinary work, a landmark muscle function, and even described how the upper in the history of medicine and science, a new era of anaconvolutions subserved the foot, the middle convolutomic investigation was launched, and the brain, like the tions the mid-body, and the lower convolutions the rest of the body, came to be understood in far greater head and neck (Ramstro¨m, 1910). Extending the condetail. Vesalius and his co-workers, who were associated cept of cortical localization to the higher functions, with the atelier of the great painter Titian, produced he also clearly linked the frontal lobes with a variety beautiful depictions of anatomy that stand equally as of intellectual activities: works of art and science (Saunders and O’Malley, If this anterior portion of the cerebrum is 1973). The seventh and last book of the Fabrica dealt wounded, then the internal senses – imagination, with the brain. Vesalius was the first to demarcate the memory, thought – suffer; the very will is weawhite matter from the gray matter, preparing the way kened, and the power of determination blunted for later scientists who investigated brain connectivity . . . This is not the case if the injury is in the back (Filley, 2001a). The cerebral cortex, however, was not of the cerebrum. (Swedenborg, 1882, p. 73) well understood, and its division into specific regions

THE FRONTAL LOBES 559 Unfortunately, these prescient insights were not apprethe brain, whereas higher functions were located more ciated until the late 19th century. Swedenborg’s works anteriorly (Gall and Spurzheim, 1810–1819). Much as this were overlooked by the medical community of his preliminary insight was to be largely confirmed in subseday, as he did not occupy a university post from which quent eras, Gall and Spurzheim undermined their arguto present his ideas, and then later turned increasingly ments by their vigorous advocacy of phrenology, which to embrace theology and mysticism. But Swedenborg held that functions of frontal and other cerebral regions has a place in medical history for being the first to could be ascertained by simple palpation of bumps and propose that specific cognitive functions could be ridges on the skull surface (Filley, 2001b). The concept attributed to the frontal lobes. of localization was seriously challenged for many years in reaction to the fanciful claims of phrenology, but Gall THE 19TH CENTURY AND and Spurzheim can be credited for their work on brain– CEREBRAL LOCALIZATION behavior relationships that would eventually lead to progress in elucidating the distributed neural networks now In a significant advance over prior centuries, the 19th seen as mediating all human behaviors (Schmahmann century witnessed the advent of detailed descriptions and Pandya, 2006). of the four cerebral lobes recognized today. The first In the mid-19th century, a major step forward in the adequate neuroanatomical delineation of the frontal understanding of the frontal lobes occurred with the lobe was made in 1807 by Franc¸ois Chaussier (1746– extraordinary case of Phineas Gage (Macmillan, 1986). 1828), who also described the currently accepted boundOne of the most celebrated in neurology, Gage’s remarkaries of the temporal, parietal, and occipital lobes able story left little doubt that the frontal lobes contri(Chaussier, 1807). This development reflected increasing bute uniquely to the human behavioral repertoire. In sophistication in neuroanatomical research, and paved 1848, Gage was an industrious 25-year-old railroad forethe way for the detailed study of brain structure that man supervising construction of the Burlington and characterized this century. In 1868, the term “prefrontal Northern Railroad in Vermont when he sustained a dracortex” was first used by Richard Owen (1804–1892) to matic penetrating brain injury. While he was laying an refer to the largest and most anterior portions of the explosive charge with the aid of a pointed tamping iron, frontal cortices (Owen, 1868), which today are widely an accidental discharge rapidly propelled the 29-kg, 109accepted as being associated with uniquely frontal funccm long, 3-cm thick rod upward through his face, skull, tions. In parallel with these advances in neuroanatomy, and brain. The tamping iron exited the head, landed 30 m scientists naturally attempted to assign functions to the away, and is now on display, along with Gage’s skull, in brain regions being recognized. Although the earliest the Warren Anatomical Medical Museum at Harvard efforts to localize cerebral function can be traced to University. Figure 35.1 depicts Gage, the tamping iron, ancient physicians who noted that injury to one side of the cranial trajectory of the missile, and areas of consethe brain could cause paralysis of the contralateral quent frontal lobe damage. Gage was rendered initially limbs, the era of cerebral localization began in earnest unconscious, but later recovered, and lived until age 36 during the 19th century (Young, 1970). with a seizure disorder but no paresis or aphasia. His perThe most notable early proponents of cerebral locasonality, however, was permanently altered, as reported lization, and the first to champion the frontal lobes as later: the seat of the highest human functions, were Franz Joseph Gall (1758–1828) and his associate Johann His physical health is good, and I am inclined to Kaspar Spurzheim (1776–1832). Gall was an accomplished say that he is recovered . . . The equilibrium or neuroanatomist who, in collaboration with Spurzheim, balance, so to speak, between his intellectual performed dissections that revealed the connectivity of faculty and animal propensities, seems to have white matter tracts linking cortical gyri with each other been destroyed. He is fitful, irreverent, indulging and forming, in their view, the basis of mental activity at times in the grossest profanity (which was not (Gall and Spurzheim, 1810–1819). Their neuroanatomical previously his custom), manifesting but little emphasis, which blended localization of cortical function deference for his fellows, impatient of restraint with the connectivity provided by white matter, repreor advice when it conflicts with his desires, at sented a remarkable new direction that proved to be a hartimes pertinaciously obstinate, yet capricious binger of contemporary systems neuroscience. As for the and vacillating, devising many plans of future frontal lobes, Gall and Spurzheim reasoned that because operation, which are no sooner arranged than animals such as monkeys and dogs have smaller frontal they are abandoned in turn for others appearing lobes than humans, lower mental functions such as more feasible. A child in his intellectual capacity instincts were likely to reside in more posterior parts of and manifestations, he has the animal passions of a

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Fig. 35.1. Illustration of the frontal lobe injury sustained by Phineas Gage after the tamping iron was propelled through the skull and brain.

strong man. Previous to his injury, though untrained in the schools, he possessed a wellbalanced mind, and was looked upon by those who knew him as a shrewd, smart businessman, very energetic and persistent in executing all his plans of operation. In this regard his mind was radically changed, so decidedly that his friends and acquaintances said he was “no longer Gage.” (Harlow, 1868, pp. 339–340.) Another important event in the localization of frontal lobe function was the association of left frontal infarction and nonfluent aphasia in 1861 by Paul Broca. From this case, a man named Leborgne who suffered an infarct that left him with only the utterance “tan,” Broca contended that the inferior frontal convolution on the left was responsible for speech production. As early as 1825, Jean Baptiste Bouillard (1796–1881) had proposed

that speech was localized in the frontal lobes, and in 1836 Marc Dax (1771–1837) suggested that left hemispheric lesions produced speech disturbances, but Broca’s stature as a scholar – and his persistence in finding many additional cases in later years – eventually led to the acceptance of the syndrome under the eponym Broca’s aphasia. This and other aphasias are considered in more detail elsewhere in this volume (Ch. 36). In the latter half of the 19th century, several neuroscientists added experimental data to the understanding of the frontal lobes. Working in Germany in the 1870s, Eduard Hitzig (1838–1907) and his colleague Gustav Fritsch (1838–1927) discovered in dogs that electrical stimulation of the frontal association cortex produced no movement, and that ablation of these cortices induced no paralysis; rather, the altered behavior of dogs with bilateral frontal cortical lesions suggested that higher mental function must somehow involve

THE FRONTAL LOBES the frontal association cortices (Hitzig, 1874). In the same decade, the English physiologist David Ferrier (1843–1928) demonstrated apathy, loss of curiosity, and impulsiveness in monkeys with bilateral anterior frontal damage; he identified an attentional problem as central to these deficits, and thought that attention was key to the intellectual function of the frontal lobes: Instead of, as before, being actively interested in their surroundings, and curiously prying into all that came within the field of their observation, they remained apathetic, or dull, and dozed off to sleep, responding only to the sensations or impressions of the moment, or varying their listlessness with restless and purposeless wandering to and fro. While not actually deprived of intelligence, they had lost, to all appearance, the faculty of attentive and intelligent observation. (Ferrier, 1876, pp. 231–232) At the end of the century and well into the next, Leonardo Bianchi (1848–1927) investigated the prefrontal cortices of both dogs and monkeys, concluding that lesions of these areas produced a “dissolution of the psychical personality” that led to poor planning, intellectual blunting, and restlessness (Bianchi, 1920). In the 1880s, Moses Allan Starr reviewed the American literature on the behavioral consequences of tumors, abscesses, and traumatic lesions of the brain, and noted that frontal lobe damage often affected attention, intellect, temperament, and personality (Starr, 1884a, b). He also observed considerable variability among patients, such that not all those with frontal lesions would have the same clinical profile, thus anticipating later investigators who would emphasize the wide range of syndromes encountered in patients with frontal damage. An important theme of Starr’s work was the lack of “self-control” exhibited by many individuals with frontal lobe involvement, which echoed the Phineas Gage story and foreshadowed much further work on the notion of disinhibition. In respect of judgment and reason the power of man surpasses that of the lower animals. The brain of man differs from that of the lower animals and of idiots chiefly in the greater development of the frontal lobes. It seems possible, therefore, that the processes involved in judgment and reason have as their physical basis the frontal lobes. If so, the total destruction of these lobes would reduce man to the grade of an idiot. Their partial destruction would be manifested by errors of judgment and reason of a striking character. One of the first manifestations would be a lack of

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that self-control which is the constant accompaniment of mental action, and which would be shown by an inability to fix the attention, to follow a continuous train of thought, or to conduct intellectual processes. It is this very symptom which was present in one-half the cases cited here . . . It did not occur in lesions of other parts of the brain here cited. (Starr, 1884a, p. 380) As the 19th century came to its close, the Czech neurologist Arnold Pick (1851–1924) made clinical observations consistent with the emerging understanding of the frontal lobes, and laid the foundation for a century of progress delineating the effects of frontal lobe degeneration. Beginning in 1892, Pick observed patients with indifference, poor judgment and insight, diminished creativity, careless dressing, antisocial behavior, and aphasia who had lobar atrophy involving the frontal and temporal lobes (Pick, 1892). Although the disease that would come to bear his name has been gradually supplanted by the term frontotemporal dementia (Filley, 2001b), Pick’s influential work called attention to a disease in which progressive frontal lobe damage induced behavioral changes that could be predicted from the location of cortical damage.

FRONTAL LOBE STUDIES IN THE 20TH CENTURY In the 20th century, three major factors contributed to the steady accumulation of advances in understanding the frontal lobes. In the first half of the century, the two world wars afforded large numbers of unfortunate soldiers with penetrating injuries of the frontal lobes who could be studied by neuroscientists. Midcentury, psychosurgery involving the frontal lobes enjoyed widespread popularity for the treatment of the mentally ill. Then, in the latter half of the century, the discipline of behavioral neurology matured and, in collaboration with neuropsychology, fostered pursuit of detailed structure–function relationships of the frontal lobes using the lesion method and increasingly sophisticated structural and functional neuroimaging techniques. The opportunity to examine large numbers of young men with frontal lobe injuries presented itself in World War I and again in World War II. Walther Poppelreuter (1886–1939), Hans Berger (1873–1941), and Ernst Feuchtwanger (1889–?) made observations of frontal lobe deficits such as impaired thinking and reasoning, perseveration, reduced attention, loss of initiative, and emotional changes including depression and euphoria (Poppelreuter, 1918; Berger, 1920, 1923; Feuchtwanger, 1923). Another notable figure of the early 20th century was Kurt Goldstein (1878–1965),

562 C.M. FILLEY who championed the idea that the central deficit after In general, the various frontal lobe surgical techniques frontal lobe damage was loss of the ability to abstract, were designed to destroy the connections assumed to typically manifested by concrete thinking (Goldstein account for mental illness by disrupting frontal-subcortiand Scheerer, 1941). The notion that the unitary capacal and limbic circuits by means of discrete frontal white city of abstraction summarized frontal lobe function matter lesions (Anderson and Arciniegas, 2004). was distinctly at variance with many investigators Although some patients did improve, the many complicabefore and after Goldstein who maintained that an tions that occurred – among them seizures, incontinence, all-encompassing concept was insufficient to capture apathy, and death – combined with shifting public opinion the many varied aspects of frontal lobe function and the introduction of effective antipsychotic medica(Finger, 1994). In World War II, the Russian neuropsytion in the 1950s, led to frontal lobe psychosurgery being chologist Aleksandr Romanovich Luria (1902–1977) all but abandoned by the 1970s. In the 1990s, however, opiinvestigated the frontal lobes by studying soldiers with nion again shifted, and limited numbers of carefully penetrating head injuries, thus beginning to establish planned procedures were done in selected cases of refrachis strong and lasting influence on neuropsychology. tory obsessive-compulsive disorder, anxiety disorder, After the war, Luria continued his studies on patients Tourette’s syndrome, aggression, major depression, with tumors and other brain lesions, and his extensive addiction, eating disorders, and self-mutilating behavior. experience with frontal lobe dysfunction helped lay These operations are now considered therapies of last the foundation for his major work, Higher Cortical resort for seriously ill patients (Anderson and Arciniegas, Functions in Man (Luria, 1962). Luria stressed the hier2004). archical organization of the brain in which the frontal The rise of behavioral neurology in the latter half of lobes exert a controlling function, and identified key the 20th century further accelerated work on frontal prefrontal operations as planning, executing, and monlobe function. This subspecialty, the emergence of itoring mental processes: which in the 1960s can be credited in large measure to Norman Geschwind (1926–1984), focused directly . . . the frontal lobes are in fact a superstructure on brain–behavior relationships from a localizationist above all other parts of the cerebral cortex, so perspective (Schacter and Devinsky, 1997). After the that they perform a far more universal function first half of the century, when the study of mental of general regulation of behaviour than the posterfunction in a neuroscientific context was relatively ior association centre . . . (Luria, 1973, p. 89) neglected due to the enormous influence of Sigmund Freud’s psychoanalysis and the displacement or death In 1935, the era of psychosurgery began with the perforof leading European researchers in the 1930s and mance of prefrontal leucotomy by the Portuguese neurol1940s, behavioral neurology began to flourish mid-cenogist Egas Moniz and his neurosurgical colleague tury. Geschwind’s landmark paper in 1965, “DisconAlmeida Lima (Valenstein, 1986). The first patient was a nexion syndromes in animals and man” (Geschwind, 63-year-old woman with psychotic depression, and her 1965), serves as a legitimate starting point for this apparent improvement quickly led to the procedure being field, and helped inspire a generation of clinical neuused for a wide variety of psychiatric disorders. In 1949, roscientists devoted to understanding the neural origins Moniz won the Nobel prize in Medicine and Physiology of behavior (Damasio, 1984). Geschwind did not focus for his work, which at the time was considered an on the frontal lobes in particular, but his influence is important advance in the treatment of severely ill patients evident in the work of Antonio Damasio, who has led for whom no effective therapy had been available important clinical studies on the effects of frontal lobe (Valenstein, 1986). Others modified the procedure, damage: including the neurosurgeon James Watts and the neuroloIn general, the vast set of cerebral cortices colgist Walter Freeman in the United States, who introduced lectively known as the frontal lobes appear to the frontal lobotomy through bilateral burr holes in 1936. have evolved to guide response selection in Convinced of the efficacy of the operation, Freeman then order to offer the organism its best chance of developed the radical technique of lobotomy using an ice long-term survival. It is probable that this overpick-like tool called an orbitoclast, with which a hole could all goal was implemented first in simple social easily be punched in the superior orbital region to perform environments, dominated by the needs for food, the frontal ablation. The widespread availability of this sex, and the avoidance of predators. Other conprocedure, office-based and performed without anesthetingencies, in ever more complex environments, sia or the presence of a neurosurgeon, led to more than were later connected with those original contin60000 lobotomies being done in the United States gencies so that the basic neural mechanism for between 1936 and 1956 (Feldman and Goodrich, 2001).

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response selection was incorporated in the decision-making mechanisms developed for newer and more challenging environments. Damage to this system disrupts many of the cognitive and behavioral abilities that have come to define humanity. (Damasio and Anderson, 2003, p. 436) Closely allied with behavioral neurology was neuropsychology, an emerging field that extended Luria’s work and advanced the formal evaluation of cognitive function by standardized assessment. Edith Kaplan and Harold Goodglass, Geschwind’s colleagues at the Boston Veterans Administration Hospital, played an important role in integrating neuropsychology into neurologic research and practice during the latter half of the 20th century (Schacter and Devinsky, 1997). Both disciplines benefited as well from the remarkable advances of neuroimaging, which began with the structural techniques of computerized tomography (CT) in the 1970s and magnetic resonance imaging (MRI) in the 1980s, and then functional neuroimaging using positron emission tomography (PET) in the 1980s and functional MRI (fMRI) in the 1990s. These techniques were far more sophisticated than previous methods, and allowed the study of in vivo brain–behavior relationships that markedly expanded on the time-honored tradition of autopsy correlation. Reliable brain– behavior correlations now appeared regularly without the need for autopsy correlation, and confidence steadily grew in the validity of localizing cognitive and emotional functions in the brain. Thus it became increasingly clear that mental states could be studied as phenomena of the brain. By the end of the century, as neuroscientific disciplines successfully advanced the biomedical model of mental function, the influence of Freud had essentially vanished in academic medicine (Tallis, 1996). Concomitantly, interest turned toward brain regions where the representation of the most complex cognitive and emotional functions could plausibly be hypothesized. The frontal lobes, the most prominent of the brain and the most recently acquired in evolution, naturally attracted much attention. Depictions of brain activity made possible by fMRI, for example (Fig. 35.2), steadily supported the conclusion that uniquely human capacities were represented within the frontal cortices and their connections (Stuss and Benson, 1986; Miller and Cummings, 1999). The investigation of the frontal lobes by behavioral neurologists, neuropsychologists, and soon their colleagues in the resurrected field of neuropsychiatry involved the study of a wide range of neurologic and psychiatric disorders, including brain tumors, neurodegenerative diseases, stroke syndromes, infections, inflammatory diseases, demyelinative diseases, traumatic brain injury,

Fig. 35.2. fMRI scan of frontal lobe function. The subject was engaged in a decision-making task that activated Brodmann areas 32 and 24 of the anterior cingulate region. (Courtesy of Jody Tanabe MD, Department of Radiology, University of Colorado School of Medicine.)

schizophrenia, depression, and obsessive-compulsive disorder. Neoplasms proved particularly intriguing because of the opportunity to observe behavioral changes before and after tumor surgery. Luria devoted much of his career after World War II to the study of frontal lobe tumors (Luria, 1962, 1973), and two of the more notable American cases were those of Brickner (1936) and Eslinger and Damasio (1985). Among the neurodegenerative diseases, frontotemporal dementia – an updated name for Pick’s Disease – assumed greater importance as this form of dementia was more frequently diagnosed, and even Alzheimer’s disease was recognized to have prominent frontal lobe involvement (Miller and Cummings, 1999). A variety of degenerative diseases with primarily subcortical pathology – among them Huntington’s disease, Parkinson’s disease, and progressive supranuclear palsy – were recognized to have neurobehavioral features resembling those seen with frontal lobe involvement, and the term frontal-subcortical dementia was proposed as an alternative to the popular subcortical dementia (Freedman and Albert, 1985). Cerebrovascular disease was seen as frequently involving the frontal lobes and their connections, particularly when dementia was the clinical result (Ishii et al., 1986). In addition, the syndrome of motor aprosodia was associated with focal infarction of the right frontal lobe, implicating a right frontal region homologous to Broca’s area as

564 C.M. FILLEY involved in the phenomenon of prosody, or the affeccingulate regions; unimodal (modality-specific) cortex, tive component of language (Ross, 1981). General parincluding the motor association cortices, the frontal esis, the form of neurosyphilis with prominent eye fields, and Broca’s area and its homologue in the involvement of the frontal lobes, continued as a probright hemisphere; and the heteromodal cortices, meanlem because of the acquired immunodeficiency syning the high-order association areas of the prefrontal drome (AIDS) epidemic, although far less so than in cortices (Mesulam, 2000). This elegant arrangement the pre-penicillin era, when up to 20% of psychiatric derives from the work of Geschwind (1965), with whom hospital admissions were prompted by general paresis Mesulam was associated at Harvard University, and (Hook and Marra, 1992). Psychiatric diseases, while in offers an updated neuroanatomical template for the general not as clearly linked with frontal neuropathollocalization of function within the frontal cortices. ogy, began to show associations with measures of Meanwhile, comparative neuroanatomical studies have structure and function in the frontal lobes; particularly demonstrated that the architectonic plan of the frontal noteworthy were functional neuroimaging data, indicortices is the same in the macaque monkey as in the cating that circuitry involving frontal cortex and basal human brain (Petrides and Pandya, 1994). This commonganglia structures in obsessive-compulsive disorder ality facilitates experimental approaches in monkeys might even be altered by psychotherapy (Schwartz using the lesion method and functional neuroimaging et al., 1996). These advances impressed Price and colto further investigate frontal lobe function (Petrides leagues (2000) as exemplifying the closing of the divide and Pandya, 1994). between neurology and psychiatry, and led them to A widely influential trend in frontal lobe neurobiolstate at the dawn of the new century that: ogy that informs present understanding is the elucidation of frontal-subcortical circuits, first described by We are just beginning to understand complex Alexander and colleagues (1986) and later elaborated human behaviors in a coherent and verifiable manby Cummings (1993). These circuits emphasize the conner, elucidating in a fundamental manner how nectivity of frontal regions, highlight the neuroanatothe brain works. Facing another turn of a cenmical basis for the prominent role of the frontal tury, we will see fundamental changes in the praclobes in movement and behavior, and offer a frametice of neurology and psychiatry – grounded work for research on a host of neuropsychiatric as in neuroscience and based on collaboration, well as neurobehavioral disorders (McPherson and resulting in the unprecedented relief of human Cummings, 2002). Five circuits have become accepted suffering. (Price et al., 2000, p. 13) as parallel but segregated systems, each involving a loop that begins in the frontal cortex, and then proceeds to the striatum, globus pallidus, thalamus, and CURRENT UNDERSTANDING back again to the frontal cortex by means of interconAs the 21st century unfolds, the frontal lobes remain a necting white matter tracts: motor (originating in the central focus in the pursuit of understanding brain– supplementary motor area), oculomotor (with its origin behavior relationships. Whereas it is problematic to in the frontal eye field), dorsolateral prefrontal, assume that the functions of the frontal lobes can be orbitofrontal, and medial frontal/anterior cingulate inferred simply from the effects of frontal lobe damage, (Alexander et al., 1986; Cummings, 1993). These converging evidence from both clinical and normal subcircuits highlight an emerging theme in cognitive jects increasingly suggests that certain operations can in neuroscience: the existence of multiple distributed fact be tentatively assigned to the frontal lobes. Many disneural networks that involve many interconnected ciplines, including behavioral neurology, neuropsychiabrain regions and subserve higher brain functions try, neuropsychology, neuroanatomy, neuroimaging, (Alexander et al., 1986; Cummings, 1993). and neuropharmacology, are making contributions to The complex cognitive and emotional operations the understanding of the frontal lobes, their connections, mediated by the frontal lobes have concentrated attenand their functional significance. tion on the frontal-subcortical circuits that are most Notable advances in frontal lobe neuroanatomy have likely associated with the neurobehavioral deficits seen been made with detailed study of the frontal cortices in in patients with frontal lesions. Despite the richness of humans and in a closely related primate, the macaque clinical descriptions dating from antiquity, individuals monkey. In the human brain, Mesulam has delineated who sustain frontal lobe damage often present with several cortical varieties distributed within the frontal perplexing and variable clinical features, and the regions: idiotypic cortex, referring to the primary motor neural basis of these syndromes has been obscure. areas of the precentral gyrus; paralimbic cortex, which The concept of frontal-subcortical circuits addresses includes the orbitofrontal cortices and the anterior these issues:

THE FRONTAL LOBES The frontal lobes play a critical role in human behavior, and some of the most dramatic neurobehavioral syndromes are associated with frontal lobe dysfunction . . . Advances in defining the anatomic relationships between the frontal lobe and subcortical structures provide a framework for linking behavioral abnormalities with frontal-subcortical circuit dysfunction. The model is applicable to neuropsychiatric as well as neurobehavioral disorders and offers insights into the pathophysiology of a variety of human behavioral syndromes. (Cummings, 1993, pp. 873 and 879) The three most crucial frontal-subcortical circuits for behavior are the dorsolateral prefrontal circuit,

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associated with executive function, the orbitofrontal circuit, concerned with comportment, and the medial frontal circuit, linked with motivation (Cummings, 1993). Figure 35.3 depicts the cortical regions representing the frontal lobe components of these three circuits. Clinical observation has increasingly supported the importance of these circuits in human behavior, as lesions anywhere within them reliably produce syndromes expected from the primary affiliation of the frontal region involved – executive dysfunction, disinhibition, and apathy, respectively (Cummings, 1993). Although in practice a mixture of several frontal disturbances often occurs, so that specific syndromes may not appear in isolation, reference to frontal-subcortical circuits has nevertheless helped explain some of the

Fig. 35.3. Drawings of the frontal lobes depicting the areas of prefrontal cortices damaged in the orbitofrontal, dorsolateral prefrontal, and medial frontal syndromes.

566 C.M. FILLEY most salient frontal lobe disturbances reported in suggests that phonological working memory tends to the past (Cummings, 1993; Filley, 2001b). Both strucinvolve the left frontal lobe and spatial working memtural (Filley, 2001a) and functional neuroimaging ory the right, more difficult or complex tasks demand (Goethals et al., 2004) have also contributed to the the involvement of both frontal regions, regardless of understanding of the frontal lobes by demonstrating the nature of the material at hand (Budson and Price, frontal components of specific distributed neural net2005). The notion of working memory has helped clarworks (Fig. 35.2). ify the long-suspected role of the frontal lobes in attenExecutive function is a complex and multifaceted tional function, and provided a useful focus for domain typically defined as a collection of interrelated empirical investigation using case studies and funccognitive operations. The specific operations included tional neuroimaging. under the concept vary by author, but executive funcComportment refers to the capacity to display tion generally refers to the capacity to plan, carry appropriate interpersonal conduct when confronted out, and complete a sustained cognitive task while with complex social situations where restraint of excluding competing distractions, monitoring progress, instinctual behavior is required (Mesulam, 2000). and modifying behavior in the light of new information Accordingly, normal comportment implies that limbic (Stuss and Benson, 1986; Miller and Cummings, 1999; impulses are integrated into an appropriate behavioral Anderson and Tranel, 2002; Elliot, 2003). As stated repertoire so that adverse social consequences are by Stuss and Benson (1986, p. 244): avoided. Orbitofrontal lesions have been securely linked with disorders of comportment, generally . . . executive function represents many of the known as disinhibition, since the time of Phineas Gage important activities that are almost universally (Harlow, 1868; Macmillan, 1986). Disinhibition has in attributed to the frontal lobes which become fact become recognized as one of the most striking active in nonroutine, novel situations that require manifestations of personality change in patients with new solutions. These behavioral characteristics frontal lobe lesions (Chow, 2000). Some authors have have been described by many authors and include invoked the descriptor “acquired sociopathy” for at least the following: anticipation, goal selecpatients who develop impaired judgment and behavior tion, preplanning (means–end establishment), after orbitofrontal injury (Eslinger and Damasio, monitoring, and use of feedback (if–then state1985), thus proposing a link to the psychiatric diagnosis ments). Each of these represent a separate experiof antisocial personality. From these origins, the conmentally testable frontal lobe function. cept of social cognition has evolved, by which is meant Whereas executive function and frontal lobe function the capacity of the brain to organize behavior in a have sometimes been considered synonymous, it is social context, and the orbitofrontal cortices as well increasingly clear that the dorsolateral prefrontal as many subcortical and limbic structures are involved regions have a selective role in executive function, (Adolphs, 2001). along with connections to subcortical structures and Motivation is the last category of higher function posterior cortical regions (Anderson and Tranel, 2002; with a strong link to the frontal lobes. This concept Elliot, 2003). In clinical terms, the recognition of has arisen out of the growing awareness of clinical executive dysfunction has become routine with states referred to as apathy or abulia (“loss of will”) focused history-taking and the use of appropriate seen in neurologic patients with damage to the medial screening measures, and it is commonplace to encounfrontal regions (Filley, 2001b). Amotivational states ter the term “dysexecutive” to describe individuals with may even take an extreme form known as akinetic a variety of brain disorders capable of disrupting this mutism, in which a person with extensive medial froncritical domain. tal damage makes no movement and offers no speech Related to the idea of executive function is another despite being clearly awake and attentive. These concept known as working memory. This notion, introremarkable clinical states have led to the suggestion duced in the later decades of the 20th century, refers that the medial frontal cortices, in particular the anteto the capacity of the brain to maintain information rior cingulate gyri, may function as the neural subtemporarily so that it can be quickly manipulated strate for the philosophical concept of free will (Baddeley, 1992). A good example is holding a tele(Damasio, 1994). Similarly, more recent accounts have phone number in mind long enough to dial it without focused on apathy as a deficit in initiating goal-directhe need to write it down. Working memory links the ted behavior that fails to engage the neural substrates processes of attention and short-term memory, and of voluntary action – cortical and subcortical – that requires the participation of dorsolateral prefrontal are otherwise prepared to undertake such action (Levy cortices (Budson and Price, 2005). Although evidence and Dubois, 2006).

THE FRONTAL LOBES 567 These developments in the understanding of frontal the development of heteromodal and paralimbic lobe structure and function have also led to cerebral regions in the brain, especially in the frontal white matter receiving more attention. In light of the curlobes. (Mesulam, 1986, p. 323) rent emphasis on systems neuroscience characterized by Recent comparative neuroanatomical studies have shed distributed neural networks (Alexander et al., 1986; additional light on this topic. Overall, the brain is known Cummings, 1993; Mesulam, 2000), the actual connectivto be proportionally larger in humans than other priity of the networks via white matter tracts has become mates of similar body size, but certain brain regions crucial. This realization has been bolstered by the fremost distinguish the human brain from that of the quent observation that lesions of white matter tracts higher primates. How humans differ from other prioften produce executive dysfunction and other frontal mates may in part be explained by frontal lobe conneclobe disturbances, suggesting that the extensive connectivity. It appears that, in relative terms, the white matter tivity of the frontal lobes has important clinical implicaof the prefrontal regions shows the largest difference tions (Filley, 2001a). A renewed effort to understand between humans and nonhuman primates (Schoenewhite matter pathways has stimulated study of the conmann et al., 2005). This observation further supports nectivity of frontal and other regions using the structhe prominence of the frontal lobes in human evolution, tural neuroimaging technique of diffusion tensor and in particular suggests that the connectivity with subimaging (Filley, 2005). At the level of neuroanatomy, cortical and more posterior cortical structures is a key detailed studies of white matter in non-human primates feature of human evolutionary development. have appeared that portend better understanding of these tracts in humans (Schmahmann and Pandya, 2006). FUTURE PROSPECTS The neurochemistry of the frontal lobes has also been clarified as the idea of frontal-subcortical circuits Today the frontal lobes are seen as occupying a unique has taken hold (Tekin and Cummings, 2002). The five position in the neurobiology of human cognition, emocircuits mentioned above all feature the excitatory tion, and behavior. Although the variability of clinical neurotransmitter glutamate and the inhibitory neurotransfeatures associated with frontal lobe damage or dysmitter gamma-aminobutyric acid, commonly known as function continues to challenge clinicians, solid lines GABA. In addition, modulatory neurotransmitters ascendof evidence now point to the role of the frontal lobes ing from the brain stem and basal forebrain – dopamine, in executive function, attention, working memory, norepinephrine, acetylcholine, and serotonin – are widely comportment, social cognition, motivation, language, distributed in the frontal lobes and affect all frontal lobe and prosody. These advances are clarifying the special functions. Dopamine has attracted particular attention by contributions of the frontal lobes that have challenged virtue of its increasingly well-established role in substance neuroscientists for centuries, and “the riddle of frontal abuse and addiction; dopamine produced in the ventral lobe function” (Teuber, 1964) has begun to yield to tegmental area projects to a putative drug reward circuit systematic investigation. that includes the prefrontal cortices, the nucleus accumStill enticing for neuroscientists, however, is the possibens, and the amygdala (Tekin and Cummings, 2002). bility that, despite the many parallel domains subserved These insights give reason for optimism that effective by the frontal lobes, a singular function can be identified pharmacotherapy can be developed for many patients with that captures their unique contribution. The prominence troubling frontal lobe syndromes. of the human frontal lobes compared to those of other priFinally, the frontal lobes have continued to attract mates points to this possibility, and suggests that some interest in evolutionary terms. The importance of fronsuperordinate control capacity mediated by frontal systal lobe expansion for human cognition has long been tems distinguishes human behavior. A popular analogy suspected; the entire period of human evolution, for has been that the frontal lobes serve as the conductor example, was described in 1928 as “the age of the fronof the symphony being played by the rest of the brain tal lobe” (Tilney, 1928). More recently, the frontal (Filley, 2001b). More scientifically, the frontal lobes are lobes, especially the prefrontal cortices, have been disoften regarded as organizing autonomous behavior via a cussed in terms of mediating a high degree of freedom supervisory role that includes the motivation for volunfrom environmental constraints and release from stitary action, the guidance of behavior in a social context, mulus-bound behavior: and many aspects of problem solving (Cummings, 1993; Mesulam, 2000). By implication, many other cognitive The behavioral repertoire of higher species is operations are seen as represented elsewhere in the brain; characterized by a far greater autonomy from the it is clear, for example, that the psychological construct environment. This autonomy and the associated intelligence, measured routinely by the intelligence behavioral flexibility appear very much linked to

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quotient (IQ), may be normal in patients with dramatic frontal lobe dysfunction (Eslinger and Damasio, 1985). The frontal lobes thus seem to have more to do with how intelligence is used rather than the IQ itself. A more subtle attribute is at work – one not easily conceptualized – and it is not surprising that no single measure of frontal lobe function has appeared. Two other intriguing areas are garnering much attention in light of emerging insights into frontal lobe structure and function. These topics illustrate the wide range of behaviors that are now seen as appropriate for scientific study, in contrast to former attitudes assigning them strictly to fields such as philosophy, sociology, and theology. One such topic, creativity, is perhaps the most cherished human mental capacity. Although no agreement exists on a definition, many neuroscientists are beginning to put forth formulations of creativity as a brain phenomenon. The frontal lobes clearly enter into these speculations, as they contribute to such fundamental aspects of creativity as inspiration, persistence, and divergent thinking (Austin, 2003; Heilman, 2005). It is not unreasonable to imagine that modern neuropsychological and neuroimaging studies will lead to preliminary explication of how the brain mediates creativity, and the frontal lobes are likely to figure prominently. In a larger societal context, an understanding of the neural basis of creativity can be expected to raise many difficult questions, such as whether medical intervention can enhance creative capacity, and if so, who will benefit? At the other extreme of human behavior is violence, the unfortunate threat to human welfare that so often and tragically disrupts interpersonal and international relationships. Considerable evidence suggests that damage to the frontal lobes is a powerful predictor of unwarranted aggression, although many other factors surely play a role in this complex behavior (Grafman et al., 1996; Filley et al., 2001). A host of social, moral, legal, and political issues emerge from considering violence as a potential effect of frontal lobe dysfunction. As this behavior is understood in neurological terms, society will be faced with vexing conundrums such as the limits of individual responsibility and the debate over punishment versus rehabilitation after violent crime. The prospects for improved understanding of the frontal lobes appear bright, and this knowledge promises to have far-reaching implications. While patients with frontal lesions often challenge clinicians with the complexity of their cognitive, emotional, and behavioral disturbances, and researchers may be daunted by the intricacies of frontal structure and function, knowledge has advanced considerably in the 200 years since the frontal lobes were delineated, and the methods with which to investigate them are increasingly powerful. As the mysteries of the frontal lobes yield

further to scientific analysis, a variety of new questions will surely arise to justify the continued attention of neuroscience and society alike.

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Swedenborg E (1882). The Brain, Considered Anatomically, Physiologically, and Philosophically. Part 1. Translated and edited by RL Tafel. Speirs, London, p. 73. Tallis RC (1996). Burying Freud. Lancet 347: 669–671. Tekin S, Cummings JL (2002). Frontal-subcortical neuronal circuits and clinical neuropsychiatry. J Psychosom Res 53: 647–654. Teuber H-L (1964). The riddle of frontal lobe function in man. In: JW Warren, K Akert (Eds.), The Frontal Granular Cortex and Behavior. McGraw-Hill, New York, pp. 410–444. Tilney E (1928). The Brain, from Ape to Man. Hoeber, New York. Valenstein E (1986). Great and Desperate Cures: The Rise and Decline of Psychosurgery and Other Radical Treatments for Mental Illness. Basic Books, New York. Willis T (1664). Cerebri Anatome: Cui Accessit Nervorum Descriptio et Usus. J Martyn & J Allestry, London. Young RM (1970). Mind, Brain, and Adaptation in the Nineteenth Century. Oxford University Press, London.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 36

History of aphasia: from brain to language PAUL ELING 1 * AND HARRY WHITAKER 2 Department of Psychology, Radboud University Nijmegen, Nijmegen, The Netherlands 2 Department of Psychology, Northern Michigan University, Marquette, MI, USA

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INTRODUCTION Until the latter half of the 20th century, the study of aphasia was mainly performed by physicians and rarely addressed by students of language; Chajim Steinthal (1823–1893) and Roman Jakobson (1896–1982) are notable exceptions (see also De Bleser, 2006). Steinthal’s plea for a psycholinguistic approach to aphasia was ostensibly ignored by the medical establishment (Jacyna, 1999; Eling, 2006a), although one should point out that the neurologists John Hughlings Jackson (1835–1911) and Arnold Pick (1851–1924) adopted principles of linguistic analysis in their studies of aphasia. On the other hand, the study of language disorders has always played a dominant role in attempts to understand the biological basis of the mind. The dominant view on the origin of languages held by the Egyptians and Babylonians was that the Gods gave the language faculty to mankind. A clay fragment from the Hittite period (c. 1500 BCE) described an episode in the life of King Mursilis II. While driving his chariot in a thunderstorm, he lost his speech. Mursilis blamed this event on the storm god, and burned his clothes, the chariot, and the horse in an effort to appease the angry god. The king’s recovery was attributed to the successful sacrifices, rather than to what was perhaps a transient ischemic attack (Whitaker, 1998). Other common themes in the early texts on language were that thinking was conceived of as speaking to oneself, and that naming a thing is necessary in order for it to exist (Lutz, 1936). The vast majority of the old texts concerned language production, i.e., articulate speech; comprehension was not considered a separate faculty until the latter part of the 19th century (Boller, 1978; Whitaker, 1998).

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Wollock (1997) analyzed ideas on the physiology of speech in medical texts from Aristotle and Galen to the 17th century, when Descartes came forth with his dualistic conceptions of body and mind (a setback from which we have yet to recover, according to Wollock). In the pre-Cartesian tradition, speech was considered a particular case of voicing special to man. Emphasis was first on the bodily instruments that are required to make noise (lungs, air, larynx), second on modulating the noise to become speech sounds (vowels and consonants), and third on producing these sounds in sequential order. In this approach, there was little attention to sentences, grammar, concepts, or the communication of messages – notions that we currently regard as central to language. In this tradition, a number of disorders were distinguished, including: traulotes – reduced control over the production of certain speech sounds; psellotes – the absence of speech sounds or syllables in speech; and ischophonia – stuttering, i.e., incorrectly connecting a syllable to a subsequent syllable, lengthening a sound, or duplicating a syllable. Today such phenomena are marginally related to the study of aphasia, although prominent in the practice of speech pathology. O’Neill (1980) analyzed a variety of descriptions of individuals who had apparently suffered from a speech disorder caused by a medical condition or a trauma. In this context, we begin our historical overview proper. Although organized chronologically, we split the time line to reflect important changes in approaches, limiting our review to speech production and comprehension, and not considering disorders of reading and writing. Moreover, emphasis will be on attempts to infer from disorders notions concerning the psychological and biological mechanisms underlying language.

Correspondence to: Paul Eling PhD, Department of Psychology, Radboud University Nijmegen, PO Box 9104, 6500 HE Nijmegen, The Netherlands. E-mail: [email protected], Tel:þ31-24-361-25-57, Fax: þ31-24-361-60-66.

572 P. ELING AND H. WHITAKER We therefore devote less attention to the clinical stroke. He could not recognize letters or read words, concerns of assessment. As for the history of speech but he was able to write to dictation. Rommel (1683) rehabilitation, see Chapter 53. presented his case under the title De Aphonia Rara, apparently surprised by the fact that his patient could not speak spontaneously but could still recite her CASE DESCRIPTIONS prayers, a nicely described dissociation between volunThe early text fragments reviewed by O’Neill (1980) (as tary and automatic speech. well as Benton and Joynt, 1960; Critchley, 1970; After a fairly strenuous walk, which she took Whitaker, 1998; Tesak, 2001; Prins and Bastiaanse, after dinner, she suffered a mild delirium and 2006) are mostly medical in nature, e.g., case descripapoplexy with paralysis of the right side. She lost tions in the Edwin Smith Surgical Papyrus and the all speech with the exception of the words “yes” Hippocratic corpus. Non-medical fragments mentioned and “and.” She could say no other words, not by O’Neill (1980) derive from Homer and the Bible, as even a syllable, with these exceptions; the Lord’s well as a variety of texts through the Middle Ages, all Prayer, the Apostles’ Creed, some Biblical of which present a classical view, typically Aristotelian verses and other prayers which she could recite and Galenic. verbatim and without hesitation but somewhat In the medical fragments, speechlessness was typiprecipitously. . .Nevertheless, her memory was cally considered a symptom signaling a bad prognosis; excellent. She grasped and understood everycases were typically not used for theorizing or analyzing thing that she saw and heard and she answered underlying language functions. Frequently speechlessquestions, even about events in the remote past, ness was mentioned incidentally, making it difficult to by affirmative or negative nods of the head. determine with precision the nature of the impairment, (Trans. in Benton and Joynt, 1960, p. 210) and not permitting an in-depth analysis of the thencurrent understanding of what we refer to as aphasia. The Swiss physician Johannes Jakob Wepfer (1620– We will therefore not attempt to mention all the frag1659) collected his observations in several works, notaments that have been uncovered. bly Observationes Medico-practicae de Affectibus O’Neill (1980; see also Luzzatti and Whitaker, 1995/ Capitis Internis & Externis, posthumously published 1996) identifies as a turning point the beginning of the in 1727. At least 13 cases, mostly open head injuries, 16th century. Giovanni De Vigo’s (1450–1525) Practica showed a clear language disorder, which Wepfer copiosa in arte chirurgia (De Vigo, 1514) contains a described as loss of memory (for analyses and translacase of traumatic speechlessness. Similar observations tion of some cases, see Luzzatti and Whitaker, 1995/ were made by Giacomo Berengario (1460–1530), Nicola 1996). Massa (1504–1589), William Clowes (1540–1604), HierIn point of fact, the classical authors typically used onymus Mercurialis (1530–1606), and Johann Schenck the terms “memory,” “verbal memory,” “speech,” and von Grafenberg (1530–1598). These works reflect a “language production” interchangeably. Presumably shift in medicine during the 16th century to an analysis this was partly because memory was measured by what of mental functions in relation to the brain – a change one could verbally retrieve from memory, and partly presumably due to the fact that physicians started to because most aspects of language comprehension were perform their own anatomical observations, rather than considered to be intellect or general cognition. Wepfer relying on typically Galenic classical texts. provided unusually detailed and accurate neurological Benton and Joynt (1960; see also Benton, 2000) and neuropsychological information. Most cases were reviewed Renaissance descriptions, to some extent simifollowed by a dissection, and etiological-pathological lar to those discussed by O’Neill (1980). These may best comments were quite sophisticated, given the Zeitgeist be characterized as observations, usually not very sysof the era. tematic and usually not meant to illustrate a particular The renowned Italian pathologist Giovanni Battista theoretical view of language or brain. Two cases from Morgagni (1682–1771) published his five volume De Sedithe 17th century, however, one by Johann Schmidt bus et Causis Morborum per Anatomen Indagatis (Mor(1624–1690) and the other by Peter Rommel (1634–1708), gagni, 1762) when he was nearly 80 (Finger, 1994). It attain a descriptive level that is notably superior to those contained a number of cases of speechlessness assothat had hitherto appeared. The aphasic disturbances are ciated with apoplexy and head trauma. Most descriptions clearly recognizable as variants of expressive aphasia. were rather short. Morgagni frequently indicated that, The Danzig physician Schmidt (1676) observed that although a patient could not speak, he might be able to his patient substituted one word for another and susunderstand spoken language. Indeed, in none of his cases tained right-sided paralysis after suffering from a is a speech comprehension deficit observed.

HISTORY OF APHASIA: FROM BRAIN TO LANGUAGE To quote: . . . he scarcely spoke at all, and when he did, he stammer’d; but he answered in such a manner, by nods and signs, to those who ask’d him questions, that you might perceive his internal senses to be strong and perfect. (Trans. in Benton and Joynt, 1960) Morgagni often examined the brain post mortem, as did Wepfer. Both men observed, on many occasions, the occurrence of a speech problem in the presence of a right-sided hemiplegia and a lesion in the left hemisphere. According to Ebstein (1914), we should refer to this association as the Valsalva (Morgagni’s teacher)–Morgagni doctrine; however, Pourfour du Petit made the same observation in 1710 (Kruger and Swanson, 2007) and Wepfer, although not published until 1727, made the same observation in the 1660s.

TOWARD AN EXPLANATION An elaborate case description is found in Johann Gesner’s (1738–1801) chapter Die Sprachamnesie, in volume two of his Samlung von Beobachtungen aus der Arzneygelahrtheit (Gesner, 1770; Luzzatti, 2002). According to Benton (1965), this can be considered the first major work devoted to the subject of aphasia. As is typical of the early compendia (Schenck’s and Wepfer’s, for example), several cases were taken for comparison to the one discussed by Gesner himself. The latter patient, 73-year-old K.D., had been in excellent health but was unexpectedly affected by a severe language impairment. In brief, his output was fluent but neologistic (Luzzatti, 2002). Benton (1965) classified his problem as one of jargon aphasia. K.D. could no longer read or write, and he had no sign of paralysis. He had been seen by several physicians, and Gesner described their observations and interpretations, referring to letters from these physicians. He concluded that the disorder cannot be ascribed to loss of intelligence, neither is it due to a generalized memory disorder, but rather it is due to a verbal memory impairment (consistent with medieval cell doctrine; see Whitaker, 2007). The nature of the impairment, Gesner specified, consists of an inability to associate images or abstract ideas to their expressive verbal symbols. Gesner’s theoretical analysis is a first attempt to provide a functional explanation of aphasia, one that would become a central issue for discussion in the late-19th century (Benton, 1965). Alexander Crichton (1763–1856) also attempted to use speech disorders as a means to understand underlying mental processes and impairments (Crichton, 1798). Like Gesner, he suggested that aphasia may be regarded as a very singular defect of (verbal) memory,

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specifically, “a defect of that principle by which ideas, and their proper expressions, are associated.” He believed that the person had a clear notion of what he wanted to say, yet could not pronounce the words (Finger and Buckingham, 1994).

LOCALIZATION OF SPEECH PRODUCTION The 19th century witnessed a dramatic change in the investigation of mental processing and its relationship with the workings of the brain. At first, the discussion focused on the structural location of mental functions; subsequently, the formulation of functional theories became equally important. The study of language disorders played a leading role in both approaches. The Austrian physician and anatomist Franz Joseph Gall (1757–1828) started the discussion, arguing that: (1) the material substance of the brain, in particular the cortex, forms the basis of mental functions (instead of the cavities inside), and (2) each mental faculty has its own seat, a circumscribed area of cortex (Lesky, 1979; Finger, 2000). On the premise that focal changes in brain volume alter the shape of the overlying skull, an idea borrowed from the physiognomist Johann Christian Lavater (1741–1801), Gall looked for bumps on the skull to help him localize specific functions. Indeed, craniometry was his primary method. He believed that studying the effects of lesions of various parts of the brain on language behavior, or the clinicopathological method, could provide support for his cranium-based localizations, although he did not have great faith in clinical findings by themselves. Gall (1822–1825) distinguished the language faculty (Sprachsinn) from the word faculty (Wortsinn), the former being an inborn capacity for (verbal) communication and the latter a store for words. He described six cases, arguing that the observed language disorder is not due to general problems with intelligence or memory or to a paralysis of the tongue: “he has only lost the capacity to speak.” Following Gall, temporally as well as theoretically, Jean-Baptiste Bouillaud (1796–1881; Fig. 36.1) collected a large set of data on patients with speech problems (Bouillaud, 1825; see Luzzatti and Whitaker, 2001). He was intrigued by Gall’s theory of localization of function in general, and by the localization of language in the frontal part of the brain in particular. He was vehemently opposed to Flourens’ work, which was intended to refute Gall’s claims of specific cortical areas. The purpose of Bouillaud’s paper was to demonstrate the existence of a specific center in the cerebrum for the control of speech movements. He thus distinguished between word meaning and the articulation of words. His approach was based on the assumption

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Fig. 36.1. Jean-Baptiste Bouillaud (1796–1881).

that two activities must be functionally separate, if they can be disrupted in isolation from each other – probably the first published formulation of the double dissociation principle. He described three patients suffering from severe speech disorders without any limb disorders. For further empirical support of his assumption he examined the casebooks of two colleagues, Franc¸ois Lallemand and Louis-Le´on Rostan, containing more than 60 relevant cases. Bouillaud claimed that in the majority of the speech disorder cases the lesion was localized in the anterior part of the brain, in agreement with Gall’s localization of the language faculty, verbal memory, right behind the eye sockets (but see Luzzatti and Whitaker, 2001, for a re-analysis of the original data). Surprisingly, he failed to remark upon the left– right asymmetry in lesions producing aphasia. Bouillaud’s repeated attempts to promulgate this theory, from the 1820s to the 1850s, remained unconvincing to the medical and scientific establishment (Bouillaud, 1830, 1848). Pierre Paul Broca (1824–1880; Fig. 36.2), however, did change the prevailing view. He was a surgeon but also the founder and secretary of the first anthropological society (in 1859). An important point of discussion was the origin of man, including the origin of language and the development of the brain. In the 18 April meeting

Fig. 36.2. Paul Broca (1824–1880).

of the Society of Anthropology in 1861, Paris, Broca mentioned in a discussion on disturbances of speech an important observation; according to the notes: M. Broca presented the brain of a fifty-one-yearold man who had died [on the previous day] in his service at the hospital Biceˆtre. For the last twenty-one years this man had lost the use of his speech. As it is planned to deposit the specimen at the Muse´e Dupuytren and to publish the complete records in the Bulletin de la Socie´te´ Anatomique, only a short re´sume´ will be given; the case is quite similar to some of those about which M. Auburtin has talked at the last meeting. (Trans. in Schiller, 1992, p. 177) The full report was published in August. Broca stated that this patient could voluntarily utter the syllable “Tan” and occasionally a few other small words, and that he had a lesion in the anterior part of the brain (Broca, 1861; see also Signoret et al., 1984). Broca indicated that this evidence supported the general claims of Gall and Bouillaud, but that the lesion in his patient, at the foot of the third frontal gyrus, did not really match the site proposed by Gall. After collecting a few additional cases, Broca claimed that a lesion in the third frontal gyrus results

HISTORY OF APHASIA: FROM BRAIN TO LANGUAGE in aphemie (aphemia), a disturbance in the articulation of words – the mechanism for expressive, voluntary speech being impaired (Broca, 1863). Armand Trousseau (1864) suggested the term aphasie (aphasia) for the disorder. In 1865, Broca claimed that only the frontal gyrus in the left hemisphere was responsible for speech, thus not only further establishing the principle of localization, but also introducing the notion of hemispheric differences, very much to his own surprise (Eling, 1984). The latter concept was quickly adopted in the literature and speech began to be interpreted in terms of cerebral dominance (Harris, 1991). The question of the role of the left versus the right hemisphere in language had actually first come to the fore in 1863, when Gustave Dax came forth with a report prepared by his deceased father, Marc Dax, one supposedly presented at a regional meeting in the southern city of Montpellier in 1836 (see also Finger and Roe, 1996, 1999; Roe and Finger, 1996). This memoir was based on some 80 cases of language disorders, half observed and the rest from the literature, but in contrast to the cases in Broca’s 1865 paper, there were no autopsy findings. Still, the right-side paralyses associated with the speech defects and the loci of the cranial defects (e.g., sword wounds, tumors) strongly suggested that language functions reside in the left hemisphere. The actual presentation of the Marc Dax memoir in 1836 has been debated (including by Broca), but not the fact that it and a supplemental, confirmatory report by his son Gustave Dax were received by two prestigious societies (one medical, the other scientific) in Paris in early 1863. The two Dax papers were subsequently published in 1865 (Gustave’s paper was shortened at this time; a full report would appear later). The record shows that Broca’s publication suggesting a special role of the left hemisphere for language was published shortly after the Dax papers had been submitted for publication. The priority issue is ably discussed in Cubelli and Montagna (1994), with more details added by Finger and Roe (1996) and Roe and Finger (1996).

LOCALIZATION OF LANGUAGE COMPREHENSION In 1843, Montpellier physician Jacques Lordat (1773–1870) provided one of the first clear descriptions of a language comprehension problem due to a brain disorder. He described his own aphasia, or alalia as he preferred to call the disorder, caused by a stroke (Lordat, 1843). Further, the French physician Franc¸ois Baillarger (1809–1890) described a woman with aphasia, who had been regarded as deaf and insane; it was soon demonstrated that neither deafness nor insanity

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could explain her comprehension problems (Baillarger, 1865). Johann Baptist Schmidt (1823–1884), an obstetrician working in Wu¨rzburg, also observed a patient who could not understand speech, although her hearing appeared intact (Schmidt, 1871; Boller, 1977). He also noted what we would today call verbal and phonemic paraphasias in her speech. He hypothesized that the capacity for combining sounds into word images may underlie these speech problems. Moreover, he pointed to the walls of the Sylvian fossa as the critical location. Carl Wernicke (1848–1905; Fig. 36.3), at the relatively young age of 26 and without much experience with aphasic patients, wrote perhaps the most influential 19th-century monograph on aphasia, Der Aphasische Symptomenkomplex (Wernicke, 1874; Eggert, 1977; Tesak, 2005). He worked in Breslau but visited the Viennese neuropsychiatrist and neuroanatomist Theodor Meynert, who supposedly inspired him to study language comprehension deficits (see also Eling, 2006b). After his stay in Vienna, Wernicke studied 10 patients, and post-mortem analyses of the lesions in four of them. He noted that the clinical picture varied from pure motor aphasia to pure sensory aphasia (his

Fig. 36.3. Carl Wernicke (1848–1905).

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terms). He claimed that speech perception is localized in the temporal lobe, in an area now known as Wernicke’s area. Moreover, he claimed that language could be conceived of as consisting of two interconnected centers, one for perception and one for speech production. Lesions in either of these centers or in the connecting pathway would result in different patterns of language impairments. Wernicke contended that a specific center for concepts was not needed, unlike some other late-19th-century authors. Concepts were, in his view, represented by sensory-motor features. Wernicke’s model is an early attempt to provide a more detailed view of language as a psychological function, relating distinct components of that function to different sites in the brain (Geschwind, 1966). However, keeping in mind that Wernicke formulated his model on the basis of patients with language disorders and not on a sophisticated view of language, it may be more appropriately regarded as a new theoretical account of aphasic phenomena. His approach became very influential, both in the domain of aphasia and in other functional domains, such as perception and motor control. His ideas were disseminated in the literature by a large number of pupils, including Liepmann, Heilbronner, Foerster, Kleist and Goldstein, among others.

DIAGRAMS Adolf Baginsky (1871; Eling, 2005), who later specialized as a pediatrician in Berlin, and Henry Charlton Bastian (1869, 1898; Marshall, 1994), working like Jackson at the National Hospital, Queen Square, also attempted to interpret language disorders in terms of a theoretical framework consisting of a series of specific language functions or centers (e.g., for speech production and comprehension, concepts, reading and writing) that were connected to each other through “pathways.” These models are often referred to as connectionist models or diagrams (see also Moutier, 1908; Morton, 1984). Although the centers were often assumed to be localized in circumscribed brain areas, frequently these authors focused on the functional characteristics of their models (Fig. 36.4). The typical structure of these models was that a language disorder occurs either by destruction of a center or disruption of a pathway. Adolf Kussmaul’s (1822– 1902) comprehensive discussion of language phenomena in general, and of these wiring diagrams in particular, provides an excellent example of how such process models can explain aphasic behavior in a functional way (Kussmaul, 1877; see also Jarema, 1993). What we now regard as the prototypical diagram was produced by Ludwig Lichtheim (1845–1928). It contained a separate center for concepts (Lichtheim,

Fig. 36.4. Baginsky’s diagram with centripetal (a–D) and centrifugal (D–f) pathways: a represents the endings of the N. acusticus, b is the center for sound perception, c is the center for sound memory; a’, b’ and c’ represent similar organs for the visual pathways; D is the center for concept formation, e is the center for coordinated movements.

1885; see also Laubstein, 1993). The model predicted seven different aphasia syndromes, but Lichtheim elaborated on only three types, motor and sensory aphasia, as well as conduction aphasia (Leitungsaphasie according to Wernicke); the latter due to a lesion of the pathway connecting the two centers. He illustrated the value of his model with four case descriptions (with pathological-anatomical data for one patient), claiming that each of the seven forms exist (Fig. 36.5). In England, Bastian (1898) had developed a similar diagram, but without a conceptual center, and in France Jean-Martin Charcot (1825–1893), the first Professor of Diseases of the Nervous System and working at the Salpeˆtrie`re in Paris, developed his famous “clock diagram” (Charcot, 1884; Lecours, 1993; Gelfand, 1999), with a conceptual center. Like Lichtheim’s model, it was intended as a pedagogic instrument rather than as a well-founded theory of language representation in the brain.

GRAMMATICAL DISORDERS As was the case from classical times, the basic language unit was the word, either a noun or a verb, in the “diagram” models. Ferdinand Finkelnburg’s (1832–1896)

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Steinthal proposed that there could be a number of disorders at different stages in this process of unpacking, resulting in disorders that are not modality specific (input–output, auditory–visual) but are related to the level of representation. For Steinthal, aphasia is a disorder at the word level, and akataphasia is a disorder at the sentence level. In a meeting with several physicians, including Virchow, Hitzig and Westphal, Steinthal failed to convince them of the relevance of his approach. John Hughlings-Jackson (1835–1911), the pioneer of British neurology, could not accept the notion of localization of speech functions in circumscribed cortical areas (see also Greenblatt, 1970). He warned that to localize a symptom, e.g., aphasia, is not the same as to localize a function (Jackson, 1878–1880). He rejected the notion of a “faculty” of language and, in line with the dominant associationist philosophy, opted for a sensory-motor view of language representation in the brain. He also claimed that the basic language unit is not the word but “the proposition”: Fig. 36.5. Lichtheim’s “House” model. A represents the center for sound images; M is the center for movement images; B is the center for concepts; a is the acoustic pathway and m is the motor pathway. 1–7 represent various forms of aphasia, depending on the destruction of a center or pathway.

model was an exception, claiming that the core problem is an “asymbolia” – “a disturbance of function in which there is a partial or complete loss of the ability to comprehend and express concepts by means of acquired signs” (Finkelnburg, 1870; Duffy and Liles, 1979). This interpretation was based on five case descriptions (two with autopsies). These patients not only had problems in reading, writing, speaking or comprehending words, but they also had problems with using or learning common signs, musical notation, the value of money, insignia of rank, and social conventions. The German linguist Chajim Steinthal (1871; Eling, 2006a) developed a psycholinguistic theory and applied it to language disorders (clinical pictures rather than patients) as a test of its validity. Linguistics at that time was basically comparative linguistics: looking for the derivation of current words from older languages. Steinthal pleaded for a different approach, one that we would now call psycholinguistics. He argued that language is a means to express an idea, usually in the form of a sentence. The idea or message is “unpacked” by psychological processes, yielding a linguistic structure that requires words, words with specific foci (morphology) that are then produced as sounds.

Speaking is not simply the utterance of words. The utterance of any number of words would not constitute speech. Speaking is “propositionising.” (Jackson, 1874/1958, p. 130) At the beginning of the 20th century, aphasiologists noted that some patients had problems not just with speech production or perception, but with speaking correctly, a phenomenon labeled “agrammatism” (see De Bleser, 1987). Arnold Pick (1851–1924), an assistant to Meynert and Westphal in Berlin, where he was also a colleague of Wernicke, was influenced by the Wu¨rzburger School, emphasizing a more holistic view of psychology and giving the sentence a more central position in language processing. Pick became interested in impaired sentence production and claimed that agrammatism arises from a lesion in the left temporal lobe, affecting language production processes rather than higher cognitive processes, as was often assumed since Steinthal (Pick, 1913). Karl Bonhoeffer (1868–1948) regarded agrammatic speech as a consequence of a lesion in Broca’s center, resulting in laborious speech (Bonhoeffer, 1902). Karl Heilbronner (1869–1914), however, argued that agrammatism is an independent phenomenon, since it is also observed in writing and sentence completion tasks (Heilbronner, 1906). In addition, he claimed that severe agrammatic speech can occur in patients who do not show any deficit in comprehension. Pick formulated an elaborate model of sentence production, distinguishing between a syntactic representation (Satzschema, sentence scheme) and word forms, which are inserted in the sentence scheme, in

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his famous Die agrammatischen sprachsto¨rungen (1913; Friederici, 1994). Pick noticed that, in agrammatic speech, the phrases that are produced are essentially intact. Therefore, what is produced is not the normal sentence but an adapted version, Notsprache (emergency speech; also referred to as Telegrammstilagrammatismus), which requires less effort. Agrammatical utterances are shorter and syntactically less specified. The German neuropsychiatrist Max Isserlin (1879–1941) defended a similar position (Isserlin, 1922; Howard, 1985). Karl Kleist (1914), also a neuropsychiatrist and under the influence of Wernicke, introduced the notion of “paragrammatism,” which he regarded as a different type of grammatical problem, one of word order. In his view, agrammatism is a kind of simplification of the word order in which, typically, subordinate clauses do not occur. In paragrammatism, however, the capacity to produce certain syntactic constructions is not lost, but the production of phrases is often interrupted or combined with alternative expressions.

AGAINST LOCALIZATION Following, and certainly influenced by, Jackson, Sigmund Freud (1856–1939) argued against the growing trend to localize language functions in brain centers (Freud, 1891; Buckingham, 1999, 2006; see also Greenberg, 1997). He thought of the “central apparatus of speech” as a continuous cortical region occupying the space between the terminations of the optic and acoustic nerves, and of the areas of the cranial and certain peripheral motor nerves. Aphasia is always the result of interruption of associations or conduction, and there is no need for a distinction between centers and pathways. For a variety of reasons, his 1891 book was neither widely known nor cited by other aphasiologists. Being a student of Charcot, and originally educated as a “diagram-maker,” Pierre Marie (1853–1940; Fig. 36.6) started a “revolution” in France by claiming that the third frontal convolution (Broca’s area) plays no role whatsoever in language (Marie, 1906). His claim was based on contradictory evidence: patients with lesions in Broca’s area that do not show aphasia, and patients with Broca’s aphasia from lesions in other parts of the brain. Marie argued that aphasia is the result of a lesion in the temporal lobe that produces an intellectual impairment – a reduction of knowledge and competence acquired didactically. For Marie there was only one form of aphasia, but it could vary in severity. “Broca’s Aphasia,” he argued, is merely aphasia with an added articulatory disorder. In 1908, an extensive debate between the localizationists, headed by another of Charcot’s pupils, Joseph Jules Dejerine (1849–1917), and the

Fig. 36.6. Pierre Marie (1853–1940).

anti-localizationists, headed by Marie, effectively ended in a draw (Lecours et al., 1992; see Chapter 40). In England the anti-localization movement was led by Henry Head (1891–1940), a great admirer of J.H. Jackson. Head sharply criticized the “diagram makers” (his term) and argued in his book, Aphasia and kindred disorders of speech (Head, 1926), that aphasia is a disorder of the formation and expression of linguistic and non-linguistic symbols (Jacyna, 2005). Head’s book was based on more than 15 years of intensive study and was considered the finest and most significant contribution to aphasiology by English neurologist Macdonald Critchley. Head explicitly extended aphasic disorders to other cognitive deficits, such as problems in arithmetic. Rather than trying to localize specific components of the language function, he thought it necessary to get a clearer picture of the language disorders. For that purpose, he designed an extensive test battery, intended to assess all aspects of the use and comprehension of language. He also investigated non-linguistic capacities. Head distinguished four types of aphasic disorders clinically: at the verbal level (word form), nominal level (meaning of word or sentence), syntactic level, and

HISTORY OF APHASIA: FROM BRAIN TO LANGUAGE semantic level, in particular, non-literal meanings of words or expressions, and of intentions. Adherents to this holistic approach not only rejected the notion of circumscribed brain centers: they also stressed that language was much more than words associated with images. The meaning, in the most extended sense (connecting language to attitudes, feelings, intentions and motives), was more fundamental. The best-known holist was the German neuropsychiatrist Kurt Goldstein (1889–1965), one of Wernicke’s last pupils. He rejected Wernicke’s view of acoustic and motor images as an insufficient psychological explanation; contending language is about meaning (Goldstein, 1948; Noppeney and Wallesch, 2000), Goldstein argued that we are conscious of meanings, not of acoustic images. The loss of the “abstract attitude” is the essential deficit in aphasia. In the contrasting “concrete attitude,” environmental stimulation determines our thinking and actions. When we refrain from environmentally determined behavior, however, we act according to an abstract attitude. In this sense, the abstract attitude may be compared to Head’s symbolic behavior – it is much broader than language in the usual meaning of the word.

THE CLINICAL APPROACH Like Head, the American neurologist Theodore Weisenburg (1875–1934) and his co-worker Katharine McBride addressed the question of the dissociation of aphasic phenomena in a clinical way. They developed a test battery and published data from groups of patients in their book Aphasia: A Clinical and Psychological Study (Weisenburg and McBride, 1935). To establish which errors or what level of errors are normal, they also examined healthy controls. With their clinical approach, the classification of aphasic syndromes emerged from the results, rather than from a preconceived theoretical model. They classified patients as follows: primarily motoric, primarily sensory, sensory-motor, and amnestic, the last reflecting word-finding problems in speech production. The psychologist Joseph Wepman (b. 1907, death date uncertain) and the speech pathologist Hildred Schuell (1907–1970) worked independently in this clinical tradition. They favored the holistic rather than the brain center approach. Wepman and Jones developed the Language Modalities Test for Aphasia (1961), while Schuell (1973) introduced the Minnesota Test for the Differential Diagnosis of Aphasia.

FROM APHASIA TO NEUROLINGUISTICS Roman Jakobson (1896–1982) had introduced neurolinguistic analysis of aphasic speech in the 1940s. From 1941, he had worked as a linguist in America, interested

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in the sound structure (phonology) of languages, Russian in particular (he was born in Russia). He analyzed its evolution in children’s speech and compared the changes he observed to speech errors in aphasia (Jakobson, 1941). Jakobson argued that there are two fundamental dimensions along which aphasic speech can be classified: disorders of “similarity” (replacements or selection errors) and disorders of “contiguity,” temporal ordering problems. His work had had little impact at the time, but was later rediscovered and applied primarily to phonological analysis of speech errors, for instance, by his student Sheila Blumstein (e.g., Blumstein, 1973). The influential American neurologist Norman Geschwind (1926–1984), inspired by Wernicke, founded the Boston University Aphasia Research Center in the 1960s (Kean, 1994). His plea for the re-introduction of the “disconnection approach” as a means of studying the relation between language (functions) and brain (centers) had a strong impact on the development of neuropsychology and the study of aphasia at the time. Many neurologists and psychologists came to Boston to train with Geschwind and neuropsychologist Harold Goodglass (1920–2002; Fig. 36.7). The renewed interest in the neuropsychology of language soon led to a shift of focus from the word (in Geschwind’s approach) to the sentence level. Goodglass, and to a larger extent Alfonso Caramazza and Edgar Zurif, triggered this change in focus in the 1970s (see also Goodglass and Wingfield, 1998). The American linguist Noam Chomsky (b. 1928) had dominated linguistics since the early 1960s with a

Fig. 36.7. Harold Goodglass (1920–2002).

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theory of generative-transformational grammar. Harry Whitaker (1969) explicitly applied generative-transformational grammar to the study of aphasia. By the 1980s, aphasia research had become an interdisciplinary field, combining linguistic (representation), psychological (processes), and neurological (anatomical and physiological mechanisms) ideas and models. This is expressed in the current label for aphasiology, “neurolinguistics,” a term used by Russian neuropsychologist Alexander Luria and French neurologist Henri He´caen in the 1960s. In conclusion, the study of the relation between language and the brain was dominated in the 19th century by the question of localization of function. In the 20th century, the focus slowly shifted toward psycholinguistically formulated models of language production and comprehension.

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Morgagni GB (1762). The Seats and Causes of Diseases Investigated by Anatomy. Translation by B Alexander (1769) from: De sedibus et causis morborum per anatomen indagatis. Facsimile edition (1960), New York Academy of Medicine, Hafner, New York. Morton J (1984). Brain-based and non-brain-based models of language. In: D Caplan, AR Lecours, A Smith (Eds.), Biological Perspectives on Language. MIT Press, Cambridge, MA, pp. 40–64. Moutier F (1908). L’aphasie de Broca. Steinthal, Paris. Noppeney U, Wallesch C (2000). Language and cognition. Kurt Goldstein’s theory of semantics. Brain Cogn 44: 367–386. O’Neill YV (1980). Speech and Speech Disorders in Western Thought before 1600. Greenwood Press, London. Pick A (1913). Die agrammatischen Sprachsto¨rungen. Springer, Berlin. Prins R, Bastiaanse R (2006). The early history of aphasiology: from the Egyptian surgeons (c. 1700 BC) to Broca (1861). Aphasiol 20: 762–791. Roe D, Finger S (1996). Gustave Dax and his fight for recognition: an overlooked chapter in the history of cerebral dominance. J Hist Neurosci 5: 228–240. Rommel P (1683). De Aphonia Rara. Miscellanea Curiosa Medico-Physica Academiae Naturae Curiosum 2 (ser 2). Jacobi Trescheri, Leipzig, pp. 222–227. Schiller F (1992). Paul Broca, Founder of French Anthropology, Explorer of the Brain. Oxford University Press, New York. Schmidt J (1676). De oblivione lectionis ex apoplexy salva scriptione. Miscellanea Curiosa Medico-Physica Academiae Naturae Curiosum 4, 195–197. Jacobi Trescheri, Leipzig. Schmidt JB (1871). Geho¨rs- und Sprachsto¨rung in Folge von Apoplexie. Alg Z Psychiatr Psych-ger Med 27: 304–306. Schuell H (1973). Differential Diagnosis of Aphasia with the Minnesota Test. University of Minnesota Press, Minneapolis, MN.

Signoret J-L, Castaigne P, Lhermitte F, et al. (1984). Rediscovery of Leborgne’s brain: anatomical description with CT scan. Brain Lang 22: 303–319. Steinthal CH (1871). Einleitung in die Psychologie und Sprachwissenschaft. Du¨mmler’s Verlagsbuchhandlung, Berlin. Tesak J (2001). Geschichte der Aphasie. Schulz-Kirchner Verlag, Idstein. Tesak J (2005). Der aphasische Symptomencomplex von Carl Wernicke. Schulz-Kirchner Verlag, Idstein. Trousseau A (1864). De l’aphasie, maladie de´crite re´cemment sous le nom impropre d’aphe´mie. Gaz Hop Civ Mil Empire Ottoman 37: 13–14, 25–26, 37–39, 48–50. Weisenburg TH, McBride KE (1935). Aphasia: A Clinical and Psychological Study. The Commonwealth Fund, New York. Wepfer JJ (1727). Observationes Medico-practicae, de Affectionibus Capitis Internis et Externis. Joh. Adam Ziegler, Schaffhausen. Wepman JM, Jones LV (1961). The Language Modalities Test for Aphasia. The Industrial Relations Center, University of Chicago, Chicago, IL. Wernicke C (1874). Der Aphasische Symptomenkomplex. Eine Psychologische Studie auf Anatomischer Basis. Cohn & Weigert, Breslau. Whitaker HA (1969). On the Representation of Language in the Human Brain. PhD dissertation, University of California at Los Angeles, Los Angeles, CA. Whitaker HA (1998). Neurolinguistics from the Middle Ages to the pre-modern era: historical vignettes. In: B Stemmer, HA Whitaker (Eds.), Handbook of Neurolinguistics. Academic Press, San Diego, CA, pp. 27–54. Whitaker HA (2007). Another look at medieval cell doctrine. In: H Cohen, B Stemmer (Eds.), Fragments of the Mind and Brain. Elsevier Science, London. Wollock J (1997). The Noblest Animate Motion Speech, Physiology and Medicine in Pre-Cartesian Linguistic Thought. John Benjamins, Amsterdam.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 37

Alexia and agraphia VICTOR W. HENDERSON * Departments of Health Research & Policy (Epidemiology) and of Neurology & Neurological Sciences, Stanford University, Stanford, CA, USA

INTRODUCTION Alexia and agraphia refer, respectively, to disorders of reading and writing. Usually these terms are restricted to indicate acquired impairments that result from damage to the brain, and are not incidental manifestations of blindness, paralysis, or another more elementary neurological deficit. Reading and writing are intimately connected to language. Thus, alexia and agraphia are often considered in relation to aphasia, an acquired disorder of language due to brain injury. Evolving concepts of alexia and agraphia have played important roles in understanding how complex cognitive functions such as reading and writing are represented within the brain and how these functions are disrupted by damage within particular brain areas. In the following discussion, note that terms such as alexia, agraphia, and aphasia are often used in their various earlier senses. The modern era of aphasiology took form in Europe during the second half of the 19th century as the vanguard of a quest to understand functional localization within the cerebral cortex, i.e., the relation between specific observable behaviors and delimited cortical regions thought to mediate these behaviors. Indeed, it is interesting that a complex behavior such as speech came to be the focus of early studies on cortical representation. Key figures in this era were Paul Broca (1824–1880), Carl Wernicke (1848–1904), and Jules Dejerine (1849– 1917). Broca helped define a role for the frontal lobe – and, more particularly, the role of the left frontal lobe – in speech production. Wernicke offered an understanding of the role of the left temporal lobe in speech comprehension and advanced the view that language functions involve specialized cortical regions interconnected by white matter pathways. Near the close of the century, Dejerine affirmed a key role for a portion of *

the left parietal lobe (angular gyrus) in reading and writing, and provided an anatomical model to accommodate the fascinating disorder of alexia without agraphia (also referred to as pure word blindness or pure alexia). Table 37.1 gives landmark publications on disorders of reading and writing during this formative era.

PRELUDE TO BROCA: BEFORE 1861 Broca’s early reports on aphemia are a convenient launching point for historical considerations of alexia and agraphia. However, the more general issue of cortical localization arose even earlier. At the dawn of the 19th century, the doctrine that the cerebrum operated as a functional whole was challenged by Franz Gall (1758–1828) and his phrenological heirs. Working primarily in Vienna and Paris, this neuroanatomist combined clinical observations with skillful postmortem dissections of the brain, where he looked for signs of pathology or anatomical variations (Gall and Spurzheim, 1810; Gall, 1825). Based on correlative studies, Gall suggested that the cerebrum and cerebellum were composed of discrete organs, each subserving an intellectual, psychological, or moral propensity. To give one relevant, well-known example, Gall (1825) observed that people with prominent eyes tended to excel at memory for words, and he viewed this prominence as an external indication of development of brain areas behind the two orbits, which included the organ of word memory and language sense. He did not propose separate organs for reading or writing. By mid-century, scientific opinion had turned decisively against organology and phrenology (Spurzheim, 1832). Particularly important to the debunking of phrenology was research by physiologist Pierre Flourens (1794–1867), chair of comparative anatomy at the museum of the Jardin des Plantes in Paris, and a

Correspondence to: Victor W. Henderson MD, MS, Stanford University, 259 Campus Drive, Stanford, CA 94305-5405, USA. E-mail: [email protected], Tel: þ1-650-723-5456, Fax: þ1-650-725-6951.

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Table 37.1 Landmark publications on alexia and agraphia Author

Year

Contribution and publication source

Louis Victor Marce´

1856

William Ogle

1867

Adolf Kussmaul

1877

Nadine Skwortzoff

1881

Sigmond Exner

1881

Albert Pitres Jules Dejerine

1884 1892

James Hinshelwood

1900

First publication to focus on writing disturbances. Comptes Rendus et Mémoires des Séances de la Société de Biologie. Usually credited with first use of the term agraphia. St. George’s Hospital Reports. First publication to consider alexia as a specific disorder; word blindness coined to describe alexia. Die Störungen der Sprache. Versuch einer Pathologie der Sprache. Early thesis on word blindness (alexia) and word deafness. De la Cécité et de la Surdité des Mots dans l’Aphasie. Cortical center for writing is proposed, analogous to Broca’s area for speech. Untersuchungen über die Localisation der Functionen in der Grosshirnrinde des Menschen. First description of isolated agraphia. Revue du Médicine. Pathological basis of alexia without agraphia. Mémoires des Séances de la Société de Biologie. First monograph devoted solely to alexia. Letter-, Word- and Mind-Blindness.

perpetual secretary to the Academy of Sciences. Through experiments in birds and other animals, Flourens (1824) demonstrated separate roles for major subdivisions of the brain. The medulla was concerned with respiration; the cerebellum with coordination; and the cerebral hemispheres with vision, audition, memory, and volition. However, within the cerebral hemispheres, Flourens (1824) maintained that these faculties were coexistent and indivisible. By any modern measure, Flourens’ lesioning and stimulation experiments were painfully crude, yet his work was conceptually and technically advanced for its era, and it convinced most scientists that organology did not pass scientific muster. Among those who did not totally reject Gall was the French physician Jean-Baptiste Bouillaud (1796–1881). Bouillaud (1825) provided short case histories of patients who had lost the ability to speak but still understood speech. Autopsies revealed lesions of the anterior (frontal) lobes. Bouillaud (1825, p. 42) proposed a “special cerebral center . . . distinct and independent” for the organ of speech within the anterior lobes, a view that partially accorded with that of Gall, who had localized the organ for language sense to a portion of the anterior lobes. In the following decades, Bouillaud added new supporting clinical material (e.g., Bouillaud, 1847–1848). Bouillaud (1825) had remarked that most patients losing the ability to speak were also unable to express themselves through writing. Other occasional reports referred to reading or writing abilities, including the celebrated autoobservation of Jacques Lordat (1773–1870), professor

and faculty dean in Montpellier, France. Lordat temporarily lost the ability to express thought through speech or to understand others. After his recovery, he remarked in reference to reading, “In losing the memory of the meaning of heard words, I had lost that of their visual symbols” (Lordat, 1843, p. 351).

Marce´ One of the first physicians to focus on writing impairments in relation to brain disease was Louis Victor Marce´ (1828–1864), better recalled now for work on anorexia nervosa and mental disorders of pregnancy. Marce´ (1856) believed that thought was expressed through writing as well as speech, and his report to the Biological Society in Paris (Table 37.1) was based on Bouillaud’s concepts of speech disorders. His primary contribution was to draw attention to writing disorders and to postulate a cerebral “principle,” “agent,” or “faculty” responsible for writing. This coordinating faculty, whose function was similar to that described by Bouillaud for speech, presided over the graphic representation of ideas, the formation of letters, and the assembly of letters into syllables and words. Marce´ (1856) described 12 patients – four of whom were personally observed – with various disturbances in speech and writing. Most important were two cases from the literature, who were unable to verbalize normally but nonetheless could write. Here, according to Marce´, only the agent that coordinates speech was injured. Although he failed to adduce examples of

ALEXIA AND patients with isolated agraphia, Marce´ believed that his cases confirmed the existence of an agent that controlled written formation of letters and words. Marce´ argued that such a writing faculty is independent of the faculty for speech, because some patients could write fluently despite their inability to speak. Further, the writing faculty is independent of hand mobility, since several patients were unable to write despite otherwise normal use of the hand. Finally, the faculty did not lie at the level of tongue and phonator muscles, since it was well known that patients with left hemiplegia and tongue paralysis could still write normally. Because speech and writing are often impaired in concert, Marce´ reasoned that writing and speech faculties were intimately connected. Despite anatomical implications of this characterization, Marce´ dealt cautiously with Gall’s discredited legacy, and carefully avoided reference to topographically delimited centers for speech or writing. The cerebrum functioned as an agent for muscle innervation and, hence, movement; such functions were mediated by fiber tracts within the cerebral hemispheres, and might indeed be discretely disrupted. However, the cerebrum was also responsible for intelligence, and intellectual functions such as speech and writing could not be further localized.

BROCA’S REPORTS OF APHEMIA, 1861^1865 Marce´ distinguished between cerebral agents for writing and speech, but he rejected the notion of focal cortical centers. However, Bouillaud’s idea of a discrete frontal lobe speech center was dramatically resurrected 5 years later by Broca, who at age 36 was already highly regarded as a surgeon, anatomist, and pathologist. Broca was a co-founder of the Anthropological Society of Paris. Beginning in February 1861 and continuing over a period of several months, Society members debated the relation between intelligence and brain volume at their biweekly meetings. In the course of these discussions, the physician Ernest Auburtin (1825–1893), Bouillaud’s son-in-law, pointed out that the brain was a complex organ. Why not, he inquired, consider its diverse parts separately? In the session of 4 April, Auburtin remarked that he had studied a patient on Bouillaud’s medical service with loss of speech but intact understanding. When this patient died, he was convinced that the autopsy would verify a softening in the anterior lobe (Aubertin, 1861). Eight days later on 12 April 1861, a 51-year-old man with similar symptoms was admitted to Broca’s surgical service. Many years before, this patient had

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suffered loss of speech and had developed right-sided paralysis; now he had gangrene of his right leg. The gangrene soon proved fatal, and at the 18 April meeting of the Anthropological Society, Broca summarized his famous case under the title, “Loss of speech, chronic softening and partial destruction of the left anterior lobe of the brain” (Broca, 1861a). A key point was that, despite the inability to speak, intellect was preserved, since the patient “understood almost all that one said to him” (p. 236). At autopsy, Broca (1861a, p. 237) found that “the frontal lobe of the left hemisphere was softened in most of its extent,” and he localized the primary site of his patient’s lesion to “the middle part of the frontal lobe of the left hemisphere” (p. 237) where damage appeared most severe. Later the same year, Broca (1861b) described this case in more detail and proposed the term aphemia to designate this disorder. Two years later Broca (1863) remarked that the lesion of aphemia appeared to be lateralized to the left hemisphere, and in 1865 he went further, drawing an analogy between handedness and speech. The left hemisphere controls motor function, and righthanders are thus left-brained. Similarly, since most lesions responsible for aphemia appeared to involve the left cerebral hemisphere, “for language . . . we are left brained . . . [W]e speak with the left hemisphere” (Broca, 1865, p. 384). At this point, Broca was yet to consider reading or writing abilities in his aphemic patients, although he would later do so, if only briefly (Broca, 1869).

STUDIES OF ALEXIA AND AGRAPHIA IN THE WAKE OF BROCA’S REPORTS: PRELUDE TO DEJERINE Implications of Broca’s electrifying reports were fiercely debated throughout the 1860s. Earlier disagreement on indivisibility of intelligence was expanded to include discussions on oral and written language, and their relations to other intellectual functions. During this seminal period, many physicians contributed case material pertinent to Broca’s clinical-pathoanatomical formulations – see early reviews by Armand Trousseau (1801–1867) and Frederick Bateman (1824–1904) (Trousseau, 1865; Bateman, 1868). For alexia and agraphia, key questions concerned whether spoken language could be disrupted without affecting written language, or vice versa, and whether separate cortical centers were required for reading or writing. Trousseau (1864), who had coined the term aphasia in preference to aphemia, belittled Broca’s view that intelligence was typically preserved when speech was lost. This preeminent Parisian physician accepted that articulate language could be disrupted in relative

586 V.W. HENDERSON isolation, but such disruption was rare without a diswriting had been spared, this patient afforded “proof that cernible effect on other aspects of intelligence. Trousthe faculty of speech and the faculty of writing are not seau (1864, p. 38) pointed out that, although some subserved by one and the same portion of the cerebral aphasics could write, most could not, not only because substance” (Ogle, 1867, p. 106). This approach and concluof right arm paralysis, “but because, in reality, they sion are strongly reminiscent of Marce´’s, but Ogle was cannot express their thought by the conventional signs willing to accept pathoanatomical correlates. Because of writing.” Reading was affected as well (Trousseau, aphasia and agraphia often occurred together and 1865). because the two varieties of speech and writing disorders (viz., amnemonic and atactic) also occurred together, Ogle Ogle (1867, p. 100) inferred that the four “distinct” centers involved must be “closely contiguous.” Moritz Benedikt (1835–1920) in Austria was probably the first to use the term agraphia (agraphie) (Benedikt, Hughlings Jackson and Bastian 1865), but credit is usually accorded to the English phyIn London, contrasting views on alexia and agraphia sician William Ogle (1824–1905), writing independently were advanced by John Hughlings Jackson (1835–1911) 2 years after Benedikt (Table 37.1). He described and Charlton Bastian (1837–1915). Both were physicians defects in “expression of ideas in written symbols or at the National Hospital for the Paralysed and Epileptic writing,” adding, “for which, for convenience, I would established at Queen Square in 1860, with Hughlings coin the name agraphia” (Ogle, 1867, p. 99). In his Jackson’s staff appointment preceding Bastian’s by 5 widely cited article, Ogle (1867) reviewed clinical years. records of 25 patients with prominent speech impairBeginning in 1864, Hughlings Jackson explored the ments; five were personally observed, and 19 had postrelation between loss of speech and right hemiplegia mortem findings. He focused not on agraphia per se in patients who had suffered cerebral embolism but on evidence pertaining to Broca’s localization of (Henderson, 2008). For Hughlings Jackson (1864, p. 32), the speech faculty to the left third anterior convolution speech was “a general term for all shades of intellectual (inferior frontal gyrus). Ogle viewed speech and writexpression, from the most general to the most particular.” ing as parallel processes, as had Marce´ two decades In this sense, his perspective was similar to Trousseau’s. before. Aphasia occurred when articulate speech was Speech included “all grades and varieties of expression precluded by cerebral injury, and agraphia occurred of ideas, chiefly by words” (p. 30). Writing, Hughlings when written communication was similarly disrupted. Jackson (1878, p. 318) later explained, “suffers more or Ogle distinguished two varieties of aphasia and two less in nearly every case of defect of speech from disease comparable varieties of agraphia. One variety was of the hemisphere.” Simply put, “inability [of the speechbased on impairment in the memory for words and less patient] to write, in the sense of expressing himself, is the second on impairment in how to say or write loss of speech.” His view of alexia was similar: “In most words. The patient with amnemonic agraphia can cases the speechless patient cannot read at all, obviously “form letters and words with sufficient distinctness, not aloud, but not to himself either, including what he has but he either substitutes one word for another or . . . himself copied” (Hughlings Jackson, 1878, p. 319). writes a confused series of letters which have apparExplaining further, “The inability to read is not due to loss ently no connection to the words intended” (Ogle, of perception nor to non-recognition of letters, &c., as 1867, p. 99). In atactic agraphia, “the power of writing particular marks or drawings, but to loss of speech” (p. even separate letters is lost” (p. 99). Ogle noted that 322). Hughlings Jackson eschewed the concept of delimthis form of agraphia is also associated with a degree ited cortical centers. He famously declared in reference of “amnemonia,” demonstrated by a patient’s inability to Broca’s area, “I do not localize speech in any such small to arrange letters printed on individual cards to spell part of the brain. To locate the damage which destroys his name. As implied by the term amnemonic, many speech and to locate speech are two different things” authors conceptualized language disorders in terms (Hughlings Jackson, 1874, p. 19). of loss of special forms of memory. Despite his unitary conception of speech, Hughlings Like Marce´, Ogle observed that agraphia usually Jackson encountered occasional patients where reading occurred in the presence of aphasia, but he described or writing were affected disproportionately. He one patient who could write despite limited speech prodescribed a woman with severe agraphia but only mild duction. Autopsy revealed a small softening in the posterproblems with spoken language (Hughlings Jackson, ior left inferior frontal convolution, a location “strongly 1864), and a man with marked reading and writing defcorroborative of Broca’s view” (Ogle, 1867, p. 106) icits who spoke “glibly and well” (Hughlings Jackson, regarding lesions of atactic (Broca’s) aphasia. Because

ALEXIA AND 1866, p. 93). In the following paragraph composed by this second patient, words in square brackets represent self-corrections and words in round brackets represent comments added by Hughlings Jackson (1866, p. 93): I do not find any improm improvement in by leth [my health] this dalt [last] few days. Bodily I seem about the same with the exempt- except that I ave, av have had indejention [indigestion]. I can recofect things for years past very well, but I am pusseld [puzzled] to find how to spell, and cannot do so with (without?) thinding [thinking] first. I seem to av have got on better this with this better (letter?) than I some thim times can. Bastian (1869) disagreed with his more senior colleague’s holistic approach to language, proposing instead separate auditory and visual perceptive centers for auditory and reading comprehension. Speech was a more direct process (auditory impressions of words are revived and then transmitted via the corpus striatum to excite muscle contractions) than writing (auditory impressions of words revive visual impressions of letters, followed by muscular movements required for writing). Thus, writing and speech could be separately affected, depending on which centres, or set of connecting fibers was injured (Bastian, 1869). Bastian distinguished agraphia (inability to write; preserved thought and speech) from aphemia (inability to speak; preserved thought and writing) and aphasia (inability to speak or write, preserved thought). In typical cases of aphasia, writing to dictation could be “abolished by an imperfection in the communications between the auditory and visual perceptive centres, by a lesion of these latter centres, or of the efferent fibers proceeding from them to the corpus striatum” (Bastian, 1869, p. 486). Agraphia, according to Bastian’s narrow definition given above, was “very rare.” He provided the case history of a 45-year-old former sailor, who had been certified insane. Several years earlier, this patient had begun to write in “an extraordinary manner . . . [H]e commenced the writing of each word correctly, and then in the place of some of the remaining letters he wrote ffg. Afterwards, the whole character of the word became altered, and duplication of many of the consonants, together with an almost invariable termination with the letters ndendd, or at least, endd, became the most noteworthy features of writing” (Bastian, 1869, pp. 234–235) (Fig. 37.1). This patient’s oral spelling resembled his written output (e.g., c-a-n-d-d for “cat”), but speech and his ability to read aloud were otherwise much better than writing skills. Bastian provided one of the earliest discussions of alexia. In reading, “the visual symbols of words call up or revive automatically (by means of connecting

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fibers between the two centres [viz., visual perceptive and auditory perceptive centers]) the words as sound perceptions, and by the aid of the two impressions combined, but principally . . . by means of the second . . . we gather the import of what we read, by the realization of the third term of the association,” the third term being memories of objects (Bastian, 1869, p. 488). Bastian (1869, p. 484) mentioned a patient who, having largely recovered from right hemiplegia and aphasia, “could not read a single word herself: the sight of the words seemed to convey to her no meaning. . . . She could even scarcely point out single capital letters.” Given the link between visual and auditory centers, Bastian suggested that reading comprehension would be greatly impaired if “communications between the visual and auditory perceptive centers were injured.”

Wernicke Thirteen years after Broca first described aphemia and 7 years after Ogle’s report on agraphia, Wernicke (1874), working in the German city of Breslau (now part of Poland), published his famous monograph that established the existence of a left temporal region involved in speech comprehension. By this point, the clinical heterogeneity of aphasia was increasingly acknowledged, but the 26-year-old Wernicke offered a plausible anatomical and conceptual framework for varieties of aphasia. Wernicke described several cortical areas, including a motor region with representations for speech production (Broca’s area) and – inspired by anatomical research of Theodor Meynert (1833–1892) – a sensory region in the first temporal convolution (superior temporal gyrus) for images of word sounds (later referred to as Wernicke’s area). He proposed interconnecting pathways, with specific clinical syndromes consequent upon the destruction of specific regions or pathways. Using the terms alexia (Alexie) and agraphia (Agraphie), Wernicke (1874) addressed reading and writing impairments. Wernicke explained that a child associates the visual image of a letter with its sound image. Writing is learned through copy, or association, of the visual sense of the image over a pathway between the sound image and the frontal region for writing movements (Fig. 37.2). Alexia and agraphia are produced by lesions in the visual region of the brain, because the visual memory of letters is required for both reading and writing. Destruction of the sensory speech area would cause agraphia as well as aphasia, because writing is executed under the guidance of the sound of words. Reading comprehension might also be affected in the uneducated person, where understanding is linked to word sounds, but not in the

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Fig. 37.1. Early example of jargon agraphia (Bastian, 1869). Writing samples from Bastian’s patient who, taking his dementia into consideration, “speaks properly, though he writes a mere jargon of letters, with a constant repetition of certain of them” (p. 236). Line 1 represented the patient’s longest “intelligible” sample, seemingly intended to read, “Royal naval medical officer belonging to Admiralty.”

ALEXIA AND AGRAPHIA

Fig. 37.2. Wernicke’s (1874) diagram of brain regions involved in reading and writing, schematically depicted on the right cerebral hemisphere.
¼ visual image of letters within the visual sensory area; a1 ¼ temporal lobe termination of the auditory nerve, including sound images of words; b ¼ frontal lobe center for speech movements;  ¼ frontal lobe center for writing movements. Learning to read aloud involves activity of
and a1, innervating center b over pathway a1–b. Writing is learned using path
– for copy. With practice,
and  become associated with sound images of words in a1.

educated person, whose understanding does not depend on conscious recognition of individual words. For a frontal lobe lesion affecting images of speech movement (Broca’s aphasia), agraphia could occur because writing often involves subliminal speech movements or because the lesion extended to the nearby center for writing movements.

Kussmaul and Skwortzoff Adolf Kussmaul (1822–1902) in Germany is usually credited as the first to identify alexia as an isolated symptom of brain disease, although his descriptions were not based on original case material. He prepared a comprehensive monograph on disturbances of speech (Table 37.1), published simultaneously in German (Kussmaul, 1877a) and English (Kussmaul, 1877b). Using the terms word blindness (Wortblindheit), text blindness (Schriftblindheit), and speech blindness (Sprachblindheit), Kussmaul recognized that alexia was usually combined with derangements in speech and writing. Clinical manifestations could vary considerably; some patients, for example, read letters but not words, or vice versa. Indeed, on occasion “a complete text-blindness may exist, although the power of sight, the intellect and the power of speech are intact” (Kussmaul, 1877b, p. 775). Kussmaul summarized several literature cases, including patients with complete word blindness but intact speech or writing. He offered a

589

complicated diagram that incorporated centers for sound images of words, visual images of words, motor coordination of spoken words, and motor coordination of written words. However, he refrained from specific neuroanatomical formulations, believing that it was premature to localize particular language functions to specific cortical regions. Alexia was the topic of a medical thesis by Nadine Skwortzoff, working in Paris (Table 37.1). Defining word blindness as “failure to comprehend signs of thoughts represented by writing,” Skwortzoff (1881, p. 33) summarized published and unpublished findings from 14 cases where alexia was a prominent symptom. Based on limited autopsy evidence from three complicated cases – and influenced by experiments of David Ferrier (1843– 1924) in monkeys that erroneously localized the primate visual center to the angular gyrus (Ferrier, 1875) – she identified the left angular gyrus as the likely region affected in alexia. With respect to mechanism, Skwortzoff noted that word blindness often accompanied speech troubles and agraphia. She suggested – after her mentor Valentin Magnan (1885–1925), who had recently presented details of two alexic patients before the Biological Society – that word blindness could be viewed as the consequence of damage to a path leading from the visual center to a postulated word-formation center; milder injury of the visual center itself could also cause word blindness.

Exner and Charcot The year that Skwortzoff’s thesis appeared, the Viennese physiologist Sigmund Exner (1846–1926) published a monograph on cortical localization based on a review of published clinical-pathological observations (Exner, 1881). In his chapter on cortical fields for speech, he identified 31 literature cases of aphasia; writing disturbances were mentioned in four. In these cases, Exner called attention to injury of the posterior portion of the left middle frontal gyrus, a region adjacent to motor cortex involved with hand movement; in one patient it was the only area grossly affected at autopsy. This left frontal region situated above Broca’s area, later referred to as Exner’s area, was conjectured to play a role in written expression similar to that played by Broca’s area in spoken expression. The plausibility of Exner’s writing center was favorably received by many researchers. Bastian (1887), for example, revised his earlier schema to include four interconnected “word centres” concerned with auditory impressions, visual impressions, “glosso-kinaesthetic” impressions derived from speech movements, and “cheiro-kinaesthetic” impressions derived from writing movements (Fig. 37.3). The glosso- and cheiro-kinaesthetic centers were believed to correspond topographically to centers

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Fig. 37.3. Bastian’s (1887) diagram of word centers and commissural pathways connecting these centers. Dashed lines represent less usual pathways. Unlike Kussmaul and Charcot, Bastian rejected a center for concepts or ideas. Aud. Word C. ¼ auditory word center; Vis. Word C. ¼ visual word center; Glosso-Kinaes. C. ¼ glosso-kinaesthetic center for speech movements; Cheiro-Kinaes. C. ¼ cheiro-kinaesthetic center for writing movements.

described by Broca and Exner. A lesion of the visual word center would lead to word blindness (alexia) and that of the cheiro-kinaesthetic word center would lead to pure agraphia. Word blindness and agraphia might occur simultaneously from damage to the visual word center if damage also impinged on the commissure connecting this center to the cheiro-kinaesthetic center; damage to this commissure alone would cause agraphia. Jean-Martin Charcot (1825–1893), recipient of the first chair in Clinical Diseases of the Nervous System at the Salpeˆtrie`re in Paris, had been drawn to the study of aphasia in the wake of Broca’s initial observations (Charcot, 1863), and he redirected his attention to this class of disorders two decades later (Henderson, 2008). Charcot – unlike Trousseau or Hughlings Jackson, but like Bastian and Wernicke – favored the possibility of multiple language centers. Charcot saw patients with limited, or isolated, deficits as opportunities to study “the fundamental forms of aphasia” (Charcot, 1883, p. 441). Indeed, he believed that “complex cases can obscure the concept of partial isolated aphasias” (Marie, 1883, p. 701). Charcot used word blindness and agraphia as paradigmatic examples of the isolated aphasias (Charcot, 1883; Marie, 1883, 1888). He described a 35-year-old proprietor, who several weeks after a stroke had right hemianopia and mild anomia, but no weakness (Charcot, 1883). When examined, “He was able to write fluently and normally, but it was impossible for him to read printed pages from a book or handwriting” (Charcot, 1883, p. 442). However, he read slowly by the laborious artifice of tracing text with his finger;

thus, reading occurred only through the act of writing. In discussing this “particular species of aphasia,” Charcot (1883, p. 469) referred to Kussmaul’s priority in describing word blindness and the concept of a visual memory for the signs of language. Citing three recent post-mortem studies, Charcot conjectured that the responsible lesion for his patient’s alexia was in the vicinity of the left inferior parietal lobule. In a lecture delivered in 1887, Charcot described an instructive agraphic patient, a 44-year-old woman who suffered an attack of right hemiplegia and speech difficulty from which she eventually recovered. She could copy after a fashion but found it impossible to write spontaneously; she had “lost the mechanism that allows the transmission of thought by written language” (Marie, 1888, p. 81). Charcot defined agraphia as “the more or less complete loss of coordinated movements communicated to the hand for the expression of thought in writing, or more simply, ‘aphasia of the hand’” (p. 81). Another patient had motor aphasia (Broca’s aphasia) but wrote well despite oral language difficulties. To Charcot, this case illustrated the incorrectness of the proposition formulated by Trousseau “that aphasics write as badly as they speak and those who don’t speak at all are totally incapable of writing” (Charcot, 1883, p. 522). Charcot believed that “the memory of a word” consists of four distinct elements, “the auditory image, the visual image, the motor image for articulation, and the graphic motor image” (Marie, 1888, p. 81). Injury to any of these produces a form of aphasia. “Aphasia is

ALEXIA AND AGRAPHIA only an amnesia,” he said (p. 82). For Charcot, clinical documentation of “partial amnesias” constituted confirmation of independent centers. However, Charcot also believed that individuals differ in their reliance on particular partial memories. These language, or memory, centers are variably differentiated from each other and, thus, an auditory center lesion sometimes causes not only word deafness (inability to comprehend spoken speech) but also motor aphasia.

Pitres The first detailed description of isolated agraphia was reported in 1884 by Albert Pitres (1848–1928) (Table 37.1), Charcot’s former student and a member of the faculty of medicine in Bordeaux. Like Charcot, Pitres emphasized the value of pure cases. Pitres’ patient had unilateral “pure motor agraphia,” involving only the right hand (Pitres, 1884). Pitres contrasted Marce´’s insights a quarter of a century before with views of Trousseau and Hughlings Jackson. According to Pitres, the latter writers assumed that aphasia was due to loss of memory for the symbolic value of signs; hence all aphasics wrote as poorly as they spoke. Pitres believed that speaking, reading, and writing depend on distinct memories: auditory memory for word sounds, visual memory for letter shapes and letter combinations, and motor memory for actions required to produce written letters. A partial memory lost in isolation could cause word deafness, word blindness, or motor agraphia. Pitres described a 31-year-old syphilitic whom he examined 18 months after the patient had suffered right-sided weakness and aphasia. He found mild right hemiparesis, but speech, reading, and the ability to spell aloud were now normal. With his left hand, the patient wrote legibly and without error. With his right, he was unable to produce letters or words spontaneously or to dictation. Although he copied words in a slavish manner, he could not transcode printed words into cursive script. In contrast to writing, he could draw geometric figures such as a circle or triangle with his right hand without difficulty. In discussing this unique case of unilateral agraphia, Pitres reasoned that his patient did not have word deafness or word blindness, since he understood what was said to him and he could read. The ability to write with his left hand indicated the absence of verbal amnesia (aphasia) or other intellectual disturbance. Because he could draw shapes with his right hand, agraphia on that side could not be attributed to paralysis. Rather, the ability to copy legibly showed that the defect was loss of memory for movements that guided the right hand in writing. Pitres saw motor agraphia as the written

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counterpart of motor aphasia (Broca’s aphasia). According to Pitres, writing could be disrupted by word blindness, word deafness, or by motor agraphia. In the first instance, patients cannot copy but can write spontaneously and to dictation; in the second, they are unable to write to dictation but can write spontaneously and can copy; and in the third, none of these writing tasks can be carried out fluently, although slavish copying is still possible. Following the teaching of Charcot, Pitres surmised that the locus for graphic memory was the posterior portion of the left second frontal convolution (Exner’s area), just as the locus for phonetic memory was the posterior portion of the third frontal convolution. The frequent coincidence of motor agraphia and Broca’s aphasia was a matter of propinquity.

DEJERINE’S CONTRIBUTIONS Born in Geneva, Switzerland, Dejerine focused on neurological disorders, first as head of the medical service at the Biceˆtre Hospital in Paris and later at the Salpeˆtrie`re, where he became the third recipient of the chair in Clinical Diseases of the Nervous System originally created for Charcot. Dejerine made several important contributions to the neurology of reading and writing (Henderson, 1984). By 1891, he had come to believe that reading and writing could be largely dissociated from other aphasic symptoms. However, he took exception to Exner and Charcot, who had postulated a specialized writing center in the left frontal lobe. “The question of agraphia is certainly one of the most controversial in the study of aphasia,” he remarked (Dejerine, 1891a, p. 97). Might there be “an autonomous center for writing localized at the foot of the second frontal convolution” (p. 97)? Dejerine advocated an alternative perspective, namely that agraphia was part and parcel of lesions that cause motor (Broca’s) and sensory (Wernicke’s) aphasias, but that reading and writing were particularly affected by damage to the angular gyrus of the left parietal lobe. His views on disorders of written language were expanded in another paper that year (Dejerine, 1891b), in which he described the neuroanatomic basis of word blindness (alexia) with agraphia, a disorder of reading and writing with relative sparing of other language functions.

Word blindness with agraphia: case of Se´jalon Se´jalon was a 63-year-old laborer, who suffered mild right hemiplegia, which did not affect speech (Dejerine, 1891b). Seven years later, he suddenly found himself unable to

592 V.W. HENDERSON read his newspaper. Shortly thereafter, on 12 February Pure word blindness: case of Courrie`re 1890, Se´jalon entered Dejerine’s Hospital service. Dejerine’s masterpiece on reading disorders appeared Dejerine’s examination revealed very mild right-sided in 1892 (Table 37.1). In his lengthy article for the Bioloweakness without sensory deficits, and a suspected right gical Society entitled “Contribution to the pathoanahemianopia. There were problems with spoken language, tomic and clinical study of different varieties of with paraphasic errors during spontaneous speech and word blindness,” Dejerine (1892) compared and conwhen repeating words. However, Se´jalon could name trasted two forms of alexia: word blindness with agraobjects shown to him, and he understood what was phia and pure word blindness. Based on clinical and said to him. Problems with written language were more autopsy findings, Dejerine argued that the essential pronounced. Se´jalon was incapable of reading printed or lesion of pure word blindness was one that isolated cursive writing, and he was unable to write (Dejerine, the left angular gyrus from visual input that conveyed 1891b, p. 198): essential information about written material. When one gives him a newspaper or a written Courrie`re was a 68-year-old right-handed merchant phrase, he looks at the newspaper or the paper of above average intelligence, who suffered transient for a moment, then faces the examiner, stating, episodes of right-sided numbness, sometimes accompa“I do not understand.” The same for letters of nied by mild weakness (Dejerine, 1892). On 23 October the alphabet, which he could scarcely name . . . 1887, while taking a walk, Courrie`re suddenly realized When one tells the patient to write, he holds that he could no longer read signs displayed along the the pen or pencil quite awkwardly . . . and if road. His symptoms persisted, and Dejerine examined sometimes he wishes to write spontaneously, to Courrie`re on 15 November. Mild motor problems with dictation or copy, he always writes [only] his the right limbs had completely disappeared, and there name, that is to say, “S ejalon.” The characters was no facial weakness or sensory loss. He was alexic that are produced are so defectively written that but not agraphic (Fig. 37.4A, top) or aphasic (Dejerine, it requires a good effort to recognize the 1892, pp. 67–69): patient’s name. His spoken language is very correct, even careWhen Se´jalon was later re-examined, paraphasic errors fully selected; he always uses appropriate terms had almost completely resolved, but alexia and agraphia and shows no trace of paraphasia . . . The remained. He was unable to write a single word; he could patient understands perfectly all that one says not copy script; and in attempting to read he recognized to him . . . Writing spontaneously and to dictaonly his name. Dejerine’s patient died on 20 November tion is perfectly preserved. One notes only when 1890. Autopsy revealed cortical softening the size of a comparing writing specimens after and before five-franc piece occupying the inferior three-fourths of the beginning of his illness that the letters are the left angular gyrus. On a horizontal section, the softenactually larger and a little more spread out. ing extended as a wedge from the angular gyrus to the Spontaneously, the patient writes as well as he occipital horn of the lateral ventricle, destroying most of speaks. In comparing the many writing specithe optic radiation (Dejerine, 1891b). Dejerine (1891b, p. mens that I had him write, one notices no mis200) summarized findings as a “clear case of word blindtakes, no spelling error, no transposition of ness produced by a lesion localized to the [left] angular letters . . . Writing to dictation is executed gyrus and extending in its depth to the ependyma of the equally easily and fluently, but reading what occipital horn.” Importantly, according to Dejerine, both the patient has written is absolutely impossible. alexia and agraphia were due to the same unique cause, Here it is indeed a question of a case of absolthe “loss of optical images of letters” (p. 200) caused by utely pure word blindness. The patient recogthis angular gyrus lesion. This localization did not originizes not a letter, not a word except, however, nate with Dejerine, of course. Skwortzoff (1881) had dishis name. He is frustrated with these phenomcussed this possibility in her thesis, where one of her ena, writing letters one after another and saying, observations had been communicated by Dejerine. Also, “I still know how to write letters; here they are; a review by the American neurosurgeon Allen Starr why am I unable to read them?” (1854–1932) had concluded that patients who were unable With respect to copied text, Courrie`re wrote “mechanito read usually had lesions in the vicinity of the left angucally . . . like he would copy some sort of drawing” lar gyrus (Starr, 1889). At about the same time, an autop(Dejerine, 1892, p. 72). sied case with similar localization was published from the Johns Hopkins University by renowned physician William Dejerine saw his patient frequently from 1887 to 1891. Osler (1849–1919) (Osler, 1891). On the evening of 5 January 1892, Courrie`re developed

ALEXIA AND AGRAPHIA slurred speech with right-sided numbness and weakness. Weakness had resolved by the following day, but now speech showed paraphasic errors. When his wife handed him a pencil and paper, Courrie`re discovered he was quite unable to write (Fig. 37.4A, bottom). Courrie`re died on the night of 15 January 1892. The gross autopsy examination showed two left hemisphere lesions, one recent and the other much older (Fig. 37.4B). Dejerine (1892, pp. 83–84) summarized clinical and pathological findings thus: During the first phase, which lasted four years, the patient presented the purest clinical picture that one can imagine of . . . pure word blindness without any alteration in spontaneous writing or [writing] to dictation. During the second phase, which lasted only ten days, complete agraphia with paraphasia came to complicate word blindness . . . To these two clinical phases correspond, as the autopsy shows, two anatomically distinct lesions in the left hemisphere: one old, occupying the occipital lobe and more particularly the convolutions at the occipital point, the base of the cuneus, as well as those of the lingual and fusiform lobules . . . The other lesion of a recent date occupies the angular gyrus and inferior parietal lobule, that is to say the region that we are accustomed to see lesioned in the case of word blindness with writing difficulties. It perfectly explains symptoms observed during the last days of this patient’s life. Dejerine reasoned that the left angular gyrus was a center for visual letter recognition, destruction of which caused alexia and agraphia. He explained that a group of letters assembled into a specific word evokes an “idea,” or meaning, by virtue of links within a left hemisphere language zone. The left angular gyrus serves as an intermediary between occipital visual areas and the auditory center for words (Wernicke’s area), which in turn is connected with the center for motor articulation (Broca’s area). Under ordinary circumstances, “the visual image of letters simultaneously arouses the auditory image and the articulatory image” (Dejerine, 1892, p. 87). With respect to Courrie`re’s older lesion, massive white matter destruction within the left occipital lobe had interrupted fibers between the occipital cortex and the left angular gyrus. The visual image of letters within the intact left visual field was perceived only as a technical design rather than as a linguistic symbol. The recent lesion, which destroyed the left angular gyrus, added agraphia to the clinical picture and would have simultaneously caused alexia had Courrie`re not already been unable to read.

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Dejerine published histopathological findings the following year, restricting the critical lesion of pure word blindness in Courrie`re’s case to “the inferior portion of the inferior longitudinal fasciculus of Burdach [which contained] physiologically differentiated fibers linking the visual zone with the language zone” (Dejerine and Vialet, 1893, p. 793). Dejerine and his American-born wife Augusta Dejerine-Klumpke (1859–1927) subsequently published exquisite figures from Courrie`re’s brain in their Anatomie des Centres Nerveux, in which degenerating visual pathways were identified using the Weigert staining technique (Dejerine and Dejerine-Klumpke, 1901). Dejerine’s (1892) case was the first clinicalpathological description of pure alexia. It identified a role for the left parietal lobe in reading and writing, and it elegantly demonstrated a clinical disorder resulting from the intra- and interhemispheric disconnection of two cortical centers. In later publications, Dejerine described other varieties of reading and writing impairments in patients with cortical motor (Broca’s) aphasia (Dejerine and Mirallie´, 1895) and sensory (Wernicke’s) aphasia (Dejerine, 1906). His work with cortical motor aphasia was based on systematic clinical assessments (Henderson, 1984), and Dejerine affirmed Trousseau’s earlier position that patients with Broca’s aphasia read and write as poorly as they speak (Dejerine and Mirallie´, 1895). These patients usually presented marked difficulties with spontaneous and dictated writing, and with similar troubles in the comprehension of written language caused by an alteration in the word concept. “In other words, aside from agraphia, there is almost always a more or less marked impairment in mental reading, which occurs for a variable period of time according to individual differences” (Dejerine and Mirallie´, 1895, p. 523). Dejerine described one patient with Broca’s aphasia who could read words but could not pronounce individual letters in isolation, and he proposed that many such patients read words based on their overall form rather than through identification of constituent letters (Dejerine and Tinel, 1908). More generally, Dejerine (1906) believed that both reading and writing were almost always affected by lesions within an extended left hemisphere “language zone,” which encompassed the inferior frontal lobe, the superior temporal lobe, and the angular gyrus. There still were cortical centers specialized for language, but functional boundaries as mapped onto brain topography were now blurred.

AFTER DEJERINE The first monograph devoted solely to alexia was Letter-, Word-, and Mind-Blindness, by the Scottish ophthalmologist James Hinshelwood (1859–1919)

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(Table 37.1). Hinshelwood (1900) described letter and word blindness as special varieties of mind blindness (visual agnosia), the former dependent upon specialized visual memories independently stored in the angular and supramarginal gyri of the left parietal lobe. Alexia represented “complete word-blindness involving absolute inability to interpret written or

printed language” (Hinshelwood, 1900, p. 43); he reserved the term dyslexia for milder reading impairment. Like Dejerine, Hinshelwood (1900, p. 32) viewed the left angular gyrus as the “visual word centre” and attributed total (pure) alexia without agraphia to injury to connecting pathways between visual perceptive centers in the occipital lobes and the left angular gyrus.

Fig. 37.4. (A) Courrie`re: writing samples (Dejerine, 1892). Top. Spontaneously produced specimen in January 1888, 3 months after the onset of word blindness. The note indicates that Courrie`re had consulted Charcot at the Salpeˆtrie`re, who had diagnosed word blindness. Bottom. Illegible specimen obtained 8 January 1892, a week before Courrie`re’s death, when the clinical picture was that of agraphia and word blindness.

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Fig. 37.4. Cont’d. (B) Courrie`re: schematic drawing of the left hemisphere of the brain showing gross pathological findings (Dejerine, 1892). Top: Lateral surface. The recent lesion is indicated by light stippling of the angular gyrus (Pc) and supramarginal gyrus (inferior parietal lobule, Pi), extending into the occipital lobe. Darker stippling indicates the older lesion of the occipital lobe. Bottom: Medial surface. The older lesion includes the cuneus (C), lingual gyrus (TO2), fusiform gyrus (TO1), and the splenium of the corpus callosum.

596 V.W. HENDERSON “Hence the visual memories of words and letters can Within the zone of Wernicke, there were no functional still be revived from within, and serve as a guide to distinctions, and lesions affected not just language, but all the graphic motor centre [in the left middle frontal aspects of intelligence derived from didactic learning gyrus]; but impressions from without from the percep(Marie, 1906b). According to this iconoclastic formulative centres can no longer reach the visual word centre tion, alexia and agraphia did not exist apart from aphasia, because of the interrupted pathways” (Hinshelwood, and the angular gyrus played no special role. “It is useless 1900, pp. 32–33). Hinshelwood described the peculiar and inaccurate to invoke the angular gyrus here. – One letter-by-letter approach to reading that could emerge cannot recognize in the latter the role of the center for during recovery from total alexia or could occur as visual images of words” (Marie, 1906b, p. 500). However, an initial finding. He cited case-report evidence for Marie admitted to pure alexia as a form of “subcortical” the double dissociation between the ability to recognize or “extrinsic” aphasia, whose lesion did not directly words and letters (“the complete independence of the impinge on Wernicke’s zone but instead affected gray visual memories of letters and of words” [ p. 77]), and white matter within the lingual and fusiform gyri and postulated that separate visual memory reposi(Marie, 1906b). tories for these two classes for linguistic information Confrontations between Dejerine and Marie on were “stored and preserved in different but probably brain and language (e.g., Klippel, 1908) at first contiguous areas” (p. 77) of the left parietal lobe. appeared inconclusive (Lecours et al., 1992). Although In contrast to Hinshelwood, authors such as Marie “undoubtedly fell a victim to his desire for theWernicke and the Swiss neurologist Constantin von oretical simplification” (Head, 1926, vol. 1, p. 75), Monakow (1853–1930) did not accept the existence of a many were ultimately convinced by Marie’s trenchant visual language center in the left angular gyrus, suggestattacks. In 1936, the American neurologist Johannes ing instead that interruption of white matter tracts deep Nielsen (1890–1969) sarcastically lamented, “localizato this region accounted for both agraphia and alexia tion in aphasia had its heyday from 1861 to 1906 and (Wernicke, 1910). An even harsher challenge to Dejerthat from that time to this the Medical World has had ine’s views on reading and writing – and, indeed, to the time to realize the errors of its ways and abandon its entire edifice erected upon the foundation of Broca naı¨ve idea that aphasia could be of diagnostic value and Wernicke – came in 1906 from Dejerine’s implacin cerebral localization” (Nielsen, 1936, p. iii). able rival Pierre Marie (1853–1940). Marie, a former The notion of language centers was increasingly intern of both Broca and Charcot, was to become the undermined by new views of cerebral function and fourth holder of Charcot’s neurological chair at the new approaches to aphasia classification. The concept Salpeˆtrie`re. Early in his career, Marie (1883) had adopted of diaschisis developed by von Monakow (1914) sugCharcot’s localizationist views on alexia and agraphia, gested that focal brain injury affects distant, but then in a series of provocative articles, Marie chalfunctionally related brain areas through loss of innerlenged dogma that assigned special roles to cortical vation. Functional localization was further challenged regions of the left frontal lobe, left temporal lobe, and by the work of those such as the American behavioral left angular gyrus. Indeed, reading and writing were psychologist Karl Lashley (1890–1958). His animal relatively recent events in human evolution, and for experiments suggested that memory traces were widely Marie it made little sense to presume specialized cortical distributed, that quantity of cortical injury was more centers for these functions (Marie, 1897). Instead, Marie important than locus of injury, and that cortical areas, acknowledged but one form of aphasia, and this was which were mutually dependent on each other, were Wernicke’s aphasia due to injury within the “so-called more or less equipotent with respect to particular functerritory of Wernicke,” or “zone of Wernicke” (Marie, tions (Lashley, 1929). 1906a, p. 244). In its expanded extent, Wernicke’s zone In London, Henry Head (1861–1940) published an encompassed cortex and subjacent white matter of the influential treatise on aphasia and kindred disorders angular and supramarginal gyri and posterior portion derived largely from careful studies of brain-injured of the left superior and middle temporal gyri. Broca’s patients from World War I. Language defects were aphasia, according to Marie, was nothing other than deficits in “symbolic formulation and expression” mild Wernicke’s aphasia (produced by slight injury (Head, 1926, vol. 1, p. 218) in which speech, reading, within Wernicke’s zone) coupled with a characteristic and writing suffered more or less in unison. Head casarticulatory disorder consequent to injury in the vicinity tigated “diagram makers” like Bastian and Wernicke, of the lenticular nucleus (caudate and putamen) deep to who with “serene dogmatism” seemed to “assume a Broca’s area. Involvement of the overlying third fronknowledge of the working of the mind and its depental convolution was a coincidence of vascular anatomy, dence on hypothetical groups of cells and fibers” but essentially irrelevant. (Head, 1926, vol. 1, p. 57). Needless to say, his new

ALEXIA AND AGRAPHIA classification scheme for aphasic disorders did not fit neatly with traditional, more familiar nosology. Kurt Goldstein (1878–1965), a pupil of Wernicke who worked in Germany and the United States, believed that one effect of brain damage is impairment in abstract attitude, a concept similar to Head’s symbolic behavior. Goldstein rejected the assumption of “a simple relation between a symptom and a lesion in a circumscribed area” (Goldstein, 1948, p. 50), and emphasized that aphasic symptoms represent the “condition of the rest of the brain, and even of the whole organism” (Goldstein, 1938, p. 256) in the struggle to adjust after focal brain injury. He acknowledged topographical distinctions among forms of alexia and agraphia that accompanied other aphasia symptoms and those that occurred as more discrete disorders. However, “[e]arlier attempts at minute construction of brain maps which were supposed to demonstrate the relationship of certain performances to circumscribed brain areas” represented “mostly futile scholarship” (Goldstein, 1938, pp. 253–254). Increasingly, it was realized that reading and writing could be disrupted in ways not previously considered. In Berlin, Hugo Liepmann (1863–1925) developed the concept of apraxia, the inability to carry out a motor task despite adequate strength (Liepmann, 1908). He reported the patient Ochs, a 70-year-old carpenter with right hemiplegia but without aphasia, who was unable to execute commands using his unparalyzed left upper extremity (Liepmann and Maas, 1907). With his left hand, Ochs was unable to write spontaneously, to command, or to copy, and he was unable to select anagram letters to spell his name. Autopsy revealed extensive white-matter infarction in the distribution of the anterior cerebral artery, interrupting communication of the left hemisphere with anterior portions of the right hemisphere. The authors attributed Ochs’ agraphia to apraxia of the left hand, caused by interrupted communication between the left hemisphere, which controls purposive movements of the left hand through the corpus callosum, and motor regions of the right hemisphere (Liepmann and Maas, 1907). In addition, they questioned past assumptions that isolated agraphia implied the existence of a special writing center. The relation between writing and body image was explored in a series of publications by Josef Gerstmann (1887–1969), working initially in Austria and later in the United States. He described a curious and controversial disorder – later referred to as Gerstmann’s syndrome – one component of which was agraphia (Gerstmann, 1924, 1927, 1930, 1940; Critchley, 1966). Associated with left parietal-occipital lesions, particularly those involving the left angular gyrus, the full

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syndrome consists of agraphia; failure to recognize, identify, name, or select individual fingers (finger agnosia); inability to distinguish left and right sides of one’s body (left–right confusion); and difficulty performing mathematical calculations (acalculia). Finger agnosia was viewed as the primary disturbance determining other components of this tetrad: “The function of writing is inconceivable without the highly integrated level of morphologic and physiologic differentiation of fingers that has developed in man, and continuation of intact ability to write is incompatible with disintegration of this development” (Gerstmann, 1940, p. 401). Somewhat later, disruption of spatial skills dependent upon integrity of the right cerebral hemisphere was recognized as causing a type of alexia (He´caen et al., 1957; Kinsbourne and Warrington, 1962), which at times could be quite severe (Henderson et al., 1982). A form of spatial agraphia was also described for patients with right hemisphere damage, characterized by widened left margins, sloping lines of text, and extra, iterative strokes within individual letters (He´caen et al., 1963). Twentieth-century localizationists who continued to support a perspective represented by Bastian, Charcot, and Dejerine included Nielsen (1936) in Los Angeles, who summarized analyses based on 240 personally observed cases of aphasia, and especially Solomon Henschen in Uppsala (1877–1930). In three monumental volumes (Henschen, 1920a, b, 1922), this Swedish physician assembled over 1300 cases on his own and from the world’s literature, tabulating neurological symptoms and the topographic extent of brain lesions identified at autopsy. On this basis, he distinguished several forms of agraphia, one of which was attributed to lesions within the left frontal region previously designated by Exner (Henschen, 1922). Both Nielsen and Henschen affirmed roles for the left angular gyrus in reading and writing, and for Exner’s center in writing. The localizationists, however, continued to represent a minority perspective through the middle of the 20th century.

Localization, fractionization, and modularity In the 1960s, the pendulum began its downward arc. Interests in language disorders and brain representation were spurred by studies of patients in whom the two cerebral hemispheres had been surgically severed to control intractable epilepsy. This research revealed unsuspected and fascinating dissociations between linguistic competencies within the two isolated hemispheres. For example, the first split-brain patient reported by Michael Gazzaniga, Joseph Bogen

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Fig. 37.5. Writing sample obtained 5 years after his surgery from the first split-brain patient studied by Gazzaniga, Bogen, and Sperry (Bogen, 1969, p. 76). The patient was asked to write using his left hand (part A, resembling the letter P), right hand (part C, I’m going home), and then left hand again (part B, resembling a check mark). For part C, note the iterative strokes in the first two words, resembling the agraphia seen after unilateral damage to the right hemisphere. Adapted; copyright by the Los Angeles Neurological Societies.

(1926–2005) and Roger Sperry (1913–1994) wrote normally with his right hand but not his left: “Prior to surgery he could write legibly with the left hand, but afterward has produced only a meaningless scribble” (Gazzaniga et al., 1962, p. 1766). Agraphia restricted to the left hand – despite the ability to draw pictures – was a general feature of these patients; reading comprehension, however, was possible to some extent in the isolated right hemisphere (Gazzaniga and Sperry, 1967; Bogen, 1969) (Fig. 37.5). During this time, traditional models of language representation were rediscovered and championed by Norman Geschwind (1926–1984) in Boston. Geschwind was a behavioral neurologist who had been “persistently troubled by the fact that people who had left their mark so indelibly in many areas of neurology, such as Wernicke, Bastian, Dejerine, Charcot, and many others, could apparently have shown what was asserted to be the sheerest naivete´ and incompetence in the area of higher functions” (Geschwind, 1964, p. 215). In his influential article on “Disconnexion syndromes in animal and man,” Geschwind (1965) resurrected published cases of Courrie`re and Ochs to emphasize the role of cerebral pathway lesions in producing syndromes of pure alexia and unilateral agraphia. Sophisticated approaches from psychology and linguistics began to focus on how brain-injured patients processed isolated words in reading or writing. Based on error types, behavioral neurologists and cognitive psychologists fractionated alexia and agraphia in new and insightful ways. For alexia, 19th-century investigators had distinguished impairments in reading letters from words and sometimes numbers (e.g., Kussmaul, 1877a; Dejerine, 1892; Hinshelwood, 1900). The prototype for the new nosology was the syndrome of deep dyslexia, the cardinal feature of which is substitution

of a word similar in meaning to the intended target (e.g., reading sick for ill, or historic for ancient) (Marshall and Newcombe, 1966; Coltheart et al., 1980). Other alexic patients were described in whom errors occurred predominately in the pronunciation of non-words (e.g., inability to pronounce binth or bome) or the reading of orthographically irregular words (i.e., words with unusual spellings, such as yacht or onion). Other word characteristics (part of speech, word frequency, word length, concreteness, visual form) were found to influence the pattern of reading errors, suggesting that normal reading involves whole-word apprehension as well as phonological decoding based on constituent letters. Similar analyses of writing were undertaken in patients with agraphia. One assumption of this approach is that processes essential to reading or writing occur within relatively discrete cognitive modules that receive, process, and output information in a manner that can be inferred from observable error patterns. Although reminiscent of Gall’s organology, these modules are not patently identified with specific brain areas. Advances in neurosurgery and neuropsychology allowed electrical stimulation of discrete regions of the exposed cerebral cortex prior to and during brain surgery, disrupting reading and writing performances in a manner that implied unsuspected variability both in cognitive performance and cortical localization. During the final quarter of the 20th century, structural brain imaging techniques, particularly computed X-ray tomography and magnetic resonance imaging, permitted clinical-pathological correlations in living patients. Techniques that evaluate brain function dynamically – including evoked potentials, electroencephalography, magnetoencephalography, positron emission tomography, and increasingly functional magnetic

ALEXIA AND AGRAPHIA resonance imaging – now allow for the study of reading and writing processes in healthy persons. In general, issues in the early 21st century are similar to those addressed by 19th-century investigators: how best to describe and understand complex behaviors like reading and writing, and how best to relate these behaviors to brain structure and function.

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Kussmaul A (1877b). Disturbances of speech. An attempt in the pathology of speech. In: H von Ziemssen (Ed.), Cyclopedia of the Practice of Medicine. Vol. 14. Diseases of the Nervous System, and Disturbances of Speech. William Wood and Company, New York, pp. 581–893. Lashley KS (1929). Brain Mechanisms and Intelligence: A Quantitative Study of Injuries to the Brain. Dover Publications, New York. Lecours AR, Chain F, Poncet M, et al. (1992). Paris 1908: the hot summer of aphasiology or a season in the life of a chair. Brain Lang 42: 105–152. Liepmann H (1908). Drei Aufsa¨tze aus dem Apraxiegebiet. Karger, Berlin. Liepmann H, Maas O (1907). Fall von linksseitiger Agraphie und Apraxie bei rechtseitiger La¨mung. J Psych Neurol 10: 214–227. Lordat J (1843). Analyse de la parole pour servir a` la the´orie de divers cas d’alalie et de paralalie (de mutism et d’imperfection du parler) que les Nosologistes ont mal connus. J Soc Med Prat Montpellier 7: 333–353, 417–433; 8: 331–317. Marce´ LV (1856). Me´moire sur quelques observations de physiologie pathologique tendant a de´montrer l’existence d’un principe coordinateur de l’e´criture et ses rapports avec le principe coordinateur de la parole. C R Mem Se´ances Soc Biol (Paris) 3: 93–115. Marie P (1883). De l’aphasie (ce´cite´ verbale, surdite´ verbale, aphasie motrice, agraphie). Rev Med (Paris) 2: 693–702. Marie P (1888). De l’aphasie en ge´ne´ral et de l’agraphie en particulier, d’apre`s l’enseignement de M le professeur Charcot. Prog Med 7: 81–84. Marie P (1897). L’e´volution du langage conside´re´e au point de vue de l’e´tude de l’aphasie. Presse Med 5: 397–399. Marie P (1906a). Revision de la question de l’aphasie: la troisie`me circonvolution frontale gauche ne joue aucun roˆle spe´cial dans la fonction du langage. Sem Med 26: 241–247. Marie P (1906b). Revision de la question de l’aphasie: que faut-il penser des aphasies sous-corticales (aphasies pures)? Sem Med 26: 493–500. Marshall JC, Newcombe F (1966). Syntactic and semantic errors in paralexia. Neuropsychologia 4: 169–176. Nielsen JM (1936). Agnosia, Apraxia, Aphasia. Their Value in Cerebral Localization. Los Angeles Neurological Society, Los Angeles, CA. Ogle W (1867). Aphasia and agraphia. St. George’s Hosp Rep 2: 83–122. Osler W (1891). A case of sensory aphasia – word-blindness with hemianopsia. Am J Med Sci 101: 219–224. Pitres A (1884). Conside´rations sur l’agraphie. Rev Med 4: 855–873. Skwortzoff N (1881). De la Ce´cite´ et de la Surdite´ des Mots dans l’Aphasie. Delahaye et Lecrosnier, Paris. Spurzheim JG (1832). Phrenology, or the Doctrine of the Mental Phenomena. Vol. 1, Physiological Part. Marsh, Capen & Lyon, Boston, MA. Starr MA (1889). The pathology of sensory aphasia, with an analysis of fifty cases in which Broca’s centre was not diseased. Brain 12: 82–101.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 38

American neurology FRANK R. FREEMON * Department of Neurology, Vanderbilt University, Nashville, TN, USA

INTRODUCTION In 1776, the newest nation in the world sat on the Atlantic coast, preparing for a long military struggle against one of the great powers of the world. Its people were a mix of English, Scots, Irish, Swedes, and Germans, with a sprinkling of other European groups. A large number of Africans were held in slavery, an institution incompatible with the stated ideals of the new democracy. Everyone knew that slavery was an evil that would eventually disappear, but they differed over the meaning of the word “eventually.” The coastal people looked to the Atlantic as a source of fish and a connection to the commerce of Europe and the world. People living inland looked westward to a vast expanse of forest and unknown territory. To the people of this new country, everything seemed new. A government could be created from Greek ideas that had lain dormant for two millennia. Enlightenment, rationality and a trust in the Providence of God promised prosperity and advancement. No one thought much of science except as a tool needed to understand and control the new environment. Neuroscience would have to wait until a great convulsion came over this new land. For the people could not decide if the North American continent was occupied by states gathered in economic and social union or a great unified nation.

THE EARLIEST DAYS Benjamin Franklin was the first American recognized by Europeans as an important scientist. While his greatest discoveries concerned basic aspects of electricity, he made many other contributions, both practical and theoretical, including some early observations important to neuroscience. He attempted electrotherapeutic treatment of paralysis, but the resultant contraction, though sometimes amazing, was not of practical *

benefit. He passed an electrical current through the brain, at first his own by accident, and produced brief amnesia (Finger, 2006). The new United States was far behind its European fathers in medical science. One new scientific idea growing in Britain and France concerned the role of the brain in thought. Science and the humanities, including theology, seemed to have drawn a line to demarcate their respective roles in neuroscience. The brain might control movements and sensation but not thought or emotions. Doctors encountered mental illness. Could this illness be due to brain dysfunction and/or was it a spiritual abnormality? The only American to investigate this problem was Benjamin Rush, a physician most noted for his “heroic” therapy for yellow fever. Like many Americans, including his friends Thomas Jefferson and Benjamin Franklin, his great variety of interests limited his accomplishments in any one area. He was even elected to a representative assembly, the Second Continental Congress. He signed the Declaration of Independence. In 1812, Rush published the first great American work of neuroscience, entitled Medical Inquiries and Observations upon Diseases of the Mind. He proposed an idea startling for its time: the brain was responsible for functions long attributed to the soul. Rush thought that readers would chastise him for arrogantly subsuming mental functions to medical enquiry. “But time I hope will do my opinions justice,” he wrote to John Adams, an old friend from the Second Continental Congress. His new book, he told the former president, proposed “to show that the mind and body are moved by the same causes and subject to the same laws” (McCullough, 2001). No matter what happened in scientific or philosophical developments, the patients came. They suffered a variety of ills, including disorders that today would be classified as neurologic. In 1828, a leading faculty

Correspondence to: Frank R. Freemon MD, 2422 Valley Brook Road, Nashville, TN 37215, USA. E-mail: [email protected], Tel: þ1-615-298-4515.

606 F.R. FREEMON member of the University of Pennsylvania encountered operation was successfully performed by one Ameria patient who had lost the ability to speak. “I found my can surgeon, Benjamin Winslow Dudley. His series of patient in bed,” he wrote in the conversational style of six successful cases came from the medical departcontemporary case reports, “evidently in full possesment of Transylvania University in Lexington, Kension of his senses, but unable to utter a word.” He tucky; he attributed his success to the clean air of the assumed that the patient had paralysis of the mouth frontier (Jensen and Stone, 1997). and tongue but when asked the patient could move these muscles quite normally. The doctor tested other TWO MEN FOUNDED CLINICAL methods of communication and found that the patient NEUROLOGY IN AMERICA wrote this phrase: “Diddoes doe the doe.” Two years History is an amalgam of the interaction of great later, a similar patient was reported by a leading physimovements with individual people. The great movecian of Charleston, a faculty member of the University ments that came together to create clinical neurology of South Carolina. This patient could neither speak nor in America came from Europe and from within Amerwrite, but he could copy words. The doctor concluded ica. The European influence concerned the developthat the patient had suffered a brain infarction that ment of ideas of nervous system function, imported did not interfere with sense organs or control of musfrom Britain and especially France. The intrinsic event cles but “something defective in the brain” prevented in North America that stimulated clinical neurology speech. A third case was reported by Daniel Drake, was the American Civil War, referred to by three genone of the most famous physicians on the frontier. erations of Americans simply as the War. The two indiThis patient had suffered trauma behind the left ear viduals whose actions created clinical neurology in with subsequent infection and became unable to speak America were Silas Weir Mitchell and William Alexanor write certain words, particularly nouns. All three der Hammond. reports appeared in the leading medical journal in Weir Mitchell was identified with Philadelphia the United States, the American Journal of Medical throughout his life. His father was a well-known local Sciences, published in Philadelphia, PA. All three physician, John Kearsley Mitchell. The latter showed described the difficulty as an amnesia for words. These his interest in European science with his purchase of three physicians, none with any special training in neuthe popular automaton known as The Turk. William rology nor any subsequent publications in the field, Alexander Hammond came from an old family that recognized that a brain disorder was present and, furhad emigrated to Baltimore from England in the 1600s. thermore, that only a portion of the brain was involved When he was an army physician at lonely outposts in because so many other functions remained unaffected. Kansas Territory, Hammond began a self-experiment They utilized the new neurological doctrine imported that showed his early interest in things neurological. from Europe, phrenology, to try to understand these Using himself as his only subject, he collected all his patients. urine output for four weeks. The first week, he rested, Phrenology had a transient popularity in America. the second, he engaged in hard physical labor, the third American physicians utilized the new European doche rested his mind (reading novels), and the final week trine as an explanatory framework for a variety of he engaged in difficult mental exercises. He then meaconditions. In addition to the “amnesia for words” sured everything he could measure in the urine to deternow known to be due to infarction in a speech-related mine changes produced by muscle activity (comparing area of the dominant cerebral hemisphere, American first and second weeks) and by mental activity (comparphysicians hypothesized that color blindness was due ing third and fourth weeks). His experimental design was to an infarction in a hypothetical cerebral organ for far beyond his chemical capabilities, but the brilliant colors. This was completely wide of the mark, howaudacity of his approach led the new American Medical ever, since blue-green color blindness is due to a Association to award him their annual prize for the best genetic defect in the retina. An American doctor also medical research in the United States. used phrenology to try to study why certain activities With this award, he convinced his superiors in the of the mind in particular patients lessened the severity army to allow him a year of personal study in Philadelof epileptic seizures. Within a few years, however, the phia. Working with Weir Mitchell, he attempted to doctrine lost its popularity and sank into a study of determine in experimental animals the nervous system cranial bumps to amuse the masses and defraud the effects of newly isolated chemical agents from snake gullible (Freemon, 1992). venom. No neuroscience resulted from their collaboraThe only surgical operation of this era that apption but they established a relationship that flourished roached the brain was trephination for post-traumatic into a new clinical field in America. hemorrhage or epilepsy. Though usually fatal, this

AMERICAN NEUROLOGY

THE WAR The development of clinical neurology had to await the great American Iliad that threatened to break apart the United States. The military action produced many injuries of the nervous system. The study of these injuries led Mitchell into the neurological hall of fame (Fig. 38.1). Success as military medical leader propelled Hammond into a huge private practice that became the first American practice of clinical neurology. The two individuals who later would define American neurology played important roles during the War. Hammond became the physician in charge of all medical actions of the Army of the United States. With great energy, he transformed the rickety medical bureau into a modern medical organization, but he had no time for neurology. Evidence for his continuing interest in the nervous system is revealed by his letter to all Union military physicians that they should include mental symptoms in all reports of head wounds. Weir Mitchell remained a civilian in Philadelphia, but served as a contract surgeon in military hospitals (today this position would be called a civilian employee of the Department of Defense). He was first assigned to a hospital converted from a police building

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on Christian Street. He used his connections with the Philadelphia medical establishment to organize a system of patient exchanges; other physicians were only too willing to send a patient with unbearable pain or unrelenting seizures to the Christian Street Hospital in return for a soldier recovering from measles or from an uncomplicated wound. After Mitchell had collected all the neurological patients in Philadelphia, he needed a larger facility. With support from his old friend Hammond, Mitchell opened the first neurological research center in the New World, built on a rural road called Turner’s Lane. Helping him was the young physician, William W. Keen, who developed his skills to become the first American neurosurgeon. Mitchell and his colleagues saw many different neurological conditions at Turner’s Lane Hospital. They encountered a patient with a gunshot wound to his neck, producing a droopy eyelid, a large pupil, and lack of sweating on the same side as the wound. This condition was later called Horner’s syndrome; if an eponym were determined solely by priority, Weir Mitchell would have a greater claim than the Swiss physician, Johann Friedrich Horner. By interviewing many soldiers at a hospital for amputees, Mitchell

Fig. 38.1. Silas Weir Mitchell examines a Civil War veteran. His private practice in Philadelphia, PA, along with the New York practice of William Hammond, became the basis for the foundation of American neurology.

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appreciated how many of these patients could feel in their minds the missing parts of their bodies. He first reported phantom limb sensation in a fictional story in a popular magazine, The Atlantic Monthly. His scientific report also appeared in a general publication, Lippincott’s Magazine of Popular Literature and Science. Mitchell and his colleagues encountered several soldiers with a horrible burning pain in a limb following a gunshot wound that did not sever a nerve. They attempted treatment by injecting morphine directly into the wound; this was the first regular use of hypodermic injection in the United States. Although the treatment was not generally successful, the clinical description was unsurpassed. In the major publication from Turner’s Lane Hospital, Gunshot Wounds and Other Injuries of Nerves, this condition was called causalgia; today it is most often called reflex sympathetic dystrophy (Mitchell et al., 1864). After the War, Mitchell continued his practice in Philadelphia. Turner’s Lane Hospital closed and has since been destroyed by urban expansion, but Mitchell continued treating these patients as civilians. Many years later his son, John K. Mitchell, who was named after Weir’s father, became a physician and continued to see these patients. Mitchell helped develop American neuroscience, but he was most proud of his service during the Civil War; in late life, he claimed that holding the American Union together was “the greatest cause the earth has known” (Freemon, 1993). After his military service, Hammond established a very successful private practice in New York City. Most physicians attributed the improvement in the medical support for the Union army to his leadership. The unusual end to his tenure as surgeon general only amplified his fame. He was ejected from the army after a court martial proceeding that all physicians considered grossly unfair. He began general medical practice in New York City and soon had so many referrals that he was able to limit his patient base to those thought to be suffering from dysfunction of the nervous system. He saw many patients and began sharing them with the medical world through a series of publications. His greatest work was the first American textbook of neurology, A Treatise on Diseases of the Nervous System (1871). This book is worth reading today. Hammond described a twisting movement of the fingers and limbs; the continuous nature of the movement led him to call this athetosis. He described many patients with aphasia. He hoped to add to the growing consensus that the left hemisphere was related to speech by describing a patient with heart disease who had multiple strokes. “Thus,” he said, “according to my views of the case, the patient had repeated attacks of cerebral embolism. When the embolus lodged in the left middle cerebral artery, there was aphasia accompanied

by right hemiplegia when the embolus obstructed the right middle cerebral artery, there was left hemiplegia, but no aphasia” (Hammond, 1871, p. 200). In his book, he frequently quoted French and British medical publications but only quoted the German literature in translation. In their later lives, both Hammond and Mitchell developed other interests, including writing popular novels. Mitchell’s practice included people with what today would be considered psychiatric problems. When faced with exhausted and confused women, Mitchell isolated them not only from family but from the entire environment. Prolonged bed rest in a dark room often brought symptomatic relief. In the late 19th century, Mitchell became famous for this rest cure; today he is infamous as modern feminism chastises him for patriarchy (Schuster, 2005). Hammond also evaluated many patients who today would be considered psychiatric. His buoyant personality and inability to compromise made him the ideal expert witness. He often testified for the defense in insanity cases; he developed a major theory concerning the control of the will over physical movements. Whenever any brain disease occurred, this will was affected and the person was no longer fully responsible for his actions.

THE LATE 19TH CENTURY The dominance of Hammond over American clinical neurology can be shown by the unchallenged presence of his neurological textbook for a generation. A new generation of neurologists, including the sons of Hammond and Mitchell, absorbed the many neurological discoveries coming from Europe, especially from the German-speaking lands, and in the 1890s a sudden burst of textbooks symbolized the waning of Hammond’s authority (Pappert and Goetz, 1995). These hefty tomes included an edited work and the first American textbook on pediatric neurology (Table 38.1). Unfortunately, this new understanding of brain and nerve diseases did not translate into any new effective medical therapies. For many young physicians, their love for neurology did not translate into patients; neurological encounters were too infrequent to generate an income. A patient with throat trouble knows to see a throat specialist but a patient with a weak or numb hand cannot imagine that his problem lies far away in his shoulder or even in his brain. Another physician must see the patient first and refer him to the neurologist. Hammond’s Civil War fame and Weir Mitchell’s popularity among the medical establishment of Philadelphia led to financial success but the new generation had no such referral flow. Many neurologists reformulated problems of daily living into a proposed neurological condition such as cerebral hyperemia or

AMERICAN NEUROLOGY

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Table 38.1

Table 38.2

American textbooks of neurology

American neurological organizations

Author

Title

Year

Organization

Founded

Early leaders

William Hammond

A Treatise on Diseases of the Nervous System Textbook of Nervous Diseases A Treatise on Nervous and Mental Diseases A Text-book on Nervous Diseases by American Authors A Treatise on Nervous Diseases of Children The Nervous System and its Diseases

1871

American Neurological Association American Academy of Neurology Canadian Neurological Society Society for Neuroscience Child Neurology Association

1875

Hammond, Mitchell

1948

Baker, Forster

1948

Penfield

1970

Nauta, Evarts

1972

Carter, Dodge

Charles Loomis Dana Landon Carter Gray Francis Dercum, editor Bernard Sachs Charles K. Mills

1892 1893 1895

1895 1898

neurasthenia. This diagnosis relieved the patient of worry about what was causing his problem but translated everyday problems into medical conditions. “The general feeling at this period,” said Charles L. Dana, one of the new generation, “was that the chief function of a neurologist was especially to make people think they were sick” (Lanska, 1997). Despite difficulty gathering enough patients for one practitioner to develop neurological expertise, American neurologists in the late 19th century published a significant number of important works. In addition to Mitchell’s nerve studies, articles still quoted today include George Beard’s description of a movement disorder he called the jumping Frenchmen of Maine, Henry Hun’s analysis of the lateral medullary syndrome, Dana’s description of familial tremor, James L. Corning’s use of spinal anesthesia, and Bronislov Onuf’s study of the sympathetic nervous system, including what today is called Onuf’s nucleus (Lanska, 2002). Neurological surgery began in the late 19th century from a marriage between medical neurology and general surgery. Some surgeons without special training or experience began operating on the nervous system, usually in close consultation with a medical neurologist. Some surgeons such as Charles H. Mayo in Rochester, MN, had no neurological assistance when he operated on a brain abscess or even a cerebral aneurysm but in most instances a medical neurologist located the lesion. No imaging techniques were available to separate a mass lesion from a brain infarction and many times the brain was exposed but no operable lesion was found. William W. Keen, who had spent many years working closely with Weir Mitchell, became the first surgeon who specialized in the nervous system (Stone, 1985).

THE 20TH CENTURY During the last years of the 19th and the early years of the 20th centuries, the United States grew in economic and industrial power. The nation surprised the world, and itself, by its success in the SpanishAmerican War and World War I. Europeans studied the vast neurological trauma that followed massive armies across Europe during the Great War. US casualties seemed staggering to Americans but were many fewer than those suffered by the European powers. The understanding of the nervous system produced by European study of war wounds was not mirrored in America. The American army suffered more deaths from the great influenza pandemic than from combat. This great pandemic swept through America, killing thousands and leaving a neurological deposit of postencephalitic complications, especially parkinsonism. American neuroscience was beginning to find itself. In St. Louis, MO, Joseph Erlanger and Herbert Spencer Gasser measured the rate of conduction of the electrical impulse in a peripheral nerve. Walter B. Cannon in Boston, MA, developed techniques to study the autonomic nervous system and introduced the concept of homeostasis. A few neuroscience advances led to improved therapy. The study of electrically induced seizures led to a model to evaluate anticonvulsant therapies. Tracy Putnam and Houston Merritt, working at Boston City Hospital, identified diphenylhydantoin, later called phenytoin. The greatest therapeutic changes in neuroscience occurred in the field of surgery. By careful attention to detail Harvey Cushing markedly improved the death rate from brain tumor surgery and trained a generation of neurological surgeons.

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The close cooperation between medical neurology and neurosurgery is best exemplified by the founding of the Montreal Neurological Institute. Opened in 1934, this institute was the brainchild of Wilder Penfield. He used local funds and a huge grant from the Rockefeller Foundation to provide a center for neurological thought that would serve the entire continent. He hoped to blend medical and surgical neurology into one specialty; this institute would “work effectively upon the unsolved problems in neurology, unhampered by the artificial division into medicine and surgery.” Not only at this location, but throughout North America, neurology and neurosurgery worked closely together throughout the 1940s and 1950s. The growth of neurological knowledge in non-surgical areas such as muscle disease and the demands of surgical technique strained this relationship. The separation of these two fields occurred in the 1960s, as symbolized by the 1965 division of the Canadian Neurological Society, an organization founded by Penfield in 1948, into separate organizations for neurologists and neurosurgeons (Table 38.2). The concept of specialty certification began early in the 20th century. The American Board of Psychiatry and Neurology was founded in 1934, after heated but secret discussion about the order of the two names. The Board has added subdivisions such as child neurology but continues to this day, although its two major wings are held together by the most slender thread. The Board examined U.S. and Canadian graduates of North American neurology training programs; successful applicants could say they were certified by the American Board of Psychiatry and Neurology, or simply board-certified. In the 1970s, the Royal College of Physicians and Surgeons of Canada began a separate certification procedure for Canadian neurologists. The number of new neurologists remained quite small until very recently; in the year 1960, for example, only 19 Americans became board-certified neurologists. Two great disasters swept the world in the 1930s and both affected American neurology. The great worldwide depression caused suffering in many groups of people. Like the general populace, American physicians had economic difficulties and many neurologists were forced to broaden their practices to include more psychiatric patients. In the poor state of Tennessee, for example, three doctors classified themselves as neurologists in 1930 but only one in 1934; the economic difficulties of the Great Depression forced two to expand their practices to include psychiatry. Until his death in 1941, the only neurologist in Tennessee was Alfred W. Harris, (Fig. 38.2, Freemon, 1985). I have interviewed many neuropsychiatrists of this era who told me that their first love was neurology but “psychiatry paid the bills.” The

Fig. 38.2. Alfred W. Harris and his family in August 1914 in London. Many American neurologists felt that their education was incomplete without a year of study at a European institution such as the neurological hospital at Queen’s Square. The outbreak of World War I forced Harris to cut short his British neurological experience.

other great disaster was the rise of fascism. This only ended after famine, war, and murder had killed upwards of 30 million people. In the 1930s, the main impact upon American neurology was the massive influx of European neurologists such as Josef Gerstmann and Robert Wartenburg as well as neuropathologists such as Viktor Hamburger. Some arrivals were rapidly absorbed into American neurology, becoming “more American than the Americans.” Immediately upon his arrival, Friederich Heinrich Lewy changed his name to Frederic Henry Lewey (Holdorff, 2002). Others such as Kurt Goldstein never really adapted to their new surroundings. The arrival of neuroscientists who did not practice medicine, scientists like Heinrich Kluver and Georges Ungar, fueled the growing division between theory and practice, between researchers holding the PhD degree and MD neurologists. After World War II, the United States federal government recognized that it had the responsibility to support research into health and disease. A federal

AMERICAN NEUROLOGY 611 institution that had existed since the early days of the determination of the exact genetic abnormality, a Republic was the Marine Health Service. More an aid repeated trinucleotide on chromosome four, treatment to commerce than public health, this organization ran remains symptomatic. The story is similar with Duchenne hospitals in every port to care for sailors too sick to muscular dystrophy. Donations from the annual teledepart with their ships. Later called the Public Health thon hosted by Jerry Lewis, familiar to American televiService, it provided a laboratory to support the examision viewers, funded research that helped determine the nation of immigrants; this laboratory became the nidus exact genetic defect on the X chromosome. The abnormal of the National Institute (singular) of Health. A diviprotein produced by the abnormal gene has been synsion of this organization to treat addiction became thesized, but this marvelous neuroscience has not yet the National Institute of Mental Health, authorized been translated into effective therapy. by Congress in 1946 but not funded until 1949. Further Probably the greatest change in neurologic practice specialized subdivisions enlarged the parent organizaconcerns imaging. Cranial computerized tomography tion to the National Institutes (plural) of Health. (CT) scanning, followed by magnetic resonance imaging Stimulated by private individuals, especially Mary (MRI) scanning, revolutionized neurology. Looking Lasker, Congress held hearings regarding a proposed through my old records, I came across several patients National Institute of Neurological Diseases. The testiwith the diagnosis “brain tumor suspect.” These indivimony of the widow of baseball player Lou Gehrig, duals were followed as outpatients until the likelihood who died from amyotrophic lateral sclerosis, proved of a mass lesion surpassed the complication rate of cereparticularly powerful. At the very last minute, probbral arteriography and air encephalography. Today, imalems of eye disease were added to create the National ging shows the tumor in a moment. The huge advance in Institute of Neurological Diseases and Blindness, clinical neurology produced by imaging has not been withcalled NINDB by a generation of American neuroloout small retreats. I recall a particular epileptic patient gists and neuroscientists. In 1968, a separate National who suffered a severe head injury while in the emergency Eye Institute absorbed the ocular portion of NINDB room. Over a period of an hour, he developed the classic and cerebrovascular disease was given special promisigns of blood accumulating over one hemisphere. nence to produce the modern National Institute of I begged the young neurosurgeon to undertake a burr hole Neurological Diseases and Stroke (Rowland, 2003). and drain the hematoma but he required corroboration of The massive growth of neuroscience in America has the clinical diagnosis by modern imaging techniques. The been financially supported by this organization but patient died in the CT scanner. Many young neurologists guided by individuals. require the patient to undergo brain imaging before their The last half of the 20th century encompasses the diagnostic mental faculties can be fully engaged. I feel as career of this reviewer. Developments cannot be evaluif my generation is the last to be able to perform a really ated without personal bias. Those of us who treated thorough neurological examination. horrible end-stage Parkinson’s disease in the 1960s are This brief review of the past century gives a picture of still in awe of the Cotzius miracle. Levodopa was to slow and steady progress from dim origins to the bright my generation of neurologists what antibiotics were tomorrow. This is a false picture. Many digressions and to internal medicine a generation earlier (Roe, 1997). false steps occurred in the past and are occurring today. Other major pharmacological advances include the Errors in the past included psychosurgery (frontal lobottriptans for migraine headaches and interferon for omy) popularized by Walter Freeman (no relation) and multiple sclerosis. Neuroscience was already expanding the attribution of organic disease to psychiatric causes. rapidly when the US government stimulated its develHow many parents’ lives were ruined when their doctors opment even further through increased funding told them, over and over again, that their child suffered throughout the 1990s; the program was called the DecTourette’s disease or some other hereditary condition ade of the Brain. The growth of knowledge in basic because the unfortunate victim had been raised by a domineurological function continues at such a speed that nant mother and an inadequate father? The false trails of this writer sometimes attends a neuroscience research today have not yet been labeled false. lecture and fails to understand a single sentence. Robert Heath in New Orleans developed an extenIn some situations, significant treatments continue sive research program involving the electrical stimulato elude us even when our basic knowledge borders tion of deep areas within the brains of psychiatric the miraculous. George Huntington in 1872 described a patients. He continued this research despite extensive hereditary disorder characterized by abnormal movecriticism of the ethics of such treatment (Baumeister, ments and mental deterioration. Huntington’s father and 2000). This type of research in psychiatric patients grandfather had been physicians to the same afflicted was discontinued, but has spread to the treatment family in Long Island, NY (Lanska, 2000). Despite the of patients with movement disorders. Without the

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slightest ethical opposition, deep brain stimulation has become a therapeutic option for parkinsonism. The gorge between psychiatry and neurology, between diseases of the mind and of the brain, still exists. The attempt by Benjamin Rush and many since “to show that the mind and body are moved by the same causes and subject to the same laws” has failed. “Time, I hope,” Rush opined, “will do my opinions justice,” but that time is not yet. We conclude with the observation that American neurology in the last few decades has been absorbed into world neurology. There is now only one neurology. If you attend a neurological meeting, even an official annual meeting of an organization with the word American in the title, you will see neurologists from every continent and almost every nation (Table 38.3). Their papers vary in quality and in the availability of technical support, but all are based on the same neurology and the same neuroscience. Neurological journals are international in scope, even if supported by a national society such as the American Neurological Association. Most new societies such as the Society for Neuroscience are fully international. Thus, the separate story of American neurology comes to an end. Table 38.3 Important neurological institutions in North America Institute

Years

Leaders

Turner’s Lane Hospital, Philadelphia, PA Neurological Institute of New York Montreal Neurological Institute National Institute of Neurological Diseases and Stroke, Bethesda, MD

1862–1865

Mitchell, Keen

1909–present

Bailey, Merritt

1932–present

Penfield, Rasmussen Lasker, Shannon

1950–present

REFERENCES Baumeister AA (2000). The Tulane electrical brain stimulation program: a historical case study in medical ethics. J Hist Neurosci 9: 262–278. Finger S (2006). Doctor Franklin’s Medicine. University of Pennsylvania, Philadelphia, PA. Freemon FR (1985). The development of clinical neurology in Tennessee. J Tenn Med Assoc 78: 78–80. Freemon FR (1992). Phrenology as clinical neuroscience: how American academic physicians in the 1820s and 1830s used phrenology to understand neurological symptoms. J Hist Neurosci 1: 131–143. Freemon FR (1993). The first neurological research center: Turner’s Lane Hospital during the American Civil War. J Hist Neurosci 2: 135–142. Hammond WA (1871). A treatise on diseases of the nervous system. Appleton, New York. Holdorff B (2002). Friedrich Heinrich Lewy (1885–1950) and his work. J Hist Neurosci 11: 19–28. Jensen RL, Stone JL (1997). Benjamin Winslow Dudley and early American trephination for posttraumatic epilepsy. Neurosurgery 41: 263–268. Lanska DJ (1997). The role of technology in neurologic specialization in America. Neurology 48: 1722–1727. Lanska DJ (2000). George Huntington (1850–1916) and hereditary chorea. J Hist Neurosci 9: 76–89. Lanska DJ (2002). Classic articles of 19th-century American neurologists: a critical review. J Hist Neurosci 11: 156–173. Mitchell SW, Keen WW, and Morehouse GR (1864). Gunshot wounds and other diseases of nerves. Lippincott, Philadelphia. McCullough D (2001). John Adams. Simon and Schuster, New York. Pappert EJ, Goetz GC (1995). Early American neurologic textbooks. Neurology 45: 1228–1232. Roe DL (1997). From DOPA to Parkinson’s disease: an early history of dopamine research. J Hist Neurosci 6: 291–301. Rowland LP (2003). NINDS at 50. Demos, New York. Rush B (1812). Medical inquiries and observations upon diseases of the mind. Kimber and Richardson, Philadelphia. Schuster DG (2005). Personalizing illness and modernity: S. Weir Mitchell, literary women, and neurasthenia, 1870–1914. Bull Hist Med 79: 695–722. Stone JL (1985). W.W. Keen: America’s pioneer neurological surgeon. Neurosurgery 17: 997–1010.

Handbook of Clinical Neurology,Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 39

An historical overview of British neurology F. CLIFFORD ROSE * Academic Unit of Neurosciences, Formerly Charing Cross and Westminster (now Imperial College) School of Medicine, University of London, London, UK

INTRODUCTION There has been a wide variety of journal articles, book chapters, collections of essays, and monographs on neurological diseases, and biographies of famous British neuroscientists, but there has been no overview on the development of neurology in the United Kingdom. This chapter makes such an attempt by considering the individual efforts of neurologists and clinical neuroscientists in Britain. Who should be included is both a personal and debatable choice, but the criterion used is that a “significant neurological contribution” was made – a definition that itself is personal and debatable, but perhaps inevitable. Specialization was unknown in the UK until the 18th century, when the Medical Society of London, founded in 1773 and the oldest continuous medical graduate society in the world, was divided equally between physicians, surgeons (including obstetricians), and apothecaries (equivalent to family practitioners). After this time there were several reasons favoring further specialization: (1) it became increasingly obvious that no one person could be an expert in every medical condition; (2) a growing realization that diseases could be localized to one organ and, especially in the nervous system, to one part of that organ; (3) the advent of monographs, journals, and specialist hospitals for specific diseases; (4) since only the wealthy could afford a specialist opinion, such a visit could add to the prestige of the patient; and (5) the financial rewards of the specialist. The United Kingdom differed from other countries in Europe and from the United States in that neurology stemmed from general (internal) medicine as opposed to psychiatry; nearly all the early founders of British neurology were general physicians (internists) or professors of medicine, with a particular interest in neurology. In countries such as Germany there could be a single head for

*

the departments of psychiatry and neurology; in Japan, neurology did not separate from the Japanese Society of Neurology, Psychiatry and Neurosurgery until the 1960s, and, even to this day specialist boards of the two disciplines are linked in the United States (Koehler, 1999). In 1886, the Neurological Society of London was founded with Hughlings Jackson as its first President. It became the Association of British Neurologists in 1933, with 25 members; nearly 40 years later it had only 200 members, about the same as the Society of British Neurosurgeons. In 1935, the First International Congress of Neurology was held in Berne, Switzerland, and although 50 British doctors attended, there was no official delegation. A motion was passed that “Neurology represents an entirely independent specialty to medicine. . . .” After World War I, Kinnier Wilson was made Physician in Charge of an independent department of neurology at Westminster Hospital, the first of its kind in any British medical school. Neurology was eventually recognized as an independent specialty, and departments started up in most medical schools. As neurology had always been regarded with awe coupled with a certain jealousy by the general physician, [it] became a respectable discipline, worthy of standing on its own feet. Neurologists became a race apart even though they continued to constitute a sort of corps d’e´lite among their colleagues in general medicine. Neurologists were responsible for more Fellows of the Royal Society than any other discipline in medicine. (Critchley, 1979, p. 191)

BEFORE WILLIS Before the 17th century, there were English doctors who mentioned disorders of the nervous system in

Correspondence to: Dr F. Clifford Rose, Retired Director, Academic Unit of Neurosciences, 7 Church Street, Little Bedwyn, Marlborough, Wiltshire SN8 3JQ, UK. E-mail: [email protected], Tel: +44-1672-870-303.

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their writings. Gilbertus Anglicus (c. 1230), in his Compendium Medicine, distinguished apoplexy from epilepsy and divided seizures into major and minor varieties. In discussing different types of stroke, Gilbertus writes: “Major [apoplexy] kills the very first day, and is incurable; the intermediate form is lethal within three days or is terminated by palsy; the third form lasts up to seven days until the death of the patient or turns into paralysis.” Gilbertus attempted this rational prognosis of stroke by correlating outcome with the severity of respiratory damage. While in a healthy person only the diaphragm is active in inhalation and exhalation, in minor apoplexy the anterior pectoral muscles are called into play, whilst the intermediate form brings in the lateral pectoral muscles, and the most severe stroke involves all the muscles of the thorax, including the posterior ones. Pyrexia had been regarded as a favorable sign, because it warmed up the patient’s body and Gilbertus gave detailed instructions to provoke fever by having “two good fires, and taking hot drinks.” Bartholomaeus Anglicus (c. 1260), in his De Proprietatibus Rerum, a broad compendium of science and medicine, also mentioned paralysis and epilepsy (Bruyn, 1982). Printing in London began toward the end of the 15th century, and it rescued precious manuscripts from moldering destruction (Gordon, 1999). The Encyclopedia of Bartholomaeus was printed in English and provides the first picture of a dissection printed in England (Carlino, 1999). This important work consisted of 19 books, with 4–7 being most relevant to medicine, and served as instruction for fellow Franciscans, who did not have the time or means to study each discipline individually. With regard to nervous disease, the doctrine of the brain was codified and consisted of a series of simple questions and answers: “Why is the brain white? It contains little blood. Why is the brain round? To accommodate as much spirit as possible. Why is the brain at the body’s summit? The most distinguished place. Why cold and moist? To moderate the heat of the heart. Why three ventricles? For sensation, thinking and memory.” The sensory impressions produced imagination in the anterior ventricle; the middle ventricle mediated rational thinking; and memory occurred in the posterior ventricle. Bartholomaeus Anglicus thought that mania could be caused by poisoning or infection in the first ventricle, and that melancholy was associated with the middle ventricle (Pagel, 1958). The leading text of this era was written by John of Gaddesden (1280–1361) who, in the Rosa Anglica (1315), described his own cases and, despite believing in the influence of the moon, is often acknowledged as the first British physician to produce a significant manuscript on neurological disorders, such as

epilepsy. John de Mirfield, also in the 14th century, described epileptic attacks, and showed that injuring the right side of the head caused left-sided paralysis. John of Ardenne’s Practica (1412) mentioned neurological disorders such as facial paralysis, loss of sensation, and paralyses, but provides less neuroscience. All of these writings were in Latin, but Philip Barrough’s The Method of Physic of 1590 was written in English. In the First Book, the initial chapter is on headache, which he divides into three: Cephalalgia, Cephalaea, and Hemicrania; there are also 12 chapters in 15 pages with an account of trigger factors. Other chapters are on Vertigo, Lethargy, Memory Loss, Apoplexy, Palsy, Falling Sickness, Cramps, and the like. Robert Pemmell’s early neurological work, De Morbis Capitis (1650), reveals contemporary knowledge of the subject and, except for its Latin title, was also written in English (Walton, 1993; Gordon, 1999).

THOMAS WILLIS (1621^1675): THE FOUNDER OF NEUROLOGY The term neurology was introduced by Thomas Willis, the celebrated physician and anatomist of the 17th century. For this, but, more especially, for his remarkable observations correlating the anatomy, physiology, and clinical disorders of the nervous system, he may be substantially claimed as the founder of neurology (Feindel, 1962). Thomas Willis (Fig. 39.1) was born in 1621 in Great Bedwyn, Wiltshire, but moved with his family to North Hinksey, near Oxford, when he was 9 years old (Feindel, 1965; Isler, 1968; Hughes, 1991; Zimmer, 2004). At age 16 he matriculated into the University of Oxford, entering Christ Church College, and helped the Canon of Christ Church, “whose wife was a knowing woman in physique and surgery, and did many cures.” In 1642, Willis graduated and began his medical studies. The introduction of the term “neurology” by Willis, along with his other discoveries in 1664, gave birth to a new specialty. Additionally, he was the first leader of a multidisciplinary team in neurological science. Willis was, in fact, an experimentalist who combined medical experience with first-hand anatomical knowledge, and he helped shift attention from the chambers of the brain to the brain substance itself, while promoting the theory of medical (or iatro-) chemistry (Finger, 2000). Within the period of 1657–1658, three epidemics swept through Oxford, providing him with ample neurological material (e.g., meningitis, encephalitis lethargica), and stimulating his interest in the brain and neurological disorders. Following the Great Plague in

AN HISTORICAL OVERVIEW OF BRITISH NEUROLOGY

Fig. 39.1. Thomas Willis (1621–1675).

1665, Willis moved to London but retained his title as Sedleian Professor of Natural Philosophy of Oxford University, having been appointed after the restoration of King Charles II in 1660. His practice in London, as had previously been the case in Oxford, grew rapidly (Dewhurst, 1980). Willis was the first to report cerebrospinal fever (meningococcal meningitis), and he also named puerperal fever. It was this research that led to the publication of his first book in 1659, Diatribae duae Medico-Philosophicae, which has been described as the “first systematic piece of epidemiology written in English.” In total, Willis published seven books, all except the last being in Latin (the others were translated into English after his death). Cerebri Anatome (1664) was his second book, but the first on the nervous system, and it covered the brain, spinal cord, and peripheral nerves (O’Connor, 2003). This was the best of his books and had nine editions in its first 20 years. It was here that “neurology” first appeared in Latin (from the Greek word meaning tendon, sinew, or bowstring), antedating its English

615

appearance by a century. Besides clinical work, it included embryology, pathology, microscopy, anatomy (using dye injection and comparative anatomy), as well as animal experiments. We owe to Willis such terms as thalamus opticus, lentiform body, and corpus striatum. While separating the functions of the cerebrum from those of the cerebellum, he was the first to use the term inferior olives and peduncles, and provided detailed descriptions of the three cerebellar peduncles (Preul, 1997, p. 107). Willis thought the cerebellum was the center for involuntary movements for three reasons: its gyral pattern, the cranial nerves serving vital functions originate there, and because handling an animal’s cerebellum caused an increase in heart rate. In contrast, he associated the cerebrum with voluntary movements, sensations, and other mental functions. It contains three centers: the corpus striatum, which is the seat of the sensus communis, as it receives all sensations; the corpus callosum, meaning the subcortical band of nerve fibers connecting the left and right cerebral hemispheres (which then included all white matter) where imagination takes place; and the cerebral cortex, where memories are stored. Willis thought the gyri control memory, whereas the will and imagination are the concern of the corpus callosum. He thus put all three psychological functions in the brain parenchyma and not in the ventricles (Preul, 1997, p. 119). Other new terms he used included hemisphere and lobe; Cerebel was the word for cerebellum, but Willis included the mid-brain and pons with it. Nowadays the term medulla is the posterior part of the brain stem, but Willis extended it from the spinal cord to his corpus callosum. Willis’ basic idea was to correlate brain form with brain function, and he also coined the word reflexious, from which we get the word reflex, meaning a very rapid, automatic input–output action of the nervous system (Finger, 2000, p. 91). His third book, Pathologiae Cerebri (1667), provides several important case reports with clear descriptions of some neurological diseases for the first time. Epilepsy was delineated from other neurological disorders, and Willis divided attacks into primary, arising in the brain, and what we now call focal, e.g., starting in the hand. He also classified them into inherited or acquired, before or after puberty, and whether they result in lost consciousness or not. This book refuted the idea that hysteria started in the womb. In 1668, Willis had observed incurable and fatal headaches could “follow abscesses and swellings of the envelopes of the brain, as well as plaques and tubercles of these membraines.” De Anima Brutorum (1672) was his fifth book and contains chapters on headache, disorders of sleep,

616 F.C. ROSE subconscious states, and vertigo. Most of his neurolthe most important lecture series in the history of neuogy is found in this book. Regarding headaches, he rology. The first Croonian Lecture was given by Alexdescribed several types depending on site, periodicity, ander Stuart, famous because he reported the reflex and severity, stating that “the pain of the head is wont concept, which he discovered by decapitating a frog to be accounted the chiefest of the Diseases of the and noting that its legs jumped when touched – Head.” He noted that headache is frequently heredisomething originally seen by Stephen Hales, who did tary, tends to begin in the morning, can be provoked not publish his findings (Gordon, 1999). by emotion, and might be preceded by hunger and folWilliam Harvey (1578–1657) is best remembered as the lowed by polyuria. He was, in fact, the first to describe discoverer of the circulation of the blood, a discovery that cluster headaches. In this text, Willis also gave the first helped topple the old science and showed the value of clear description of myasthenia gravis as well as assoexperimentation (Singer, 1957). Yet “Harvey’s interest in ciating atrophy of the internal capsule with longthe nervous system was not in any way passing or superstanding hemiplegia. ficial” (Gibson, 1982, p. 283; also see Brain, 1959). In HarAs an iatrochemist, Willis approached nerve actions vey’s three books, De Motu Locali Animalium, De as chemical processes. He wrote of fibers and, since he Generatione, and Prelectiones, one can see his concepmentioned the microscope, they might have been true tions and clinical observations of the nervous system. nerve fibers, which he described as being made up of Harvey accepted crossed paralysis and was familiar “mini hair-like nervules” collected in the same bundle with hydrocephalus, as well as with changes in the size for the sake of better conduction. Of great importance of a pupil. While De Motu Cordis (1628) contained no is that he performed autopsies on his patients to correnew neurological advances, in De Motu Locali Animallate pathology with symptoms and signs during life. ium (1672), he classified different types of gait. His Best known for his description of the branches and “tripping on the towtoe” is suggestive of spastic parajunctures of the vessels at the base of the brain, Willis plegia. He also gave a good description of muscular was aware that what would thereafter be called the fasciculation. Although an excellent clinical observer, “circle of Willis” had been recognized before. But he e.g., of the association of obesity and somnolence illustrated these vessels properly and described their in boys, he was wrong in thinking that hysteria was significance, noting that, if one vessel were blocked, uterine in origin (Brain, 1959). Harvey frequently the brain would still be supplied by the other vessels. referred to the structure and function of the nervous Notably, the first detailed description of the vascular system, and the last 13 of his 98 folios were devoted supply of the spinal cord was also by Willis. to this subject. The neurological conditions he menWillis died in 1675 and was buried in Westminster tioned include hydrocephalus, epilepsy, apoplexy, Abbey. Before him, the brain was a mystery. After paralysis, loss of sensation, blindness due to cerebral him, the parts of the central, peripheral and autonomic disease, delirium, and coma (Hunter and Macalpine, nervous systems were much better recognized and 1951, p. 130). associated with neurological functions and disorders. Francis Glisson (1597–1667) was also interested in His work provided the needed foundations for neurolmuscular movements. Up to the 17th century, it was ogy to advance. thought that the nerves were hollow and swelled the muscles by inflating them with animal spirits, but THE 17TH CENTURY: OTHER Glisson, who was Regius Professor of Medicine at THAN WILLIS Cambridge, refuted this hypothesis by showing that, when a man contracted his arm muscles in a tube of Almost everything that distinguishes the modern water, the water level did not rise. world from earlier centuries is attributable to Glisson also discovered and drew attention to irritabilscience, which achieved its most spectacular triity, which he viewed as a biological property not dependumphs in the 17th century. (Russell, 1996) ing on consciousness. Albrecht von Haller (1708–1777) William Croone (1633–1684), a founding Fellow of the would elaborate on Glisson’s theory of irritability, which Royal Society, studied muscle physiology and pubhe separated from sensibility. Glisson also contributed lished his major work on this subject in 1664. He lecto neuroanatomy, and as a clinician employed suspension tured in anatomy to the Company of Surgeons, and for the treatment of spinal deformities. theorized that a spirituous liquid “flowed in and mixed Humphrey Ridley (1653–1708) wrote the first Engwith the nourishing juice of the muscle,” which then lish neuro-anatomical book The Anatomy of the Brain “swell’d like a bladder blown up” (Brazier, 1982). His (1695), up-dating Willis with 10, rather than seven, crawife endowed the Croonian Lectures of both the Royal nial nerves. He named the restiform body and first Society and the Royal College of Physicians, probably described a pineal tumor (Gordon, 1999).

AN HISTORICAL OVERVIEW Thomas Sydenham (1624–1689) was a physician who, among other things, studied convulsions and noted the different prognoses in children and adults (Temkin, 1971). Known as the “Hippocrates of English Medicine,” his claim to fame in neurology is the eponymous disease, Sydenham’s Chorea, which he described in 1686. Since this was now recognized as a disorder of the central nervous system complicating rheumatic fever, Osler criticized Sydenham for using the term “chorea,” which had been coined by Paracelsus to describe the “dancing mania” of the Middle Ages (Ashwal, 1990). Osler’s point was that Sydenham had added to the confusion between the dancing mania of the Middle Ages (St. Vitus’ Dance) and rheumatic chorea.

THE 18TH CENTURY William Heberden (1701–1801) was a general practitioner in London, whose Commentaries, based on 7000 patients, was published the year after his death. He wrote: Headache [migraine?]: The most violent headache will frequently harass a person for the greater part of his life, without shortening his days, or impairing his faculties or unfitting him, when his pains are over, for any of the employments of active or contemplative life. . .they almost always become milder, and generally vanish towards the decline of life. (Heberden, 1802, pp. 91–99) Epilepsy: The fit makes the patient fall down senseless; and without his will or consciousness presently every muscle is put in action . . . In these strong and universal convulsions, the urine, excrements, and blood are sometimes forced away, and the mouth is covered with foam, which will be bloody, when the tongue has been bitten, as it often is in the agony . . . The true epilepsy most usually shows itself in childhood or youth; but there is hardly any time of life, from the first day of it to extreme old age, at which it has not been known to make its first appearance. (Heberden, 1802, pp. 156–161) Tremor: . . . a tremor has often continued for a great part of a person’s life, without any appearance of further mischief . . . hard drinkers have it continually; and some degrees of it, usually attend old age. (Heberden, 1802, p. 429) Heberden also wrote about transient cerebrovascular insufficiency, which sometimes went on to complete paralysis. “A numbness of the hand has come on the first day, on the second a faltering of the voice, and a palsy on the third” (McHenry, 1969, p. 134).

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William Cullen (1712–1790) was one of the first lecturers in medicine to take a particular interest in neurological diseases, and thought that most diseases were nervous in origin. He classified them into four divisions: the first was comate, which is loss of voluntary motion and included apoplexy and palsy; the second was adynamia, which is loss of motion and included syncope; the third was spasm, which included epilepsy and chorea; and the fourth was versaniae, where judgment is impaired. He felt that life was a function of nervous energy and that muscle was a continuation of nerve (McHenry, 1969, p. 133). These were all elaborated in his section “Of Neuroses and Nervous Disorders” in First Lines of the Practice of Physic, for the use of students (Cullen, 1771). Robert Whytt (1714–1766) became a professor of medicine in Edinburgh at the age of 33 and is perhaps the most important neurologist of the 18th century, having detailed tuberculous meningitis, raised intracranial pressure with acute hydrocephalus arising from tuberculosis meningitis (Whytt’s disease), cerebral edema (“dropsy of the brain”), and amaurosis fugax (transient monocular blindness). His 1751 treatise, An Essay on the Vital and Other Involuntary Motion of Animals, was particularly important. In the 18th century it was physiological research that occupied much of scientific medical enquiry, and the greatest single contribution that 18th-century physiology made to clinical neurology was to elaborate on the concept of reflex action, and Whytt demonstrated that only a small segment of the spinal cord was necessary for some reflexes. Whytt did not believe that muscle contraction was due to an influx of animal spirits or that it was independent of the nerves. His views were published in 1751 and 1755, and his 1765 treatise, On Nervous, Hypochondrical or Hysterical Diseases, was the best book on nervous diseases since that of Willis. He was the first to describe the pupillary light reaction, and postulated that light stimulated the nerves in the retina with the impulses reflected out along the nerves specific for innervating the iris; he found that a hydrocephalic child had fixed pupils that did not react to light. Although tuberculosis of the nervous system was first described by Whytt, he thought it was just an inflammation of the ventricles. He also wrote Observations on the Dropsy of the Brain, which was published in 1768. In The Works of Robert Whytt, there are 13 essays with two appendices. One essay is titled, “Observations on the nature, causes and cure of those disorders which are commonly called nervous, hypochondriac or hysteric” (Whytt, 1768, pp. 487–714). In his time, Whytt was looked upon as an authority on hysteria, although some of his ideas were not anchored in hard science.

618 F.C. ROSE John Fothergill (1712–1780) described trigeminal an invariably fatal sign. Sudden death was more likely neuralgia (1776) and migraine headache (1777–1784) in to be due to disease of the heart than the brain. He a three-volume treatise that was edited by John Coakquoted Fothergill, who held that apoplexy in general ley Lettsom. Other 18th-century clinicians to describe arose when, in the head, there was “more blood than neurological syndromes include Percival Pott, who ought to be there” (Spillane, 1981, p. 169). Cooke described spinal caries causing paralysis due to cord described a stroke patient where “animal functions pressure, Underwood (1789) on polio, Lettsom on polyare suspended, while the vital and natural functions neuropathy, and Crookshank on encephalitis lethargica. continue; respiration being generally laborious and frequently with stridor . . . Genuine apoplexy, I believe, FIRST HALF OF THE 19TH CENTURY seldom destroys life in less than one or two hours . . .” “Palsy” was divided into hemiplegia, paraplegia, and It appears – that to get any adequate comparison partial palsies. Affected limbs were usually colder, with the 19th century, we must take not any prewasted, and shrunk, becoming softer, flaccid, and someceding century . . . , but rather the whole precedtimes edematous. In hemiplegia, there is loss of ing epoch of human history. (Wallace, 1901) language and speech, and intellectual and emotional During the first half of the 19th century, Parkinson control could be affected, usually after an apoplectic published on his eponymous disorder, Bentley Todd fit. Unilateral effects are typical, and apply not only to described post-epileptic paralysis, and Marshall Hall the limbs, but the face, tongue, and chest, with recovery wrote about the development of reflex action. usually beginning in the leg. Sometimes there is double James Parkinson (1755–1824) was born in Hoxton hemiplegia, but sensation is never completely lost. The (London), apprenticed to his father, and studied medicine lesions are often like those of apoplexy. for 6 months at the London Hospital. He was active In paraplegia, the lower limbs are more frequently politically and a well-known paleontologist, but is best affected. In young children, the onset is usually slower known neurologically for his 1817 Essay on the Shaking than in adults and, as they walk, there is “an involunPalsy, where he wrote that his patients had “involuntary tary crossing of the legs.” He described this scissors tremulous motion, with lessened muscular power, in parts posture of cerebral palsy long before Little (who also not in action and even when supported; with a propensity worked at the London Hospital). Partial palsies could to bend the trunk forwards and to pass from a walking to arise from the brain, spinal cord, or the nerves, a running pace; the senses and intellects being uninjured.” and they could be motor, sensory, or mixed. One of He had observed only six cases: two encountered in the the commonest causes of palsy at this time was lead street; one seen walking at a “running pace” accompanied poisoning. by a helper; one patient he was treating for abscesses; one Charles Bell (1774–1842) was born in Edinburgh. whose tremor was improved by a stroke; and the last in the Whilst still a medical student he published A System final stages of the condition. Five of his six cases had a of Dissections, and after graduating joined the surgical festinant gait. His first case, which he described as “a staff of the Edinburgh Royal Infirmary. An excellent tedious and most distressing malady,” had been kept artist, he illustrated his own books, such as Engravings under observation for many years, and may have been a of the Arteries of the Nerves of the Brain (1800–1802). case of multi-system atrophy. While all the signs had been At the age of 32, he began lecturing in London on previously individually described, his contribution was to anatomy and art and in 1806 published Essays on the show that they all belong to a single malady. Parkinson Anatomy of Expression in Painting (Gardner-Thorpe, had noticed the flexed posture of the body, but did not 1999, 2004, 2006; Rose, 2003a, 2004). describe rigidity that appears as the disease progresses. In 1809, Bell went to Portsmouth to study gunshot John Cooke (1756–1838), physician to the London injuries of the wounded evacuated from the battle of Hospital, gave the Croonian lectures in 1820, 1821, La Corunna (against Napoleonic forces); more interand 1822, which formed the basis of A Treatise on Disested in anatomy than surgery, he painted many cases eases of the Nervous System, published in two volumes and made fine drawings. He showed that the fifth crain 1820 and 1824. It is divided into three sections: Aponial nerve is both motor and sensory, reporting paralyplexy (1820), Palsy (1821), and Epilepsy (1823). sis from a lesion of the motor side in 1821 (Bell’s “On Apoplexy” includes an essay on “Apoplexia Palsy). He was the first to describe myotonia, and Hydrocephalica” (acute internal hydrocephalus), where reported early cases of pseudo-hypertrophic muscular he discussed the different etiological theories but dystrophy. favored inflammation, pointing out that the condition In a letter on 12 August 1810, he wrote “on facts the affected children and was invariably fatal. Cooke most important that have been discovered in the history found that, in stroke, contraction of the pupils was of science” – namely, that when he stimulated the

AN HISTORICAL OVERVIEW anterior, but not the posterior, nerve root in animals, the supplied muscle twitched. Thus, he provided the first experimental evidence of the motor functions of the anterior roots. He then continued to work on the spinal roots, although he disliked animal experiments. He also delineated for the first time several “respiratory” nerves, which included the vagus and accessory nerves, as well as the long nerve of Bell. In 1811, he published (privately) his Idea of a New Anatomy of the Brain, which included his groundbreaking work on the anterior and posterior spinal roots (Rose, 1999, 2003a, b). Here, he also presented other seminal ideas on nervous function, including: (1) the cerebrum and cerebellum are different in form and function; (2) parts of the cerebrum have different functions; and (3) nerves are not single but bundles of different nerves, united for distribution, but distinct in function as was their origin from the brain. The book on anatomy by John and Charles Bell was the most important work of its kind in the British Isles during the early part of the 19th century. In this book, Bell showed how the skull, which protects the brain, changes from infancy to old age. Human expression is not explained by the mind’s influence on features; the muscles along the eye are a lively feature, a large eye being a sign of beauty; laughter is not restricted to the facial muscles; joyful expression is anticipatory of gratification. Finally, we should note that Bell anticipated Johannes Mu¨ller’s principles of “specific nerve energies,” stating that sense organs are specialized to receive only one form of sensory stimulus, and that he wrote about “muscle sense.” His “sixth sense” was used to explain how we can stand upright with feet together, or differentiate coins in our hands, with our eyes closed (Spillane, 1981, p. 29). Marshall Hall (1790–1856) graduated from the University of Edinburgh and subsequently moved to London to become a successful practitioner. Although he published over 100 papers and 19 books, he never had a staff appointment at any hospital (Rose, 2003b). His office was in his home, where he experimented with frogs, snakes, and eels, and found that a separated tail would twitch on being touched by a scalpel. He studied this phenomenon for 25 years and wrote many papers on reflex action, which was independent of the brain and acted through the spinal cord; he not only coined this term, but also introduced the terms spinal shock and reflex arc. Hall discovered the reflex nature of balance and sphincteric control, and showed that a reflex does not require volition, sensation, or instinct – all that is required is a stimulus, afferent and efferent nerves, and an intact spinal cord. His initial presentation to the Royal Society was published in 1833, and his seminal work, Lectures on the

OF BRITISH NEUROLOGY 619 Nervous System and its Diseases, followed in 1836. He distinguished between the facial paralysis due to a cerebral lesion (when one eye does not close) and a facial nerve lesion (when the eyelids do close). He first divided the nervous system into two parts, cerebrospinal and ganglionic (or sympathetic), but later suggested three: cerebral (voluntary and sentient), true spinal (excitomotory), and ganglionic. Hall noted that, when yawning or sneezing, a paralyzed person could have an automatic movement of the arm, even though the patient could not move it voluntarily. In addition to these automatic or mass movements, he elaborated the grasp reflex in neurological disorders. He considered apoplexy a form of congestion or hemorrhage in the brain, but did not differentiate the various types of attacks. At that time, it was thought that the cerebral hemispheres were the seat of volition and sensation, but not of movement, and, for this reason, he felt the medulla was the site of origin for an epileptic convulsion. Until 1860, physicians (other than Thomas Willis) had largely neglected disorders of the nervous system, but Richard Bright (b. 1789) had taken an interest in apoplexy (cerebrovascular disease) and Robert Graves (b. 1796) made contributions from Dublin. Although the name of Graves is best known for its association with thyrotoxicosis, he was the first to describe peripheral neuritis of which he saw an epidemic in Paris in 1828: It began (frequently in persons of good constitution) with sensations of pricking or severe pain in the integuments of the hands and feet, accompanied by so acute a degree of sensibility that the patients could not bear these parts to be touched by the bedclothes. After some time . . . a diminution, or even abolition, of sensation took place in the affected members, they became incapable of distinguishing the shape, texture or temperature of bodies, the power of motion declined, and finally they were observed to become altogether paralytic. The injury was not confined to the hands and feet alone but, advancing with progressive pace, extended over the whole of both extremities. Persons lay in bed powerless and helpless and continued in this state for weeks and even months. At last, at some period of the disease, motion and sensation gradually returned, and a recovery generally took place, although in some instances, the paralysis was very capricious, vanishing and again reappearing. (Graves, 1884) Robert Bentley Todd (1809–1860) was described by James Collier as “by far the greatest clinical neurologist that Britain had produced until the time of

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Hughlings Jackson.” Born in Dublin, he went to university there and became a lecturer at the school in Dean Street, London, which was associated with Westminster Hospital, but failed to obtain the post of physician there. In 1831, he became professor of physiology and morbid anatomy at King’s College, where a medical faculty had just been established, but without clinical amenities (Lyons, 1982). In 1835 Todd edited a massive five-volume Cyclopaedia of Anatomy and Physiology, in which he introduced the terms afferent and efferent. His lectures on physiology for his medical students were the first of their kind in the United Kingdom, and other medical schools in Britain soon followed. He was an Honorary Physician at King’s College Hospital from 1839 to 1859, during which time he published Clinical Lectures on Paralysis (1854), which was the first of three volumes on clinical neurology – until 1860 there were virtually no doctors engaged exclusively in neurology, and this textbook became the standard for medical students. He wrote that “in some of the cases, the palsy at first occupied the muscles connecting the humerus to the scapula, especially the deltoid, which was wasted . . . Considerable pain in the deltoid muscle generally preceded the paralysis . . . ”; this may well have been the first report of neuralgic amyotrophy. In his book Clinical Lectures on Paralysis, Disease of the Brain and Other Affections of the Nervous System (1845), he reported on various forms of paralysis, which involved 83 personal cases. They included postictal weakness, now called Todd’s paralysis, which he described in 1849: “A paralytic state remains sometimes after the epileptic convulsion – particularly when the convulsion has affected only one side or one limb: that limb or limbs will remain paralytic for some hours, or even days, after the cessation of the paroxysm, but it will ultimately perfectly recover” (1849). He separated out the different types of stroke whether due to hemorrhage or clot, and other forms due to trauma, tumor, atrophy, or inflammation (including syphilis). There were also less common forms of spinal or peripheral hemiparesis. He did not accept spinal or medullary causes of epilepsy, and suspected that the convolutions might be involved. He was the first to recognize the functions of the dorsal columns, and described lead palsy and tabes dorsalis. Todd was the first to confirm the electrical basis of brain activity in the 1840s (Spillane, 1981; Lyons, 1982, pp. 137–150). He stimulated rabbits with electricity to produce epilepsy and founded our modern electrical concepts of epilepsy, which he promulgated in the Lumleian lectures in 1849. Working with Michael Faraday (1791–1867), instead of the term electricity, he used such terms as “nervous power,” “nervous force,” and

“nervous energy,” but eventually settled on “nervous polarity.” He thought the brain had battery-like properties, which led to a seizure “with the violence of the discharge from a highly charged Leyden jar.” Augustus Volney Waller (1816–1870) was born in Kent and worked as a general practitioner in Kensington. He worked at microscopy and published two papers in Philosophical Transactions of the Royal Society, the second of which was on “degeneration in the peripheral part of a nerve,” now known as Wallerian degeneration. Sir John Russell Reynolds (1828–1896) published Diagnosis of Diseases of the Brain, Spinal Cord and Nerves in 1855, when aged 27: it was one of the first systemic treatises in English, which presented the state of clinical neurology before the National Hospital opened in 1860. In his book, he gave a clinical classification of neurological disorders rather than a physiological or anatomical one. He recognized that convulsions could occur throughout life without brain abnormality, which he called epilepsy, whereas those who had proven brain lesions were regarded as having epileptiform or epileptoid attacks. In all cases of convulsions, there were major or minor disturbances which the French called, respectively, haut mal or petit mal. He distinguished between brain tumors, where there is intense headache, paralyses, and convulsions, and chronic meningitis, where the headache is less marked but there is irregular fever, and wrote that with chronic softening there is no pain, but progressive failure of intelligence and mobility. Of the sedatives for epilepsy, he began with opium, which was popular at that time, but then tried a variety of other drugs including belladonna and stramonium; chloroform was used in the actual attacks, i.e., in status epilepticus. He attempted to distinguish epilepsy from hysteria.

THE NATIONAL HOSPITAL, QUEEN SQUARE British neurology arose in the middle of the 19th century, largely with the establishment in 1858 of the National Hospital for the Paralysed and Epileptic in Queen Square, London. (McHenry, 1969, p. 303) Until the end of the 18th century there were no special hospitals in Britain for specific diseases, other than for leprosy, insanity, or consumption. At that time, little was known about the functions of the nervous system or its disorders, and even less attention was paid to the cerebral cortex. Although a unilateral paralysis of the limbs was recognized as due to a stroke or head injury, only injuries of the peripheral nerves, because of their anatomy, were fully recognized. This was the period

AN HISTORICAL OVERVIEW when the National Hospital became the neurological hospital where such luminaries as John Hughlings Jackson, William Gowers, David Ferrier, and later Kinnier Wilson and Gordon Holmes worked. It was also the period when neurological journals appeared, the first being Journal of Nervous and Mental Disease (1876) and Brain (1878). The first physicians appointed to the National Hospital in December 1859 were Jabez Ramskill and Charles Edouard Brown-Se´quard. Ramskill recommended that the treatment of epilepsy, his special interest, should be included as part of the hospital’s work, and his case notes from 1863 to 1865 showed that, of the 354 records, roughly 75% had epilepsy, and 10% had right hemiplegia and aphasia. The first reported case of potassium bromide for the treatment of epilepsy was by Ramskill (1863), after which it became the recommended treatment. In his book on the National Hospital, Gordon Holmes (1954) stated that an electrical apparatus was “urgently requested,” and an electrical room was established in 1867, which eventually contained “every variety and perfection of scientific apparatus without parallel in Europe.” Still, the staff were not uniformly persuaded of its usefulness. Although Russell Reynolds published a book titled Lectures on the Clinical Uses of Electricity (1871), his more eminent colleague William Gowers had little good to say of electrotherapy, finding it unacceptable in tabes dorsalis, muscular atrophy, chorea, writer’s cramp, migraine, and paralysis agitans. In contrast, he found it useful in hysterical paralysis, of considerable value in neuralgia, and cautiously justified in the rehabilitation of poliomyelitis. Ramskill’s reports showed that he distinguished between speech, language, articulation, voice, and ideation. Before February 1864, there was no reference in the English literature to Broca’s work in 1861 on cortical lesions and loss of speech (Lorch, 2004). Ramskill was one of the first British physicians to use the term aphemia for loss of speech, which he consistently used as a diagnostic category. After a short report appeared in the British Medical Journal, Trousseau suggested the term aphasia instead of aphemia on philological grounds. Because Brown-Se´quard preferred to spend his time on animal experiments and often complained of ill-health, Ramskill was over-burdened with patients. When Ramskill requested an assistant, Hughlings Jackson was appointed. The National Hospital was the first to be established for the care and cure of neurological disorders, and it became traditional that consultant members of the staff also had appointments at general hospitals. In this way nearly all the teaching hospitals of London were represented on the staff of the

OF BRITISH NEUROLOGY 621 National Hospital, but this changed when most teaching hospitals developed their own specialized departments of neurology. Thomas Grainger Stewart (1860–1930) published a paper on multiple neuritis in 1881 with the title, “On Paralysis of Hands and Feet from Disease of the Nerves.” He reported three cases, one of which had been autopsied, and considered the clinical picture distinctive in “that sensory symptoms preceded the motor, the tendon reflexes were lost, the muscles wasted, and the skin of the hands and feet was thin and glossy.” The process may take weeks or perhaps months and improvement usually begins in the arms, but there can be recurrences. Grainger Stewart’s paper was the first in which peripheral neuropathy was so clearly recognized in the English-speaking world. The examination of reflexes was introduced in 1878 by Grainger Stewart and Farquar Buzzard, after which the importance of the tendon reflexes became increasingly recognized. Sir James Risien Russell (1861–1939), who was born in British Guiana of mixed racial stock, studied medicine at Edinburgh and on the continent, but then became affiliated with the National Hospital and University College Hospital. He collaborated with Victor Horsley on anatomical researches, often in Horsley’s Cavendish Square house. They worked on the cerebellum and its connections, the brachial and lumbosacral plexuses, and the cortical representation of the larynx. He also published on the variations of the knee jerk. James Collier (1870–1935) worked with Hughlings Jackson on respiratory movements in chloroform anesthesia, with Kinnier Wilson on amyotonia congenita, and with Gowers on what he described as “ataxic paraplegia.” The definitive description of subacute combined degeneration of the spinal cord was by Collier (with Risien Russell and Batten in 1900). We owe him the idea of false localizing signs in brain tumors and probably the term motor neurone disease, words with which British neurologists embrace both amyotrophic lateral sclerosis and progressive muscular atrophy. The lateral spinothalamic tract was traced to its termination in the thalamus, initially by Frederick Mott and later by Collier and Buzzard (Denny-Brown, 1953). Robert Foster Kennedy (1884–1952) studied medicine at Queen’s College, Belfast, but unable to find a post in the UK, he went to the recently established Neurological Institute in New York, the first neurological center in the United States. This institute moved later to the Bellevue Hospital and is now part of Columbia University Medical School. Eighteen months later he published “Retrobulbar neuritis as an exact diagnostic sign of certain tumors and abscesses in the frontal lobes” in the American Journal of Medical

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Sciences. An even more important article was published in 1911 in JAMA, where he showed that anosmia, ipsilateral optic atrophy, and contralateral papilloedema was indicative of a frontal lobe tumor – the Foster Kennedy Syndrome.

THE LATTER HALF OF THE 19TH CENTURY English neurology continued to flourish with more specialists entering the field, e.g., Charles Edward Beevor (1854–1908), who gave a more precise distribution of the blood supply to the brain, but is perhaps best known today for Beevor’s sign, which shows paralysis of the abdominal rectus muscles. Charles Edouard Brown-Se´quard (1817–1894), mentioned above, is now best remembered for his eponymous syndrome following hemisection of the spinal cord. Born in Mauritius, he qualified as a doctor in Paris in 1846, with his doctoral thesis on the physiology of the spinal cord, which showed that perception of pain and temperature are not dependent on the dorsal columns, as Charles Bell had thought. Brown-Se´quard also proved that the pathways for pain and those for touch are separate in the spinal cord. In 1852, he wrote on the quantification of sensory deficits. It was known that if two points of a compass were applied at the same time to the skin, whether one or two points were felt depended on (1) the distance between the two points, and (2) the region of application of the points. He recognized that two-point discrimination could be used to measure the degree and changes of sensory loss over time. He found that when the spinal cord was transected, pain is not appreciated below the site of the lesion, and that lateral hemitransection causes contralateral sensory loss. In addition to this interest in the physiology of the nervous system, he founded three journals. Invited to join the staff of the newly opened National Hospital, Queen Square, he stayed there for less than 4 years. He spent the rest of his life studying epilepsy, and was one of the first to treat the condition with bromides. He stressed that neurological symptoms could be due to either abnormal cerebral activity or functional loss in a brain region, a concept new at that time. He was also one of the first to describe what is now known as writer’s cramp and recognized the difficulty in its treatment, pointing out the need to eliminate repetitive movements. At the age of 61 he was appointed to the Chair of Experimental Medicine of the Colle`ge de France, which had been his life-long ambition. Samuel Wilks (1824–1911) wrote Lectures on Diseases of the Nervous System in 1878, which for a time was the standard source for medical students. Part I

concerns aphasia, apoplexy, and other brain diseases; Part II deals with the spinal cord; Part III with functional and general diseases; and Part IV with nerves (including headaches) and general remarks on electricity. Wilks had earlier made his name in pathology, publishing Lectures on Pathological Anatomy in 1869 with subsequent editions in 1875 (with Moxon) and 1887. In 1868, he wrote a paper on “Drunkards’ or alcoholic paraplegia,” but did not ascribe this to peripheral neuritis, and thought it a disease of the spinal cord. He was the first to show that syphilis affects the internal organs of the body and not just the exterior. Wilks published observations on the pathology of some nervous diseases in Guy’s Hospital Reports in 1866, and in 1877 reported there on cerebritis, hysteria, and bulbar paralysis. Edward Liveing (1832–1919) wrote one of the first clinical books on migraine in 1873 entitled On Megrim and Sick-headache, and Some Allied Disorders. A Contribution to the Pathogenesis of Nerve-storms. His thesis was that nerve-storms are caused by transient paroxysms of the normal nervous system (Pearce, 1999). Hughlings Jackson (1835–1911) – the Father of British Neurology (Fig. 39.2) – was born in Yorkshire and worked at the York Dispensary under Dr. Thomas Laycock, who was particularly interested in the nervous

Fig. 39.2. Hughlings Jackson (1835–1911).

AN HISTORICAL OVERVIEW system. Jackson completed his medical education at St. Bartholomews Hospital, London, and became absorbed with neuro-ophthalmology, stating it was “the luckiest thing in my medical life that I began the scientific study of my profession at an ophthalmic hospital.” Not long after beginning his clinical work, he used the ophthalmoscope (invented by Helmholtz in 1871) and recommended its use with neurological patients. Although he wrote on aphasia, headache, optic neuritis, neurosyphilis, stroke, vertigo, and chorea, Jackson was best known for his writings on epilepsy (especially focal or Jacksonian attacks). His work on epilepsy can be divided into three periods: from 1861 to 1863, it became a focus of interest; from 1864 to 1870 he worked on A Study on Convulsions (1870); and the period after this was for revision, elaboration and broadening of judgment (Temkin, 1971, p. 329). The clinical studies between 1861 and 1870 of these attacks showed that they occur in those areas with the largest cortical representations, e.g., the face or hand. The experiments of Ferrier and others stimulating the cortex with an electric current causing epilepsy convinced Jackson (1870) that the cerebral convolutions are the true source of unilateral convulsions, writing: “A convulsion is but a symptom, and implies only that there is an occasional, an excessive, and a disorderly discharge of nerve tissue on muscles. This discharge occurs in all degrees; it occurs with all sorts of conditions of ill-health, at all ages, and under innumerable circumstances.” Jackson pointed out that epilepsy and “epileptiform seizures” differed only in degree. Genuine epilepsy was associated with loss of consciousness, whilst unilateral motor convulsions were considered as “epileptiform seizures.” Jackson’s contribution was to appreciate that generalized convulsions and “epileptiform” seizures both depend on where the discharges start and how much cortex is involved. He described the “march” of the seizure and how some patients exhibit dreamy states. His definition, “Epilepsy is the name for occasional, sudden, excessive, rapid and local discharges of grey matter”, was perhaps one of the greatest contributions ever made to the study of epilepsy, because it stressed the role of the cortex (Arts, 1996, pp. X–VII). Hughlings Jackson’s contributions on aphasia were also important for neurology. In 1861, Broca had shown that lesions of the inferior frontal lobe can affect spoken language; by 1865, he realized such a lesion is nearly always on the left side. In 1864, Jackson associated loss of speech with right hemiplegia, implicating the left middle cerebral artery and the cerebral cortex, and maintaining that the defect is not one of talking but of language. Patients with Broca’s aphasia, he believed, know what they want to say but cannot

OF BRITISH NEUROLOGY 623 say it, i.e., they cannot translate inner language into speech. Jackson noted that aphasic patients also have difficulties in writing and using sign language, and he separated intellectual from emotional speech – Broca’s aphasia being loss of the former, with recurring utterances being emotional. Until 1875, it was thought that the motor pathway begins in the corpus striatum and not the cerebral cortex, but Jackson noted somatotopic representation, firstly in the corpus striatum and then in the motor cortex, and finally in the entire nervous system with higher levels controlling the lower. He proposed three evolutionary levels of sensorimotor mechanisms: the lowest being the spinal cord, medulla, and pons; the middle being the Rolandic region; and the highest in the prefrontal lobes. This reflected an evolution from automatic to purposive behaviors, with dissolution or failure tending to occur in reverse order. Each of these levels could have “negative” symptoms, e.g., loss of movement, speech, or consciousness, and “positive” symptoms, such as abnormal movements and increased reflexes, due to loss of higher control (York, 1999). Jackson had a unique way of handling questions of symptoms, cerebral localization and the hierarchical levels of the nervous system. He gave the name concomitance to the relationship of the mind to the brain where both exist in parallel but do not influence each other. He stated, “There is no physiology of the mind any more than there is psychology of the nervous system.” Whereas previously cerebral localization applied to psychological processes like volition or imagination, he localized only motor and sensory phenomena, i.e., physiological processes. It has been argued that this was the real beginning of neurology proper (Arts, 1996, p. VIII). Jackson published no books, but some 300 papers, many in obscure journals, and with a style that does not make for easy reading. His central themes were cerebral localization, an understanding of unilateral disease (unilateral seizures, hemiplegia, aphasia, and hemichorea), and evolution of the nervous system – themes that are still important to neurologists today. Sir William Broadbent (1835–1907) stated that Jackson was “acknowledged as a chief amongst neurologists . . . he has been a pioneer in nervous physiology and pathology, both in methods and results, has continuously raised our ideas of nervous action to a higher plane of thought . . . Bringing to bear . . . the speculations of evolutionary physiology.” In the 19th century few neurologists attempted to understand aphasia, but it was the century of anatomico-clinical correlations, and the concept of Broca’s area was easily understood. Interested in speech, Broadbent gave the third Hughlings Jackson Lecture on

624 F.C. ROSE aphasia (Jackson had given the first) and was one of the (1880), and Aphasia and Other Speech Defects (1898). first to report on word-blindness (McHenry, 1969, p. 120). He thought there were discrete areas of the brain for Sir David Ferrier (1843–1928) studied medicine at reading, writing, and understanding the spoken word, the University of Edinburgh. After qualifying as a docdescribing patients with word blindness and word deaftor in 1868, he did research on the structure of the corness. He was given priority for these terms by Head, pora quadrigemina, for which he obtained his MD but was criticized as a “diagram maker” because he degree with gold medal (Gibson, 1982). While visiting was in favor of localized speech regions, such as Brothe West Riding Asylum in 1873, Ferrier, then the Proca’s and Wernicke’s areas. Bastian coined the term fessor of Forensic Medicine at King’s College Hospikinesthesia to describe sensations stemming from tal, London, discussed cerebral localization with the movements, which influenced Sherrington. Bastian Asylum’s Director, Dr. James Crichton-Browne, and showed that complete section of the spinal cord prowas consequently invited to work in the new laboraduced areflexia and hypotonia below the level of the tories. His animal experiments used the relatively recent section (Bastian’s law), and described the anterior technique of stimulating the brain with an electrical spino-cerebellar tract which later became known as current, following up on the dog research of Fritsch Gowers’ tract with the latter’s more complete descripand Hitzig, who excited the motor cortex with direct galtion (York, 2003). vanic current. Ferrier used an alternating (faradic) curSir William Gowers (1845–1915) was appointed the rent, which produced more discrete effects, and first medical registrar at the National Hospital in 1870, studied movement-related brain areas after the animals where he became physician 2 years later. He had been had recovered from anesthesia. He published the assistant to Hughlings Jackson but, although indebted results of his first stimulation and ablation experiments to him, his approach was more analytical, and described in 1873, in the West Riding Lunatic Asylum Medical some of the earliest cases of many neurological Reports, providing support for Jackson’s theory of cordisorders, including: vasovagal attacks, musicogenic epitical epilepsy. He went on to delineate the motor and lepsy, dystrophia myotonica, and palatal myoclonus. sensory areas in monkeys, while associating the frontal He introduced the term knee-jerk, and his popular regions anterior to the motor cortex with higher funcbook, A Manual of Diseases of the Nervous System tions (e.g., attention). At the International Medical (1886–1888), largely illustrated by himself, became the Congress of 1881 in London, a historical debate “Bible of Neurology.” In it, he clearly described the occurred between Ferrier and Goltz on cortical localistatus of the neurological examination, and dealt with zation, from which the former emerged victorious. a variety of topics, from the spinal cord tumors to aphaA chair of neuropathology was created for him in sia, admitting the latter was a complicated subject. 1889 at the medical school of King’s College, and he Another of Gowers’ strong interests was epilepsy, became Physician to West London Hospital, the Hospiand he wrote two important books on this subject: Epital for Epilepsy and Paralysis, Maida Vale, and assislepsy and Other Convulsive Disorders (1881) and The tant physician to King’s College Hospital, and in 1874 Borderland of Epilepsy (1907). His other published to the National Hospital. His 1876 monograph, The books included Pseudohypertrophic Muscular DystroFunctions of the Brain, dedicated to Hughlings Jackphy (1879), Medical Ophthalmoscopy (1879), and Diagson, gave a comprehensive account of what was then nosis of Diseases of the Brain (1887). known of the functional neuroanatomy of the brain At the end of the 19th century, pediatric cases were and was written in a modern style (Young, 1990). His referred to Gowers at the National Hospital from the next book, The Localisation of Cerebral Disease, came Hospital for Sick Children, which was just around the out in 1878 and was even more clinical. That year, he corner in Great Ormond Street. His first paper on musalso joined three other physicians to start the journal cular dystrophy in a boy who died aged 14 was in 1874 Brain. Ferrier’s work was instrumental in persuading and was co-authored by J. Lockhart Clarke (1817–1880), Rickman Godlee to remove a brain tumor in 1884 who had worked on the spinal cord. (Greenblatt, 1997), and Godlee praised Ferrier for In 1879, Gowers gave a series of lectures at the opening the field of neurosurgery. National Hospital that included, besides his personal Henry Charlton Bastian (1837–1915) was appointed cases of pseudohypertrophic muscular paralysis, now physician to the Hospital for the Epileptic and Paralknown as Duchenne’s muscular atrophy, another 139 ysed (later the National Hospital, Queen Square) in previously published cases. Onset of the disease is 1868, and he wrote several neurological sections for usually before the age of 6 years; standing is lost Russell Reynolds’ A System of Medicine. He published between 10 and 12 years; and death is from 14 to 18 years. On the Various Forms of Loss of Speech in Cerebral Muscle enlargement is most often in the calves, but Disorders (1869), The Brain as an Organ of Mind could involve glutei, deltoids, and tongue. The proximal

AN HISTORICAL OVERVIEW limb muscles are affected before distal parts, and the waddling gait results from gluteal weakness. Of the cases reviewed, the majority were males and nearly half of all cases were familial, inheritance being through the maternal side. He thought the disease was one of the most interesting but at the same time particularly sad: interesting on account of its peculiar features and mysterious nature; sad because physicians cannot influence its course, and because it is a disease of early life (Abroms, 1990). It was here that he described Gowers’ sign, “whereby a child with proximal weakness in the lower extremities used the upper extremities placed on the knees and thighs to get himself upright.” This sign of rising from a seated position in pelvic girdle weakness had been described by Bell and by Duchenne. Walter Holbrook Gaskell (1847–1914) and John Newport Langley (1852–1925) were two neuroscientists who worked in Cambridge on the autonomic nervous system, with Gaskell laying its histological foundation (Kuntz, 1953). Langley introduced the terms pre-ganglionic and ganglionic (1893), sympathetic system (1898), and parasympathetic system (1905) (Windle, 1953, pp. 142–145). Sir Frederick Mott (1853–1926) studied dorsal root sections in monkeys, thalamic connections of the medial lemniscus, and the projection to both sides of the brain from one ear, most of his important work taking place in London. In 1913 he demonstrated, for the first time in Britain, spirochaetes in the brains of patients with general paralysis of the insane. He was a friend of Maudsley, who agreed to bequeath a large sum of money to endow a hospital for the psychoneuroses, but it was some time before the Maudsley Hospital was built at Denmark Hill, which then became the headquarters of the pathological services for all the London mental hospitals. Mott retired from the Maudsley in 1923, but continued his teaching and research in Birmingham until his death (Baker and Golla, 1953, pp. 340–342).

THE 20TH CENTURY Sir Charles Scott Sherrington (1857–1952) shared the 1952 Nobel Prize in Physiology with Lord Adrian, for their work on the central nervous system. In 1891, he followed Victor Horsley as Professor and Superintendent of the Brown Institute for Advanced Physiological and Pathological Research in South London. Four years later he left for Liverpool, where he was professor of physiology for 18 years. He studied reflexes and used the terms reflex and final common path. Sherrington also did cortical mapping and introduced the term decerebrate rigidity. In 1905, he was invited to lecture at Yale, and his lectures were published the following year as The Integrative Action of the Nervous System

OF BRITISH NEUROLOGY 625 – a classic of neurophysiology that showed how simple circuits could combine to account for complex behaviors, such as walking without stumbling. In 1913, he went to Oxford to become professor of physiology, and continued to study the organization of the nervous system well into his 90s (Gibson, 2001). A lover and collector of books, he also wrote on Jean Fernel, a leading figure in Renaissance physiology and medicine. Sir Henry Head (1861–1940) was born in London and attended Cambridge. After qualifying as a doctor from University College Hospital, he wrote his MD thesis in 1892 on disturbance of sensation, which led him to study herpes zoster, a disease characterized by well-defined rashes, which allowed him to map the human dermatomes. In 1898 he was appointed to the consultant staff of the London Hospital, and in 1903, with the help of Rivers, he studied cutaneous sensation on himself by cutting a branch of his radial nerve. Their classification of protopathic (e.g., dull pain, temperature) and epicritic (e.g., finely localized touch) sensations is notable, though no longer in vogue. In 1911, he published with Gordon Holmes on cerebral sensory disturbances; he later worked with brain-injured soldiers of World War I and understood their language problems from the writings of Hughlings Jackson (Rose, 2006). Head’s contributions to spinal reflexes and aphasia were significant, and his two-volume Aphasia and kindred disorders of speech, published in 1926, is considered a classic in the field. Head edited Brain from 1910 to 1925, when he also retired from the London Hospital, suffering from Parkinson’s disease (Gardner-Thorpe, 2001). Frederick Eustace Batten (1865–1918) was one of the first physicians to specialize in pediatric neurology and is now considered to be one of its founding fathers (Dyken, 2002). He was associated with the Hospital for Sick Children in Great Ormond Street, London, and was a pathologist at the National Hospital. His contributions to adult neurology included a paper in 1900 on subacute combined degeneration of the spinal cord (with Risien Russell and Collier). He also wrote on multiple sclerosis and may have been the first to describe dystrophia myotonica, which he called myotonia atrophica. He was an editor of Garrod’s Textbook on Diseases of Children (1913) and published over 100 articles in that field. He described progressive spinal muscular atrophy one year after Werdnig (1891), and one year before Hoffman’s (1893) more complete description. Sir Grafton Elliot Smith (1871–1937) and Alfred Walter Campbell (1868–1937) were both born in Australia. Smith qualified as a doctor from the University of Sydney in 1892 and came to Cambridge in 1896 to continue his research into cerebral morphology. His main work was on comparative neuroanatomy, with particular attention to the cortical fissures, but he

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maintained an interest in speech and binocular vision. He held the chair of anatomy in Manchester, but then went to University College, London, where he founded the Institute of Anatomy (Walker, 1953). Campbell qualified as a doctor from Edinburgh, obtaining the gold medal for his MD thesis on “The pathology of alcoholic insanity.” He worked for 13 years in the pathology laboratory of Rainhill Asylum (near Liverpool) where, with the help of Sir Charles Sherrington, he studied cortical cytoarchitectonics, leading to the publication of his Histological Studies on the Localisation of Cerebral Function (1905), a work that was extended by Elliot Smith (1907). He also worked with Henry Head on the nerve roots in herpes zoster (Von Bonin, 1953, pp. 16–17). Gordon Holmes (1876–1965) attended Trinity College, Dublin, won a scholarship to study neuroanatomy in Germany, and became house physician at the National Hospital to Hughlings Jackson, who taught him careful neurological examination, including ophthalmoscopy. One of his main interests was neuro-ophthalmology (papilloedema, familial optic atrophy), but he also worked with Henry Head on cortical sensory losses (Rose, 2003c). During World War I, he became consultant neurologist to the British Armies in France, after having worked on trauma to the central nervous system. He reported the effect of gunshot wounds on the cerebellum in 70 soldiers and evaluated the effect of occipital trauma on vision. It was with this experience that he showed the retinotopic relationship to the visual cortex. S.A. Kinnier Wilson (1878–1937) studied medicine in Edinburgh and was appointed resident to Professor Byrom Bramwell, who was particularly interested in nervous diseases. Kinnier Wilson went to the National Hospital, and studied patients with extrapyramidal rigidity, involuntary movements, and dysarthria; he followed these patients until they died, and was able to obtain post-mortem results, which confirmed that the caudate nuclei had softening and that there was lobular cirrhosis of the liver. In 1912 he published a paper in Brain under the title of Progressive Lenticular Degeneration. His two-volume neurological textbook was published in 1940, 2 years after his death (Westermark, 1993).

CONCLUSIONS The deaths of Head (1861–1940) and Holmes (1876– 1966) “marked the close of an era in British neurology that had its acme before World War I.” Head’s period was closely associated with the peak of neurology in England, which “began with Hughlings Jackson and Gowers . . . and ended with Sir Francis Walshe, Sir

Charles Symonds and Lord Brain” (McHenry, 1969, pp. 325–326). The paucity of neurologists in Great Britain had once led to the statement, “The United Kingdom must have one of the worst neurology services in the Western World.” It was only in the 19th century that physicians began to specialize in neurological disorders, and the great British names of neurology identified the many diseases that made up the subject. The most important, but not all, of those people have been noted in this chapter, but perhaps the most significant figure was Hughlings Jackson, the Father of Neurology, who finalised a clinical examination of the nervous system that is now used by neurologists throughout the world (Koehler, 1999, p. 62). The type of patients seen by neurologists has changed significantly between the founding of the Association of British Neurologists in 1933 and recent times. Thus, the modern neurologist rarely sees general paresis of the insane, tabes, syphilitic ocular palsies, Pott’s disease, subacute combined degeneration, poliomyelitis, Sydenham’s chorea, diphtheritic palsies, and various other disorders. No doubt this list of now rare diseases will lengthen as the neurological researches reported in this chapter continue.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 40

History of neurology in France FRANC¸OIS CLARAC 1 * AND FRANC¸OIS BOLLER 2 CNRS, P3M (Plasticité et Physio-Pathologie de la Motricité), Marseille, France 2 INSERM, Marseille and Paris, France, and Bethesda, MD, USA.

1

INTRODUCTION It is often thought that neurology in France started in the middle to late 19th century, thanks to the work of Broca, Charcot and others. This is true to some extent, but obviously the accomplishments of these men were preceded by a long evolution in medical thinking. The first part of this chapter will deal with that aspect of history. We will then present the most relevant history of the 19th and early 20th centuries and will conclude with a presentation of more recent personalities as well as historical and political events that have shaped today’s neurology in France. The history of medicine and of neurology in France is tied to the development of the universities, the importance of the Church and of religion in general, and its peculiar geographical location. France is close not only to the “Latin” world (Italy and Spain), but also to the Muslim, Anglo-Saxon and German worlds. For many centuries, France also had (and to some extent still has) a very high degree of centralization with every aspect of society revolving around the capital, Paris, located at the strategic center of the “Hexagone” as France is referred to at times. For instance, the French Neurological Society was long called the Socie´te´ Neurologique de Paris and only became the Socie´te´ Franc¸aise de Neurologie in 1949. In medieval times, however, universities were somehow an exception to this extreme centralization. This is because universities were municipal entities and therefore tended to be highly democratic institutions of learning. The University of Paris, which was founded in the 12th or 13th century, was long the main cultural pole of France, but for many years, medicine was more developed in Montpellier (Bariety and Coury, 1963). In turn, Strasbourg had a very different history of medical

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development (He´ran, 1997). The history of neurology in Montpellier, Strasbourg and other major universities outside of Paris will be briefly outlined in later sections.

EARLY DEVELOPMENT OF NEUROLOGY Origins How much neurology was there in the Middle Ages and subsequent years? Certainly during those years, the training of regular physicians hardly included any teaching of neurology in the modern sense. What was known about the brain concerned mainly its cavities (the ventricles). For this reason, infections were referred to for a long time as hydrocephalus rather than meningitis (see Ch. 28). Teaching consisted mainly of reading and preparing commentaries on the works of Hippocrates, Aristotle and Galen with some influences from the works of the Islamic physicians and philosophers such as Ibn Sina (Avicenna) and Ibn Rushd (Averroes). After having successfully demonstrated knowledge of the works of these authors, one could aspire to the triumph of the doctorate. A black hat, a red foulard, a golden belt and ring consecrated a “practitioner,” whose medical armamentarium consisted mainly of purges and bloodletting. There may not have been doctors who specialized in neurology, but there were certainly many patients with neurological symptoms. Beside the “usual” victims of strokes, tumors, head injuries and other common neurological diseases, neurological patients included the victims of some of the great epidemics that ravaged Europe during these years. This included leprosy, which is often accompanied by neurological symptoms that affect mainly the peripheral nervous system. Syphilis, which appeared in a devastating fashion after

Correspondence to: Franc¸ois Clarac, Directeur de Recherche Eme´rite, CNRS, P3M (Plasticite´ et Physio-Pathologie de la Motricite´), 31 Chemin Joseph Aiguier, 13402 Marseille, Cedex 20, France. E-mail: [email protected], Tel: 00-33-491164139, Fax: 00-33-491775084.

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the 16th century, probably was not usually accompanied by striking neurological symptoms because patients often died before the development of neurosyphilis, which typically occurs in the tertiary stage of the disease, 5–30 years after infection. Ergotism (long-term ergot poisoning) was once a common condition resulting from eating rye bread contaminated by Claviceps purpurea, a fungus containing toxic alkaloids. The condition occurred in epidemic proportions in the Middle Ages and was known by a number of names, including ignis sacer (the holy fire), Devil’s curse. Ergotism can be gangrenous or convulsive. The latter is characterized by a number of symptoms including crawling sensations in the skin, tingling in the fingers, vertigo, tinnitus, headaches, disturbances in sensation, hallucination, painful muscular contractions leading to epileptiform convulsions, vomiting, and diarrhea. There are also mental disturbances, such as mania, melancholia, psychosis, and delirium. In France the condition was known as mal des ardents (burning disease) or feu de Saint Antoine (St. Anthony’s fire). Similarly to what happened in Salem (see Miller’s The Crucible and Raymond Rouleau’s 1956 film The Witches of Salem), some ergotism victims may have been considered bewitched by the devil and barbarously punished. The epidemics of ergotism subsided when country people started eating wheaten flour and treating their crops against fungi (Clarac and Ternaux 2008). One of the first persons in France to actively deal with the brain and the nerves was not a physician but a barber-surgeon, Ambroise Pare´ (1517–1590), who practiced in and around the battlefields as well as in Paris. He is best known for having introduced artificial limbs, but he also treated traumatic brain injuries, instructing surgeons to find and remove bone fragments that might have been driven into the brain. His fame was such that he was called to attend King Henry II who had been mortally wounded in a duel (the other “consultant” was Vesalius) and was later named surgeon to King Charles IX. One of the major figures of the 17th century, Rene´ Descartes (1596–1650), introduced in his writings his dualistic vision of brain functions: higher rational processes derive from the soul while others, like a machine, follow the principles of physics (Bennet and Hacker, 2002). The “mechanicist” description of the human body attributes a crucial role to the pineal gland (the epiphysis), considered to be the interface between the physical ensemble and the soul in humans (Clarac, 2005a, b). When death comes, the machine disappears but the soul remains, albeit only for humans (Ochs, 2004). Neurology during that period is described in detail elsewhere (see Ch. 8).

A few years after Descartes, Franc¸ois Pourfour du Petit, anatomist, physiologist, ophthalmologist and surgeon (1664–1741), attended medical school in Montpellier, graduating in 1690. He then moved to Paris where he attended lectures at the Charite´ Hospital (now known as Hoˆpital Broussais-La Charite´) and at the Jardin du Roi. This botanical garden (now known as Jardin des Plantes) had been created in 1635, following those already existing in places such as St. Gall in Switzerland, Pisa, Padua and other Italian universities, as well as in Montpellier. It was mainly intended for the education of physicians and apothecaries. After his studies in Paris, Franc¸ois Pourfour du Petit served for many years as physician in the armies of Louis XIV and installed improvised “laboratories” near the battlefields where he performed dissections. He was particularly interested in the relationship between the brain and the spinal cord in humans and in animals (Barbara, 2006). He demonstrated the pyramidal tract crossing. He also described (in 1727) an oculopupillary syndrome due to an irritation of the sympathetic nervous system. It consists of mydriasis, increased intraocular pressure, exophthalmos and widening of the palpebral fissure. It is the mirror image of the Bernard–Horner syndrome (see below). Julien Offray de La Mettrie (1709–1751) was a French physician and philosopher, the earliest of the materialist writers of the Enlightenment. He was born at Saint Malo. After studying theology in the Jansenist schools for some years, he decided to enter the medical profession. In 1733 he went to Leiden to study under Boerhaave, and in 1742 returned to Paris, where he was appointed surgeon to the guards. During an attack of fever he made observations on himself with reference to the action of quickened circulation upon thought, which led him to the conclusion that psychic phenomena could be accounted for by organic changes in the brain and nervous system (Jeannerod, 1983). This conclusion was published in his earliest philosophical work, the Histoire naturelle de l’âme (Natural history of the soul, 1745). So great was the outcry caused by its publication that de La Mettrie was forced to leave France. He found refuge in Prussia where King Frederic the Great awarded him a position at the court and a pension. Jean-Paul Marat (1743–1793) is well known for having been an advocate of violent measures that helped launch the Reign of Terror during the French Revolution, and for having been stabbed to death in his bathtub by Charlotte Corday. It is less known that he was a physician and an ophthalmologist and that he wrote, in 1784, a Mémoire sur l’electricité médicale (Essay on medical electricity). His “electricity bottle” was used for patients affected by pain, paralysis, and even some psychopathies, and he based his cures on animal research.

HISTORY OF NEUROLOGY IN FRANCE 631 The idea of relating electricity to nervous phenomchild” from the Aveyron, a boy who had been admitted ena can be traced to 18th-century research on so-called to the institute for the deaf and dumb but was later electric fish, especially the torpedo and eel of Surinam, educated at Itard’s own home. His work in this domain though the application of the idea to frogs, barnyard was immortalized in a 1970 film (L’Enfant Sauvage – animals, and humans is usually associated with Luigi The Wild Child) directed by Franc¸ois Truffaut who Galvani (1737–1798), who synthesized what was then also plays the role of Itard. Itard has also been recogknown and added some experiments of his own at nized for his description of what would later be called the end of the 18th century (Boller et al., 1989). As Gilles de la Tourette’s syndrome (Lajonchere et al., for the medical applications of electricity, they began 1996). in the mid-1740s and were carefully evaluated by the Precursors of scientific medicine Abbe´ Nollet (1700–1770) and Benjamin Franklin (1706–1790), and enthusiastically promoted by John THE FRENCH REVOLUTION AND ITS Wesley (1704–1791), among others (Malony, 2005; MEDICAL CONSEQUENCES Bertucci, 2006; Finger, 2006a, b). In the 19th century, The medical and scientific advances that occurred in Armand Duchenne de Boulogne would create new the late-18th century and in the early-19th century were interest in the uses of medical electricity (see below). due to the concurrence of a robust scientific philosoThe family of Fe´lix Vicq-d’Azyr (1746–1794) was phy, the reorganization of hospitals, and the simultafrom Normandy, but he came to Paris and accomneous presence of exceptional men. The first years of plished brilliant medical studies. Like Pourfour du the French Revolution (1789–1793) had been cataPetit, he attended the Jardin du Roi where, thanks to strophic for medical and scientific advances because his teachers, the young Vicq-d’Azyr acquired a definite most existing teaching institutions were suppressed. taste for anatomy. He started teaching anatomy in However, out of the chaos, new and original medical Paris, but for reasons of poor health went back to Norand scientific thinking appeared, stimulated by the mandy, where he started studying the nervous system writing of philosophers, the importance of the Encycloof fish. He mapped out the comparative anatomy of pedia movement, and the intellectual liberalism that different organs in relation to other fish species and favored the emergence of new ideas. to other vertebrates. He was made a member of the We have already mentioned the creation of the Acade´mie des Sciences in 1774 and later was elected E´coles de Sante´. These years also saw the creation of to the even more prestigious Acade´mie Franc¸aise. the externat and internat (externship and internship, Vicq-d’Azyr’s treatise on comparative anatomy, pubsee Yakovlev, 1970). This re-organization ensured that, lished in 1786, was a landmark, thanks in part to the for the first time, medical students had a privileged fact that he had introduced the use of alcohol to fix relationship with both the university and the hospital. CNS specimens. He identified for the first time many of Several great names of that time rethought Desthe cerebral convolutions, as well as several deep gray cartes’ dualism and proposed views closer to a strict nuclei such as the basal ganglia, the red nucleus, the locus materialism. Some were to influence the neurologists coeruleus and the substantia nigra. The mamillo-thalamic of later years. The most prominent is Pierre-Jean tract was also described by him and bears his name. His Cabanis (1757–1808). In 1795, aged only 38, he became great originality derived from his habit of approaching professor of hygiene at the Medical School of Paris anatomy from the perspective of comparative anatomy, and a few years later received the chair of legal always establishing correlations between human and animedicine and history of medicine. His principal work, mal structures and showing that comparable structures Rapports du Physique et du Moral de l’Homme (On are found in different species. the Relations between the Physical and Moral Aspects After the French Revolution, Vicq-d’Azyr proposed a of Man, (Cabanis, 1802)), is a sketch of physiological brand new plan for studying medicine. Hence the Conpsychology. For Cabanis, psychology is directly linked vention (the Revolutionary Parliament) voted the creation to biology and sensations (“sensibility”) are part of the of three E´coles de Sante´ (Schools of Health) in Paris, highest grade of life and the lowest of intelligence. All Strasbourg and Montpellier on 4 December 1794. As will the intellectual processes are evolved from sensibility, be seen, these E´coles very much shaped the future develand sensibility itself is a property of the nervous system. opment of medicine and particularly neurology. The soul is not an entity, but a faculty. Just as the Jean Marc Gaspard Itard (1774–1838), a French phystomach and intestines receive food and digest it, so sician and educationalist, gained recognition through the brain receives impressions, digests them, and his methods of education for children with mental produces thoughts. Hence, his famous sentence: “The retardation, which were based on training the senses. brain secretes thoughts like the liver secretes bile.” He published reports on the education of the “wild

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Cabanis’ work has recently been revisited by Turgeon and Whitaker (2000) who have argued that his general notion of nervous energy makes him one of the pioneers of modern neuropsychology. On a more anecdotal note, Cabanis has long been rumored to have provided poison to Condorcet, the philosopher, mathematician and political scientist who used it to commit suicide while in prison. The street leading to Sainte Anne Hospital in Paris is named after him.

THE

FIRST NEW GENERATION

The scientific approach to medicine known as the anatomo-clinical method was mainly championed by Laennec and Charcot. However, Xavier Bichat (1771–1802) may have been one of the first to use this method, while seeing patients and teaching medicine at the Hoˆtel Dieu, Paris. Bichat wrote about the nervous system, which he thought is divided in two parts: one is in charge of “organic life” and deals with all the asymmetrical viscera regulating metabolic functions. The other deals with “animal life” which includes control of symmetrical parts. The latter system regulates sensory motor functions and also memory, will and intelligence. Bichat believed that the two cerebral hemispheres must work harmoniously, and therefore thought that a unilateral brain lesion could produce more disruption than a bilateral one. A Paris hospital carries his name. Philippe Pinel (1745–1826), born in Toulouse, is regarded by many as the founder of modern psychiatry. A legend was to grow up about Pinel singlehandedly liberating the insane from their chains. This legend has been commemorated in paintings and prints. In fact Pinel condoned the use of threats and chains when other means failed. It was actually JeanBaptiste Pussin (1745–1811), a former patient who had become a sort of “physician assistant,” who replaced iron shackles with straitjackets at Biceˆtre in 1797, after Pinel had left for the Salpeˆtrie`re. Pinel followed Pussin’s example three years later, after bringing Pussin to the Salpeˆtrie`re. Pinel also studied patients with cognitive impairment and is often credited with introducing the term “dementia,” which was, however, used previously (Boller and Forbes, 1998). A statue of Pinel stands proudly at the main entrance of the Salpeˆtrie`re. Jean Etienne Esquirol (1772–1840) (Fig. 40.1) was also from Toulouse. He studied medicine there and in Montpellier. He came to Paris in 1799, started working at the Salpeˆtrie`re, and became Pinel’s favorite student. He is probably one of the most underrated medical authors in the field of dementia. His book Des Maladies Mentales (Esquirol, 1838) provided accurate descriptions of dementia and demented patients (pp. 44–75): “une affection ce´re´brale . . . caracte´rise´e par l’affaiblissement de la

Fig. 40.1. Jean Esquirol (1772–1840).

sensibilite´, de l’intelligence et de la volonte´” (a cerebral disease characterized by an enfeeblement of sensibility, intelligence and of the will) and “l’homme en de´mence est prive´ des biens dont il jouissait autrefois; c’est un riche devenu pauvre” (a demented man is deprived of the goods he used to enjoy; he is a wealthy person who has become poor). These definitions remain quite apt today. Esquirol also described patients with almond-shaped eyes, a flat nose, a thick tongue and mental retardation, an early description of what Down (1828–1896) was later to call “mongolism” (Roubertoux and Kerdelhue´, 2006).

The birth of scientific neurology PHRENOLOGY Scientific knowledge of the functions of various cortical areas is usually thought to have started with Franz Joseph Gall (1758–1828), because Immanuel Swedenborg’s earlier work in this area is too often ignored (Finger, 1994, 2000). Gall was born in the Grand Duchy of Baden (now part of Germany) and attended medical school first in Strasbourg and then in Vienna. Around 1800, Gall started elaborating the idea that some parts of the cerebrum might be related to specific features and attempted to connect physical and psychic functions to specific cerebral convolutions, that he

HISTORY OF NEUROLOGY IN FRANCE 633 thought were related, to the shape of the skull. The the aid of a light behind them, he could see six layers authorities considered his theories so materialistic and of alternate white and gray laminae. This was particuthus scandalous and contrary to religion that he was larly conspicuous posteriorly, where the line described forced to leave Austria. He came to Paris in 1802. by Francesco Gennari is also known as the white stripe Gall referred to his doctrine as “craniology” and of Baillarger. It corresponds to the internal granular later “organology,” and correlating “head bumps” with layer of the cerebral cortex. Baillarger also described functions was his main method, although he also relied the connections between white and gray matter in the on comparative anatomy, development, and occasioncerebral cortex (Haymaker and Schiller, 1953). ally on the study of brain-damaged individuals. It was Charles Ollivier d’Angers (1796–1845) may be conGall’s pupil, Johann Gaspar Spurzheim (1776–1832), sidered as one of the first to have described in some who popularized the term phrenology. Gall and Spurzdetail the pathology of the spinal cord. His teachers heim’s work gave them a fame which soon went included Dupuytren, Magendie and Bichat. In 1823, beyond France and even Europe since many physicians he presented a medical thesis dealing with the anatomy came from North America to study with them. and the pathology of the spinal cord. He continued to Phrenological theories were far from universally study these subjects for the rest of his life. He has been accepted. One of the most vocal opponents to Gall and credited for introducing the term “syringomyelia” and to phrenology was Pierre Flourens (1794–1867). After for the first clinical description of multiple sclerosis studying medicine in Montpellier, he went to Paris and (Grossmann et al., 2006). soon turned his attention to the nervous system. He pubTHE BIRTH OF EXPERIMENTAL MEDICINE lished a treatise titled Recherches expérimentales sur les propriétés et les fonctions du système nerveux dans les Franc¸ois Magendie (1783–1855) published in 1822 what animaux vertébrés (Experimental research on properties he thought was the first proof that there is a functional and functions of the nervous system in vertebrate anidivision of the spinal cord and the spinal roots into mals) (Flourens, 1824). His opposition to Gall rested on motor anterior and sensory posterior roots (Olmsted, ablation experiments that convinced him that all psychic 1944). This was bitterly disputed by Charles Bell functions are located in the cerebral hemispheres, which (1774–1842) who insisted that he had shown the same he considered as a single entity (Clarke and Jacyna, in a private pamphlet “submitted for the observation 1987). This concept of “equipotentiality” had originally of his friends” in 1811 and that Magendie had plagiarbeen entertained by Albrecht von Haller (1707–1777), ized him. It appears almost certain that Magendie among others. It has had adepts as recently as the 20th was not aware of Bell’s findings. History has reconcentury (Orbach, 1961). ciled the two enemies since the fact that the anterior spinal nerve roots contain only motor fibers and posEARLY-19TH CENTURY NEUROANATOMISTS terior roots only sensory fibers is usually known as Current knowledge of cortical anatomy owes much to the “Bell–Magendie law.” two French anatomists: Franc¸ois Leuret (1797–1851) Born in the Beaujolais region, Claude Bernard and Pierre Gratiolet (1815–1865). Together, they (1813–1878) started his professional life as a writer, published a first volume of Anatomie Comparée du first in Lyon and then in Paris, but was advised to study Système Nerveux Considéré dans ses Rapports avec medicine instead. He became Franc¸ois Magendie’s l’Intelligence (Comparative Anatomy of the Nervous favorite pupil. Bernard’s initial interest was clinical System Considered in its Relationship to Intelligence) pharmacology and his discovery that curare blocks in 1839. Leuret died while compiling a second volume, muscular contraction can be considered as a precursor which Gratiolet completed in 1857 (He´caen and Lente´riof subsequent work on the neuromuscular junction. Laura, 1977). As stated by Schiller (1970), in that treatise He studied the sympathetic nervous system, and a we find for the first time nearly all the convolutions syndrome characterized by a triad of miosis, ptosis, as we know them. Gratiolet enumerated and classified and enophthalmos, due to a lesion of the cervical sympathem and gave the cerebral lobes their current names. thetic nerve trunk, was described by him in animals, Nevertheless, he did not believe that this implied and by Horner in humans, in 1869, hence the name functional localization, and he remained a dedicated “Bernard–Horner syndrome.” “unitarist” for his entire life. Many of Bernard’s achievements, such as the introFranc¸ois Baillarger (1809–1890) worked during the duction of the concept of “milieu intérieur” (a precursame period as Leuret and Gratiolet. He found that sor of Walter Cannon’s [1871–1945] homeostasis), are by cutting thin slices of fresh cortex, placing them only indirectly related to neurology. He, however, between two pieces of glass and observing them with inspired the development of modern neurology by

634 F. CLARAC AND F. BOLLER being the first to clearly delineate the basis of scientific left-leaning political activist, Bouillaud pursued a brillimedicine (Bernard, 1865). Unlike many scientific wriant academic career and, by 1861, he was doyen (Dean) ters of his time, Bernard wrote about his own experiof the faculty, member of L’Institut de France and head ments and thoughts, and used the first person. What of La Charite´ Hospital. makes scientists important, he stated, is how well they Paul Broca was born in Sainte Foy-la-Grande, a have penetrated into the unknown. In areas of science small town in the Gironde where several other illustriwhere the facts are known to everyone, all scientists ous men (including Gratiolet) were born. In 1861, at are more or less equal – we cannot know who is great. the age of 37, he became Chief of the Surgical Service But in the area of science that is still obscure and of Biceˆtre. A particular incident triggered the curiosity unknown the great are recognized: “They are marked of Broca who until that time had been mainly interested by ideas which light up phenomena hitherto obscure by surgery and anthropology. During the 21 February and carry science forward” (Bernard, 1865). session of the Socie´te´ d’Anthropologie, which Broca Bernard’s achievements were recognized during his had founded, Gratiolet presented the skull of a Totonac lifetime. He succeeded Magendie at the Colle`ge de Indian from Mexico and argued that intelligence is not France. (This is a higher research establishment located related to the weight or to the volume of the brain. This in the Latin Quarter of Paris, close to the Sorbonne. It triggered a heated discussion between “localizationists” was created in 1530 and ever since has had a faculty and “unitarists,” the former being strongly supported by made up of the most prominent teachers and researchAubertin, who, following in the footsteps of Bouillaud, ers. The lectures are free and open to anyone. The presented cases to support cortical localization for Colle`ge does not grant degrees, but has research laboraspeech at the front of the brain (Schiller, 1979). tories, as well as one of the best research libraries in Within a week, a Biceˆtre patient called Leborgne Europe). Claude Bernard was also given a chair at (known as “Tan” within the hospital because that is the Sorbonne. He was later elected at the Acade´mie all he could say, apart from monosyllabic words and Franc¸aise, succeeding Flourens. One of Lyon’s universia curse), a long-time hemiplegic with a variety of probties is named after him. lems, died from cellulitis on Broca’s surgical ward. In a paper published in 1861 in Bulletins de la Socie´te´ Anatomique de Paris, Broca presented a detailed PAUL BROCA (1824–1880) AND LOCALIZATION account of his post-mortem examination of Tan’s brain OF LANGUAGE (there had been a preliminary report to the anthropoloThe early history of aphasia is presented elsewhere in gical society; Broca, 1861). What he observed was a this volume (see Ch. 36). The idea that mechanisms superficial lesion in the left frontal lobe: Leborgne’s related to language could be “localized” emerged probrain, arguably the most significant single brain in gressively in the course of the 19th century. An early the history of neuropsychology, has never been cut, proponent of such an idea was Jean-Baptiste Bouillaud but a CT scan performed in the early 1980s showed (1796–1881). Bouillaud had been a pupil of Magendie that in addition to a lesion in “Broca’s area,” there and was highly influenced by Franz Gall. On the basis was also parietal and subcortical involvement (Signoret of numerous clinical examinations and autopsies, he et al., 1984). proposed that le centre de la parole (the center for This finding was confirmed a few weeks later by speech) is localized in the frontal lobes. This idea was another case (patient Lelong) in which an autopsy also presented in a communication read in front of the Acarevealed damage that included the third frontal convolude´mie Royale de Me´decine on 21 February 1825. Memtion on the left side. A definite conclusion that the fronbers of the Academy were quite skeptical because he tal gyrus in the left hemisphere is responsible for speech was a member of the Phrenology Society, even though was reached a few years after Broca first argued for a it had clearly stated that he did not concur with all its frontal localization for speech (Broca, 1865). opinions. In addition, his descriptions of patients and The “priority” of Broca’s observation, its accuracy, of autopsies failed to convince the clinicians, because and the name that should be given to the syndrome, they were not sufficiently precise (Finger, 1994, 2000; were all disputed in public discussions and papers. Luzzatti and Whitaker, 2001). Concerning priority, in 1863 Gustave Dax (1815–1893) Strong criticisms were expressed by many of his colcame forth with a report prepared by his deceased leagues including Gratiolet and Gabriel Andral (1797– father, Marc Dax (1770–1837), supposedly presented 1846). This question was the topic of fierce debates for to the Montpellier Medical Society in 1836. There is decades, continued, among many others, by his no question that Dax’s paper on the left hemisphere pupil and son-in-law Ernest Aubertin (1825–1865). dominance for speech had been written in 1836, but Despite this controversy and also despite being a there remains the nagging issue of whether it had

HISTORY OF NEUROLOGY IN FRANCE been a public document (no support for this has been found). Still, Broca was probably aware of this paper. The Marc Dax and Broca papers on cerebral dominance appeared in print in 1865, with Gustave Dax presenting data supporting his father’s findings and the claim for priority (Joynt and Benton, 1964; Cubelli and Montagna, 1994; Finger and Roe, 1996; Roe and Finger, 1994). Today, the lateralization of speech is sometimes called the Broca–Dax law or the Dax–Broca law, a fitting tribute to both men. The major problem with Broca’s observations was that language disorders were not always associated with lesions of the frontal lobes. Sometimes the lesions were elsewhere and sometimes the frontal lobes were damaged, but without aphasia as a lasting consequence. Of course, we now know that the “language area” extends well beyond “Broca’s area” to parts of the parietal and temporal lobes. These problems began to be addressed when lateralization was recognized, but there still were exceptions, as Broca himself noted in 1865. What name should be given to this language disorder? Jacques Lordat (1773–1870), in an autobiographical observation, had used the term alalie (see Boller, 1978; Lecours, 1992; and below where Montpellier is discussed). Broca proposed the term aphémie. Armand Trousseau (1801–1867) wrote that aphemia in Greek means idiocy and indicated that the correct term should be aphasie. Trousseau was wrong; the term aphemia was etymologically correct. However, because Trousseau had so much stature, his term aphasie or “aphasia” was almost universally adopted (Young, 1990). Broca hardly contributed to the field of language disorders in subsequent years, perhaps because he had been embittered by so much controversy, but also because he was interested in so many other things, such as ancient trepanation, the family of man, and the limbic lobe (Schiller, 1979). In 1880, he was nominated to the post of lifetime Senator, but only enjoyed this very honorific position for a short time because he died 6 months later, aged 56. A statue of Broca stood for many years near the Medical School but was melted down by the occupying Germans during World War II. A major Institut National de la Sante´ et de la Recherche Me´dicale (INSERM) research center, a Paris street and a Paris hospital are named after him. Charcot also participated actively in the study of language, even providing Broca with cases. Around 1880, he introduced to France the new theories of Carl Wernicke (1848–1904). In 1883, he gave a set of lectures which included a diagram that has remained quite famous, the so-called bell schema inspired by the 1877 article of Kussmaul (1822–1902) and associationism theories (for more modern approaches to language

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connectionism see Geschwind, 1965, and Devinsky, 1997). This figure is composed around a ringing bell, suggesting the supposed neural paths that “connect” hearing the bell with the understanding of its meaning by the subject. At the center of his theory is memory for words and the four centers defined by his anatomo-clinical studies of aphasia: the third frontal convolution, location of the memory for the movements that are indispensable to articulate the words; the first temporal convolution, location of the auditory memory for words; the inferior parietal lobe, location of visual memory for words; and the foot of the second frontal convolution, location of memory for movements of hands and fingers. Lesions of these different areas should produce, respectively, motor aphasia, verbal deafness, verbal blindness and agraphia. The schema presents these four centers, to which must be added those for hearing and vision as well at the center for ideation.

THE SALPÊTRIÈRE AND JEAN-MARTIN CHARCOT (1825^1893) Neurology in France was marked during the second half of the 19th century by the “larger than life” figure of Charcot (Goetz et al., 1995). The work that he accomplished in the Salpeˆtrie`re hospital, the many duties he assumed, the lectures he gave regularly, the patients that he treated, often the most prestigious people in the world, as well as his worldly activities contributed to making him one of the major figures of his time. Charcot’s use of the anatomo-clinical method is described elsewhere (Ch. 15). The main aspects of Charcot’s life and work are described here.

Charcot’s glory and his association with Vulpian Jean-Martin Charcot was born in a “middle-class” area of Paris on 29 November 1825. Nothing is known about what oriented him toward a medical career. He had excellent drawing abilities, and his draftsmanship allowed him to represent places he visited, the unusual patients and the attitudes of those who surrounded him, and even himself (Bogousslavsky, 2004). He started medical training in 1843 and was named interne in 1848. When Charcot went to the Salpeˆtrie`re (Fig. 40.2), it was certainly not a prestigious hospital despite its size. At the start, it had been a gunpowder depot. The young Louis XIV decreed that it should become, together with Biceˆtre, part of the General Hospital of Paris. Building started between 1671 and 1687 with a church in the shape of a Greek cross. Already in 1679, the Salpeˆtrie`re sheltered 4000 pensioners, most of them women, and at the time of the Revolution, the number

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Fig. 40.2. La Salpeˆtrie`re in 1882.

had grown to 8000. Following the reorganization of hospitals in 1801, the number was reduced to 4000. Charcot was to spend his entire professional life at the Salpeˆtrie`re. In 1862, Charcot started working with Fe´lix Alfred Vulpian (1826–1887), who was one of his best collaborators, but left the Salpeˆtrie`re in 1869. It is difficult to imagine what that hospital and other similar ones were like at the time (Milos Forman has provided a plausible evocation in the fictional representation of a psychiatric asylum in Vienna for the 1984 film Amadeus). In the common wards, one would hear cries and shouts, see frightening and desperate faces, and incoherent behaviors, gaits and attitudes. Tension and anxiety were exacerbated even further by the indiscriminate mixture, inconceivable today, of mentally normal but crippled patients, those with psychiatric pathology, and those who were “incurable.” It has been guessed that the administrative and health care personnel alone consisted of 700 persons (Goetz et al., 1995). There were, however, only 7 doctors, 5 of whom were “alienists.”

When Charcot gave his first clinical lectures in 1866, the place was hardly visited by anybody. There was no amphitheater, and teaching could only take place in the wards. The key to Charcot’s success was the unique quality of his teaching. He prepared his lectures with great care and he gained an extraordinary reputation, not only in Paris but throughout Europe (Bogousslavsky, 2004). He soon became the Matre at the Salpeˆtrie`re and he was able to attract the best specialists and to surround himself with extraordinary pupils. As stated by Goetz et al. (1995), “this was an immense living museum of pathology that Charcot and Vulpian started deciphering, interpreting and classifying.” Charcot’s service was huge, including over 200 patients part “incurables”, and part “cripples”. It is probably due to the influence of Duchenne (see below) that Charcot became interested in diseases of the nervous system rather than in rheumatic diseases and their visceral complications (Sanders, 2002). It is interesting to compare Charcot’s career with that of Vulpian, who came from an aristocratic but impoverished family. Despite his brilliance, Vulpian

HISTORY OF NEUROLOGY IN FRANCE 637 failed the entry examination into the prestigious E´cole Ch. 15). He developed the work with his student GomNormale. In order to make a living, he got a job at the Natbault (1844–1904), when they described a symmetrical ural History Museum, where Flourens recognized his sclerosis of the lateral spinal column and the anterior talent and had him enter medical school. In 1853, he wrote pyramids of the brain stem (Gombault, 1871–1872). a thesis on Cranial Nerves III to X, the origins of which Charcot described also the paralysis agitans in detail were still vague at that time. He became interne with and suggested that this syndrome should be named ParCharcot at the Pitie´ and there a lifelong friendship began. kinson disease (PD) after the discoverer of the disease When Charcot and Vulpian entered the Salpeˆtrie`re (Goetz, 2006). Together with Vulpian, he pointed out, together, he was the one who convinced Charcot to for the first time and contrary to what Parkinson had include the study of histology among his areas of interest. said, that there are cognitive symptoms in PD (Boller, It was actually Victor Cornil (1837–1908) who taught 1980). Charcot also worked on hysteria and, even though microscopy to Charcot (Bonduelle, 1994). one can express reservations on his approach to the proVulpian taught physiology of the nervous system blem, “he laid much of the groundwork for Janet and until 1866, when he was given the chair of pathological Freud, both his pupils” (Wechsler, 1970). Charcot’s conanatomy previously occupied by Cruveilhier, despite a tributions to psychiatry have been reviewed elsewhere great deal of opposition from the bishops and the cle(Gelfand, 2000). rical party in the Senate. Vulpian was involved in a He gave two lectures a week. Tuesday was the day deep conflict with the clergy, because his teaching of official teaching with presentations of actual and his lectures were considered materialistic. In 1872 patients in the presence of a distinguished crowd, not he moved to the chair of experimental and comparative only of physicians, but also of politicians and writers anatomy, while at the same time holding a position at from Europe and the United States. On Friday he delivthe Paris Charite´. Charcot took his position. ered formal lectures mainly for his students in the Vulpian was elected member of the Acade´mie de library. Charcot for the most part read a prepared text. Me´decine in 1867, succeeded Charles Adolphe Wurtz His lack of eloquence in these circumstances was com(1817–1884) as dean of the faculty of medicine at the pensated by the concise precision of the text. University of Paris in 1875, and the following year One of his lectures has been immortalized in a was made a member of the Acade´mie des Sciences. painting by Andre´ Brouillet (1857–1914) (Fig. 40.3). Together with Charcot and Brown-Se´quard, he The painting deserves some consideration (Signoret, founded the journal Archives de Physiologie Normale 1983). It seems that Charcot himself commissioned et Pathologique. it. One can see the Matre while he comments on the condition of Blanche Wittman, a famous hysteria The achievements of his colleagues, especially of patient, supported by Babinski with Marguerite Charcot and his students, including the Dejerines, kept Bottard (Charcot’s faithful nurse) ready to give a Vulpian from the international recognition that might hand. No less than 16 pupils of Charcot are reprenormally have been expected. Charcot and Vulpian’s sented. Bonduelle has recently pointed out that the careers developed in parallel without any evidence of man on the front row is not Gilles de la Tourette, as overt rivalry, but, as will be seen, that was not the case commonly thought, but Paul Richer (1849–1933), who among their pupils. was interested in illustration and wrote books about Charcot also encountered opposition from the hysteria in art with Charcot. At the periphery, one also Napoleonian clique and from the clerical party. Howfinds literary and other personalities, including the ever, after he finally managed to obtain the Chair of writer Paul Are`ne (1843–1896), Jules Claretie (1840– Anatomy, his reputation started growing exponentially 1913), administrator of the Come´die Franc¸aise, and in France and abroad. January 1882 saw the inauguraAlfred Naquet (1834–1916), a radical-socialist député tion of the Chair of “maladies du système nerveux” (Member of Parliament) who helped re-establish (diseases of the nervous system), the first in the world. divorce in 1884. This was also thanks to the help of his friend Le´on Patients were selected by the pupils and Charcot Gambetta (1838–1882), then Prime Minister, who had would see 8–10 in a session. His lectures were transthe French Parliament vote a credit of 200 000 Francs lated by pupils including the Italian Gaetano Rummo, to create the chair. thanks to whom the bell schema appeared in print During his immensely productive period between for the first time (Gasser, 1995; Traykov and Boller, 1862 and 1870, Charcot gave a series of masterly clinical 1997). Sigmund Freud (1856–1939), who had attended descriptions, several of which dealt with movement disthe Salpeˆtrie`re for a few months between 1885 and orders. Applying this anatomo-clinical methodology, he 1886, also translated some lectures. A friendship of described in detail amyotrophic lateral sclerosis (ALS) sorts arose between Charcot and Freud, who was in an article with Joffroy (Charcot and Joffroy, 1869;

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Fig. 40.3. Brouillet’s painting.

invited to the Matre’s house on some occasions. Charcot expressed his gratitude to Freud for having translated the lectures, but there is not much evidence that Freud influenced Charcot’s thinking. The reverse is certainly true: Freud cherished Charcot’s teachings and a reproduction of Brouillet’s painting stood in his office in Vienna and later in London. The original painting was shown at the Salon in 1887. It was then bought by the Acade´mie des Beaux Arts and, for some obscure reason, was sent to the Nice Museum where it remained hidden in the vaults. Reproductions of the painting circulated widely, but it was thought that the original had been lost until Jean Le´pine, son of the Lyon neurologist, found and displayed it at the Pierre Wertheimer Hospital in Lyon. It has recently been restored and it can now be admired in the grand staircase that leads to the History of Medicine Museum in Paris. Following the Tuesday lectures, there was a dinner, usually restricted to family and very close friends. After dinner, Charcot often gave a reception at his magnificent mansion on the Boulevard Saint Germain. Among the remarkable persons who attended regularly,

one could mention Alphonse Daudet (1840–1897). He was a close friend of the Charcots, but he was also a patient of the Matre (Bonduelle, 1993). Years before, the author of Lettres de mon Moulin had contracted syphilis and began experiencing disabling and very painful sequels. Charcot had him undergo “suspension therapy” sessions that only made his suffering worse (Dieguez and Bogousslavsky, 2005). After his death, his wife violently criticized Charcot for these cruel treatments. Charcot always had close relations with clinicians and scientists from other countries, and spoke fluent English and German. His notoriety culminated in 1881 when, following a celebrated trip to Russia, he was invited to the International Congress of Medicine held in London in August. He gave a demonstration and a lesson on the arthropathies of locomotor ataxia. He had dinner with the Prince of Wales and, during the final gala, fireworks reproduced his portrait together with that of Paget (1814–1894) and the German surgeon von Langenbeck (1810–1887). At the Salpeˆtrie`re, the Medical Library and the main amphitheater are named after Charcot.

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Charcot’s contemporaries and pupils In addition to Vulpian, Charcot was influenced by many neurologists who played important roles, some of them his predecessors, others his contemporaries and pupils. They were often picturesque characters.

ARMAND DUCHENNE

DE

BOULOGNE

Armand Duchenne de Boulogne (1806–1875) is one of those who influenced Charcot greatly, thanks to his knowledge of the motor system. He came from a family of fishermen, traders and sea captains who had resided in Boulogne-sur-Mer since the beginning of the 18th century. His father was said to have been “a buccaneer” (Rondot, 2005). He attended medical school in Paris, starting it at age 21, and obtained his diploma 5 years later. His teachers included Laennec, Dupuytren, Cruveilhier and Magendie. He returned to Boulogne and practiced medicine there, but a few years later, because he found “insufficient scope for his interests” (Adams, 1970), he went back to Paris where he lived for the rest of his life. In Paris he started practicing, demonstrating extraordinary skills in analyzing clinical problems. He supplemented classical neurological examination with “electropuncture” and other types of electrical stimulation, which allowed him to study the role and the functions of individual muscles. During his first years in Paris, no one took him very seriously and his colleagues actually made fun of this man who would go around “with an electric box and a battery” (Parent, 2005). However, his diagnostic ability started to be recognized after Trousseau and Charcot became convinced of his skill and turned into admirers. Thanks to his precise methodology, Duchenne was able to make significant contributions to the description of a large number of neuromuscular pathologies, including the conditions now known as Duchenne’s muscular dystrophy (to which Aran, Cruveilher and Luys also contributed) and progressive locomotor ataxia, known today as tabes dorsalis (Duchenne de Boulogne, 1867; see also Schiller, 1995; Jeannerod, 2006). Duchenne studied facial expressions in relation to facial muscles and, on the basis of those studies, provided physiological explanations concerning emotions such as fear and joy. He published photographs (at a time when photography was in its infancy) that attracted the attention of Charles Darwin, who used some of them in his famous book dealing with the emotions of animals and humans (Darwin, 1872).

GEORGES GILLES

DE LA

TOURETTE

Georges Gilles de la Tourette (1857–1904) came from a family of physicians and graduated in medicine in Poitiers, but came to Paris in 1881. He became a house

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physician at the Salpeˆtrie`re in Charcot’s department. During his career, he wrote many papers and books as well as historical papers related to psychiatry and neurology. He is best known for having been the first to propose a connection between the various manifestations of his maladie des tics (Lajonchere et al., 1996). His mentor Charcot favored the euphonic eponym of maladie de Gilles de la Tourette, commenting, “Quel joli nom pour une maladie aussi horrible!” (‘What a pretty name for such a horrible disease!’) A lecture by Charcot on this topic has recently been critically discussed (Kushner et al., 1999). A famous patient with the syndrome was Madame de Dampierre, a noble woman who had actually been described by Jean Itard as mentioned above. Other famous cases (more or less ascertained) have been said to include Wolfgang Amadeus Mozart, Charles Dickens, Eric Satie, Emile Zola and more recently the writer and politician Andre´ Malraux. In his later years, Gilles de la Tourette showed a marked delusional syndrome and other signs of what was probably tertiary syphilis. He was admitted to a psychiatric institution near Lausanne, where he died 3 years later.

JOSEPH BABINSKI The family of Joseph Babinski (1857–1932) had fled Poland following an uprising against the Russian occupation in 1848. Babinski (1857–1932) remained a bachelor his entire life, living with his brother Henri, to whom he was greatly devoted, as he was to his country of origin. He met Charcot through the circumstances of having been placed second in a medical competition; the reward was a post on Charcot’s service in 1885 (Khalil, 1979). He arrived at the Salpeˆtrie`re Hospital at the very height of Charcot’s career, shortly after Charcot had been named Professor of Diseases of the Nervous System. In this environment, Babinski participated in all of the major efforts of the Charcot program, and his early career was inextricably linked to Charcot’s success. When he qualified for the competitive faculty post of agrégé (associate professor), Charcot’s influence was waning. Babinski failed the examination, likely as a result of fixed balloting by the President of the Jury, Charles-Joseph Bouchard (1837–1915), who had been Charcot’s prote´ge´ but had become his rival. Babinski and his fellow Salpeˆtrie`re colleague who also failed, Gilles de la Tourette, officially protested but the vote remained unchanged. In private correspondence related to this fateful competition, A. d’Arsonval (1851–1940) wrote to Brown-Se´quard: “Hence, the reign of Charcot at the Medical School is over.” Babinski never received a faculty position in the French medical system and never worked at the Salpeˆtrie`re after his mentor’s death. Instead, he ran the medical service

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that included neurology and neurosurgery cases at the nearby Pitie´ Hospital, a post that was not illustrious. It provided him, however, with material for neurological studies that would result in important contributions to cerebellar ataxia and neurosurgical cases that would be studied by him and his colleagues, Thierry de Martel (1875–1940) and Clovis Vincent (1879–1947) (Babinski, 1934). He first published the description of his famous “sign” in 1896 in a communication of just 28 lines (Babinski, 1896). In its simplicity and physiological implications, the “Babinski’s sign” hardly has an equal in medicine (van Gijn, 1996). Chapter 16 describes in detail the history and interpretations of the extensor plantar sign. Babinski embodied the 19th and early-20th century image of the self-made man, born of displaced immigrant parents, but well integrated into the fabric of traditional French society (Fulton, 1933).

CHARLES-EDOUARD BROWN-SE´QUARD Charles-Edouard Brown-Se´quard (1817–1894) was a physiologist from Mauritius (Aminoff, 1993, 2000; Laporte, 2006). He never worked at La Salpeˆtrie`re, but in December 1875 and January 1876 he had animated discussions with Charcot about localizations in the cortex at the Socie´te de Biologie stating, in translation, “I regret to say that I am in complete disagreement with Monsieur Charcot. I cannot accept the localization theories as they are promulgated at the present time” (Gasser, 1995). Brown-Se´quard had worked on several topics that Claude Bernard also dealt with including the cervical sympathetic chain and the vasoconstrictor nerves. On several occasions, the two men took opposite views and engaged in bitter controversies. Brown-Se´quard is best known for the syndrome that bears his name and which follows hemisection of the spinal cord. There is ipsilateral spastic paralysis and loss of proprioception, and contralateral loss of pain and temperature sensation. He later became, somehow uncritically, an eager believer in organotherapy, going as far as attempting to isolate testicular hormone to counteract senescence. This made him the object of derision, but some now consider him the father of modern hormone replacement therapy and of experimental endocrinology. At the end of a very agitated life (Olmsted, 1970; Aminoff, 1993), Brown-Se´quard became a French citizen and succeeded Claude Bernard at the Colle`ge de France where he finally settled for the last 15 years of his life.

THE SALPÊTRIÈRE AFTER CHARCOT Following Charcot’s death, a considerable vacuum occurred soon after the funeral ceremonies were over. Struck at age 67 by an acute pulmonary edema (probably

the consequence of myocardial disease), he was brought back to Paris and laid to rest under the dome of the St. Louis Church at the Salpeˆtrie`re. A national funeral with a mass took place, despite Charcot’s outspoken anticlerical pronouncements. The medical faculty was now faced with the difficult task of finding a successor. Some of his pupils and followers had found positions, but others were qualified and eager candidates for his position. Probably the most deserving was Jules Dejerine. Other good candidates included Joseph Babinski and Edouard Brissaud (1852– 1909), Pierre Marie and Alexis Joffroy (1844–1908), even though the latter had just obtained the directorship of Sainte Anne (see below). Following deliberations that lasted 3 months, the faculty decided not to make any final choice and named Brissaud for one year only, to assure a smooth transition. Finally, in a decision that satisfied nobody, the chair was given to Fulgence Raymond (1844–1910) whose main claim to fame was to have been Charcot’s chef de clinique. Raymond hardly achieved anything at the Salpeˆtrie`re. He kept the chair until his death and was succeeded by Dejerine. Dejerine’s sworn enemy and rival, Pierre Marie, took the chair in 1918, at age 64, and, against his will, was forced to relinquish it in 1923 (to George Guillain).

Jules Dejerine Jules Dejerine (1849–1917) (Fig. 40.4) was French but was born in Geneva. During his early years, he was better known for his athletic activities than for his academic achievements. His life changed when he became interested in biology and comparative anatomy. He attended the laboratory of Jean-Louis Pre´vost (1838–1927), who had returned to Geneva after having been an interne under Vulpian. At age 22, he decided that he should pursue his clinical studies in Paris, where he went by train “in a third class compartment, with no more than a brief introduction to Vulpian given to him by Pre´vost” (Zabriskie, 1970). Even though Paris was in political turmoil following the end of the Franco-Prussian war, the abdication of Napoleon III, and the Commune, he went straight to work under Vulpian and became Me´decin des Hoˆpitaux in 1882, and Professeur agrégé in 1886. In 1888, he married Augusta Klumpke (1859–1927) (Fig. 40.4), daughter of an American gold prospector; she was to become the first woman to be named Interne des hôpitaux de Paris (a nomination that required the intervention of the Minister of Education) and later on, in 1913, the first woman to become chair of a national neurological society (Bogousslavsky, 2005, 2007). Throughout their lives together, she was a collaborator who participated in most of his clinical and anatomical studies.

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Fig. 40.4. Jules Dejerine (1849–1917) and Madame Dejerine ne´e Augusta Klumpke (1859–1927).

Jules Dejerine was named Chief of Neurology at Biceˆtre, where he stayed for 8 years before rejoining the Salpeˆtrie`re in 1911. The fact that he was given Charcot’s chair, despite not having been his pupil, illustrates once again how the Matre had aroused strong “anti-Charcot” feelings that came to surface after his death! Dejerine collaborated with many people. He is famous for his work on muscular dystrophy with Louis Landouzy (1845–1910), Friedreich’s disease with Andre´Thomas (1867–1963), hypertrophic neuropathy with Jules Sottas (1866–1943), and the thalamic syndrome with Gustave Roussy (1874–1948). Andre´-Thomas has described how Dejerine and his collaborators worked. First they would accumulate a large amount of material. After the nervous tissue was fixed and identified, it was analyzed in serial cuts following Marchi’s technique. All the centers were mapped several times and the pathways were followed with extreme and meticulous care. Dejerine was visited by the greatest neurological authorities of the time, including Sherrington, Hitzig, and Ferrier. Several of his books have remained classics in the field. They include Sémiologie des Affections du Système Nerveux (1914) and his Traité d’Anatomie des Centres Nerveux. The latter represents years of intensive travail, and is a remarkable synthesis of the centers and of the pathways of the central nervous system (CNS). His Traité includes the first complete description of the pyramidal tract in humans. He showed that all the pyramidal fibers originate from the cortex and not from the subcortical nuclei as had been commonly thought. Dejerine successfully argued

that paralyses do not have a lenticular origin, but are due to lesions that are either cortical, subcortical, capsular, or brainstem in origin (Dejerine, 1914). Dejerine also contributed to neuropsychology, his most famous legacy being his work on word blindness (also referred to as alexia without agraphia), which he thought was the result of lesions of the supramarginal and angular gyri, which disconnected the calcarine region. He also performed considerable work on language and aphasia (see below). In addition to his discoveries and to his books, Dejerine left another legacy, his pupils, who, in addition to the aforementioned Gustave Roussy and Andre´-Thomas, included Jules Tinel (1879–1952). The latter is associated with an eponymous sign: pressure over a nerve trunk that has been damaged or is regenerating following trauma causes a sensation of tingling and pain in its distribution up to the site of regeneration. Other prominent pupils were Jean Lhermitte (1877–1959) and The´ophile Alajouanine (1890–1980). Dejerine died in the dark hours of World War I “having spent himself in the exhausting service of an Army hospital” (Zabriskie, 1970). His wife carried on their work until her death in 1927.

Pierre Marie Pierre Marie (1853–1940) was born into a wealthy, bourgeoise family in Paris. He started by studying law, but chose to study medicine and was an interne of Broca, Bouchard, and finally Charcot (in 1882, the year when the Matre was awarded the chair of

642 F. CLARAC AND F. BOLLER Maladies du système nerveux). His thesis in 1883 Following these meetings, the opposition between included a description of tremor in hyperthyroid the two men remained absolute. Pierre Marie never patients. Main areas of subsequent research and cliniopenly admitted that he had been wrong, but in later cal work included acromegaly and familial muscular studies under the title Les aphasies de guerre (“A peroneal atrophy (with Charcot). study of localized war-related lesions”), he quietly Greatly dismayed by not having received Charcot’s came back to positions that were more in line with chair at the death of the Master, he transferred his those of Broca, Charcot, and Dejerine. activities to Biceˆtre and established a service that It is worth noting that this famous dispute had been attracted visitors and pupils from many countries. In preceded just a few weeks earlier by a debate dealing 1918, he succeeded Dejerine at the Salpeˆtrie`re. Among with hysteria. This one put an end to Charcot’s theories his famous pupils was Charles Foix (1882–1927), who on hysteria. Babinski had then strongly argued that was one of the first to study focal brain lesions on hysterical symptoms could be reproduced by suggesthe basis of the arterial supply of these areas, but tion and that mere persuasion could cure them (he crewhose career was interrupted by premature death (a ated the term Pythiatisme). hospital in Ivry, close to Paris, is named after him). Marie became particularly interested in aphasia. His The next generation pupil Franc¸ois Moutier collected many cases. They Pierre Marie’s successor for Charcot’s chair was were published in a monumental thesis titled L’aphasie Georges Guillain (1876–1961), who continued the tradide Broca. Pierre Marie tried to convince the world that tion of Charcot’s lectures. Together with a younger Broca had been wrong about localizing speech in the collaborator and friend, Jean Alexandre Barre´ third left frontal convolution, even with his first case. (1880–1967), who later went to Strasbourg, and with Ever the iconoclast, he provocatively titled one of his Andre´ Strohl (1887–1977), he described the syndrome papers (in translation), “The third left frontal convoluof “radiculo-neuritis with hyperalbuminosis of the tion plays no special role in the function of language.” cerebrospinal fluid (CSF) without cellular reaction.” In his biography, Bailey (1970) indicated that Marie Strohl’s name has somehow mysteriously disappeared never entered the laboratory because he was very sen(in most instances) from the eponym, probably because sitive to formalin and would only look at fixed brains he was not a clinical neurologist, but an electrophysiolthrough a window. So much for his “examination” of ogist, and his contribution had been limited to electrical Leborgne’s brain! Another episode illustrates the power reactions (Boller and Duyckaerts, 1999). that he had. After his favorite pupil Moutier displeased Guillain also published papers related to many other him for reasons that have never been ascertained, he conditions, including Friedreich’s ataxia and myoclonic was prevented from pursuing a carrier as a neurologist jerks. His collaborators included Pierre Mollaret (1898– and was forced to become a gastroenterologist! 1987), who was later to describe coma dépassé (deep, The opposition between Marie and the traditional often irreversible coma), and the neuropathologist Ivan school represented by Dejerine became official during Bertrand (1893–1965). Guillain received many honors a debate that took place in the course of three meetings and was a member of French, American, and Japanese held at the French Neurological Society in 1908 academies of science. (Lecours et al., 1992). Pierre Marie claimed that aphaHe had many illustrious pupils including Michel sia was, in fact, a form of dementia, and that motor Bonduelle who became head of neurology at Saint aphasia is only a problem of “anarthria.” Dejerine Joseph Hospital, as well as a scholar in the field of hisopposed this point and reiterated Charcot’s ideas tory of neurology (and to whom this chapter is dediincluding his “bell” schema. Marie insisted, and vircated). Guillain’s pupils included also The´ophile tually denied any cerebral localization: how could our Alajouanine and Raymond Garcin. Their three names illiterate ancestors have a “visual center for words”? are united in the Guillain–Alajouanine–Garcin synHow could such a “center” be transmitted from one drome, consisting of unilateral paralysis of all or generation to another? The discussion was very heated. nearly all cranial nerves. It is caused by tumors of A demand was made by both parties to have another the nasopharynx and base of the skull that do not look at Leborgne’s brain and Dejerine wanted to secaffect the brain. When Guillain retired in 1947, tion it, but the dean of the faculty refused it. Augusta Charcot’s Chair went to Alajouanine. Dejerine also intervened and talked about the affected The´ophile Alajouanine (1890–1980) (Fig. 40.5) came cortical pathways, describing once again the fibers from a humble family in central France and came to underlying F3. There was also a heated argument about Paris in his early 20s, uncertain whether he would the origin of language. Dejerine argued that nothing become a professional writer, but then decided to was “innate” and that everything is acquired.

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Fig. 40.5. The´ophile Alajouanine (1890–1980).

study medicine (Boller, 2006a). He is well known to neurologists because of the condition known as Foix and Alajouanine’s syndrome, also known as angiodysgenetic necrotizing myelopathy. He also contributed to our understanding of aphasia and can be considered one of the fathers of neurolinguistics. Perhaps because his interest in the arts was well known, he examined many famous artists. This led to a publication in Brain in which he described the effect of aphasia on the artistic production of a writer (Valery Larbaud), of a musician (Maurice Ravel), and of a painter whom he did not name, but whose identity, Paul Elie Gernez, is now well established (Alajouanine, 1948; Boller, 2005, 2006a, Boller et al., 2005). Raymond Garcin (1897–1971) was born in Martinique (Guilly, 1971). He went to medical school in Paris where, in addition to Guillain, his teachers included Fernand Widal (1862–1929), specializing in infectious diseases, and Eugene Apert (1868–1940), a pediatrician who described acrocephalosyndactyly in 1906. He started working at the Salpeˆtrie`re in 1930. His work included research on cranial nerve pathology, neurosyphilis and cerebellar ataxia. He had been a physician assistant during World War I and, when World War II arrived, he was embedded in a neurosurgical unit. After the war he was first at Saint Antoine Hospital and then at the HoˆtelDieu until, in 1948, he went back to the Mazarin Pavilion of the Salpeˆtrie`re. A Chair of Clinique Neurologique

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was created for him in 1959. He created an electron microscopy unit, which he continued to supervise even after his retirement in 1968. His pupils included Serge Brion, a neuropathologist whose contributions included a description of the alien hand syndrome (Brion and Jedynack, 1972), and Jean Lapresle, who was to head neurology at Biceˆtre. The neurology service of Sainte Anne is called Centre Raymond Garcin. Franc¸ois Lhermitte (1921–1998) was the enfant prodige of French neurology (Derouesne´ and Boller, 2007). He co-authored a popular textbook, Traité de Pathologie Médicale, with Pasteur Valery-Radot and Jean Hamburger when he was only 28 and had not yet finished his internat. His thesis has remained a classical study of the pathophysiology and therapy of multiple sclerosis. His main interest was neuropsychology and particularly the frontal lobes. This interest kept growing and resulted in new clinical observations, including how some frontal patients spontaneously use objects or imitate other people’s (particularly the doctor’s) gestures. It is quite striking to see Lhermitte demonstrate these and other disorders with his extraordinary clinical skill (fortunately they have been preserved on film). For his entire life, Lhermitte remained a close friend of his neighbor Paul Castaigne (1916–1988, see Richet, 1989). As for the other great neurologist and neuropsychologist at Sainte Anne, it must be said that He´caen and Lhermitte often pretended to ignore each other (but see Lhermitte et al., 1985). Franc¸ois Lhermitte was one of the few French neurologists in modern times to be a member of both the Acade´mie de Me´decine and the Acade´mie des Sciences. After Lhermitte and Castaigne’s retirement, the Neurology Clinic became a Federation (Fe´de´ration de Neurologie). A series of INSERM units carry on the research tradition initiated by Castaigne and Lhermitte.

NEUROLOGY IN PARIS OUTSIDE THE SALPÊTRIÈRE Most persons associate neurology in Paris with La Salpeˆtrie`re. It is true that many major figures in neurology worked there, but some crucial figures have operated in Paris without ties to La Salpeˆtrie`re. Two such figures are Jean Lhermitte, who worked at Paul-Brousse Hospital, and Henry He´caen, who was at the Sainte Anne Hospital. The Sainte Anne Hospital deserves special mention because it illustrates the relations between neurology and psychiatry in Paris (and in France). Lack of space prevents us from presenting the history of important neurology services in other Paris hospitals, including Biceˆtre, Lariboisie`re, St. Joseph, Henri-Mondor, Bichat, Ambroise Pare´, and others.

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Jean Lhermitte Jean Lhermitte (1877–1959; Fig. 40.6) was actively involved in practice, research and teaching of neuropathology including histology (Boller, 2005). As early as 1914, he co-authored with Gustave Roussy a classical treatise of neuropathology (Roussy and Lhermitte, 1914). With Pierre Marie, he wrote an early description of the pathology of Huntington’s disease. He also worked on olivo-ponto-cerebellar atrophy, on the pathogenesis of cerebrovascular diseases, and on many other pathologies of the nervous system. He was a prominent clinical neurologist and is known all over the world for having described a characteristic phenomenon, Lhermitte’s sign, also called Barber Chair phenomenon, said to be typical of multiple sclerosis. It consists of an electric-like shock sensation extending down the spine upon flexion of the neck. Lhermitte called himself a neuropsychiatrist, but when reading the topics he covered under that label, one sees that he was clearly interested in brain and behavior relationships and in what we now call neuropsychology. He wrote extensively on many subjects ranging from phantom limbs to disorders of consciousness and constructional apraxia. He studied hallucinations

Fig. 40.6. Jean Lhermitte (1877–1959).

and described peduncular hallucinosis (patients are aware that what they “see” is not present). Lhermitte’s legacy is related in great part to his pupils, who included, in addition to his son Franc¸ois, Lucien Cornil, Oscar Trelles (see Ch. 49), Henry He´caen and Julian de Ajuriaguerra.

Henry He´caen Henry He´caen (1912–1983; Fig. 40.7) was a native of Brest, in Brittany (Boller, 2006b). After a brief turn as a Navy doctor, he went to Paris where he selected Sainte Anne as his place of training because he wanted to become a psychiatrist. There he came to know Julian de Ajuriaguerra and for a while their carriers developed in parallel. They were both trained in psychiatry by Henri Ey and received special training and inspiration from Jean Lhermitte, with whom they published and who wrote an affectionate introduction to their book, the 1949 edition of Le Cortex Cérébral, the first textbook of neuropsychology ever written in any language. He´caen was not happy as a psychiatrist, perhaps because “the ways and means of psychiatry were

Fig. 40.7. Henry He´caen (1912–1983).

HISTORY OF NEUROLOGY IN FRANCE 645 unsatisfactory to his Cartesian mind” (Lhermitte because, without being preoccupied with the arcane et al., 1985). He was more inclined toward neurology. aspects of classic academic life, he was free to pursue In 1952, he spent several months at McGill’s Montreal his own interest and fully develop his potential. Neurological Institute (MNI) where he worked with Wilder Penfield and Brenda Milner. After that trip, Sainte Anne Hospital he started publishing in English. Two papers propelled The Sainte Anne Hospital (now Centre Hospitalier him onto the international scene. The first was with Sainte Anne) (Fig. 40.8) was founded by Queen Anne de Ajuriaguerra on “Balint’s syndrome,” published of Austria in the 17th century. It is principally a psychiain Brain (He´caen and Ajuriaguerra, 1954). Even more tric institution and was for a long time referred to as an important was “The syndrome of apractognosia due “asylum.” Its history illustrates the relationships that to lesions of the minor cerebral hemisphere,” pubexisted between psychiatry and neurology in France, lished in Archives of Neurology and Psychiatry starting with Charcot himself (Gelfand, 2000). (He´caen et al, 1956) in collaboration with Penfield, Psychiatrists were referred to as alienists and were for Bertrand and Malmo. This paper further opened the a long time “second class citizens” in the French academic eyes to the role of the right hemisphere, which was world. Antoine Bayle (1799–1859), who was the first to not getting sufficient attention at this time. describe general paresis (neurosyphilis), was an alienist. He´caen went back to Sainte Anne where, for many For many years, the direction of Sainte Anne was attriyears, he had to be content with a few offices in the buted to neurologists, starting with the Anglo-French basement until 1968, when the group moved to the newly Benjamin Ball (1833–1893; Boller, 1980). Valentin Magnan constructed Centre Paul Broca. Over the years, He´caen (1835–1916) was considered the best alienist of his time and and his group grew steadily in size and influence (Benton, had co-authored papers with Charcot. Nevertheless he was 1983), and his INSERM Unit 111 became known over the rejected twice, first when Ball was named and again when world as one of the leading facilities in the field. Ball retired, because the directorship was given to Alexis He´caen did not invent the term “neuropsychology,” Joffroy, a favorite pupil of Charcot. The post of Director which had been used by, among others, William Osler, was then given to other persons with a predominantly neuKurt Goldstein, Karl Lashley and Don Hebb (Finger, rological background, such as Gilbert Ballet (1853–1916), 1994). However, it can be stated that he was the first Ernest Dupre´ (1862–1921), Henri Claude (1869–1945). to use it in its present meaning when, in 1962, he Joseph Levy-Valensi (1879–1943) was a pupil of Henri founded the Groupe de Neuropsychologie et NeurolinClaude and had extensive training in both neurology and guistique (Zangwill, 1988; Boller, 1999). He defined psychiatry. In October 1939, he had been made professor neuropsychology as “la discipline qui traite des foncof history of medicine. He was named director of Sainte tions mentales supe´rieures dans leur rapport avec les Anne in 1942, but was not allowed to take the position structures ce´re´brales” (“the discipline that deals with because of the discrimination laws promulgated by the higher cortical functions and their relationship to cereVichy government. Because of his exceptional achievebral structures”) (He´caen, 1972, p. 5). ments, it is said that he had a letter from Mare´chal Pe´tain He was very prolific, writing over 300 articles and stating “Messieurs les Allemands, cet homme est un books. His research has touched practically all aspects grand Français, n’y touchez pas” (“Gentlemen from Gerof neuropsychology, with major emphasis on hemimany, this man is a great Frenchman, do not molest spheric cerebral dominance and aphasia (He´caen and him”). Unfortunately it was not enough to save him: he Dubois, 1969; He´caen and Lante´ri-Laura, 1977). He died in a concentration camp in Auschwitz. was among the first in Europe to carry out carefully Psychiatry became autonomous only after the May planned group studies. Among the deficits he investi1968 events. (Note: this refers to a rebellion that started gated were agraphia, acalculia, dressing apraxia, and among students of Nanterre and the Sorbonne, then visual agnosia. spread much beyond the universities, ending up in a In 1965, He´caen was named Directeur d’Études at semi-insurrection that almost toppled the government of the prestigious E´cole Pratique des Hautes E´tudes General De Gaulle.) However, Sainte Anne had long har(now E´cole des Hautes E´tudes en Sciences Sociales). bored many illustrious psychiatrists. They include Henri As stated by Lhermitte et al. (1985), “given the rigidity Ey (1900–1977), one of the founders of modern psychiatry of the French medical pyramid and considering his in France. Another was Jean Delay (1907–1987), who academic background, the royal roads of the Salpeˆwas made Director of Sainte Anne in 1946. He and Pierre trie`re and of Biceˆtre were closed to him,” and he was never officially named professor, simply because the Deniker (1917–1998) collaborated with Henri Laborit positions he could have aspired to were occupied (1914–1995) in the clinical development of chlorpromaby others. This was perhaps a blessing in disguise zine. Other famous Sainte Anne psychiatrists are Pierre

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Fig. 40.8. Sainte Anne Hospital.

Pichot, president for 6 years of the World Psychiatric Association, as well as the psychoanalyst Jacques Lacan (1901–1981). It was customary for the psychiatry students at Sainte Anne to work in neurology and sometimes make important contributions to the field. For instance, in 1926 Lacan co-authored with Alajouanine a paper that includes the first clinical description of progressive supranuclear palsy (PSP). Paradoxically, there was no dedicated neurology service at Sainte Anne until 1969, when such a service was established by Pierre Rondot. Before this, in 1948, Marcel David (1898–1986), a pupil of Clovis Vincent, developed one of the first neurosurgery services in France at the Sainte Anne Hospital. David’s service included Jean Talairach (1912–2007) (Fig. 40.9) who is famous for his creative research work leading to a novel stereotaxic frame and the development of human stereotaxic neurosurgery in France and around the world. Among Talairach’s achievements, perhaps the best known is the development of several human brain atlases culminating with the Co-planar Stereotaxic Atlas of the Human Brain, published in 1988 in collaboration with Pierre Tournoux (Talairach, 1988). This 3-dimensional atlas is currently used all over the world.

The increasing activity in the field of human partial epilepsy around Jean Talairach, Bancaud and their colleagues, with more than 200 articles, reviews and books, remains to this day a hallmark of the E´cole de Sainte Anne. Contributions included the clinical semiology and surgery of partial epilepsies, the physiopathogenesis of reflex epilepsies and of kojewnikoff’s syndrome (with the participation of Claudio Munari, Suzanne Trottier and Patrick Chauvel). In addition, a large number of neurologists, neurosurgeons, and radiologists, from France and abroad, visited the Service de Neurochirurgie Fonctionnelle to learn stereotaxy, neurology and epilepsy surgery. Another important contribution of Jean Talairach in the Sainte Anne Hospital was to initiate the construction of the “Paul Broca” INSERM Research Center next to the Hospital, where several research groups (Unite´s de recherche INSERM) were established starting in 1968. In addition to Talairach, Bancaud and He´caen, the Center saw the Units of Jean-Charles Schwartz, Claude Kordon (1934–2008), and, more recently, of their pupils. In this setting, several major discoveries have taken place in the field of clinical and basic neurosciences, such as descriptions of the role of the proprioceptive afferents in motor seizures, the early characterization of somatostatin

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Fig. 40.9. Jean Talairach (1912–2007).

receptors leading to the development of clinically relevant agonist drugs for the treatment of acromegaly, and the discovery of the D3 dopamine receptor and the H3 histamine receptor. Research at the Centre Paul Broca has always tended to form a continuum between basic and clinical research on human mental and neurological diseases.

FRENCH RESEARCH INSTITUTES AND REORGANIZATION OF THE UNIVERSITIES Several recent events have considerably modified the medical scene in France. In particular, the face of research has completely changed following the Foundation of the Centre National de la Recherche Scientifique (CNRS) in 1939 and of INSERM in 1964.

Centre National de la Recherche Scientifique (CNRS) The government that took power under the leadership of Le´on Blum in 1936, the so-called Front Populaire, decided to promote basic research. Jean Perrin, Nobel

Prize laureate in physics, was one of the leaders in these initiatives. Just before World War II, a High Committee of Scientific Research was created and the CNRS was officially born on 19 October 1939. The goal was to select the best laboratories and to coordinate activities in order to draw a higher output of quality scientific research. Just as the war was ending, in 1944, Joliot Curie gave the CNRS its current structure. One of the ideas was to separate research institutes from universities, so that some researchers could dedicate all their time to research. In the beginning, the organization started with only 2000 researchers. There were 7000 in 1950. Today, CNRS includes 30 000 persons, 11 500 researchers, 14 500 engineers and technicians and about 1200 laboratories. Research is promoted by a National Committee, which defines the CNRS’s main orientations. General De Gaulle’s return to power and the foundation of the Fifth Republic saw a significant increase in research funds. Similarly, Franc¸ois Mitterand’s Presidency in 1981 coincided with considerable impetus for research.

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Institut National de la Sante´ et de la Recherche Me´dicale (INSERM) In terms of health research, the National Hygiene Institute (NIH) of France had been founded right after the World War II, with Robert Debre´ (1882–1978), a pediatrician, playing a major role in establishing it. That organization was, however, too limited. The Association Claude Bernard, a foundation dedicated to the development of medical research, proposed to give more funds to medical laboratories. The idea was strongly supported by the heads of important clinical departments (mainly in Paris), whose intent was to keep under medical control all that had to do with medical and health research (Lazar, 2004). On 18 July 1964, INSERM was created following the directions of Robert Debre´, whose son was De Gaulle’s Prime Minister. INSERM was partly modeled after the National Institutes of Health in Bethesda, Maryland. INSERM has always had a very ambitious scientific policy. Presently, INSERM has 339 laboratories with about 13 000 persons, 6500 of whom are paid by it. Around 1995, Philippe Lazar, Director General of INSERM from 1982 to 1996, instigated the development of Instituts Fe´de´ratifs de Recherche (IFR), in order to organize several units around a common research theme. Today both CNRS and INSERM are very active. It can be said that nearly all the best laboratories of neurology, neurosciences, and cognitive sciences are in these organizations. For the CNRS, about 33% of the life sciences laboratories are dedicated to neurology; for INSERM it is about 20%. Another consequence of the turmoil of the 1960s was a complete transformation of the universities. The medical faculties jumped from 11 to 42. Paris was split into 10 different faculties, Lyon into 4, Bordeaux into 3 (now 4), Marseille into 3, and Toulouse and Strasbourg into 2. Some consider this fragmentation excessive and there is a trend toward reunification of some of these different faculties. There is also talk of an integration between the two major organisms for research (CNRS and INSERM) and the universities. As stated above, in 1968, in the wake of the events of May, all chairs were abolished.

NEUROLOGY OUTSIDE PARIS As mentioned above, France has always been a very centralized country, and this tendency accentuated even further following Louis XIV and the two Napoleons. All activities of the government and of other institutions took place in Paris, where everything converged and everything was decided. Medical and scientific matters followed the same pattern, and for a long time nothing was considered worthwhile outside of Paris except perhaps for Strasbourg and Montpellier. The French

Revolution made this centralization more official. But during the 20th century, things started to change and the provincial schools of medicine became medical faculties, typically associated with major scientific laboratories. Out of the many excellent university-based neurology departments, we shall look specifically at six. Again, space limitations prevent us from discussing more, including Caen, Dijon, Grenoble, Lille, Limoges, Nancy, Nice, Poitiers, Rennes, and other cities.

Montpellier The Montpellier Medical School was founded in 1220 when local teachers formed a Universitas Medicorum, which prospered and attracted students from all over Europe. Illustrious alumni and visitors to Montpellier included Guy de Chauliac (1298–1368), who notoriously failed to heal Petrarch’s great love, Laure de Nove. Rabelais graduated in Montpellier in 1530. Around that time Vesalius studied and perhaps graduated there as well, before moving to Paris and later to Padua. During the 17th century, the school of Montpellier remained at the first rank of French medicine, providing the majority of the King’s physicians. At this time, the first clearly neurological and psychiatrical works were published in Montpellier. One of many prominent Montpellier physicians was the anatomist Raymond Vieussens (1641–1715), who wrote about neurological anatomy, including Neurologia universalis (1685) which contains several original descriptions of brain structures. The 18th century in Montpellier, as well as in other parts of the medical world, was the era of doctrines. Three main schools of medical philosophy coexisted: reductionism (which considered the living phenomena as totally explained by chemical or physical laws), animism following the theories of G.E. Stahl (1660–1734), which explained life by the action of the soul, and finally vitalism, which was the prominent doctrine in Montpellier under the leadership of The´ophile de Bordeu (1722– 1776), doctor in Montpellier in 1743, and Paul-Joseph Barthez (1734–1806), professor in 1761. For the Montpellier vitalists, life was viewed as a specific phenomenon, one that cannot be reduced to matter or to soul. Bordeu thought that sensitivity was the characteristic of life. In contrast, Barthez proposed that life is the result of the action of a principe vital. This concept of vital principle helped Barthez to explain thermoregulation and to give a preview of the modern concept of reflex. For some historians, Barthez’s doctrines are precursors of the concept of self-regulation of the living body. As stated above, during the French Revolution, all universities were suppressed. Montpellier became one

HISTORY OF NEUROLOGY IN FRANCE 649 of only three E´coles de Sante´. It was decided that it peduncles that involves the red nucleus and causes a would be located in what used to be the bishop’s disorder of speech, paralysis of lateral conjugate gaze, palace, and it is still there. ipsilateral VI nerve palsy, and anesthesia of the Vitalism remained the official medical philosophy face and the remainder of the body with contralateral of the school throughout the 19th century, despite hemiplegia. Paris’ evolution toward a more scientific neurology. Following Cestan, Marcel Riser (1891–1975) was an Jacques Lordat (1773–1870), professor of physiology, important figure at the medical faculty of Toulouse. was Barthez’s heir. His vitalist philosophy helped During World War I, he had been a military surgeon him to understand the language defect he suffered and participated in the French colonial war in Morocco, from in 1825, which, as mentioned above, he called the so-called Rif war. He sustained an injury to his left alalie. Lordat saw it not as a mechanical defect, or a brachial plexus, which resulted in his inability to use his decrease in intellectual abilities, but a specific type of left arm. In Toulouse, he worked with Cestan and was alteration deriving from an abnormality of the vital his chef de clinique in neuropsychiatry between 1919 force. and 1925. He worked on syphilis and cerebrospinal At the end of the 19th century, one of the leading fluid. He also wrote an anatomo-clinical analysis of professors at Montpellier was Joseph Grasset (1849– spinal-cord tumors and performed experiments on 1918), internist, neurologist and philosopher. As a medcerebral vasomotor phenomena in monkeys, using ical philosopher, his name is associated with the new procedures. He followed the Charcot tradition of Grasset phenomenon, a condition where a patient with having his hospital neurology consultation open to hemiparesis lying on his back can raise either leg sepaneurologists from France and abroad. rately, but is unable to raise both legs together. More As in the rest of France until 1968, there was a single recently, Pierre Passouant (1913–1983), professor of chair for both neurology and psychiatry. Riser orgaexperimental pathology, has published mainly in the nized neurology in Purpan and psychiatry at the La field of diseases of sleep. At the present time, MonGrave clinic. It is said that Riser was as accomplished tpellier is still very active in different neuroscience disin psychiatry as he was in neurology (Laboucarie´, ciplines; its neurological school is mainly oriented to 1976). His book Pratique Neurologique summarizes his the study of Alzheimer’s and related degenerative disresearch and main ideas. A Toulouse memory eases. The School of Montpellier, one of the most rehabilitation center is named after him and his pupils ancient of the Western world, continues to have its included Jean Ge´raud and Andre´ Rascol (1927–2002). own image, characterized by a strong interest in hisCurrently, Toulouse has several laboratories for tory, medical philosophy, a global vision of medical neurosciences including units attached to INSERM science, Hippocratism and humanism. and CNRS. Current interests include neuronal plasticity, pharmacology of extrapyramidal disorders, and neuropsychology. Toulouse The University of Toulouse was founded in 1229, the third university in France after Montpellier and Paris. Following the French Revolution, it was closed. Toulouse had to wait until 1891 to have a new school of medicine (Repingon, 2004). Two medical faculties were created in 1963: that of Purpan, located where the old Medical School used to be, and a new faculty at Rangueil. The first chair of neurology in Toulouse was awarded to A. Re´mond (1863–1932). He held the chair of mental illnesses from 1898 to 1913. Raymond Cestan (1872–1934) was Re´mond’s successor. He studied at the medical faculty in Paris, and became interne des hôpitaux under the direction of E´douard Brissaud and Joseph Babinski at the Salpeˆtrie`re. He received his doctorate in 1899. He became chef de travaux under Fulgence Raymond. In 1901, he co-authored the description of the syndrome known under the name of Raymond Cestan syndrome, a lesion of the cerebral

Bordeaux The University of Bordeaux was founded in 1441 when Henry VI was King of England and, nominally, of France as well. These were years in which Bordeaux’s allegiance vacillated between England and France. St. Andre´ Hospital is even older, having been started in 1390. One of the leading figures in the history of neurology is Albert Pitres (1848–1928) (Fig. 40.10). He was born in Bordeaux and studied in Paris where he worked with Charcot first as an interne, then as his assistant. In 1877, his work at the Salpeˆtrie`re culminated with a thesis on the functional anatomy of the cerebral hemispheres. He also worked at the Colle`ge de France where he learned histology with Louis Ranvier (1835–1922), the man who described regularly spaced gaps in the myelin sheath around an axon known as nodes of Ranvier. Pitres wanted to continue his career in Paris, but when the new faculty of

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Strasbourg

Fig. 40.10. Albert Pitres (1848–1928).

medicine opened in Bordeaux, he returned to his native Aquitaine. In 1880, he became professor of anatomy and histology, and in 1881, professor of internal medicine. He was dean of the faculty from 1885 to 1905. In 1884, he published the first detailed clinical case study of pure agraphia (see Barrie`re and Lorch, 2003, for an English translation). Ten years later, Pitres published a paper on pure agraphia. After Charcot’s death, Pitres dedicated himself mainly to anatomy. His book on the cranial, spinal, and peripheral nervous system (coauthored with Testut in 1925) is significant for its clarity and illustrations. When he retired in 1919, Pitres had the satisfaction of seeing the faculty building finished and located in Place des Victoires. Other important researchers associated with this school are Paul Delmas-Marsalet (1898–1977), Pierre Loiseau (1926–2004), Jacques Faure, Jean Didier Vincent, Michel Le Moal, and Bernard Bioulac. The latter had worked with Y. Lamarre in Montreal and studied the cortical units of the motor cortex in chronic and deafferented monkeys. Together with Abdelhamid Benazzouz, he demonstrated that a high frequency stimulation of the sub-thalamic nucleus can abruptly stop the main deficits of Parkinson’s disease (Benazzouz et al., 1993). Shortly thereafter, Alim-Louis Benabib in Grenoble adapted this therapy to humans. Recent data confirm the usefulness of this technique (Samson, 2007). A new Franc¸ois Magendie Center dedicated to the neurosciences was created in 1998.

Because of its geographical location (on the Rhine close to Germany), the city of Strasbourg has a special history and has played a peculiar role in French neurology, representing a sort of interface between the German and the French schools. Until 1681, the city enjoyed the status of a free city with considerable autonomy. Strasbourg kept much of this freedom even after it became part of the French Kingdom under Louis XIV. The university, particularly the medical faculty, remained “autonomous and Lutheran.” After the French Revolution, Strasbourg became part of a French département. Following the reorganization in 1794, the medical faculty became one of the three E´coles de Sante´ de la Re´publique. In 1819, the first chair of pathological anatomy was awarded to Jean Frederic Lobstein (1777–1835), who was to codescribe Osteogenesis imperfecta, known colloquially as glass-bone disease (Ekman–Lobstein syndrome). It has been argued that this was the first chair of its kind in the world. Following the French defeat of 1870, the Germans annexed Alsace and Lorraine and wanted to create a great University of Strasbourg, one meant to be a showcase of German medical science. Famous names passed through Strasbourg during these years. Wilhelm Waldeyer (1836–1921), one of the first to propose the neuron theory, participated in the creation of the German faculty. Friedrich Goltz (1834–1902) was another. He had been appointed to the University of Halle, but was given the chair of physiology at the foundation of the new university. He studied the effect of larger and larger cerebral lesions in dogs, which he kept alive long after the operation. He was a strenuous partisan of the concept of “cerebral unity,” as opposed to Ferrier and others who favored cerebral localization, especially of higher functions. The great clinician Adolf Kussmaul (1822–1902) taught in Strasbourg from 1876 to 1888. He wrote a classic book on aphasia where he characterized word deafness and word blindness (Kussmaul, 1877). The French physicians who refused to integrate under the German occupation moved en bloc to Nancy, where the French government created a medical faculty in 1872. Despite the fact that most teachers had come from Strasbourg, the two universities almost completely ignored each other. On 28 July 1919 Alsace became French again and a chair of neurology, the second of its type in France, was created for Jean-Alexandre Barre´. His fame goes beyond the “Guillain–Barre´ syndrome.” In a way, his work prolonged that of Babinski. He described a series of reflexes and a maneuver aimed at demonstrating

HISTORY OF NEUROLOGY IN FRANCE 651 alterations of the pyramidal system. He was one of the himself a surgeon and physiologist. After his studies first to describe symptoms of vertebro-basilar insuffiin Lyon, he visited the USA in 1913 and met Harvey ciency. He made an important contribution to the Cushing (1869–1939), who convinced him that surgery pathology of the vestibular system. He retired in 1950. contributed to understanding physiology. Back in In 1920, neuroscientists in Strasbourg decided that, in France he practiced in Lyon, but was also active in order to keep the level that had been reached by the Strasbourg and Paris. His name is attached to a synGermans, they needed to attract exceptional personalities. drome which had been described as far back as the Andre´ Meyer (1875–1956) founded the Institute of Phybeginning of the 19th century (Graham, 1814). It is siology, directed by Georges Schaeffer (1882–1953) until caused by atheromatous involvement or occlusion of 1939. At the start of World War II, the University of Strasthe abdominal aorta by a thrombus just above the site bourg’s seven faculties departed again, this time to Clerof its bifurcation. The main symptoms are fatigue mont Ferrand in central France. This created many and cramps in the lower limbs, intermittent bilateral problems because the Alsatians could not integrate there. claudication and, in males, inability to maintain penile Strasbourg was occupied by Germany until 1945. erection. Leriche also showed the importance of vasoAfter the war and the return of Strasbourg to motor reactions in pathology. He wrote papers on norFrance, Franc¸ois Thiebault (1901–1968) succeeded mal, pathological and surgical physiology with Albert Barre´ and created a department of neurological Policard (1881–1972) who was professor of histology sciences (in 1950). He had trained under neurosurgeon at the medical faculty of Lyon. Clovis Vincent and Jean Nageotte (1866–1948). His Leriche had been a colleague of Alexis Carrel work dealt with viral encephalitides and he advanced (1873–1944). We are told that they did not like each neurosurgery. His successor was Francis Rohmer. In other, even before Carrel developed his eugenicist the1965, Paul Mendel created a Neurochemistry Center ories and became closely associated with the fascist and in 1977 Paul Chambon created a Molecular Genetregime of Vichy France. Carrel won the Nobel prize ics Unit. Thus, although the Strasbourg school had in 1912 (for work performed in the United States) and been disrupted several times by wars, it was also one of the institutes of the faculty of Lyon was named greatly enriched by its French and German roots, which after him. However, in 1996, after years of embarrasproved a fertile ground for scientific development. sing publicity, the governing board of the University of Lyon decided to strike out Carrel’s name and to rename its school of medicine after the less controverLyon sial physician Rene´ Lae¨nnec. Neurology in Lyon has two poles: the Antiquaille, Leriche’s most brilliant pupil was Pierre Wertheimer which sits on the hill next to the Fourvie`re Basilica, (1892–1982) who created an authentic Lyon school of and the east pole, at the outskirts of the city (Bouchet, neurosurgery. He too went to North America (in 1987). There, in Bron, the Vinatier Hospital (an asylum 1937), where he met Harvey Cushing in Boston and for insane people) was founded by Joseph Arthaud in Wilder Penfield (1891–1976) in Montreal. Back in Lyon, 1877. In 1930, a large general hospital (now named he participated in the creation, within Vinatier, of a Hoˆpital Edouard Herriot) was built nearby, including modern neurology and neurosurgical hospital inauguservices for neurology and neurosurgery. rated in 1963 and now bearing his name. There was always an obvious rivalry between the Michel Jouvet (1925–), a pupil of Henri Hermann two places. A Chair of Mental Diseases was given to (1892–1972; see Cier and Mornex, 1972), started as a Arthaud who organized the teaching of psychiatry at neurosurgeon but became famous for his sleep the Vinatier. The first neurology service was created research. Since 1935, the time of Fre´de´ric Bremer at the Antiquaille in 1897. Prominent neurologists were (1892–1982), it was known that cats with midbrain active there, including Jean Le´pine (1876–1967), who sections (cerveau isolé) were in a state of permanent was dean of the medical faculty from 1920 until World sleep. In 1949, Magoun and Moruzzi had shown that War II. He studied syringomyelic syndromes, particuhigh frequency stimulation of the mesencephalic retilarly traumatic syringomyelia. He was also interested cular formation produces an awakening reaction. in “neurasthenia,” thus becoming a pioneer of psychoNathaniel Kleitman (1895–1999) had shown that sleep somatic medicine. He organized a new medical faculty, consists of a series of alternating cycles. Together with which opened in 1930. He was strongly attached to the William Dement, they related sleep to fast electroenceRepublic and was dismissed from his position by the phalography (EEG) rhythms and to eye movements. occupying Germans for the duration of the war. In the 1950s, sleep research evolved in two direcThe Hoˆpital Edouard Herriot was the site for the tions: EEG studies in humans and experimental work of Rene´ Leriche (1879–1955), who considered research in animals (mainly cats). The latter direction

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was followed by Jouvet, who had spent a year in Magoun’s laboratory. William Dement (1958) had just described stages of sleep characterized by fast EEG activity and phasic eye movements. Jouvet had the idea of adding electromyographic studies to better define the overall picture. Together with Franc¸ois Michel, he defined what was named paradoxical sleep (PS), to be differentiated from slow EEG sleep and different also from awakening, even though the EEG is comparable (Jouvet and Michel, 1958). Jouvet and his colleagues observed desynchronized activity at the mesencephalic and pontine levels, accompanied by rapid eye movements and complete muscular atonia, during PS. They studied the so-called pontine hypnic center, showing that coagulation of the raphé pontis caudalis interrupted all the PS activities. Could the phasic eye movements be related to dreams? Jeannerod and Mouret (1963) had serious doubts about a strict correlation between the two. Jeannerod et al. (1965) studied the ponto-geniculooccipital (PGO) waves and showed that they may be the signal that generates paradoxical sleep (PS). It was also shown that they are more frequent during child development, paralleling a greater percentage of PS during sleep. Jouvet further demonstrated that PS exists only in higher vertebrates (for a recent study on paradoxical sleep networks, see Debru, 2006). Lyon has also seen the development of integrated cognitive neurosciences, as epitomized by the work of Marc Jeannerod and his colleagues in the INSERM Unit 94 (Experimental Neuropsychology) and with the more recent creation of the Institut des Sciences Cognitives (ISC), also originally led by Jeannerod. The ISC works in close collaboration with an advanced imaging center, the Centre d’Exploration et de Recherche Me´dicale par Emission de Positons (CERMEP).

Marseille The Mediterranean city of Marseille was founded about 26 centuries ago, probably by Phocean Greeks from Asia Minor (see Serratrice, 1996). During the Roman period, the city (known as Massilia) seems to have had a medical school inspired by that of Alexandria. After the end of the Roman Empire, the city declined. A full-fledged faculty of medicine (faculte´ mixte de me´decine ge´ne´rale et coloniale et de pharmacie) was only created in 1930. Neurology was initiated in Marseille by Henri Roger (1881–1955), but its major development was due to Henri Gastaut (Fig. 40.11), who was born in Monaco in 1915 and can be said to have been the glory of Marseille until his death. Following

Fig. 40.11. Henri Gastaut (1915–1995).

brilliant studies in Marseille leading to a medical degree in 1945, he became interested in epilepsy and spent 6 months in Bristol, UK, with Grey Walter. There he became thoroughly familiar with the EEG. He received the chair of pathological anatomy in 1953 and of clinical neurophysiology in 1974. He held that chair until 1984 when he became emeritus. In 1960, Gastaut created the St. Paul Center for epileptic children, now the Henri Gastaut Hospital. He was mainly interested in different epileptic seizures and their classification. He analyzed the different states of consciousness and various types of sleep. He was able to characterize photosensitive epilepsy, the syndrome of hemiplegia, hemiconvulsion and epilepsy (HHE) and childhood-onset epilepsy known as Lennox–Gastaut syndrome. In 1953, Gastaut and his colleagues showed that generalized epilepsy originates in the brain stem rather than in the cortex. Gastaut was elected dean of the faculty of medicine (1967–1970) and President of the University of Aix-Marseille II (1970–1978). Internationally, he was President of the International League against Epilepsy from 1947 to 1971 and President of the Federation of the EEG societies from 1957 to 1971. He was also a leading expert for WHO. Between 1950 and 1980, he organized Les Colloques de Marseille d’Epileptologie.

HISTORY OF NEUROLOGY IN FRANCE The last one, Henri Gastaut and the Marseilles School’s Contribution to the Neurosciences, was an official tribute from the international community (Broughton, 1982). These meetings played a great role in the creation of the International Brain Research Organization (IBRO). Neurosurgery started in Marseille in the 1930s with Marcel Arnaud (1896–1977) in association with Jean Paillas (1909–1992). When Arnaud left Marseille to become the head neurosurgeon of the French Army in Indochina, Paillas created a service of neurosurgery at La Timone. He was active in the field of traumatology and participated in the creation of the French Neurosurgical Society and of La Revue de Neurochirurgie. In the 1950s, Paillas and his pupils used the newest technologies in anesthesia, neuroradiology, and EEG. Georges Morin (1903–1979) arrived in Marseille in 1943, became assistant dean in 1947, and dean in 1952. Under his leadership a new faculty of medicine was built. The inauguration took place in May 1958 with the Timone Hospital created later (1970). He wrote “Physiologie du syste`me nerveux central” Masson (1948), a book that was used by several generations of students. In 1963, CNRS built a new Institut de Neurophysiologie et Psychophysiologie (INP) which Morin directed with the help of Jacques Paillard (1920–2006). It was one of the first institutes dedicated to comparative neuroscience. Notable researchers included Jacques Paillard, Ange´lique Arvanitaki-Chalazonitis (1901–1983), and Robert Naquet (1923–2005). At the present time, neurology and the neurosciences occupy different campuses and function in close connection with hospital services and research laboratories sponsored by INSERM and by CNRS.

CONCLUSIONS Medicine and neurology have been shaped by the specific geography and political organization of France. Violent events, such as the French Revolution, the Commune and the three wars against Germany, have played an important role. More recently, other events, such as those of May 1968, have significantly contributed to the peculiar characteristics of French neurology. The creation of CNRS in 1939 and that of INSERM in 1964 have been instrumental in giving unique features to French neurology and neuroscience in general. Today, neurology is thriving in France, but not in ways that could have been imagined 100 or more years ago.

ACKNOWLEDGMENTS This chapter is dedicated to Professor Michel Bonduelle who kindly and sagaciously guided us throughout the various phases of preparation of this chapter. The

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following colleagues provided very useful material and comments: Julien Bogousslavsky, Jean Cambier, Christian Derouesne´, Jacques Epelbaum, Stanley Finger, Bernard Guiraud-Chaumeil, Marc Jeannerod, Elisabeth Koss, Thierry Lavabre-Bertand, Philippe Lazar, Michel LeMoal, Michel Poncet, Olivier Rascol, Emmanuel Repingon, Jacques Touchon, and Suzanne Trottier. We are also indebted to the following persons who gave permission to use some of the figures: Madame Marie Ve´ronique Leroux-Hugon, curator of the Charcot library (Fig. 40.2); Madame Marie-Ve´ronique Clin-Meyer, curator of the museum of History of Medicine in Paris (Fig. 40.3); Madame Rene´e He´caen (Figs 40.6 and 40.7); and Madame Pierett Ribie`re, curator of the Sainte Anne Museum (Figs 40.8 and 40.9). Figure 40.10 is from www.baillement.com/imagebis/pitres.gif.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 41

The history of neurology in Scandinavia JOHAN A. AARLI 1 * AND RAGNAR STIEN 2 Department of Neurology, Haukeland University Hospital, Bergen, Norway 2 Department of Neurology, Ullevaal University Hospital, Oslo, Norway

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NEUROLOGY IN SCANDINAVIA The existence and treatment of neurological diseases are mentioned in written documents dating back more than 1000 years in Scandinavia. The development of neurology as a clinical specialty, which started at the end of the 19th century, is different within the Scandinavian countries. In Denmark and Finland, as in most of continental Europe, neurology evolved from psychiatry. In Sweden, neurology separated from internal medicine. In Norway, the new specialty developed on the basis of electrotherapy. Neuroscientists from all Scandinavian countries have contributed extensively to our knowledge of the nervous system and its diseases. There are two Scandinavian Nobel laureates in neurobiology.

The concept of Scandinavia The Scandinavian countries are Denmark (with the Faeroe Islands and Greenland), Finland, Iceland, Norway, and Sweden with a total population of approximately 25 million inhabitants. Denmark and Norway (with Iceland) formed a union from 1380 to 1814 while Finland was included in greater Sweden until 1809, when it became a grand duchy under the Russian tsar. Finland became independent in 1917. Norway and Sweden formed a political union from 1814 to 1905. Iceland continued its union with Denmark until 1944 when Iceland was declared an independent republic. The Scandinavian languages are very similar, and Danes, Norwegians and Swedes do communicate without translation. The Icelandic language derives from the Old Norse language, but is usually not understood by the other Scandinavians. The Finnish language is of Finnish-Ugrian background and is not used by other Scandinavians. At Scandinavian neurology meetings, the language spoken is usually English. *

The Scandinavian countries have great similarities in social and political life, and all have well-developed health care and social security systems, and a relatively large number of neurological departments. This makes Scandinavia suitable for community-based studies of common disorders.

The development of academic medicine in Scandinavia The oldest universities in Scandinavia are Copenhagen in Denmark and Uppsala in Sweden. Uppsala is the oldest, founded in 1477. Copenhagen was founded in 1479. The King of Sweden decided to set up new universities in the outlying regions of the Swedish state. Estonia and Finland were ruled from Sweden, and the University of Tartu in Estonia was opened in 1632 and the University ˚ bo (Turku) in 1640, followed by Lund in 1668. of A Uppsala soon developed an important research center, with Linnaeus as the leading scientific personality. Copenhagen represented the only center for higher education in Denmark (with Iceland and the Faeroe Islands) and Norway until 1811, when the Royal Frederik’s University in Christiania (since 1939 the University of Oslo) was founded. The University of Iceland in Reykjavik was established in 1948.

The Norse tradition In the Scandinavian countries numerous ancient skulls, up to 5000 years old, have been found showing signs of trepanation performed while the patient was alive. The reason for the operation might have been to cure epilepsy, headache or psychosis. In the Viking and medieval periods Nordic medicine seems to be in accordance with academic teaching in southern Europe. “Health poems” were known: in “Ha´vama´l,” probably created in Norway

Correspondence to: Johan A. Aarli, Department of Neurology, Haukeland University Hospital, N-5021 Bergen, Norway. E-mail: Johan. [email protected], Tel: +47-55284611, Fax: +47-55975165.

658 J.A. AARLI AND R. STIEN in the 9th or 10th century, some lines are nearly identical that the cerebrospinal fluid is produced in the ventrito lines in “Regimen Sanitatis” of Salerno, showing cles and then spreads through foramina (named after probably common sources. One of the prescriptions indifar later neuroanatomists) to the surface of the brain. cates that the Vikings knew the constrictive effects of He explains hydrocephalus as an obstruction of this ergotamine (“bad rye”) on blood vessels. The only medflow of fluid. ical doctor that got his own saga, Hrafn Sveinbjarnarson (d. 1213) of Iceland, belonged to a family with a long traCLINICAL NEUROLOGY dition of educating doctors. It is notable that both males In most countries, neurology as a clinical specialty has and females were considered doctors (“læknir”). Hrafn developed either from internal medicine or emerged treated epilepsy and performed skilled operations in from psychiatry. the same way as they did at the only academic school of medicine at that time, in Salerno. We even know that he undertook a long voyage to Italy around 1195 and that Sweden he visited the parts of Italy “south of Rome.” Two internists from the 19th century dominated the In the same period, a Danish monk, Henrik Harpesintroduction of clinical neurology in Sweden – Magnus treng, wrote a “herbal book” with prescriptions for Huss and Per Henrik Malmsten. treatment of different diseases, including headache, Magnus Huss (1807–1890) was professor of internal epilepsy and palsies, in the same common European medicine at the Karolinska Institute and head of the tradition. Quite a number of parts and fragments of Serafimer Hospital in Stockholm. His main work was different “books of medical treatment” show the same the monograph Alcoholismus chronicus with detailed accordance with the medical knowledge at the same descriptions of neurological manifestations seen in this time in the rest of Europe. condition. In 1840, Huss calculated that 20% of all patients admitted to the department of internal mediTHE DEVELOPMENT OF cine at the Serafimer Hospital suffered from disorders NEUROSCIENCES of the nervous system. Medical schools were founded at many universities in The first chair of neurology in Sweden was established Europe in the 14th century. Students from Scandinavia in 1887, only 6 years after Charcot’s appointment in Paris, attended many of them, most often Padua in Italy and as a private donation to the Karolinska Institute. It was Leiden in the Netherlands, and came back to their home named after Magnus Huss’ successor as professor of countries to develop medical research. One of them, medicine, Per Henrik Malmsten, who had demonstrated Caspar Bartholin (Bertelsen) the Elder (1585–1629), a great interest in neurology and had written clinical was the progenitor of a distinguished Danish family of papers on various neurological conditions (extramedulscholars. He was the first to describe the function of lary spinal cord tumor, cerebellar cystic malformation the olfactory nerve. His son Thomas Bartholin the Elder and transverse myelitis). Malmsten’s son, who was also (1616–1680) discovered the lymphatic system simultaa physician, donated the great sum of 100 000 riksdaler neously with and independently of the Swede Olof Rudto the Karolinska Institute as a basis for the new chair. beck (1630–1702). The eponyms “Bartholin’s glands” The Malmsten chair of neurology was the fourth clinical and “Bartholin’s duct” refer to Thomas’ son, Caspar chair in Stockholm separated from internal medicine. PreBartholin the Younger (1655–1738). viously, pediatrics, syphilology and psychiatry had been Thomas Bartholin was the teacher and inspirator of established as separate academic specialties. the most important neuroscientist of the time, Niels The first professor of neurology was Per Johan Wising Stensen (Nicolaus Steno or Stenonius) (1638–1686). (1842–1912). He had, as was true of many contemporary Stensen studied neuroanatomy in Leiden with Sylvius, neurology professors, studied neurology and neuroand Stensen’s duct is named after him. In a famous pathology with Charcot in Paris. Wising withdrew from lecture in Paris in 1665 he outlined new ideas about his position for reasons of health, after a brief period of the anatomy of the brain and heavily criticized earlier only 3 years. His department, the first in Sweden, had anatomists, like Willis and Descartes. The lecture was 20 beds situated at the Serafimer Hospital in Stockholm. published in French (“Discours sur l’anatomie du cerWising organized an outpatient clinic and made tuition veau”) in 1669. Stensen also published astonishing in neurology mandatory in medical education. He studied observations on the biomechanics of muscle (“De musspinal paralysis and mercury poisoning. culis et glandulis observationum specimen,” CopenhaWising’s successor, Frithiof Lennmalm (1858–1924), gen 1664), and (in 1669) a description of a calf with remained in the chair for 32 years. He also served as hydrocephalus where he, for the first time, observed head of the Karolinska Institute for several years, and

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in radiology. His thesis, “Apparatus and technique for Roentgen examination of the skull,” and the pioneer work Das Ventriculogram (1935, 1938), greatly influenced the development of neuroradiology. If Lysholm were known for no other advance than his stationary grid, his name would be remembered. Herbert Olivecrona (1891–1980) is the founder of Swedish neurosurgery. In the early 1930s, utilizing technical innovations of his own, Lysholm became a master at demonstrating and localizing posterior fossa tumors, which Olivecrona then operated on. Olivecrona was a true pioneer who made major contributions in practically all fields of conventional neurosurgery. Antoni had a special interest in the diagnosis of intraspinal tumors. The first operation for an intraspinal tumor was performed by Victor Horsley in 1887, and the first in Sweden took place in 1899. It soon became clear that the exact clinical diagnosis of intraspinal tumors was often misleading, and it was not until contrast myelography with thorotrast was introduced that preoperative diagnosis became reliable. Antoni realized the importance of spinal fluid examination, and studied spinal fluid physiology and pressure mechanics.

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Fig. 41.1. Nils Antoni (1887–1968), professor of neurology at the Karolinska Institute, Sweden.

was influential in the Nobel Prize elections, which had started in 1901. Lennmalm’s main scientific interest was focused on syphilis. Lennmalm’s successor from 1924 was Henry Marcus (1863–1939), a psychiatrist with an interest in cerebral localization, and in basal ganglia disorders, and he remained in the chair until 1931. Nils Antoni (1887–1968) was professor of neurology between 1931 and 1954 (Fig. 41.1). Antoni changed the scene for neurology in Sweden and was the dominating personality in Swedish neurology. He expanded his department and trained a generation of young neurologists who later became leaders of the new Swedish university clinics in neurology. In this period, the neurosciences rapidly developed in Sweden with Erik Lysholm in neuroradiology and Herbert Olivecrona in neurosurgery. In clinical neurology the expansion in the 1950s was accompanied by progress in electrophysiology and neurochemistry. Together with the medical engineer Georg Scho¨nander, Erik Lysholm (1891–1947) constructed the Lysholm skull grid, which became the first Swedish export article

Academic medicine had been taught in Finland since the establishment in 1640 of the Royal Academy of Turku, during the reign of Queen Christina, when Finland was still ruled from Sweden. In 1828 the Academy was transferred to Helsinki. A teaching hospital was established in Turku in 1759 and medical studies gained popularity under the active professor Johan Haartman (1725–1787). He was a pupil of Linnaeus from Uppsala. Haartman introduced variolation in the Nordic countries. Ernst Aleksander Home´n (1851–1926), a pathologist by training, became professor of pathological anatomy in Helsinki in 1886. Home´n had first studied in Leipzig and in Berlin, and performed neuropathological work at the University of Paris and the College de France under the guidance of Vulpian and Ranvier. Here, he studied secondary spinal tract degeneration. Home´n demonstrated that the secondary degeneration starts in the axon and then involves the myelin sheath, while the glial cells are the last to be affected. He had also followed Charcot’s clinical demonstrations and he became a pioneer in experimental neuropathology. He established a clinical neurological ward, modeled after La Salpeˆtrie`re, which became the first department of neurology in Finland. Three of Home´n’s pupils became of special importance for the development of neurology and psychiatry in Finland. Christian Sibelius (1869–1922), brother of the composer Jean Sibelius, had studied morphological

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and clinical aspects of carbon monoxide poisoning, and became the first full-time professor of psychiatry at the University of Helsinki. He was succeeded by another of Home´n’s disciples, Harald Fabritius (1877–1948), who had studied the morphology of changes after spinal knife injuries. Jarl Hagenstam (1860–1935) became the first extraordinary professor of neurology at the University of Helsinki in 1918. In 1961, an independent chair and a department of neurology were established at the University of Helsinki.

Denmark In Denmark, neurology started as neuropsychiatry. From 1860 to 1870 and onward, clinical neurology developed from the Community Hospital of Copenhagen (Department VI, Psychiatry) and the so-called Outpatient Department for patients of limited means. The pioneers were Carl Georg Lange – “nerve-Lange” (1834–1900) (Therkelsen, 2000); Frederik Kristoffer Hallager – “Denmark’s first epileptologist” (1849–1921); Alexander Friedenreich – “the Nestor of neurology” (1849–1932); and Knud Pontoppidan – “the aristocrat of neurology” (1853–1916). From Department IV, called “the Salpeˆtrie`re of Copenhagen,” a series of important neurological publications appeared. An independent department of neurology was established in 1929, with one of the physicians from Department VI, Viggo Christiansen (1867–1939), as head. In 1934, he was appointed the first professor of neurology in Denmark.

Norway Norwegian neurology has completely different roots than those of other Scandanavian countries. In the 1830s the professor of surgery at Rikshospitalet, Oslo, introduced electrotherapy in his department. This method turned out to be so popular that his junior doctors were too busy performing electrostimulation and had little time for their surgical education. He then suggested that the hospital appoint an “electriseur,” who came into operation in 1858. In 1883 the position was vacant, and the hospital management asked a young doctor, Christopher Blom Leegaard (1851–1921), to take over the responsibility for electrical treatment. Leegaard agreed, but with the specific assumption that he should have his own outpatient clinic for neurological diseases and that he should lecture the medical students in diseases of the nervous system. The professors of internal medicine rebelled, but Leegaard’s wishes were granted. Leegaard had studied neurology and neuropathology in Paris and Vienna. In 1893 he was appointed assistant

Fig. 41.2. Georg H. Monrad-Krohn (1884–1964), professor of neurology at the University of Oslo.

professor of neurology, and in 1895 he became professor and head of the first Norwegian department of neurology. In 1921 Georg H. Monrad-Krohn (1884–1964) (Fig. 41.2) followed Leegaard as professor of neurology at the University of Oslo. For four decades he dominated Norwegian clinical neurology. He had a personal influence on nearly all new specialists trained in that period, and was instrumental when new departments were formed and in who were to lead them. He was a central figure at international events in clinical neurology in his time. His book, The Clinical Examination of the Nervous System (The Blue Bible), made him world famous. It was first published in Norwegian in 1914, then in English in 1921 (11th edition in 1958), in French in 1925, in Spanish in 1943, and in German in 1950. There were also numerous reprints and revisions in between the editions. Sigvald Bernhard Refsum (1907–1991) succeeded Monrad-Krohn in 1954. Apart from the disease named after him (vide infra), he was President of the World Federation of Neurology from 1973 to 1981 (two terms). He also introduced the electroencephalography (EEG) technique in Norway in the early 1940s by means of equipment developed by Fritz Buchthal, Copenhagen. Arne Torkildsen (1899–1968) studied neurosurgery for 1 year at Queen Square and 4 years (1930–1934) with Wilder Penfield in Montreal. He came back to Oslo,

THE HISTORY OF NEUROLOGY IN SCANDINAVIA Norway, in 1935 and became responsible for the neurosurgical section at the department of neurology at the State Hospital (Rikshospitalet). In 1939, he introduced a new technique for operative treatment of hydrocephalus (ventriculocisternostomy, Torkildsen’s shunt). The technique was the first successful procedure for shunting of cerebrospinal fluid and soon became internationally known and accepted as the standard operation for obstruction of the aqueduct. In 1950, he defended his doctoral thesis at the University of Copenhagen, describing the technique and the results of the operation. He was professor of neurosurgery at the University of Cairo, Egypt, from 1950 to 1954.

Iceland In 1941 a young doctor, Kjartan Ragnar Gudmundsson (1906–1977), started a private outpatient neurological clinic in Reykjavik, Iceland. He was educated in Sweden and Denmark. In 1957 he was appointed consultant at Landspitalinn, and in 1967 he served as head of the new department of neurology at the same hospital. He was the first professor of neurology in Iceland, from 1974 to 1977. He was succeeded by Gudmund Gudmundsson (1927–1996) who was trained in London and Gothenburg.

NEUROANATOMY Niels Stensen’s (Nicolaus Steno or Nicolaus Stenonius) outstanding contributions to early neuroanatomy have already been discussed. The polar explorer and Nobel peace prize laureate Fridtjof Nansen (1861–1930) started his scientific career as a curator at the Bergen Museum, Norway. His tutor was Gerhard Armauer Hansen (1841–1912), the discoverer of the leprosy bacillus. Hansen was interested in the effects of leprosy on the nervous system and had published papers on the nervous system in non-vertebrates. He worked with Louis Antoine Ranvier in Paris and was one of the first to describe the muscular end-plate (“the nerves never merge with the muscle, but end in a triangular swelling,” 1878). Nansen became interested in similar problems and finished his thesis, “The structure and combination of the histological elements of the central nervous system,” in 1887, after having learned Golgi’s silver impregnation technique in Pavia. The thesis contains several important observations like the splitting of the afferents entering the spinal cord in caudally and cranially running fibers. He is regarded as one of the founders of the neuron theory. He is probably the first to publish evidence showing that the syncytial theory was wrong:

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I have yet not observed a single case of indubitable anastomosis between protoplasmic processes. I believe, thus, that I am entitled to affirm that a direct combination between ganglion cells, by direct anastomosis of the protoplasmic processes, does not exist. (F. Nansen, thesis, Bergen, 1887, pp. 155–156) Gustaf Magnus Retzius (1842–1919), professor of anatomy at the Karolinska Institute, was a leading neuroanatomist. His monograph Das Gehörorgan der Wirbeltiere, published between 1881 and 1884, was based upon his personal studies of the inner ear in numerous species. Retzius was one of the early supporters of Cajal’s neuron theory and became a personal friend of Cajal. Another of his major works was Das Menschenhirn (1900), published in two grand volumes with 800 figures. Jan Birger Jansen (1898–1984) could be considered the founder of “The Oslo School of Neuroanatomy” in the 1930s. The most important contribution to clinical neurology is Alf Brodal’s (1910–1988) book Clinical Neurology in Relation to Neuroanatomy (1st edition 1948). Particularly the cerebellum and its connections have been intensively studied. Jansen started these studies mainly because the Norwegian whaling industry could provide large specimens of cerebellums from whales.

NEUROPATHOLOGY Ernst Aleksander Home´n (1851–1926) of Helsinki is mentioned above. In 1900 a new professor of internal medicine, Salomon Henschen (1847–1930), was appointed at the Serafimer Hospital. Lennmalm and Henschen were contemporaries. Both were internists with a special interest in neurology. Henschen became the dominating personality and had influence upon European neurology. Salomon Eberhard Henschen had been called to Uppsala in 1881. One year later, he became a professor of medicine and chief of the clinic for internal diseases. He was attracted to neurology by two patients, one with hemianopsia and one with aphasia, and he started to track down the anatomical basis of these disorders. He established the first neuropathological laboratory in Sweden. The first of his series of studies on the visual pathways, which would bring him international renown, appeared in 1888. Henschen first studied the projections from the retina to the calcarine cortex. He then continued with the auditory, gustatory and olfactory pathways. Henschen was one of the first to apply the Golgi–Cox technique in his studies of the histology of the calcarine cortex. He also studied the anatomical background for aphasia, amusia, agraphia and

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Fig. 41.3. The European neurology delegation on their way to examine Vladimir Iljitsj Lenin in 1923.

acalculia, and published his observations in Klinische und anatomische Beiträge zur Pathologie des Gehirns, altogether eight large volumes that appeared between 1890 and 1911. Henschen first presented his observations on the visual pathways in London in 1892, later in Paris, Rome and Berlin, but was met by critical comments until 1903 in Madrid, when Cajal turned out to be a strong supporter. During his career, Henschen became a leading authority on the correlation between clinical symptoms and brain anatomy. When Vladimir Lenin suffered a stroke in 1923, with aphasia and right hemiparesis, and the Russian medical authorities wished to have an independent opinion on his condition and prognosis, Henschen was asked to be a member of the European delegation that went to Moscow to examine the Russian leader (Fig. 41.3). He was then retired, but, even though he was an internist, he was regarded as a leading expert on aphasia among European neurologists. The other medical authorities in the group were Otfrid Foerster and Oscar Minkowski from Breslau, Adolf von Stru¨mpell and Oswald Bumke from Leipzig, and Max Nonne from Hamburg. On the basis of the clinical findings and the family history, Henschen pointed out that the disorder would be rapidly progressive.

CLINICAL NEUROPHYSIOLOGY Ragnar Granit (1900–1991), a Nobel prize laureate, performed important neurophysiologic studies in Helsinki, Finland. In 1928 he spent 6 months at Sir Charles Sherrington’s laboratory at Oxford and returned there as a Fellow of the Rockefeller Foundation in 1932–1933. He spent the years 1929–1931 as Fellow in Medical Physics at the Johnson Foundation of the University of Pennsylvania. Returning to Helsinki, Granit held the office of professor of physiology from 1935 and was formally appointed in 1937. In 1940 he was called to Harvard University and to the Karolinska Institute of Stockholm, in the end deciding in favor of the latter. From 1920 to around 1947, his main research was in the field of vision, beginning with psychophysics in the 1920s and ending up with electrophysiological work from the early 1930s onward. He next took up muscular afferents, in particular the muscle spindles and their motor control. Granit studied the projection of afferents of the spinal cord and separated tonic and phasic motor neurons. He algebraically established summation of excitation and inhibition upon motor neurons, and made use of the intracellular approach

THE HISTORY OF NEUROLOGY IN SCANDINAVIA for the investigation of motor control. Nils Antoni and Ragnar Granit established the first central laboratory for clinical neurophysiology and the first EEG registration in Sweden was performed in 1948. Ragnar Granit was awarded the Nobel prize in physiology and medicine in 1967, together with Haldan Keffer Hartline and George Wald, for their discoveries concerning the primary physiological and chemical visual processes in the eye. Eric Kugelberg (1913–1983) succeeded Nils Antoni as Malmsten professor of neurology. Kugelberg became one of the pioneers of clinical neurophysiology, and was an international leader in the use of electromyography and histochemistry. He performed the first electromyography (EMG) recording in Sweden in 1944. Singlefiber EMG was introduced by Erik Sta˚lberg (b. 1930) in Uppsala in the 1970s. The method came into widespread international use after the monograph he wrote with Joze Trontelj was published in 1979. Fritz Buchthal (1907–2003) was born in Germany but settled in Denmark as a refugee from the Nazis in 1933. He had been working with muscle physiology in Germany. Buchthal developed methods for recording muscle potentials and introduced the concentric needle electrode in the diagnosis of myopathies and neuropathies, as well as for conduction velocity in peripheral nerves. He retired as professor in 1977 but continued his work in California until the 1990s.

MOVEMENT DISORDERS Arvid Carlsson (b. 1923) became professor of pharmacology at Go¨teborg University, Sweden, in 1959. When he began his pioneering studies, scientists thought that dopamine worked only indirectly, by causing brain cells to make another neurotransmitter, noradrenaline. Using a sensitive test that he had devised, Carlsson detected particularly high levels of the compound in areas of the brain that controlled walking and other voluntary movements. In animal experiments he showed that depletion of dopamine impairs the ability to move. When Carlsson treated dopamine-depleted animals with the amino acid l-dopa, the symptoms disappeared and the animals moved normally again. This led to the use of l-dopa as a treatment for Parkinson’s disease. In 2000 Carlsson received the Nobel prize in medicine and physiology, with Paul Greengard and Eric Kandel, for studies of signal transduction in the central nervous system, especially the dopamine system. Lars Leksell (1907–1986) became a professor of neurosurgery in Lund, Sweden, in 1958. He succeeded Olivecrona in 1960 as professor of neurosurgery at the Karolinska Institute. Leksell was a pioneer of stereotactic neurosurgery. The Leksell Stereotactic Frame was,

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and still is, in wide use today. Leksell and his collaborators also stand among the pioneers in the surgical approach to the treatment of Parkinson’s disease. Lund became an international center for experimental studies of neural transplantation, and the first transplantation of adrenal tissue to the striatum was performed at Lund in 1986. For a long time, the transplantation data from Lund remained the gold standard for transplantation surgery in Parkinson’s disease in Europe.

CEREBROVASCULAR DISORDERS The concept of autoregulation of the cerebral blood flow is based on Danish neuroscience. In 1934 Mogens Fog (1904–1990) published his studies on the pia vessels and their reaction to changes in blood pressure. Niels A. Lassen (1926–1997), David Henschen Ingvar (from Sweden) and Erik Skinhj (1918–1983) developed methods for measuring the cerebral blood flow (based on injections of radioactive isotopes). This group formulated the laws that describe the relation between blood pressure and cerebral circulation. Phrases like “luxury perfusion” and “Robin Hood syndrome” were coined by Lassen and his co-workers. Another branch of the Danish cerebrovascular research is the migraine studies initiated by Jes Olesen (b. 1940). David Henschen Ingvar (1924–2000), who was professor of clinical neurophysiology in Lund from 1966 to 1990, was one of the major figures in brain physiology and circulation of the 20th century. His research included wide sectors of the clinical neurosciences. Together with Niels A. Lassen, Ingvar devised a new radio isotope technique to measure regional cerebral blood flow. This led to a new era in the study of regional brain function. In 1974 Ingvar presented, for the first time, new regional cortical patterns related to language perception and production. These observations led to a re-evaluation of the classical models for cortical speech functions. Gunnar Gudmundsson (1927–1996), professor of neurology at the University of Iceland, studied the distribution of cerebral hemorrhage in Iceland. He and his group at Reykjavik described a special hereditary cerebral hemorrhage with amyloidosis, hereditary cytostatin C amyloid angiopathy, which is different from the Dutch form of hereditary cerebral amyloid angiopathy.

PERIPHERAL NEUROPATHIES Myotonia congenita, Thomsen’s disease, is named after the Danish general practitioner Asmus Thomsen, who himself suffered from the disease. He described the condition in 1876 and pointed out that it was an inherited disease.

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Melkersson–Rosenthal syndrome is named after the Swedish doctor E. Melkersson, who described the combination of recurrent facial palsies and facial edema in 1928, and the German, K. Rosenthal, who 3 years later added the lingua plicata and the trend for the condition to run in families. Eric Kugelberg described, together with Lisa Welander (1909–2001), a form of spinal muscular dystrophy with late onset. Welander first described myopathia distalis hereditaria tarda (Welander’s disease). This is an autosomal dominant myopathy with late-adult onset and characterized by slow progression of distal muscle weakness. The disorder is considered a model disease for hereditary distal myopathies and is almost only seen in Sweden and some parts of Finland. Kugelberg’s research in myology was carried further by his successor, Lars Edstro¨m (b. 1938), whose research group found that the disease is linked to chromosome 2p13. Neurology remained a specialty connected only with the Karolinska Institute in Stockholm, until the first chair of neurology outside Stockholm was created in Lund in 1950. The first professor there was Gunnar Wohlfart (1910–1961). Wohlfart had trained with Nils Antoni at the Serafimer Hospital in Stockholm between 1939 and 1944. His research activity was focused on histopathological studies of diseases of skeletal muscle, and he became an authority on motor neuron disorders.

NEUROGENETICS The Finnish Disease Heritage (FDH) consists of some rare hereditary diseases that are more prevalent in Finland than elsewhere. The FDH does not include so-called common diseases that are also hereditary (for example cardiovascular diseases). The rare diseases composing the FDH cover almost all fields of medicine, but several of them are neurological disorders, such as diseases causing mental retardation, visual impairment or deafness and blindness. On the other hand, some hereditary diseases common elsewhere (phenylketonuria and cystic fibrosis) are clearly rare in Finland. The majority of the hereditary diseases existing in Finland are not part of the FDH and their prevalence is the same in Finland as elsewhere. Otto Christian Stengel (1794–1889) worked as a general practitioner in the mining city of Rros in Norway. In 1826 he published in the Norwegian medical journal Eyr a very distinct description of a family with neuronal ceroid-lipofuscinosis, later also known as Batten–Spielmayer–Vogt’s disease. For centuries the inhabitants of a large valley in the south of Norway, Setesdalen, had been aware of an inherited disease characterized by involuntary movements and

dementia. In 1860 a local general practitioner, Johan Christian Lund (1830–1906), published his observations on this disease, described the main symptoms and illustrated the dominant inheritance with several pedigrees. This happened 12 years before George Huntington published his report on the same hereditary progressive chorea and his name became connected with it. In 1889, before Kinnier Wilson (1912), Home´n described the clinical and pathological features of hepatolenticular degeneration, but interpreted it as caused by syphilis. Brain (1916; 39: 74–114) contains a paper titled “A new familial infantile form of diffuse brain-sclerosis.” The author was Knud Krabbe (1885–1961), one of the most outstanding personalities in Danish neurology. When the famous “Psychiatric Department VI” in 1933 was divided into a psychiatric and a neurological department, he was the latter’s first chief. The described disease, globoid cell dystrophy (galactosylceramide-betagalactosidase deficiency), is usually called Krabbe’s disease. Another inborn error of metabolism with profound effects on the nervous system was described in 1934 by Asbjrn Flling (1888–1973) in Oslo, Norway. He called the syndrome “Oligophrenia phenylpyrouvica.” Later the name became “phenylketonuria.” The low phenylalanine diet in Flling’s disease was probably one of the first reasonably effective treatments in this type of inherited disease. Sigvald Refsum described in 1946 an inherited clinical entity he called heredopathia atactica polyneuritiformis. Later it was shown that the condition was caused by a deficiency in the metabolism of phytanic acid. Today it is usually called Refsum’s disease or HMSN type IV. Kari Stefansson, who had trained in Iceland, but was a former professor of neurology, neuropathology and neuroscience at Harvard (1993–1997), founded deCODE in 1996 and established a genomics company in Reykjavik, Iceland, with the intention to search for disease genes in the Icelandic population. At an early stage, they established a gene coding for essential tremor.

MULTIPLE SCLEROSIS Charles Poser, in Boston, Massachusetts, has postulated that the susceptibility to develop multiple sclerosis emerged as a mutation in the southern part of Denmark/northern part of Germany, and spread with the Vikings. In 1953, Roy Swank published a study of the epidemiology of multiple sclerosis in Norway. He found that the prevalence of the disease was highest in the valleys in the East of the country, and lowest on the islands and along the fiords in the West and North. The report was important because it induced a series of epidemiological

THE HISTORY OF NEUROLOGY IN SCANDINAVIA studies. These investigations confirmed some regional differences, without revealing any explanation. In 1944 the Danish ophthalmologist, Viggo Jensen, described the instability of eye movements in multiple sclerosis, for years called “Viggo Jensen’s syndrome.” Torben Fog (1912–1987), Denmark, was probably the most profiled Scandinavian researcher in the field of multiple sclerosis. He introduced the model of experimental allergic encephalomyelitis in Scandinavia. He was instrumental when the Danish MS Registry was started in 1956. Since then all Danish MS patients have been registered and followed, creating immense knowledge about the epidemiology, development and prognosis of the condition. In 1998 Norway established its MS Registry, based in Bergen.

INFECTIONS A large poliomyelitis epidemic in Stockholm in 1887 was studied in detail by John Gottlieb Rissler, who was an amanuensis at Wising’s department. He examined five patients dying in the acute phase of the disease and described the inflammatory changes of the spinal cord and was the first to describe phagocytosis of anterior horn cells by macrophages. He published the first study of the histopathological aspects of acute poliomyelitis and his thesis was the first Swedish dissertation in neurology. A pediatrician, Oscar Medin (1847–1927), and a pathologist, Ivar Wickman (1872–1914), who had trained with Dejerine in Paris and with Home´n in Helsinki, studied the epidemiology of the disease and put forward a hypothesis of parenteral infection and spreading of virus along nerves. In 1889, in a lecture in Bergen, Christopher Blom Leegaard put forward the hypothesis, based upon his observations of how the disease spread, that poliomyelitis was an infectious disorder. Carl Georg Lange (1834–1900) in 1872 explained tabes dorsalis as an ascending degeneration of the posterior spinal tracts secondary to an infectious neuritis in spinal roots. The description by Jean Nageottes 22 years later is usually given priority. The concept of “slow virus infection” was first introduced by Bjrn Sigurdsson (1913–1959) in Iceland. Carleton Gajdusek, who received the Nobel prize in medicine and physiology in 1967, regarded Sigurdsson as one of his scientific inspirators because of his studies on the sheep disease scrapie, which has similarities with Creutzfeldt–Jakob disease in humans. Important scientific work on scrapie and other possible prion diseases has since been performed at Keldur, Iceland, now the Institute of Experimental Pathology at the University of Iceland.

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EPILEPSY: FROM PSYCHIATRY TO NEUROLOGY Frederik Kristoffer Hallager (1849–1921), Denmark, was a psychiatrist and mainly interested in epilepsy. He rejected the idea that epileptic manifestations were of psychiatric origin, stated that epilepsy could be treated and healed, and was instrumental when special institutions for the treatment of epileptics (“epilepsi-koloniene”) were founded. Similar institutions were founded in the other Scandinavian countries and represented a better alternative than the older asylums, where the unlucky epileptics were put away. The first was established in Denmark (Filadelfia) in 1897, and an epilepsy hospital was established near Kuopio, Finland, in 1900.

THE DEMENTIAS During World War II, Gunnar Wohlfart became engaged in the study of taxi drivers intoxicated with “Gengas” – a wartime substitute for gasoline that was obtained by burning pre-treated wood in a special container placed on cars. This wood also produced carbon monoxide in low concentrations, and many drivers developed fatigue, headache and irritability. The condition was considered an occupational disorder, and Wohlfart later started a subdivision of occupational medicine that developed into a separate department. Wohlfart was a pioneer in developing departments of neuro-rehabilitation. In later years, Danish investigations have shown the occupational hazards of toxic fumes from modern industrial paints. Inhalation of these fumes may cause “painters’ encephalopathy.” The so-called concentration camp syndrome is largely defined on the basis of Danish and Norwegian investigations and follow-up of some thousands of prisoners from the Nazi concentration camps during World War II. Malnutrition, infectious diseases and stress may cause chronic dysfunction in almost any organ of the body including the brain. Similar findings have appeared in sailors from merchant ships during the war, and the “war sailor syndrome” seems to be caused only by the constant stress.

NEUROLOGICAL JOURNALS Acta Neurologica Scandinavica was first established as an international neurological journal in English that also could serve as a forum for Scandinavian neurology. With the internationalization of neurology, Acta has developed into a journal covering neurology from all parts of the world. The international journal for the study of headache, Cephalalgia, was founded in 1979 by professor Ottar Sjaastad (b. 1928) of Trondheim, Norway. Sjaastad

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was the chief editor until 1989, and he defined new entities of headache like hemicrania partialis continua and cervicogenic headaches.

THE NATIONAL NEUROLOGICAL ASSOCIATIONS In 1900, long before neurology became an approved specialty in Denmark, a few enthusiastic neuropsychiatrists founded the Danish Neurological Society. For many years this was an almost private club with about 15–20 members. When the Society celebrated its 100-year anniversary the number of members had increased to more than 400. The Norwegian Neurological Association was founded in 1920. It was very active until 1941 when the Quisling Nazi government took control of the Norwegian Medical Association. The Neurological Association was then formally discontinued as a protest, but was reorganized in 1945 after the end of the German occupation. Today the Association has about 350 members. The Swedish Neurological Association was founded in 1938 by the initiative of Nils Antoni. The Finnish Neurological Association was formed in 1961. Long before that the neurologists had been organized under the Finnish Psychiatric Association (from 1913), later renamed the Finnish Psychiatric-Neurological Association (1948).

REFERENCES Brodal A (1948). Neurological Anatomy. In Relation to Clinical Medicine. The Clarendon Press, Oxford. Hansen GHA (1881). Termination des nerfs dans les muscles du corps de la sangsue. Archives de Physiologie 2: 739– 741. Henschen SR. Klinische und anatomische Beitra¨ge zur Pathologie des Gehirns. Almqvist and Wiksell, Stockholm (volumes I–IV); Nordiska Bokhandeln, Stockholm (volumes V–VI); the author’s own publication, Stockholm (volume VII–VIII). Krabbe K (1916). A new familial infantile form of diffuse brain sclerosis. Brain 39: 74–114. Lysholm E (1931). Apparatus and technique for roentgen examination of the skull. Thesis. Acta Radiologica (Suppl) 12: 1–120. Lysholm E, Ebenius B, Sahlstedt H (1935). Das Ventrikulogramm. I Teil. Ro¨ntgentechnik. Acta Radiologica (Suppl) 24: 1–75.

Lysholm M, Ebenius B, Lindblom K, et al. (1937). Das Ventrikulogramm. II Teil. Dritter und vierter Ventrikel. Acta Radiologica (Suppl) 26: 1–199. Monrad-Krohn GH (1954). The Clinical Examination of the Nervous System. HK Lewis, London. Nansen F (1887). The Structure and Combination of Histological Elements of the Central Nervous System. Thesis. John Grieg, Bergen. Poser C (1994). Dissemination of multiple sclerosis: a Viking Saga?, Ann Neurol 36 (Suppl. 1) pp. 8–14. Retzius GH (1884). Das Geho¨rorgan der Reptilien, der Vo¨gel und der Sa¨ugethiere. Samson & Wallin, Stockholm. Retzius GH(1896). Das Menschenhirn, Studien in der makroskopischen Morphologie. Norstedt, Stockholm. Swank RL, Lerstad O, Strom A et al., (1952). Multiple sclerosis in rural Norway; its geographic and occupational incidence in relation to nutrition. N Engl J Med 246: 721–728. Therkelsen J (Ed.) (2000). Festskrift. Dansk Neurologisk Selskab 1900–2000. Lægeforeningens, Copenhagen.

FURTHER READING Haltia M, Kivalo E (1992). The early development of neurology in Finland. Cogito (lt. J. Neurol) (Suppl) 1: 29–31. Marquardsen J (1989). The history of neurology in Denmark. Cogito 1: 25–27. Norio R (2003). Finnish Disease Heritage I–III. Human Genetics 112: 5–6. Norrving B (1989). The development of Swedish Academic Neurology. Cogito 1: 33–34. Norrving B (1992). Poliomyelitis. Development of concepts in the 19th century. Cogito (lt. J. Neurol) (Suppl): 59–61. Sivenius J (1989). History of epilepsy treatment in Finland. Cogito 1: 21–23. Sourander P (1970). Scandinavian brain research at the end of the 19th and the beginning of the 20th century. In: Yearbook of the Museum of Medical History. Sma˚landspostens Boktryckeri AB, Stockholm, pp. 1–21. Stien R (2004). Neurology of the Nordic sagas. In: F Clifford Rose (Ed.), Neurology of the Arts. Imperial College Press, London, pp. 389–399. Winkelman NW (1953). Salomon Eberhard Henschen. In: W Haymaker (Ed.), The Founders of Neurology. Charles C. Thomas, Springfield, IL, pp. 179–184.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 42

Neurology and the neurological sciences in the German-speaking countries HANSRUEDI ISLER * Private practice, Hochhaus zur Schanze, Zürich, Switzerland

INTRODUCTION Several salient features have affected the development of neurology in the German-speaking countries. First, one should mention the Germanic preoccupation with Weltanschauung, or world-view, linking science and spirituality. Vitalists insisted on Lebenskraft, life-force, as the specific property of living beings. The controversial medical sects of animal magnetism and phrenology insisted on dogmatic principles, and yet advanced research and the scope of clinical medicine. And there were great teachers with open minds and brilliant students. The impact of the Vitalist Johannes Mu¨ller and his mechanistic students on natural science and medicine was unparalleled, to think of only three of his many illustrious pupils: Hermann von Helmholtz, Rudolf Virchow, and Emil du BoisReymond. The dominance of the Germanic discipline of neuropsychiatry from 1845 to the 1970s played a key role. Modern psychiatry and neurology evolved together, and neuropsychiatrists might be absorbed by their mental patients during the day, and equally absorbed by their brain tissue slides at night, as in the case of the close friends Alzheimer and Nissl at Frankfurt. Evaluating the way neurology evolved in the German-speaking countries brings yet more areas together, and demands a broad interpretation of neurology. The study of the growth of clinical neurology will bring philosophy, psychiatry, neuroanatomy, chemistry, psychology, physiology, and even general surgery into the picture, as they were all instrumental to this development.

*

FROM THE MEDICAL REVOLUTIONS OF THE 16TH TO THE END OF THE 18TH CENTURY The 16th century: a new language, two medical revolutions, and the brain Medical texts were written in Latin up to the mid1830s, but the Swiss physician Paracelsus (1494–1541) used German for direct impact. He replaced the scholastic medicine of Islamic and Galenic origin with his own empirical and chemical doctrines. He explained the pathogenesis of mental and convulsive disorders in chemical and physical terms, and described convulsions and insanity after head trauma, recommending chemical remedies and even poisons, including arsenic and antimony. He replaced traditional mystical notions with natural explanations, but also with mystical concepts of his own. Andreas Vesalius (1514–1564), then in Padua, replaced Galenic anatomy with illustrations of his own dissections. He rejected the medieval localization of brain functions in the ventricles, and established a new anatomy of the nervous system. He chose a student of Paracelsus, Oporinus at Basel, as publisher for his great atlas, De Humani Corporis Fabrica, of 1543. Another Paracelsan, Felix Wuertz of Basel (1518– 1574), wrote in German the first tract on pediatric surgery (published 1616, see Fig. 42.1; English translation 1656). He tried to abolish the common practice of treating open skull fractures with ointments and medicated rags, thus preventing cerebral edema by abstaining from introducing any foreign substance, “lest the brain revolt and boil up from the wound” (Wuertz, 1563).

Correspondence to: Hansruedi Isler MD, Neurologist FMH, Private Practice, Hochhaus zur Schanze, Talstrasse 65, CH-8001 Zu¨rich, Switzerland. E-mail: hansruedi.isler @hin.ch, Tel: þ41-3611359, Office: þ41-2102898.

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Fig. 42.1. Felix Wuertz, Basel (1518–1574), friend of Paracelsus: A Beautiful and Useful Children’s Booklet, Basel 1616, many editions up to the mid-17th century – “First work dealing with infant surgery” (Morton, 1970). Wuertz (1563) warned against the usual insertion of ointments and rags into open skull wounds, lest the brain “boil up.” He said that children who complained of headache should be taken seriously, and protected from light, judging from his own experience.

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The 17th century: Bacon’s new science invades medicine During and following the medical revolution initiated by Paracelsus and Vesalius, new patterns of discovery replaced Aristotelian logic and natural philosophy (Jones, 1936; Hoppen, 1970). Bacon, Copernicus, Galilei, Kepler, van Helmont, Gassendi and others created the “new science” of nature based on observations and experiments. In 1628 William Harvey (1578–1657) introduced scientific methodology in medicine by proving that the circulation of the blood could be measured. In his wake, Thomas Willis (1621–1676) developed neurology and coined this term. He conducted systematic brain research based on autopsies, comparative anatomy, animal experiments, his own biochemical and reflex theories, and the work of interdisciplinary teams. Willis’s Anatomy of the Brain of 1664 inaugurated neurology, including the name, and his book of 1672, the Soul of Animals, was the first textbook on neurophysiology and neurological diseases. Willis’ Swiss contemporary and correspondent, Johann Jakob Wepfer (1620–1695), reformed the knowledge of strokes and the cerebrovascular system in 1658. He introduced dye injection of cerebral vessels, created experimental toxicology with a team of collaborators in 1679, and recorded cases of neurological diseases of the head, which were published posthumously in 1727. In this book we find trigeminal neuralgia, surgical treatment of subdural hematoma, basilar migraine, and migrainous stroke. It was frequently quoted by Tissot in his Traité des nerfs (see below).

Contrasting views of the body–soul problem, and of brain research In the second half of the 17th century, Willis’ student, John Locke (1632–1704), and his antagonist, Gottfried Wilhelm Leibniz (1646–1716), emancipated themselves from Aristotelian scholastic philosophy with the help of Gassendi’s works. Contrary to Descartes, Gassendi (1592–1655) held that animals and the human body have a material soul, which is the link between the body and the immortal rational soul of man. This notion was adopted by Willis. But Leibniz simplified the body– soul problem: both cannot interact at all; there is only a pre-established harmony between the two. Locke and Sydenham criticized the early use of the microscope in research and denounced many physiological arguments of the 17th century as science fiction. Skeptics, such as Niels Stensen and, in the 18th century, Albrecht von Haller, criticized Willis’ descriptions of brain tracts and reflex action as figments of imagination. The belief of the followers of Leibniz in the impossibility of causal interaction of body and soul,

and the criticism of speculative brain research by Sydenham, Locke, Stensen, Haller, and others, resulted in declining interest in research on the nervous system.

The 18th-century mainstream: Albrecht von Haller (1708–1777) Haller, a renowned Swiss-German poet from Bern, was deeply religious, and yet a protagonist of the Enlightenment. At age 28, he became the leading figure in the new Hanoverian university at Go¨ttingen, where the imprint of his personality still lasts. His experimental physiology, topographic anatomy, and medical bibliography in Latin and French were monumental in extent and extremely influential. They were also instrumental for many discoveries of the 19th century. The Austrian emperor Joseph II reformed medical education in his empire according to Haller’s views (Lesky, 1965). Haller was a major contributor to the Encyclopédie of Diderot and d’Alembert, where his anatomical tables were published (Lough, 1973). He improved the topographic anatomy of the brain, the spinal cord, and the peripheral nerves. His doctrine of irritability for muscles and sensibility for nerves did not improve the understanding of nerve function, but had a considerable following. When Franc¸ois Boissier de Sauvages tried to demonstrate electric nerve conduction, Haller (1762, IV, 378– 380) dismissed the idea. Haller’s skepticism contributed to the loss of interest in brain research in the 18th century until, one year after his death, his friend S.A.D. Tissot of Lausanne stressed the importance of nervous diseases in his clinical Traité des nerfs (1778–1780). This work was a main source for 19th-century French neurologists and was soon translated into German.

Animists and Vitalists from Stahl to Mu¨ller: interaction of body and soul In the same period, a contrasting school of medical thinking arose in Germany: Animism, later turning into Vitalism. In 1694 Georg Ernst Stahl (1660–1734) became professor of medicine at the Pietist Prussian University of Halle. His psychosomatic doctrine of the soul, which controls the body in health and disease, was an extreme version of Gassendi’s and Willis’ concept of the “soul of animals” as the principle of function of the nervous system. Stahl’s school survived during the first half of the 18th century. Stahl’s other line of research was his chemistry, and he proposed phlogiston as the substance of combustion in burning bodies (not oxygen in the air, which had been investigated by Mayow, Boyle, Hooke and Willis before, and was rediscovered later by Priestley and Lavoisier).

670 H. ISLER Stahl’s Skiamachia, a heated dispute with Leibniz body by near-touching gestures. In analogy to electroon the role of the soul, was published in 1720. Stahl’s therapy, which had been popular since the invention Animist school, continued by Juncker, was open, howof a storage device, the Leyden bottle, in 1745, he ever, to new ideas. Notably, Kru¨ger proposed electrodesigned a storage device for his magnetic force, the therapy in a lecture at Halle in 1743 (published in baquet, and methods for conduction of this force. 1744) and Kratzenstein, his student, reported the first Mesmer cured blindness in a young woman, which successes with it (in Denmark) in 1745. The first acamade him famous, but also led to problems for the girl, demic dissertation about this new cure was defended and his prospects in Vienna deteriorated. He left for at Halle by Oppermann in 1746 (Fig. 42.2). Paris in 1778. There he found considerable support, but Stahl’s disciple, Johann August Unzer (1727–1799; also heavy criticism, which eventually led to official Fig. 42.3), adopted Willis’ concepts of reflex action inquiries. The investigations led to early double-blind and traceable tracts in the brain. This was rejected by tests of his theory, which was found to lack physical Haller, but followed by Johann Christian Reil (1759– correlates, and the Franklin commission of 1784 wrote 1813; Fig. 42.4), head of the Vitalist school, who coined that his cures could be completely explained by sugthe term “psychiatry,” founded psychiatric hospitals gestion (Gauld, 1992; Finger, 2006). Nevertheless, for humane treatment of the insane, and perfected the Mesmer’s techniques and clinical successes paved the method of hardening brains in alcohol by adding alkali. way to suggestion and hypnosis in the medical practices This method allowed Reil to trace tracts by the blunt disof the schools of Bernheim and Charcot, and to new section method introduced by Willis, shedding light on ideas of putative physical effects on functional illness, possible pathways for reflex action. These advances such as patients’ condition (Gauld, 1992). enabled him to define the insula, the lemniscal system, One protagonist of animal magnetism, Justinus the lenticular nucleus, the claustrum, the internal and Kerner (1786–1862), discovered botulinum toxin and external capsules, and the corona radiata. He believed investigated it (1821–1822) by animal experiments and that the structure of the brain consisted of convolutions a self-test (Gru¨sser, 1982). It became an important drug and nuclei, but he could not explain their interactions. for neurological treatment 175 years later. Unzer also inspired Georg Prochaska (1749–1820; Another Viennese neuroscientist, Franz Joseph Gall Fig. 42.5), who held the chair of physiology at Vienna (1758–1828), came forth with the concept of multiple up to 1820. He devised an early electrical theory of organs of the mind, based on the physiognomy of “nerve-force” (earlier proposed by Sauvages, and Mesmer’s friend Lavater. Gall was an outstanding brain rejected by Haller). Essential texts by Unzer and Proanatomist. Like Willis (1672, ch. 4) a century earlier, he chaska were translated into English (Laycock, 1851). In believed that he could define specific parts of the brain this way the forgotten neurological concepts of Willis as the “organs” or instruments of the soul. He studied returned to England via the German-speaking countries. the gray and white matter, the cranial nerves and their “Animism” and “Vitalism” became increasingly disorigins, and traced several tracts. He identified the corparaging terms during the 19th century, and the depreciatex as the origin of cerebral functions, and proposed tive attitude toward this school continued from Haller’s specific cortical organs as the instruments of the soul, critical remarks to recent interpretations of the history localizing the memory for words in both frontal lobes. of medicine. But the Vitalists saved the knowledge of Like Willis, Gall made use of findings from clinical 17th-century brain research and neuropsychiatry, despite cases and pathological and comparative anatomy. He the prevailing belief in the separation of body and soul. even observed one case of a left frontal lesion with The most important Vitalist after Reil was Johannes Mu¨laphasia and right hemiplegia, explaining that unilateral ler who initiated the explosive growth of science and medlesions damage the balance of the bilateral brain icine during the 19th century (Fig. 42.6). organs. As he believed that the skull was a precise bony cast of the brain, he examined the skulls of thousands of probands and patients, among them 500 imprisoned Animal magnetism, phrenology and brain criminals. He proclaimed that mental diseases are brain research: one-way to Paris diseases (Lesky, 1979), and that criminals should be In 1766 Franz Anton Mesmer (1734–1815) in Vienna educated, not punished (Lesky, 1965). wrote a thesis about the influence of the moon and Gall called his doctrine “organology” at first, the planets on the course of disease. He believed that derived from Willis’ concept of brain parts as the human body responded to their forces like the “organs.” But this theory of discrete cortical organs sea with its tides, and treated patients according to this as tools of the soul angered the Emperor Francis II theory of “animal gravitation.” Later he explained that and his personal physician, Stifft. They feared that it he restored the flow of the “magnetic fluid” in the would lead to materialism, and they suppressed his

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Fig. 42.2. Thesis on electrotherapy, 1746, Oppermann/Juncker. Stahl’s and Juncker’s Animist medical school at Halle encouraged innovations. J.C.U. Oppermann defended his thesis on the then new electrotherapy in 1646, and another one on “hemicrania horaria” in 1647, anticipating chronic paroxysmal hemicrania.

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Fig. 42.3. Johann August Unzer (1727–1799). A follower of Stahl, Johann August Unzer renewed the brain research of Willis – his theory of localization, method of following tracts, and concept of reflex action. An abridged English translation of his neurophysiology was published by Hughlings Jackson’s teacher, Thomas Laycock, in 1851. Laycock traced Unzer’s concepts back to Willis through Wedel.

popular private lectures on the brain and its organs. He left Vienna in 1805, toured Europe while presenting his doctrines, and, like Mesmer, made his way to Paris, where he settled in 1807. His assistant, Johannes Spurzheim (1776–1832), whose doctrine eventually diverged from that of Gall, propagated his system in Britain, whence it reached the USA. Spurzheim called his system “phrenology,” a term that has since that time been more broadly applied, so as to include Gall’s system too. Spurzheim’s doctrines in particular had a great influence on “moral” psychiatry in these countries (Lesky, 1965; Finger, 2000). Gall’s work is also discussed in Chapter 40.

THE 19TH CENTURY: THE IMPACT OF JOHANNES MLLER,VITALIST, AND HIS STUDENTS WHO TURNED AGAINST VITALISM Johannes Mu¨ller in Berlin: new patterns of discovery Moritz H. Romberg’s textbook of neurological diseases, from 1840 to 1846, inaugurated neurology in Berlin. But

Fig. 42.4. Johann Christian Reil (1759–1813), head of the Vitalist school, followed Unzer’s and Prochaska’s doctrines of voluntary, partly conscious and unconscious brain functions, and their ways of brain research. He perfected the method of preserving brains and discovered unknown tracts, the insula of Reil, the nuclei and other distinct parts of the brain. He strove to reform the care of the insane, declared that mental diseases were brain diseases and introduced the term “psychiatry.”

this clinical work was far less crucial for the development of neurology than the innovations in the neurological sciences initiated by his contemporary in Berlin, Johannes Mu¨ller (1801–1858). With his own work and through his students, Mu¨ller was the man behind the discovery of the animal cell and the nerve cell with its axon and dendrites, the neuroglia, neuromorphology, cellular pathology, electrophysiology, nerve conduction velocity, the ophthalmoscope, sensory physiology, experimental psychology, and the physiology of hearing, sound, and speech production. Indeed, Mu¨ller launched his students on their particular trajectories, and some of them developed entirely new scientific disciplines. Yet he was a Vitalist in the tradition of Reil (Lohff, 2001; Finger and Wade, 2002; Otis, 2007). Mu¨ller was a professor of anatomy and physiology, and director of the anatomical theater and the anatomical-zootomical museum in Berlin from 1833. He integrated physics, chemistry, microscopical anatomy, and psychology with physiology. When he first investigated

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Fig. 42.5. Georg Prochaska, a “Vitalist” eye specialist, was Professor of Physiology at Vienna from 1791 to 1820. He followed Unzer’s Willisian research methods and established an electro-galvanic theory of nerve action. His neurophysiological essay was translated into English in 1851 by Thomas Laycock, together with Unzer’s abridged Principles of Physiology.

“phantastic visual phenomena” (1824–1826), he founded the doctrine of specific nerve energy, stating that the modality of the sensory impression elicited by a stimulus depends on the sensory organ, not on the stimulation. Mu¨ller and Purkinje were among the first to use microscopical-anatomical research in a systematic way, after microscopy had been relegated to the status of a toy by the 17th–18th-century skeptics Sydenham and Locke. Mu¨ller’s students were to harvest most of the fruits of this new method, but Mu¨ller’s influence was a consistent factor in their work. In 1835 Mu¨ller mentioned the similarity of chorda dorsalis elements in the embryo to plant cells, described the nucleus of cartilage cells, and recognized that the elements of the black pigment in the eye and of fatty tissue were of the same kind as the chorda elements, thus preparing the ground for Schwann’s discovery of the animal cell in 1839. Mu¨ller coined the term Bindegewebe (connective tissue) to

Fig. 42.6. Johannes Mu¨ller, Vitalist, 1801–1858, Berlin, assembled the available scientific methods, microscopy, morphology, biochemistry, physiology, psychology, teaching interdisciplinary research which led to electrophysiology and cellular pathology. His school established the scientific infrastructure of medicine.

replace the earlier Zellgewebe (cellular tissue). His new comparative anatomy derived the more complicated forms of animals from simpler forms by embryological observation. Mu¨ller’s Handbuch der Physiologie (1834–1840) included psychology, as well as the physical and chemical correlates of physiological processes, and allowed for a better appreciation of the excretory glands. This work was translated into English in 1840, and into French in 1845, and it became instrumental in the psychosomatic developments in French neurology and psychiatry. When Mu¨ller died, he had to be replaced by four professors. Some of his most successful students, Bru¨cke, du Bois-Reymond, and Helmholtz, conspired, as they said, against any future publications of Vitalist ideas.

Mu¨ller’s students who revolutionized science, medicine and neurology Ernst Wilhelm von Bru¨cke (1819–1892), a German, was called to Vienna in 1849, because the morphological and descriptive method of the Vienna School had to

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be augmented by modern physiology (Lesky, 1965). Bru¨cke had wanted to become a painter, and his interest in art and theories of art never left him. In his Latin thesis of 1842, “On the diffusion of liquids through dead and living septa [semipermeable membranes],” he intended to replace the “vital force” of the Vitalists by measurable physico-chemical forces. His life’s work was dedicated to the search for evidence of the role of these forces in physiological processes. He brought German laboratory medicine to Vienna, and his students combined it with traditional Viennese bedside medicine. He was the teacher of Tu¨rck, Obersteiner, Quincke, Freud, Breuer, and Wagner von Jauregg. Bru¨cke saw the advantages of combining physiological and microscopical techniques with chemical methods, and he began to study chemistry autodidactically as soon as he became interested in the intestinal tract, where his microscopical studies yielded new insights on the function of the villi and of “Peyer’s glands.” He became a pioneer of enzyme research, and he transcribed the mechanistic theory of cell function into a biological one. Bru¨cke and his laboratory initiated or mediated many discoveries by guest researchers, among them Tu¨rck and Czermak’s laryngoscope, and Tu¨rck’s use of Helmholtz’s ophthalmoscope in neurological disorders. According to Helmholtz, Bru¨cke’s questions about light reflected by the retina led Helmholtz to the invention of the ophthalmoscope. Bru¨cke also investigated the whole field of speech, from its neurological sources to the movements of the lips, and from aphasia (which, because of Bru¨cke, became Freud’s main topic in clinical neurology) to phonetic peculiarities of Arabic words. “Principles of physiology and systematic relationships of speech sounds” (in German, Bru¨cke, 1856) eventually led to the invention of the “labiograph,” which measured the duration of syllables in verses, and to the “physiological principles of Modern High German verse” (1871). Emil du Bois-Reymond (1818–1896) was the son of a watchmaker from the French-speaking Prussian duchy of Neuchaˆtel in Switzerland. As a young student he met Johannes Mu¨ller, whose depressive behavior he disliked at first. But Mu¨ller invited him to work in his laboratory and museum and launched him on a most successful career. Du Bois-Reymond developed the modern science of electrophysiology and became Mu¨ller’s successor in the Berlin chair of physiology and permanent secretary of the Berlin Akademie der Wissenschaften (Academy of Sciences). Du Bois-Reymond was the first to demonstrate electric currents in nerves, 50 years after Galvani’s frog experiments, provoking heated reactions from supporters

of Italian priority claims. He demonstrated electrical activity of muscles and nerves at rest and during movement. In 1842, he published Ueber den sogenannten Froschstrom und die elektromotorischen Fische (“On the so-called frog current and on the electromotor fish”). He had written a thesis in Latin on “The arguments on the electrical fish that are found in ancient authors,” and in 1848, 1849 and 1860 gave a comprehensive account of electrophysiology in the three volumes of Untersuchungen über die thierische Electricität (“Investigations on animal electricity”), the basic textbook of his new science of electrophysiology. The historical introduction is still the most complete description of the previous development of the subject, and includes several quaint descriptions of du Bois-Reymond and his science, including his German version of an Italian sonnet on Mrs. Galvani, and his own woodcut of a panicking horse about to drown in a South American swamp after a discharge by an electric eel; an image based on the verbal description of Alexander von Humboldt, who witnessed the epic battle of horses and eels in 1800. These tendencies, paradoxically coupled with mechanistic hard-headedness, enabled him to reconcile the valid data from Galvani’s romantic school of “animal electricity” with those from Volta’s more mechanistic research in electrophysics. After 1850, he promoted his new “physics of nerves and muscles” in French and English-speaking countries by traveling first to Paris and then to Britain. In functional neurology, arguing from his experiences with his own migraines, he proposed the pathogenetic theory of “white” migraine, resulting from angiospasm, or sympathetic overactivity, as opposed to Mo¨llendorff’s theory of “red” or angioparalytic migraine, attributed to sympathetic failure. Friedrich Leopold Goltz (1834–1902) of Ko¨nigsberg investigated decerebrate frogs and frogs deprived of their spinal cords. His demonstrations fascinated Sherrington, who went into neurophysiological research with him. In 1870, Goltz showed that vertigo is related to disorders or irritation of the semicircular canals, attributing the effect to hydrostatic pressure. This was superseded by the endolymph flow theory of Mach and Breuer in 1873. Ernst Haeckel (1834–1919) was literally recruited as a student by Mu¨ller, who took him on an excursion to Helgoland where they studied marine zoology for one month. He was a prolific artist and Mu¨ller directed him toward morphology. He continued his studies under Koelliker and Virchow at Wu¨rzburg. Haeckel became the protagonist of Darwin’s evolution theory. In its defense, he wrote Die Welträthsel (“The world’s riddles”) in 1899, which was soon translated into English and about 30 other languages. He

NEUROLOGY AND THE NEUROLOGICAL SCIENCES IN THE GERMAN-SPEAKING COUNTRIES 675 established the “biogenetic principle” where ontogentactile end organs, Pacini’s corpuscles. In 1883, he esis replicates phylogenesis. described the development of the eyes and the organ Haeckel’s student, Richard Semon (1859–1918), of smell in human embryos. In 1885 he declared that expanded his “biogenetic principle,” creating, in 1904, the cell nucleus is the seat of heredity. In 1889 he “Mnemism.” He proposed that genetic memory is identifinally proved that all nerve fibers are nothing more cal to individual memory, since both enable living beings than continuous processes from nerve cells. to record experiences as “engrams” and to “ekphore” Koelliker was the principal teacher of Friedreich. (actualize) them. This late Vitalist concept of a basic propAnd when Santiago Ramo´n y Cajal first presented his erty of living matter was accepted by several leading neusilver impregnations of nerve fibers to an international ropsychiatrists, who integrated it in their “neurobiology” audience, Koelliker recognized this as an historical and “psychobiology.” This group included Forel, Monabreakthrough – he reviewed Cajal’s slides with him kow, Eugen Bleuler, and Adolph Meyer. and then declared his support for Cajal’s neuron theory Hermann von Helmholtz (1821–1894), a military surto this audience. geon, wrote a medical thesis in Latin on the structure of Carl Ludwig (1816–1895) had initiated physiological the nervous system of invertebrates. After correctly estiresearch in Marburg and in Zu¨rich. In 1855 he came mating the speed of the nervous impulse (around 1850), to Vienna, where he taught at the Josephs-Akademie his main field of research became sensory physiology. for army surgeons. Bru¨cke and Ludwig brought He invented the ophthalmoscope, his “Description mechanistic physiology to Vienna. In 1865, he left for of an eye-mirror for the examination of the retina in Leipzig, which he made into a center for physiologists the living eye,” in 1851. He gave the instrument to his of all countries. Sensory physiology had already been friend Bru¨cke when he visited him in Vienna, and established there by Fechner, and was to be further Bru¨cke gave it to Tu¨rck who immediately discovered enhanced by Wundt, who established his own laboratory papilledema as a symptom of brain tumor. there in 1879, and by Ludwig’s successor, Hermann. Helmholtz also developed plausible theories of color Ludwig was of the same anti-Vitalist persuasion as vision and of hearing. Die Lehre von den TonempfinBru¨cke and his friends, and he explored the physiology dungen (in literal translation, “The doctrine of the of autonomic nerves and identified vasomotor centers perception of sounds”, (Helmholtz, 1863)), published in the medulla oblongata (with Thiry in 1864). in 1863, contains Helmholtz’s resonance theory. Ludwig was a great inventor of research instruments Helmholtz, like Fechner, who was 20 years his and his well-endowed laboratory at Leipzig made Wundt’s senior, Mach, who was 17 years younger, and Wundt laboratory of experimental psychology look poor in comcombined research in physics with studies in sensory parison. One of Ludwig’s early inventions was his “Kymophysiology. But Fechner and Mach were professors graphion,” which was to become the main recording device of physics who became neurophysiologists, while in physiological experiments for the next 120 years. Helmholtz, a physician, became a professor of physics Hermann Munk (1839–1912) was one of Johannes late in his life (Wundt, in contrast, became the father Mu¨ller’s last students. His appointment to the Berlin of modern experimental psychology). In 1847 HelmVeterinary School in 1876 permitted him to make full holtz had published his Ueber die Erhaltung der Kraft use of a physiological laboratory. He studied localiza(“On conservation of force”) in Berlin, confirming tion of visual, acoustic, and somatosensory functions Robert Mayer’s doctrine of 1842, and Leibniz’s earlier in dogs and macaques. After precise ablations of the theory. In his later years he studied the laws of occipital cortex, he identified contralateral hemianopia, electricity and related subjects. whereas previous researchers had erroneously Friedrich Gustav Jakob Henle (1809–1885) demondescribed monocular blindness. He also discovered strated, with Koelliker, involuntary muscle fibers in typical cortical and psycho-visual blindness (Rindenthe blood vessel walls, and described end organs of senblindheit und Seelenblindheit). The great impact of sory nerves, the endothelium, and the vascular loops in his achievements – localization of the principal sensory the kidneys named after him. “Modern knowledge of functions of the brain – and his influence on later the epithelial tissues starts with Henle” (Morton, 1970). researchers, such as von Monakow and Brodmann, Rudolf Albert von Koelliker (1817–1905), from Zu¨rhave not been sufficiently appreciated. ich, in Wu¨rzburg, described smooth muscle fibers, and Eduard Friedrich Wilhelm Pflu¨ger (1829–1910) wrote the first textbook of human histology. He was established the laws governing the make-and-break stiinstrumental in the further development of neuroanatmulation of nerves by galvanic current in 1859. His omy and cellular pathology, and was especially interjournal Pflügers Archiv der gesamten Physiologie ested in nerve endings. Together with Henle, he was a mainstay of physiological research up to the described (in 1842) the structure and function of the 20th century.

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Robert Remak (1815–1865) was one of the first Jews to receive an academic position in Germany. He described unmyelinated sympathetic fibers in 1836, axon cylinders of myelinated fibers and dendrites in 1837, the continuity of nerve cells with their axons in 1838, and the three germ layers and the main differences between dendrites and axons in 1855. In 1844, he gave the first microscopical illustration of the six-layered cortex that had been demonstrated macroscopically by Baillarger in 1840. He first described the tangential cortical fibers and nerve cells within the heart. Remak coined the phrase omnis cellula e cellula, meaning every cell comes from a cell, thus preparing the ground for Virchow’s highly influential “cellular pathology.” Matthias Jakob Schleiden (1804–1881) described the cellular structure of plant tissue and the nucleus of plant cells in his Beiträge zur Phytogenesis (“Contributions to the generation of plants,” (Schleiden, 1838)). Casual talks with his colleague Theodor Schwann (1810–1882), professor of anatomy and physiology at Louvain, motivated Schwann to describe the animal cell and the myelin (Schwann) sheath of nerves in his Mikroskopische Untersuchungen über die Uebereinstimmung in der Struktur und dem Wachsthum der Thiere und Pflanzen (“Microscopical investigations of the analogy in structure and growth of animals and plants,”) (Schwann, 1839). This pivotal work and Schleiden’s equally important Beiträge zur Phytogenesis were published in English by the New Sydenham Society in 1847. Rudolf Ludwig Karl Virchow (1821–1902) discovered neuroglia in 1854. He created cellular pathology (Die Cellularpathologie in ihrer Begründung auf Physiologische und Pathologische Gewebelehre, (Virchow, 1858)), “one of the most important books in the history of medicine” (Morton, 1970), on foundations laid out by Mu¨ller, Remak, Schleiden, Schwann, Koelliker, Henle, and others. He was the sovereign master of pathology for decades. He was also interested in physical anthropology and craniology, and in public hygiene. The perivascular spaces in the brain are named after him. Wilhelm Wundt (1832–1920) founded experimental psychology. As a student he solved a prize question on the neural control of respiration with animal experiments, and published a paper on it with Mu¨ller in Berlin. He worked as a physiologist in Helmholtz’s laboratory at Heidelberg and published his Beiträge zur Theorie der Sinneswahrnehmung (“Contributions to a theory of sensory perception”) from 1858 to 1863 (Wundt, 1858–1863). Wundt combined experimental and historical research. His Grundzüge der physiologischen Psychologie (“Principles of physiological psychology”) of 1873–1874 was one of his most important early books. The second volume of 1874 has been acclaimed as the first comprehensive textbook of experimental psychology (Bringmann et al., 1980a). William James reviewed it in depth in 1875, with

the amusing conclusion that “unless consciousness served some useful purpose, it would not have been superadded to life.” In 1874, Wundt was made professor of “practical” or inductive philosophy at Zu¨rich where his lectures included experiments in sensory physiology. He moved to Leipzig in 1875, where he opened the first formal psychology laboratory in 1879 (Bringmann et al., 1980b). In 1881, he founded the first journal for psychology research. Among Wundt’s trainees were some Americans, who went back to their country to teach and conduct research in new psychology departments, among them William James. He also worked with some eminent European physicians, such as Kraepelin and Mo¨bius, reinforcing the already vigorous movement of neuropsychiatry by adding neuropsychology to its instruments. Wundt’s physiological (experimental) psychology was first influenced by Helmholtz’s “unconscious inference,” then it turned to “elementarism,” approximating English associationism, and the ideas of J.S. Mill, describing the mind in terms such as the elements of sensation, sub-divided in time. In 1896, Wundt proposed a 3-dimensional theory of interaction of sensory and affective elements. In 1902, the doctrine of apperception (perception of the act of perception, and of the perceiving subject) was integrated into the 3-dimensional theory, and feeling was interpreted as “the mark of the reaction of apperception upon sensory content.” General consciousness contained a smaller region of clearer “focal” consciousness, where processes are apperceived. Attention, especially attention span, was an aspect of apperception, and could be explored in experiments. In Wundt’s laboratory most researchers experimented on one another, using esthesiometers, tachistoscopes and chronoscopes, researching visual and acoustic psychophysics in the tradition of Fechner and Helmholtz, later also on touch, space perception, and time sense, continuing work initiated by Mach and other followers of Fechner’s ideas. Wundt’s laboratory became best known, however, for its reaction time experiments, which anticipated the expectation potentials of 20th-century electroencephalography (EEG) research (see James, 1875). Wundt was a multi-faceted individual and he also promoted what he called Volkerpsychologie (folk psychology), which dealt with subject matter that did not seem amenable to experimentation and quantification. This part of his psychology, which was less well known outside of Germany, included language development, the psychology of religion, and social-psychological phenomena.

NEUROANATOMY Neuroanatomy was the mainstay of German-language neurology from the early 18th to the mid-19th century. J.F. Blumenbach (1752–1840) continued Haller’s tradition

NEUROLOGY AND THE NEUROLOGICAL SCIENCES IN THE GERMAN-SPEAKING COUNTRIES 677 in anatomy in Go¨ttingen for 65 years. His passionate studies of the variations of human skulls created the term “Caucasian.” In German literature he is known as the founder of physical anthropology. He saw an evolutionary force (nisus formativus, 1781) at work in living creatures. Karl von Baer introduced the concept of evolution in its present sense into biology (leading to Hughlings Jackson’s evolutionary concept of neurology, by way of the Go¨ttingen MD, Thomas Laycock). Inductive methods, such as microscopy in anatomy, introduced by Mu¨ller, Purkinje, Koelliker, and Henle, and the introduction of embryology in comparative anatomy by Mu¨ller, von Baer, and Owen, gave rise to a new mechanistic neurophysiology, which rebelled against older Vitalist and “natural philosophy” ideas. The development of the peculiar Germanic specialty of neuropsychiatry provided the impetus for major achievements in neuroanatomy, neuropathology and neurophysiology by neuropsychiatrists such as Greisinger, Meynert, Flechsig, Freud, Gudden, Hitzig, Forel, Monakow, and Alzheimer (McHenry, 1969; Morton, 1970; Meyer, 1971; Spillane, 1981; Clarke and Jacyna, 1987; Zu¨lch, 1989).

Classic neuroanatomists of the late-18th and first half of the 19th century Samuel Thomas Soemmerring (1755–1830), in Mainz and then in Munich, studied the anatomy of the sensory organs and the brain. His textbook of human anatomy of 1791–1796 was popular in Germany for a long time, and it contained only facts he himself had observed. His classification of the 12 cranial nerves of 1778 replaced that of Thomas Willis from 1664, and is the one we are still using. He declared that the brain is the organ of the mind. But he was the last important brain researcher to relapse into the medieval notion that the sensorium commune, the common terminal of the senses, is contained within the ventricles, a concept Andreas Vesalius had ridiculed as a student (whereas Descartes still believed in it 150 years later). Karl Friedrich Burdach (1776–1847) published three volumes on “the structure and life of the brain” from 1819 to 1826. He gave an overview of the state of neuroanatomy and neurophysiology, and coined the terms “putamen” and “globus pallidus.” He explored the posterior column of the spinal cord, named after him. He edited six initial volumes of a handbook of physiology with Mu¨ller, von Baer and others, from 1826 to 1840; it was followed by Mu¨ller’s own handbook. Christian Gottfried Ehrenberg (1795–1876), in Berlin, had accompanied Alexander von Humboldt on his expedition into Asia in 1829. In 1833, he first described what we now call nerve cells as club-like bodies and granules in the spinal ganglia, the retina, and the cerebral cortex,

before Schwann applied Schleiden’s concept of plant cells of 1838 to animals, and found the animal cell as their basic constituent. Friedrich Arnold (1803–1890) of Zu¨rich and Heidelberg had, in the period of 1831–1840, described cerebral fiber tracts and several nuclei and ganglia. Among them are the external arcuate fibers (Arnold’s bundle) and the ganglion oticum (Arnold’s ganglion). He also studied the anatomy and physiology of the autonomic nervous system, emphasizing its cranial parts in man.

Clinical and pathological neuroanatomy Nikolaus Friedreich (1825–1882), of Wu¨rzburg and Heidelberg, was a student of Koelliker and Virchow. Friedreich was an internist and a clinical neuropathologist, best known for his work on posterior column degeneration, tabes dorsalis, hereditary ataxias, and muscular atrophy. He was the teacher of Wilhelm Erb who perfected clinical electrophysiology before the advent of electromyography. Ludwig Edinger (1855–1918) was a clinical neurologist and neuroanatomist in Frankfurt am Main, where he founded the service of neurology. His Ten Lectures on the Structure of the Central Nervous Organs of 1885 was one of the best-known books in the field. He is known as the eponymist of the Westphal–Edinger nucleus (1885) and the Edinger fibers (1887).

General anatomists as neuroanatomists Wilhelm Waldeyer (1836–1921), Professor of Anatomy at Strassburg and Berlin, introduced the terms “neuron” and “chromosome.” He first published a popularized article on the neuron theory (in 1891), much to the chagrin of Cajal and Forel who had done the basic research that led to it. They complained that Waldeyer’s paper had first been published in a newspaper, the Berliner Tageblatt, and wondered how anybody who published in this manner could be a scientist. Wilhelm His the elder (1831–1904) worked in Basel and Leipzig, and was a student of Remak. He graphically reconstructed the unfolding of the human brain and established the embryological foundation of neuron theory. He showed that epidermal cells can only be derived from the outer germ layer. He coined the terms dendrite, neuropil, neuroblast and spongioblast.

“Brain psychiatry,” the mainstream: the neuropsychiatrists Although German-language neurology had been founded by internists, the neuropsychiatrists took it over in the mid-19th century. They advanced neuronatomy so far as to objectively localize specific brain functions and their pathways, and at the same time, the same group

678

H. ISLER was elected professor of internal medicine at Zu¨rich, where he founded the Burgho¨lzli psychiatric hospital, which soon became a leading center of neuropsychiatry under Gudden, Hitzig, Forel, and Bleuler. Greisinger left for Berlin in 1865 where he headed the new department for mental diseases, and became Romberg’s successor as director of the polyclinic of medicine. He imported the no-restraint treatment of mental patients, and introduced rational psychological methods based on Herbart. His mental nosology prevailed and was replaced later by that of Kraepelin and then that of Bleuler. He distinguished focal from diffuse cerebral disorders, and described cysticercosis of the brain (Bleuler, 1951; Lo¨ffler, 1951; Thiele, 1956; Ackerknecht, 1967; Howells, 1975; Schott and To¨lle, 2006). Bernhard von Gudden (1824–1886; Fig. 42.8) was the first director of Greisinger’s new psychiatric hospital in Zu¨rich, the Burgho¨lzli, and the first professor of psychiatry there in 1869. He was appointed professor

Fig. 42.7. Wilhelm Greisinger (1817–1868) published his textbook of mental diseases in 1845, after two years’ experience in an asylum, declaring that mental diseases are brain diseases. This was the beginning of the era of German-language neuropsychiatry. From 1850 to 1852 he worked in Cairo and wrote a textbook of tropical medicine. After 1860 he founded the Zu¨rich mental hospital Burgho¨lzli, later headed by Gudden, Hitzig, Forel and the Bleulers.

developed modern clinical psychiatry (Regierungsrat des Kantons Zu¨rich, 1933, 1951; Forel, 1935; Kolle, 1956, 1959, 1963; Ackerknecht, 1967; Spillane, 1981; Clarke and Jacyna, 1987; Jagella et al., 1994; Hell et al., 2001). Wilhelm Greisinger (1817–1868; Fig. 42.7) studied at Tu¨bingen where he preferred reading Mu¨ller’s physiology handbook to taking notes on obsolete university courses (Thiele, 1956). He reorientated his medical thinking according to the physiology of Mu¨ller and his students, especially Helmholtz, planning to establish a new physiological medicine. After two years’ psychiatry in Zeller’s Asylum in Winnenthal he published his textbook of mental diseases in 1845. He proclaimed “Geisteskrankheiten sind Gehirnkrankheiten,” mental diseases are brain diseases, and thus founded neuropsychiatry. Similar concepts were proposed by Ferrier, Holland and Wigan (1844) in Britain, and by Dietl (1845) in Vienna, but only Greisinger’s initiative took hold (Lesky, 1965). When he worked in Cairo from 1850 to 1852 he wrote the first German textbook of tropical medicine, with a study of hookworm disease, Greisinger’s Disease. In 1860 he

Fig. 42.8. Bernhard von Gudden (1824–1866) studied secondary degeneration as the principal method for following brain tracts. He studied transections of the whole brain of animals after placing gray matter lesions in one side, so that he could compare the undamaged side with the side of the lesion. He needed precise cuts of even thinness throughout, and developed a microtome for the purpose, with his assistant Forel and a mechanic, Katsch.

NEUROLOGY AND THE NEUROLOGICAL SCIENCES IN THE GERMAN-SPEAKING COUNTRIES 679 of psychiatry and director of a psychiatric hospital in Emil Kraepelin (1856–1926) trained with Gudden in Munich in 1872. He invented his own method of folMunich for 4 years, then went to Leipzig to study brain lowing cerebral tracts, using the first usable microtome anatomy with Flechsig. He left after a few months, and he developed with his assistant, Forel, and a precision followed Wilhelm Wundt (1832–1920), adopting his mechanic, Katsch. He removed sensory organs or craexperimental psychological approach. Wundt in turn nial nerves of animals. He then made serial cuts recommended him to Erb in whose polyclinic he through the whole brain, which enabled him to follow acquired practical knowledge of peripheral neurological the same tract on the side of the lesion he had inflicted disorders. He went on to work in several psychiatric hosand on the unaltered control side, a very elegant solupitals, and was appointed professor of psychiatry in tion. This method was adopted by many international Dorpat, in Heidelberg, and from 1904 in Munich, where researchers who came to his laboratory to learn it. It he founded the German Institute of Psychiatric was later complemented by Flechsig’s developmental Research, with the help of the Rockefeller Foundation. studies. Kraepelin saw himself as a psychiatrist, but neuroWith this technique, Gudden discovered many nuclei psychiatry marked his work, from its moderate theoreand tracts near the midline, some named after him, and tical foundations, Wundt’s psycho-physical parallelism, “Gudden’s law,” stating that cortical lesions do not to the demand for clear scientific definitions, and, result in degeneration of peripheral nerves. As a perparadoxically, to the demand for complete separation son, he was unique: Forel, who was his assistant from of psychiatry and neurology, adopted from Erb. In 1873 to 1877, remarked that, if one could mix up all 1912 he was called to the vacant neuropsychiatric chair possible contrasts and contradictions, one would obtain (Romberg and Westphal’s) in the Berlin polyclinic. He a Gudden. Forel also said that he learned from him accepted under the condition that his chair be limited how not to direct an asylum (Forel, 1935). But Kraepeto psychiatry, and that a second chair of neurology lin, the founder of “imperial psychiatry,” stayed with without psychiatry be created. This was rejected, and Bonhim from 1878 to 1882. In 1886 Gudden was put in hoeffer, a partisan of neuropsychiatry, took the chair. charge of King Ludwig II of Bavaria, who was considKraepelin recognized that only longitudinal clinical case ered insane. Both went on a walk without attendants, studies could help psychiatry out of its uncertainties, and were found drowned in the adjacent lake and he concentrated on the case presentations for his stu(Gru¨nthal, 1956). dents. His “imperial psychiatry” survived longer than any Eduard Hitzig (1838–1907) studied electrotherapy of previous system, and his influence on the development of neurological diseases, then motor functions of the psychiatry as a whole can hardly be overestimated. brain. With zoologist Gustav Theodor Fritsch (1838– Following Mo¨bius he distinguished exogenous from 1891) he studied electrical stimulation of the brain in endogenous psychoses but he is known chiefly for his disdogs and monkeys. They found that stimulation of tinction between manic-depressive illness and dementia the frontal lobe in the dog induced movements of the praecox, partly identical with what Bleuler later called contralateral limbs. They localized the cortical motor schizophrenia. In collaboration with Wundt, he renewed centers, and the probable cortical origin of particular the psychophysical laboratory investigations introduced forms of epilepsy, which Hughlings Jackson had preby Meynert, investigating the effects of fatigue, alcohol dicted a few months earlier. In 1875 Hitzig was and other disturbing factors on cerebral performance appointed medical director of the psychiatric hospital (Zu¨lch, 1989; Schott and To¨lle, 2006). Burgho¨lzli in Zu¨rich where he initiated the neurological Franz Nissl (1860–1919) solved a prize question of career of a student, von Monakow, by sending him to the Munich faculty on the pathology of cortical nerve Gudden. cells. He wrote in his thesis that nerve cells and nerve Hitzig left Zu¨rich in 1879, after heated confrontafibers required different fixations and dyes: alcohol tions with an administrator and politicians who had and aniline dyes (magenta red, later toluidine blue) no respect for his patients. He wrote on the insanity for nerve cells, chromium salts for fibers. He wrote of the querulous (Querulantenwahnsinn) in 1895, on that his work was unfinished and incomplete, and conthe material aspects of the soul in 1896, on vertigo in tinued working on these topics for the rest of his life. 1898, on his physiological and clinical investigations Nissl went to Frankfurt where he collaborated of the brain in 1904, on “world and brain” in 1905, closely with Alzheimer. This ended after 6 years, and on the belt-like sensory symptoms of tabes named when Alzheimer joined Kraepelin at Heidelberg, but after him. Between them, Fritsch, Hitzig, and Fritsch’s was taken up again when Nissl came to Heidelberg friend Munk established the essential features of fronin 1903. Nissl is the eponymist of the Nissl dye, tal, parietal, occipital, and temporal lobe function toluidine blue, and the “Nissl-Schollen,” the chromo(Bleuler, 1951; Riese, 1959; Spillane, 1981). phile Nissl bodies in nerve cells now known as the

680 H. ISLER endoplasmic reticulum. From 1904 to 1918 he Auguste Forel (1848–1931) was born in Morges on published, with Alzheimer, their histological and histothe shore of Lac Le´man and studied ants for most pathological investigations on the cerebral cortex, with of his life. He is therefore often referred to as an Nissl’s analysis of dementia paralytica and Alzheimer’s entomologist and, as such, he was represented on a account of the neuroglia, together with papers by their Swiss banknote (1000 CHF) in use until 1998. He also students. Nissl’s assistant Karl Jaspers (1883–1960), had a career in brain research and psychiatry. He stupsychopathologist and philosopher, said that he learned died with Meynert, who accepted his thesis on the thafrom Nissl’s example how a scientist keeps himself lamus, and Gudden, for whom he developed his from becoming uncritical, and how a straightforward microtome. With Gudden’s degeneration method and but tactful boss creates a climate that favors the best their new microtome, he followed the acoustic nerve kind of discussion. In 1918 Nissl was called to Munich into the brainstem (1885) and advanced the anatomy by Kraepelin to head his new psychiatric research instiof the tegmental region, where he described several tute, but he soon died of his chronic renal disease. He structures that had been unknown. kept fighting against the neuron theory for many years In 1887 he and Wilhelm His independently ass(Nissl, 1903; Spatz, 1959). embled the material for the neuron theory, which was Alois Alzheimer (1864–1915) trained together with appropriated and named by Waldeyer in 1891, and Nissl, specializing in brain pathology. He worked with championed by Ramo´n y Cajal. In 1879, he was Kraepelin in Heidelberg, then directed Kraepelin’s pathoappointed director of the Zu¨rich psychiatric hospital logical-anatomical laboratory in Munich. He was made Burgho¨lzli, and Professor of Psychiatry after Gudden, professor of psychiatry in Breslau in 1912. He studied Hitzig and Huguenin. He became engaged in the treatthe histopathology of the brain, anatomical changes in ment and prophylaxis of alcoholism, crusading with general paralysis, arteriosclerosis of the brain, and enthusiasm for abstinence from alcohol. He was also changes in old age, dementia, idiocy and the epilepsies. intensely interested in hypnosis. He provided the anatomical background for Kraepelin’s Forel endeavored to improve humanity by promotsystems, and Kraepelin coined the term “Alzheimer’s dising the “useful” races and gradually eliminating the ease” (1906), against Alzheimer’s wishes (Meyer, 1959). lowest ones. This eugenic concept was later misapproPaul Julius Mo¨bius (1853–1907), in Leipzig, studied priated by Rudin and then by the Nazis. When Richard theology, philosophy, and medicine, qualifying as Semon published his Mneme in 1904 (see above), preacher, PhD and MD. He followed Fechner’s psychoForel’s help ensured its success, and the later Zu¨rich physical thinking, and his styles of writing. He tried to neuropsychiatrists Adolph Meyer, Eugen Bleuler, Conrestore the central importance of the mind–body relastantin von Monakow, and Rudolf Brun adopted tionship, and dared to propose the use of metaphysics Semon’s theory. as a remedy for the barrenness of experimental psycholConstantin von Monakow (1853–1930) left Russia ogy, after years of training with Wundt. He discovered for Zu¨rich as a schoolboy and established neurology the hyperthyroid pathogenesis of Graves’ (Basedow’s) as a university discipline in Switzerland in 1894. He disease and the syphilitic pathogenesis of tabes, and worked under Hitzig in the psychiatric hospital Burexplained hysteria as an emotional disease. Mo¨bius gho¨lzli before graduating, and Hitzig sent him to Gudwas an iconoclast in neurology, which cost him his acaden in Munich, where he learned Gudden’s method of demic career, and a successful opinion leader in general secondary degeneration of brain tracts by serial cuts. medicine and in psychiatry, where his basic concept of This enabled him to begin his own brain research. As exogenous and endogenous psychosis was adopted by a psychiatry assistant in an alpine asylum he worked Kraepelin and Bonhoeffer. on rabbits in his spare time, and identified the lateral Mo¨bius exposed the merely suggestive effects of geniculate body as a part of the visual system, a breakelectrotherapy. Erb, who perfected electrotherapy and through which put him in the vanguard of international electrodiagnostics, complained that Mo¨bius’ concept brain research. was a threat to mechanistic medicine, whereas Freud He then returned to Zu¨rich, where he started his prisaid that modern psychotherapy began with the School vate interdisciplinary neurological policlinic and brain of Nancy and Mo¨bius. The name still survives in research laboratory from scratch. Both were later Mo¨bius’ sign, a convergence deficit in Graves’ disease, incorporated in the university, and in 1894 Monakow and in Mo¨bius’ disease, ophthalmoplegic migraine. was installed as professor of neurology, the first in Today he is still discredited for his essay “On the phySwitzerland, against the wishes of the faculty. He consiological feeblemindedness of the female,” dated tinued to treat psychiatric patients and, from 1880 to 1900, and condemned by the arch-emancipationist, 1897, studied the visual and acoustic pathways, and Forel (Schiller, 1982; Steinberg, 2005). the connections of the thalamus and cortex. This

NEUROLOGY AND THE NEUROLOGICAL SCIENCES IN THE GERMAN-SPEAKING COUNTRIES 681 research culminated in his “Gehirnpathologie” (brain pathology) of 1897 in Nothnagel’s wall-to-wall handbook. From 1895 to 1914, he published on localization in the forebrain and developed the principle of “diaschisis” to explain how a lesion would cause loss of function in nerve cell groups at a distance from the lesion. Mere loss of crucial functional connections could shut down entire populations of neurons. Monakow distinguished geometric and chronogenic localization of lesions and functional loss, where, analogous to diaschisis, lesions of known speech or motor centers would cause loss of related functions varying with elapsed time. After 1914, deeply moved by World War I, he turned to ethics, postulating a biological conscience, syneidesis. His brain research was continued by his successor, Miecislaw Minkowski. His language was difficult to translate, and only one work was published in English; but his influence on the Vogts, on European neurology, and on neuropsychology was decisive (Riese, 1959; Gubser and Ackerknecht, 1970; Jagella et al., 1994). Adolf Meyer (1866–1950; Fig. 42.9), from Niederweningen near Zu¨rich, trained under Forel in Zu¨rich, wrote a thesis on the forebrain of reptiles, and received further training in neurology in London (with Hughlings Jackson), Edinburgh, and Paris. He worked in the USA as a neuropathologist, doing research on comparative neuroanatomy, then as a pathologist. He was made professor of psychiatry at Johns Hopkins, and chief psychiatrist of its hospital, and stayed there for 40 years. Meyer maintained a neuropsychiatric approach in his “psychobiology,” a term he developed together with his friend Monakow in Zu¨rich, whom he visited at length whenever he went to Europe. Of his selected works, one volume contains neurological, the other psychiatric, texts. He designed a system of psychiatric history-taking and exploration, which was adopted in the United States for more than 30 years. His training program for psychiatrists was equally pervasive. When Wundt’s psycho-physical parallelism was introduced by his disciples in American psychology and psychiatry, Meyer provided the alternative. His psychobiology, in keeping with the monism of Monakow, and the open views of William James, proposed a monist integration of matter and its function, which could not be separated. Meyer drastically denounced “the medically useless contrast of mental and physical” categories in JAMA in 1915. In the same spirit, he tried to integrate psychiatry with the other hospital services. This was achieved only after his death as “consultation liaison psychiatry” by his senior assistant, Engel, and it became internationally accepted (Diethelm, 1959).

Fig. 42.9. Adolf Meyer, from Niederweningen, Zu¨rich, trained with Forel at the Burgho¨lzli mental hospital, Zu¨rich, and with Hughlings Jackson in London. He then worked as a neuropathologist in the USA and ended up as professor of psychiatry at Johns Hopkins in Baltimore, MD. From there he reformed US psychiatry. He was a typical neuropsychiatrist like his friend Monakow. He denounced the traditional mind–body dualism as useless for medicine, and developed “psychobiology” along the lines of Monakow’s “neurobiology.”

Eugen Bleuler (1857–1939) was Forel’s successor as director of the Burgho¨lzli Hospital, and was installed as professor of psychiatry, like Monakow in neurology, against the wishes of the faculty. He set out as a neuropsychiatrist, writing about the physiology of muscle and nerves, pontine lesions with optokinetic symptoms, synesthesia, complicated aphasia, gliosis in epileptics, and the treatment of herpes zoster, along with psychiatric papers. In 1882, he went to Charcot in Paris to study hypnosis. About 1891, he began to read the writings of another neuropsychiatrist, Freud, and accepted his new doctrines. He opened the way for psychoanalysis in university psychiatry, against the resistance of German psychiatrists. His senior assistant, Carl Gustav Jung (1875–1961), joined him in the reception of Freud’s teachings, and later developed his own psychoanalysis, while Bleuler

682 H. ISLER kept his distance from both schools. In 1911 Bleuler brain slices, and thought that Meynert’s imagination modified Kraepelin’s “dementia praecox,” introducing was 10 times greater than his own. But it was Meyhis own neologism “schizophrenia” for this group of nert’s fertile imagination, together with his unrelenting psychotic disorders, and maintaining, contrary to Kraedrive, which raised the Vienna School of Neurology to pelin, that they often onset later in life, but rarely end the level of the Salpeˆtrie`re and the National Hospital of in dementia. “Schizophrenia” was not the first neoloNervous Diseases, Queen Square. A sample of his neugism derived from the Greek root “schizo,” to split: rological experiments was later incorporated in WittMonakow’s term diaschisis (see above) had been genstein’s tractatus. Meynert’s clinical assistant derived from it. Bleuler tried to understand schizophreSigmund Freud inherited his passion for theorizing, nic symptoms as variants of normal feelings and while the Vienna neurologists and Wernicke continued actions, and in 1921 he published a book in which he his structural brain research (von Stockert, 1959; Lesky, wrote that human thinking, feeling, and behavior could 1965). be derived entirely from the properties of the brain Richard von Krafft-Ebing (1840–1902) trained with (Hell et al., 2001). Friedreich and Greisinger. He worked in Baden-Baden, Bleuler, Monakow and other Zu¨rich neuropsychiaStrassburg, and then in Graz as director of the psychiatrists met regularly on Saturdays at the Burgho¨lzli to tric hospital. He wrote textbooks of forensic psycholdiscuss neurological and psychiatric topics. Walter ogy, psychiatry, and psychopathology. Today he is Rudolf Hess (1881–1973), ophthalmologist and profesknown for his Psychopathologia Sexualis, a textbook sor of physiology, wished to take part in these meetof sexual perversions. When a psychiatrist with differings, and said that this would be the best introduction ent beliefs was appointed director over Meynert in to the functions of the brain. He then investigated the Vienna, the controversy between university psychiatry emotional functions of the diencephalon and the retiand asylum psychiatry exploded, and Meynert had to cular formation in free-moving cats, and won the be given a hospital of his own. Krafft-Ebing succeeded Nobel prize in 1949 (Hell et al., 2001; Scharfetter, 2006). in bridging the gap. Meynert saw psychiatry as a Theodor Meynert (1833–1892), in Vienna, studied cerscience of explanations, but Krafft-Ebing said that it ebral histology with serial cuts, using the pre-microtome should only describe nosology (Lesky, 1965). method of Stilling, whose work he continued. Meynert Heinrich Obersteiner (1847–1922) trained in Bru¨cke’s explored regional structures in the visual cortex, the laboratory and took charge of a psychiatric hospital. His olfactory lobes, and the hippocampus, and described research focused on the cerebellum, on tertiary syphilis cytoarchitectural differences (1867–1868), distinguishing of the nervous system (where he was one of the first neocortex from allocortex. Sensory perception was to recognize the syphilitic nature of dementia paralyexplained in terms of cortical patterns arriving from the tica), and on the use of hypnosis in psychiatric patients. radiations of the underlying white matter, and modulated He founded and developed, with Meynert, his own neuby arrival time. Meynert distinguished projection fibers rological institute in Vienna (1882), the nucleus of the and association fibers, and he arrived at a concept of Vienna School of Neurology, which attracted a great motor anterior and sensory posterior regions before number of students from all over the world. In 1905 Hitzig and Jackson. He also worked on aphasia, on the he donated it to the State. His Instruction to the Study structure of the brainstem, and on the psychiatry of of the Structure of the Central Nervous Organs (in Gerthe forebrain, and proposed an antagonism between the man) of 1888 was an international success (Lesky, 1965). cortex and the basal ganglia, which could lead to extraErnst Fleischl von Marxow (1846–1891), an assistant pyramidal disorders under disease conditions. He found of Bru¨cke, detected contralateral galvanometric asymlesions in the neostriatum in rheumatic chorea. Based metries on the scalp after sensory stimulations in 1883, on his own observations, Meynert developed grandiose and predicted the later development of the electroencedynamic theories of cerebral function and disease. In phalogram in 1890. He also worked on color vision melancholia the arteries were constricted, while control (Lesky, 1965). of associative and motor functions was decreased, Sigmund Freud (1856–1939) began his neuroanatowhereas in mania the situation was reversed. His Klimical training at the maritime biology station in nische Vorlesungen über Psychiatrie auf wissenschaftliTrieste, then worked for 6 years in Bru¨cke’s physiolochen Grundlagen (Clinical Lectures on Psychiatry on a gical laboratory in Vienna, where he published six neuScientific Basis), of 1890, classified mental diseases rophysiological papers. He then did clinical psychiatry according to anatomical criteria (Meynert, 1890). The with Meynert, and finally went to study with Charcot book marked the apogee of neuropsychiatry. in Paris, where he became interested in hysteria and Auguste Forel, who spent 7 months with Meynert, hypnosis. These interests led to the development of found it difficult to follow what he saw in his thick psychoanalysis with Breuer. Freud used electrotherapy

NEUROLOGY AND THE NEUROLOGICAL SCIENCES IN THE GERMAN-SPEAKING COUNTRIES 683 early on in his clinical work, but then realized it had no Paul Emil Flechsig (1847–1929) was inspired by Meyphysical effect. His works in aphasiology and in pedianert’s work on the structure of the mammalian brain tric neurology were instrumental to the development of and explored serial brain sections of human newborns. these clinical fields (Lesky, 1965). He observed early myelinating fibers and tracts, preSigmund Exner von Ewarten, Bru¨cke’s successor in senting his preliminary results in 1872. He continued Vienna in 1891, investigated the physiology of the retina. to investigate the tracts in the human brain and spinal In 1881 he was involved in the discussion about the value cord, and named the pyramidal tract. The posterior spiof cortical localization, and he took a moderate position, nocerebellar tract is named after him. He mapped out maintaining that there are cortical areas of functional sensory, association, and motor areas. His research localization but that their borders may overlap. He meaon myelination of the internal capsule and other tracts sured the vibrations of the small bones of the inner ear advanced their topography and showed that tracts only by his “otomicrophone” and the acoustics of rooms with become fully functional when their myelination is comhis “acoustometer,” and established a phonogram archive pleted. He followed myelination in serial cuts much as for the sounds of languages and dialects. He also meaGudden and his students followed secondary degenerasured the latency of the blink reflex. In 1891 he explained tion. In 1877 he was made professor of psychiatry, and the appearance of upright images in the faceted eyes of in 1882, only after systematically learning clinical psyinsects, and 3 years later published a book in which he chiatry of which he had known nothing, he opened attempted to explain every aspect of human life by variahis “Irrenklinik” (lunatics’ clinic), where students from tion in cerebral conditions (Lesky, 1965). around the world came to him, including Bekhterev Karl Wernicke (1848–1905), professor of neurology and Oscar Vogt, who later criticized his myelogenetic and psychiatry in Breslau, and later director of the psychiastudies, and became his arch-enemy (McHenry, 1969). tric and neurological hospital at Halle, trained with MeyKonstantin von Economo (1876–1931), of Rumanert in Vienna. He is considered the founder of modern nian-Greek descent, studied engineering and medicine aphasiology, integrating several key concepts of Meyin Vienna. After graduation in 1901, he worked in nert’s, such as the projection and association systems, with and visited many institutes, and treated brain injuries his own concept of a psychological reflex arc connecting during World War I. Starting in 1912, he investigated the sensory with the motor speech centers. He “discovthe cytoarchitecture of the cerebral cortex, and pubered” sensory (Wernicke’s) aphasia and gave it its temlished a large atlas on the cytoarchitecture of the adult poral localization. Wernicke also localized other focal human cerebral cortex in 1925 (with Koskinas). In 1917, disorders, and described polioencephalitis superior hemorvon Economo began his studies on encephalitis rhagica or “Wernicke’s encephalitis.” He was the teacher lethargica, a “sleeping” disorder that now bears his of Liepmann, Lissauer, Goldstein, Kleist, and Foerster, name, and in 1929 published a book on its sequelae without whom 20th-century German neurology would and treatment (Stransky, 1959). not have developed as it did (Finger, 1994). Otfrid Foerster (1873–1941) was born, studied mediKarl Westphal (1833–1890) was Romberg’s succescine, and worked in Breslau. He knew Kraepelin and sor as professor of psychiatry and neurology at the Wernicke before graduating. This made him choose Charite´ in Berlin. He explored the spinal lesions in genneurology. He went for two years to Dejerine in Paris eral paralysis, and in 1878 he wrote about the loss of for neurology and to Frenkel in Heiden, Switzerland, the patella reflex in tabes, thus introducing this part for rehabilitation therapy, as recommended by Werof the neurological examination. Erb wrote about the nicke. He developed his own neuroanatomy, neurophypatella reflex and other muscle stretch reflexes at the siology, and neurosurgery despite his lack of basic same time, and the two papers were published together training in surgery, with the help of his encyclopedic (McHenry, 1969). knowledge of clinical neurology which he deployed Gottlieb Burckhardt (1836–1912), director of the psyfirst in the supplement to Lewandowski’s handbook chiatric hospital at Pre´fargier, Neuchaˆtel, Switzerland, (6 volumes, 1911–1914; supplement 1929), and later in is considered a pioneer of psychosurgery. In 1891, he the 17 volumes of the handbook of Bumke-Foerster described six agitated mental patients with auditory (1935–1937), the most comprehensive overview before hallucinations who underwent frontal and temporal the Handbook of Clinical Neurology of Vinken and cortical ablations. His work was based on Goltz who Bruyn. He introduced precise rhizotomy and anterolathad found in 1888 that dogs could be made placid by eral chordotomy for pain relief, and intraoperative cortical ablations. He was severely criticized after electrical brain stimulation in patients under local few patients improved, one committed suicide, and anesthesia, a line of research that Wilder Penfield later one had convulsions and died after a week (Finger, continued at the Montreal Neurological Institute. Neu1994). rologists and neurosurgeons from the USA and the UK

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visited and learned from him up to the late 1930s. In 1934 the Rockefeller Foundation financed a new neurological institute at Breslau for his research. One of his Jewish assistants, the late Sir Ludwig Guttmann (1899– 1980), who had to emigrate to the UK in 1939 despite Foerster’s help, developed the modern treatment and rehabilitation of paraplegics there: a late effect of Foerster’s pioneering spinal surgery. Foerster was also Lenin’s physician in Moscow after his stroke, from 1921 to the autopsy in 1923, when Oskar Vogt inherited Lenin’s brain, as it were (Zu¨lch, 1956). Oskar Vogt (1870–1959) and Ce´cile Vogt-Mugnier (1875–1962) met in Paris in 1898, and worked together until 1959. After first experiences with serious entomology and histology as a schoolboy, Oskar Vogt decided to go into research on the anatomical basis of psychic phenomena, and on genetics of living beings. He studied psychiatry, psychology, neurology and brain anatomy in Otto Binswanger’s psychiatric hospital at Jena (1893–1894), then went to Forel’s polyclinic in Zu¨rich, where he learned hypnosis and Forel’s methods of brain research. In 1895 Forel appointed him sole editor of the journal for hypnotism, which Vogt turned into a Journal f € ur Psychologie und Neurologie (titles in German) in 1902. Toward the end of 1894 he went to Flechsig in Leipzig to learn his “myelogenetic” method of studying tracts by observing the myelination of fibers. Like Kraepelin, he could not stand Flechsig for long, and turned to Wundt and to Mo¨bius, while also going into private practice, where he relied on hypnosis. In 1898 he moved to Paris to study clinical neurology under Dejerine at the Salpeˆtrie`re, where he observed the advantages of research done jointly by Dejerine and his German wife, Augusta Dejerine-Klumpke, and found his own French wife, a brain research assistant (Fig. 42.10). In 1898 Vogt opened his neuropsychiatric practice in Berlin, with a small research laboratory where he and Ce´cile studied brain anatomy, at first on about 30 brains donated by Ce´cile Vogt’s teacher at the Biceˆtre hospital in Paris, Pierre Marie. This Neuro-Biologische Centralstation became their first institute. Vogt claimed in 1902 that a neurologist should master the complete range of normal, pathological, and comparative psychology and neurobiology, and he and his wife and their collaborators implemented this plan, in sharp contrast to Kraepelin’s psychiatry without neurobiology. Vogt introduced the terms “neurophysiology” and “neurochemistry” in 1902. The Vogts generated a system of neologisms at least comparable to that of Monakow, from whose neuroanatomy and neuropathology they derived much of their research. Their critical assessment of Flechsig’s myelogenetic doctrine, with its excessive generalizations, led to a new view of the

Fig. 42.10. The Vogts. Oskar Vogt and Ce´cile VogtMugnier founded four neurological institutes, and gave interdisciplinary brain research its greatest impetus. They survived two world wars and both the Stalinist and Nazi tyranny nearly unscathed, losing only their Moscow Institute and their monumental Kaiser Wilhelm Institute near Berlin to these mad systems. Their broad-based neurophysiological studies eventually inspired Richard Jung’s combination of neurophysiology and clinical neurology, which formed and structured the post-1945 neurology services in Germany. Copyright # 2003, Nature Publishing Group.

architecture of the brain. Careful studies of myelin preparations from the white matter of the hemispheres allowed them to distinguish areas with distinct myelogenesis, even in adult brains, and these differences were then compared to the architecture of corresponding cortical areas where Meynert had already distinguished four layers. Monakow’s diaschisis model was extended to include transneuronal degeneration and aging of neurons, which occurs when they cease to receive habitual stimuli from preceding neurons. Inactivity accelerates aging, activity delays it. Subunits consisting of brain tissue age according to their individual patterns. Such topistic units (grisea) succumb to disease, as in carbon monoxide poisoning, where selective necrosis of the pallidum serves as an example of a locally specific pathology. These concepts enabled the Vogts to combine the results of myelogenetic studies (such as the Paris thesis of Ce´cile Vogt of 1900 on the myelinization of the cerebral hemispheres in the cat) with fiber studies by experimental and pathological degeneration. In 1901 Korbinian Brodmann (1868–1918) joined their institute. The three studied the structure of the cerebral cortex, and confirmed its six-layered structure, described by R. Lewis in 1878. They found that the macroscopic pattern of the brain surface with its sulci had no physiological correlate, and that the early or late myelinization did not permit them to draw conclusions

NEUROLOGY AND THE NEUROLOGICAL SCIENCES IN THE GERMAN-SPEAKING COUNTRIES 685 as to function. Identification of specific fiber systems and Brodmann’s cytoarchitecture typology led to demarcation of specific areas whose functions were then investigated by electrical stimulation of the cortex of animals. Ce´cile Vogt’s stimulations of the simian brain later became instrumental for Foerster’s and Penfield’s topographies, and later research on monkeys. Many of her results were confirmed by Foerster, who conducted electrostimulation experiments on human patients while doing brain surgery under local anesthesia. The Vogts investigated pathological changes with similar methods, especially in the basal ganglia. They found that whole systems of neurons were affected by disease, sometimes in specific ways, and they developed a “pathoarchitecture” out of their cellular and vascular architecture of the brain. They found that pathological processes in brain cells follow the pattern of physiological development, aging, and death. In 1925 Lenin died of a stroke. Oskar Vogt was asked by the Soviet Government to establish an institute for the investigation of Lenin’s brain in Moscow. It became the Vogts’ second institute. They trained Russian researchers in Berlin and collected many transections of brains from the Soviet Union. In 1929, Oskar Vogt pointed out that an unusual number of large pyramid cells in the third cortical layer showed that Lenin had been an “association athlete.” This was exploited by the Soviet propaganda machine, and later condemned by the Nazis, who proclaimed that Lenin had had nothing but Swiss cheese in his head. When the Soviet regime became ever more totalitarian under Stalin, Vogt turned the Moscow institute over to Russian researchers in 1930, taking some Russian geneticists with him to Berlin where he incorporated a genetic department in his institute. The Berlin institute had become the Kaiser Wilhelm Institute, the Vogts’ third institute, and they received funds, partly from the Rockefeller Foundation and the Krupps, to build a big complex on the outskirts of Berlin. This was completed in 1930, including a research hospital with 60 beds, and a physics laboratory where Jan F. To¨nnies (1902–1970) (Jung, 1975) constructed new apparatus for psycho-physiological investigations, such as the first ink polygraph (“neurograph”) for recording Berger’s brain currents, the EEG. When the Nazis took over in 1933 they denounced the Vogts as “white Jews” (Ce´cile Vogt was the daughter of converted Jews) and tried to evict them from their institute, but it took them until 1936 to succeed. Meanwhile the Vogts managed to build their fourth brain research institute in Neustadt in the Black Forest, sponsored by the Krupp family, where the couple continued their successful brain research up to Oskar’s and Ce´cile’s deaths in 1959 and 1962 (Hassler, 1959; Jung, 1975; Richter, 2007).

Hans Berger (1873–1941), mentioned above, worked in the psychiatric hospital in Jena from 1897 to his retirement in 1938 (from 1919 as director and professor of psychiatry). He investigated cranial circulation, the temperature of the brain, somatic effects of psychic states, and the state of the art of psychophysiology (1921). Then he concentrated on thorough presurgical examinations of brain tumor patients, and investigated the effects of local lesions on mental functions, particularly on calculation. In his training years in the hospital he began to experiment on cerebral action potentials, at first by inserting wires in trephined patients into the skin over the burr holes, and later from contact electrodes on the scalp. He conducted this research for over 20 years in a secluded laboratory where nobody else was admitted, precisely from 5 pm to 8 pm. In 1929, 5 years after his first success, he published the first report on the human electroencephalogram. He wrote 14 papers on the subject and presented his results in two international congresses in 1937. But he was depressed by the War and in 1941 took his own life (Kolle, 1956; Jung, 1975). Richard Jung (1912–1986) continued the Vogts’ and Berger’s work. He was taught cerebral stimulation techniques by Walter Rudolf Hess (1881–1973) in Zu¨rich and by Foerster in Berlin. Hess believed that observed facts were only valuable in a biological context. Hess had been introduced to brain research by Monakow and Bleuler. Jung inherited J.F. To¨nnies from the Vogts’ Kaiser Wilhelm Institute, together with the conviction that neurological research must be carried out in animal laboratories coupled with hospital wards for human patients. The association with To¨nnies, the champion of EEG technology up to 1970, brought him to the forefront of clinical neurophysiology when he founded his neurophysiological institute at Freiburg, Germany. He spread modern electroencephalography throughout Europe, and managed to place his disciples in most chairs of neurology in Germany, where they continued their research in animal laboratories coupled with hospital wards (Jung, 1975; Baumgartner, 1987). Roland Kuhn (1912–2005) was in charge of neurology, electroencephalography and psychotherapy in the psychiatric hospital at Mu¨nsterlingen, Switzerland. While testing a new neuroleptic substance, imipramine, on his patients in about 1955, he discovered its antidepressant effect. It was the first tricyclic, and it opened the way for the development of the current choice of antidepressants.

CLINICAL NEUROLOGISTS While Johannes Mu¨ller combined the basic sciences for medicine, Johann Lukas Scho¨nlein (1793–1864), in Zu¨rich, created a German model of clinical medicine.

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His thesis of 1816 was titled “Von der Hirnmetamorphose,” about the metamorphosis of the brain, a study of comparative anatomy. In the German-speaking countries, neurology was a part of internal medicine up to the end of the 19th century. The beginning of German clinical neurology may be dated from 1840 or 1847. In 1840, Ludwig Tu¨rck obtained a clinical position in Vienna, and in 1847 he opened the first neurological ward. Moritz Romberg published his textbook of nervous diseases from 1840 to 1847. Moritz Heinrich Romberg (1795–1873) translated Marshall Hall’s and Bell’s classic texts in German, and arranged the neurological diseases in a new system in his textbook, expanding the previous systems of Aretaeus and Willis. An English translation was soon made. Romberg’s term “neurosis” covered those nervous diseases that are not inflammatory. He described the test of balance named after him, which he used for the detection of tabes. In 1840, he was appointed director of the Royal Polyclinic at the Charite´ Hospital in Berlin. There he introduced clinical research on somatic disorders of the nervous system, and displayed the results in his textbook. His 1856 description of pain in the thigh from incarcerated obturatory hernia is an early example of referred pain. Ludwig Tu¨rck (1810–1868) opened the first neurological ward in Vienna in 1847. Tu¨rck’s specialty was the connection between clinical observations, animal experiments, and autopsy findings. He explored the segmental sensory innervation, which was mapped only toward the end of the century by Head, Kocher, and others. He studied secondary degeneration in the spinal cord using animal experiments in Bru¨cke’s laboratory, and human autopsies. He found that the degeneration of motor tracts progresses downward, in sensory tracts upward, and he described this degeneration in the human pyramidal tract in 1849, one week after Waller had demonstrated secondary degeneration of the glossopharyngeus and hypoglossus in frogs. When Bru¨cke gave him the ophthalmoscope he had received from Helmholtz, Tu¨rck immediately used it to find choked disks and retinal hemorrhage in brain tumors. His description of multiple sclerosis was one of the earliest (see Finger, 1998). Wilhelm Erb (1840–1921) was made director of the Leipzig Poliklinik in 1880, where he set up a neurological outpatient clinic. In his inauguration speech, he pleaded for the separation of neurology from psychiatry, since it was no longer possible for one man to obtain sufficient knowledge of both fields. He continued his hopeless fight for separation, which was to be the main objective of the German Society for Neurology, of which he became the first president in 1906.

Erb was a pupil of Friedreich at Heidelberg, and he worked on muscle disorders, bulbar myasthenia (Erb– Goldflam disease, first described by Willis in 1672) and some forms of muscular dystrophy (Erb–Duchenne muscular dystrophy: the shoulder–arm variety). He developed an electrophysiological method for detecting denervation in muscle in 1868. Erb’s handbook of electrotherapy became a bible of sorts for neurologists. In his research on spinal and nervous diseases, he discovered the syphilitic nature of tabes, and he described, with Westphal, the absence of the knee jerk in tabes, thus introducing the knee jerk as a clinical routine test. Hermann Oppenheim (1858–1919) was proposed as Westphal’s successor as director of the psychiatric hospital in 1890. Rejected by the Prussian government because he was Jewish, he set up his own neurological outpatient clinic and confined himself to purely neurological clinical research, thus anticipating the separation from psychiatry by more than 70 years. The fruit of his research was his textbook of neurological diseases, which came out in seven editions from 1894 to 1923, and was internationally accepted because of its clear didactic structure. Oppenheim’s sign is a Babinski homologue, whereby dorsal flexion of the hallux is obtained by friction along the edge of the tibia. Heinrich Irena¨us Quincke (1842–1922), internist in Berne and Kiel, developed lumbar puncture and the evacuation of hydrocephalus by puncture in 1891. He described siderosis, poikilocytosis, pulsation of capillaries, and the angioneurotic edema named after him.

NEUROPHYSIOLOGISTS Gustav Theodor Fechner (1801–1887) was professor of physics in Leipzig from 1834 to 1840, where he did research on his own after-images until he developed a crippling photophobia that confined him to a dark room for 3 years, and enhanced his passion for philosophical thinking after the manner established by Leibniz. His interest in sensory physiology was connected to his work on esthetics and to his humorous writings (“Proof that the moon is made of iodine; Comparative anatomy of the angels; Why the sausage is cut askew”). Philosophical esthetics and sensory physiology had already been connected at Leipzig in the 18th century, when Johann Georg Sulzer first described electrical stimulation of the tongue by a bimetal strip. Along with Ernst Heinrich Weber (1795–1878), professor of physiology and anatomy at the University of Leipzig, Fechner was a founder of psychophysics, a field that involves measuring perception (e.g., absolute and difference thresholds). He refined the Fechner– Weber law, stating that the intensity of sensation increases with the logarithm of the physical intensity

NEUROLOGY AND THE NEUROLOGICAL SCIENCES IN THE GERMAN-SPEAKING COUNTRIES 687 of the stimulus (in 1859). His main book was Elemente der Psychophysik, and appeared in 1860 (Fechner, 1860). His influence on Hering, Mach and Mo¨bius was decisive. Ewald Hering (1834–1918), a student of Fechner in Leipzig, taught physiology at Vienna, Prague, and Leipzig. He was the successor of Ludwig in Vienna, of Purkinje at Prague, and again of Ludwig in Leipzig. Following Fechner’s philosophical methods and his views on psychophysical parallelism, he proposed “memory as a general function of organized matter” in 1870, reviving Glisson’s and Leibniz’s ideas, and establishing the concept which led to Richard Semon’s “Mneme” of 1904. Hering compared memory to genetic information, discussing the similarities and differences. The main theme of Hering’s research was the physiology of vision. He transformed Helmholtz’s physiological optics into a doctrine of optical spatial and color sense (Lesky, 1965), opposing Helmholtz’s trichromatic theory of color vision in his Doctrine of Light Sensation of 1872–1875 (he believed that Helmholtz was “yellow blind”). Hering also worked on binocular vision, depth vision, eye motility, eye muscle bruits, regulation of respiration and circulation, neuromuscular physiology, and temperature sense. In Vienna and Prague his research was closely connected with that of Ernst Mach, the physicist whose Principles of the Doctrine of Movement Perception (in German) of 1875 followed upon Hering’s monograph on vision of 1873, using nearly the same title (Hering, 1872–1875). Ernst Mach (1838–1916) is known to a wider public as the eponymist of the velocity of sound. Despite his habilitation in physics in 1861, he invested most of his research activities in the mechanistic physiology that had been introduced in Vienna by Bru¨cke and Ludwig. He endeavored to establish his own philosophical principles, developing an epistemology based on the physiology and psychology of the senses. He did not trust metaphysics and, as he said, guided by his understanding of Kant, and relying on Fechner and Herbart, he finally approximated Hume’s skepticism. He thus became one of the founders of the philosophical school of empiriocriticism. In 1861 he presented Fechner’s Elements of Psychophysics to the Vienna Society of Physicians. In 1867 he was made professor of experimental physics in Prague, where he continued to cooperate with his friend Hering, who inspired him for his monograph on Principles of the Doctrine of Sensation of Movement (1875). On 6 November 1873, he established theoretically what Joseph Breuer was to conclude from his experiments on pigeons on 14 November 1873, and what Crum Brown was to publish on 19 January 1874, from experiments on himself, namely that the semicircular canals are sensory organs for the perception of rotations of the head by positive

or negative angular accelerations: the Mach–Breuer theory of the flow of endolymph that superseded Goltz’s previous theory of hydrostatic pressure of the endolymph (Lesky). Mach’s comprehensive publication on sensory physiology followed in 1886: Sinnesphysiologische Beiträge zur Analyse der Empfindungen (“Sensory-physiological contributions to the analysis of perceptions” (Mach, 1886)).

CONTRIBUTIONS OF GENERAL SURGEONS TO NEUROLOGY Benedikt Stilling (1810–1879), of Kassel, inventor of very important surgical innovations, postulated sympathetic vasomotor nerves in 1840. He explored the spinal cord, the medulla oblongata, the pons and the cerebellum using thin unstained serial cuts with a razor in several planes. With J. Wallach, he made maps of their findings in magnifications of 10–15 times, which he published in oversize volumes. He followed most of the cranial nerves to the gray matter in the brainstem, and established the concept of the nerve nuclei. Meynert’s anatomical research was entirely based on Stilling’s work, which he continued in the forebrain. The pioneer orthopedic surgeon Jacob von Heine (1800–1879) wrote about Little’s disease (congenital spastic paraplegia) and established the clinical picture of poliomyelitis in 1840 and 1860 (Heine–Medin disease). Emil Theodor Kocher (1841–1917) of Bern, famous for his thyroid surgery and research that won him the Nobel prize, published the first complete map of segmental innervation in 1896, following Head’s example. In 1900 he motivated Harvey Cushing to study brain edema in the physiology laboratory in Bern. This led to Cushing’s decisive improvement of brain surgery, the prophylaxis and treatment of cerebral edema, with mortality dropping to 10% from the previous 70% (Bucy, 1979). Carl Ludwig Schleich (1859–1922) further developed local anesthesia based on Halsted’s use of cocaine in surgery. August Karl Gustav Bier (1861–1949) introduced spinal anesthesia (1899) and hyperemia in surgical therapy (1903). Ernst Ferdinand Sauerbruch (1875–1951), inventor of the negative pressure chamber for pulmonary surgery, treated lung diseases by phrenicotomy (1913) and myasthenia gravis by thymectomy (1912). This remained an important part of the treatment of myasthenia before the interferons. Sauerbruch wrote a brilliant if philosophical monograph on pain (1936).

CROSSING THE BOUNDARIES From its founding in 1664, progress in neurology always depended on the will and ability to cross boundaries. The most difficult one was the barrier between soma and psyche. It was overcome by two dogmatically

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firm individuals, Gassendi and Willis, on the strength of their theological know-how and affiliations. The Pietists, Stahl and Juncker at Halle, were able to expand the solution of Willis, where the soul controls the body, and to hand it down to their successors, the Vitalists. In this way, not only Willis’ psychosomatic approach, but also his theory and method of brain research, were developed and transmitted to 19th-century scientists, mechanistic materialist monists who believed that brain functions sufficiently explained all of human nature. Necessary preconditions of success were artistic temperament, as exemplified by Meynert, Bru¨cke, Haeckel and du Bois-Reymond, and the gift of invention, as in the cases of Stilling (first extraperitoneal ovarectomy, corneal transplant, etc.), of Gudden and Forel (secondary degeneration in whole brain transections, microtome), and, of course, Mu¨ller (assembling all the basic sciences for medicine). Transcultural competence (Monakow, Forel, the Vogts) and even the study of insect civilizations (Forel’s ants and Vogt’s bumblebees) helped to disregard the traditional boundaries. The study of brain tracts was accessed from both ends of life: early myelination in embryos and children (Flechsig) and degeneration in disease (Tu¨rck, Gudden, Forel). And this was complemented by stimulation experiments in animals and humans (Fritsch, Hitzig, Foerster, C. Vogt). Above all, fantasy was needed, since neurologists had to construct their own science fiction if they wanted to bring their observations into context. Clinical neurology could not, and cannot, be understood without brain research, and this leaves no place for the putative boundary between neurology and psychiatry. Hence the tragic failure of Erb and Kraepelin to get their disciplines separated; they appear like Laokoon and his family wrestling the snake. And hence the progress of Germanic neurology, not on the straight and narrow road but twining about it, like the serpent about the medical caduceus.

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Otis L (2007). Mu¨ller’s Lab. Oxford University Press, London. Regierungsrat des Kantons Zu¨rich (Ed.) (1951). Zu¨rcher Spitalgeschichte, vol. 2. Regierungsrat des Kantons Zu¨rich, Zu¨rich. Richter J (2007). Pantheon of the brains: the Moscow Brain Research Institute 1925–1936. J Hist Neurosci 16: 138–149. Riese W (1959). A History of Neurology. MD Publications, New York. Scharfetter C (2006). Eugen Bleuler Polyphrenie und Schizophrenie. vdf Hochschulverlag, Zu¨rich. Schiller F (1982). A Mo¨bius Strip. Fin-de-Sie`cle Neuropsychiatry and Paul Mo¨bius. University of California Press, Berkeley, CA. Schleiden MJ (1838). Beitra¨ge zur phytogenesis. Arch Anat Physiol wiss Med: 137–176. Schott H, To¨lle R (2006). Geschichte der Psychiatrie. C.H. Beck, Mu¨nchen. Schwann T (1839). Mikroskopische Untersuchungen u¨ber die Uebereinstimmung in der Struktur und dem Wachsthum der Thiere und Pflanzen. Sander, Berlin. Spatz H (1959). Franz Nissl. In: K Kolle (ed.), Grosse Nervena¨rzte, vol. 2. Georg Thieme, Stuttgart. Spillane JD (1981). The Doctrine of the Nerves. Oxford University Press, Oxford. Steinberg H (2005). “Als ob ich zu einer steinernen Wand spra¨che.” Der Nervenarzt Paul Julius Mo¨bius. Eine Werkbiografie. Hans Huber, Bern. Stransky E (1959). Constantin von Economo. In: Kolle K (ed.) Grosse Nervena¨rzte, vol. 2. Georg Thieme, Stuttgart, pp. 180–185. Thiele R (1956). Wilhelm Greisinger. In: K Kolle (Ed.), Grosse Nervena¨rzte, vol. 3. Georg Thieme, Stuttgart. Virchow RLK (1858). Die Cellularpathologie in ihrer Begründung auf Physiologische und Pathologische Gewebelehre. A. Hirschwald, Berlin. von Stockert G (1959). Theodor Meynert. In: K Kolle (Ed.), Grosse Nervena¨rzte, vol. 2. Georg Thieme, Stuttgart. Willis T (1672). De Anima Brutorum, quae Hominis Vitalis ac Sensitiva est, Exercitationes duae. Prior Physiologica. . .altera Pathologica. . . . Oxoniae, e Theatro Sheldoniano. Wuertz (also Wirtz) F (1563). Practica der Wund-Arzney. Basel, apud Petrum Pernam. Basel, Sebastian Henricpetri (1616): including the posthumous first publication of the tract on pediatric surgery by Wuertz “Ein scho¨nes und nutzliches Kinderbuechlin”; English translation 1656 (Morton, 1970). Wundt WM (1858–1863). Beitra¨ge zur theorie der sinneswahrnehmung. Z.rat.med. 1858, 4,229–293; 1859, 7, 279–318, 321–396; 1861, 12, 145–262; 1862, 14, 1–77; 1863, 15, 104–179. Wundt WM (1873–1874). Grundzu¨ge der Physiologischen Psychologie. 2 parts. Leipzig, W. Engelmann. Zu¨lch KJ (1956). Otfrid Foerster. In: K Kolle (Ed.), Grosse Nervena¨rzte, vol. 3. Georg Thieme, Stuttgart. Zu¨lch K (1989). Historical development of German neurology. Cogito (Milano) 1: 15–20.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 43

The development of neurology in the Low Countries ANTOINE KEYSER * Department of Neurology, Radboud University Medical School, Nijmegen, The Netherlands

INTRODUCTION Geopolitical background It seems relevant to start with a sketch of the origin of the Low Countries, or the Netherlands, as they are officially known, as a geopolitical entity. The history of its origin has consequences for the development of the specialty of neurology during later periods in both the southern part (Belgium and Luxemburg) and the northern part of the Netherlands. The contours of the Netherlands became apparent in the 15th century when Philip the Good (1396–1467), Duke of Burgundy, acquired lordship over Flanders, Brabant, Limburg, Holland, Zeeland, and Gelderland; in this way the Netherlands became a part of a large state extending south to Burgundy and Dijon. Philip was the first to try to weld these Burgundian Netherlands into a coherent political entity. He established the States General, a gathering of representatives of all the various provincial States, and a central Chamber of Account. Under his reign the University of Louvain was founded in 1425. That university also served as a unifying factor for the Burgundian Netherlands. In the course of this development, Brussels became the center of administration of the Netherlands, the place where the Ducal palace was built in 1451. After the death of Philip’s successor, Charles the Bold, in 1477, his daughter Mary of Burgundy (1477–1482) was forced to concede the Grand Privilege in 1477, implying that the States General were allowed to gather on their own initiative whenever they saw fit. Holland and Zeeland obtained a similar but different Grand Privilege, affirming a certain degree of autonomy for the States of Holland and Zeeland (Israel, 1998). Until the first half of the 16th century, during the reign of Emperor Charles V, this state of affairs *

continued. As a result of the religious quarrels between the traditional Catholic Church and the Protestant Reformation movement that had already started during the latter’s reign, under his successor Philip II of Spain an insurrection ensued and a war of independence was waged by the Dutch against the Spanish rulers that continued into the 17th century. After this 80-year-long war, the independent Dutch Republic of the Seven United Provinces was established in 1648 in the north, the Spanish troops retreating to the southern parts of the Netherlands. After the childless decease of the Spanish King Carlos II (1665–1700) this southern part of the Netherlands fell to the Austrian branch of the Habsburg dynasty at the beginning of the 18th century, and from then on was referred to as “the Austrian Netherlands.” It comprised much of the territory of modern Belgium and Luxemburg. This state of affairs continued until the Napoleonic wars, when France conquered all of the Netherlands. Earlier, the French revolution had already exerted a profound influence on the Netherlands. In the Austrian southern part, academic life had come to a standstill after 1789, as all universities had been closed and even suspended, as they were in France. In the northern part of the Netherlands (the Republic of the Seven United Provinces), the French Revolution also led to a number of political changes. As a result the north continued under a new legislature as the Bataafse Republiek (Batavian Republic). Later, under Napoleon Bonaparte, a number of medical schools in the south were allowed to train military surgeons and physicians for the French armies. The universities, however, remained suspended. In the northern part things were different. Here Napoleon’s brother, Louis Bonaparte, was invested as King in 1806,

Correspondence to: Antoine Keyser MD, PhD, Neurologist, 935 Department of Neurology, University Medical Center St Radboud, Radboud University, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: [email protected], Tel: þ31-24-3232664, Fax: þ31-24-3618837.

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and he steered a rather independent course. He allowed more freedom to his subjects and encouraged the functioning of the universities in his part of the Netherlands. In 1815, after the final defeat of Napoleon and the subsequent collapse of his empire, the Vienna Congress decided to construct a new strong state along the northern borders of France, the Kingdom of the Netherlands, comprising the territories of both the former Republic of the Seven United Provinces in the north and the Austrian Netherlands in the south, thus in a sense restoring Charles V’s heritage. That year, King William I was installed as the first monarch of this newly established Kingdom (Fig. 43.1).

Bilingualism The use of French as the official language in a large part of the southern Netherlands had its early origin in the time of the Burgundian dukes, but became more generally established during the 18th century. After the transition from the Spanish to the Austrian Habsburg rule, the southern Netherlands was effectively governed from Vienna, by a local governor installed in Brussels. During the reign of Maria Theresa (1717–1780), decrees and governmental decisions still were translated into the local language and the enlightened contemporary rulers in Vienna respected the national identity of the southern Netherlands.

Fig. 43.1. The geographic position of the Low Countries and the location of the universities.

THE DEVELOPMENT OF NEUROLOGY IN THE LOW COUNTRIES The language of the court and of the diplomatic services was French. This fact, and because the southern Netherlands were repeatedly invaded and occupied by French troops in the later part of the 18th century, caused the higher social circles of the nation increasingly to adopt the French language. In medicine, Latin remained the common language. Therefore, the bilingualism of the southern Netherlands was not a major problem in the teaching of medicine during this period, as all medical students were supposed to be conversant in Latin. After the Belgian uprising in 1830, however, the use of the French language intensified in an endeavor of the new nation to create an identity different from that of its Dutch-speaking northern neighbors. With this development, the Flemish Dutch-speaking part of the population was put at a great disadvantage, as all higher education was now in French. Flemish second-class citizenship lasted for more than 100 years, until, finally, in the 1930s, the Flemish emancipation movement gained momentum and a certain degree of bilingualism developed. General bilingualism of the government could not, however, be achieved, and in 1932 it was decided to accept the rule that one of the two languages should be preponderant in each province according to the language of the majority of its population. This rule was not applied to university teaching until the 1960s, when, after a student revolt (and the fall of the government), academic teaching was allowed either in Dutch or in French, according to the province where the university was situated.

THE EMERGENCE OF THE SPECIALTY OF NEUROLOGY Background Since its establishment in 1896, the Belgian Society of Neurology and its members have been active in producing a comprehensive body of scientific publications, but the neurologic services in the Belgian hospitals and the teaching facilities at the Belgian universities largely remained embedded in the internal medicine departments. The same applied to neurosurgery, which in Belgium for many years remained subordinated to the general surgical departments. If one compares the development of the specialty of neurology in Belgium and the Netherlands, the difference is striking. In the northern Netherlands, neurology has strong roots in psychiatry. In Belgium, on the contrary, neurology for a long time stayed within the realm of internal medicine. It is interesting to consider the various factors that have contributed to these differences. They partly have to do with the prominent part played in the 19th century by individual physicians with strong personalities, but the relationship between the authorities and the medical world also developed differently.

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In the northern Netherlands, psychiatrists in the 19th and early-20th centuries produced many publications on neurological subjects, whereas physicians in internal medicine treated acute neurological disorders (e.g., cerebrovascular disease, poliomyelitis, and meningitis) from the beginning. The list of publications of such an eminent general internist as Pieter Klazes Pel (1852–1919) reflects the fact that fundamental contributions to the diagnosis and treatment of acute neurological diseases were made by physicians specializing in internal medicine. The same can be observed in Belgium, e.g., in Lie`ge, where Charles Frankinet (1886–1970), from the internal medicine department, contributed to neurological patient care. The number of patients suffering from behavioral disturbances and movement disorders that primarily came to the attention of psychiatrists (and sometimes were even institutionalized in the asylums) gradually declined, pari passu with better understanding of the nature of the underlying disturbance of the central nervous system. This came about because psychiatry in those years was usually practiced on an explicitly biological basis. Consequently, many psychiatrists in due course acquired knowledge and skills that made them conversant with neurology, and often they even chose to work as neurologists.

The Netherlands J.C. Schroeder Van der Kolk (1797–1862), who was a Professor of Anatomy and Physiology at Utrecht University, had been impressed by the prize-winning essay of Josef Guislain (1826) from Ghent, Belgium, on the requirements of good psychiatric care, and had sponsored the reform of the local psychiatric asylum in Utrecht in 1827. He became interested in psychiatric disorders and published on the relationship between the body and soul. Despite some governmental proposals for a countrywide reorganization of psychiatric patient care, however, no real measures were taken. This may have partly been due to the Belgian Uprising (1830) that caused considerable turmoil in the country and did not end until Belgium’s independence was recognized in 1839, dividing the Netherlands into two entities: the Kingdom of Belgium in the south and the Kingdom of the Netherlands in the north. Before this event, in 1837, Schroeder Van der Kolk delivered a rectorial oration at Utrecht University in which he openly criticized the deplorable state of affairs in the psychiatric asylums and publicly urged rapid changes. Finally, in 1841, this resulted in the first official law on the care of psychiatric patients, requiring medical supervision of psychiatric asylums. Pressure to reform was kept up by Dr. J.N. Ramaer (1817–1887), one of Schroeder Van der Kolk’s pupils. Together with four colleagues, Ramaer established

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the Netherlands Association of Psychiatry in 1871. Their endeavors resulted in a second law on the care of psychiatric patients in 1884, which forbade the admission of patients with neurological disorders to the same institutions that cared for psychiatric patients. Before 1884, patients with tic disorders or dystonic movement disorders and other neurological dysfunctions had often been hospitalized in the same asylum as the so-called incurable lunatic patients. The founding of the Netherlands Association of Psychiatry in 1871, and the passing of a law on the Care of the Insane, were turning points in the history of the development of both psychiatric and neurological medicine in the Netherlands (Frederiks et al., 2002). Physicians specializing in psychiatric disorders at that time wanted to learn more from meticulous anatomo-pathological studies of the central nervous system after their patients died. Since 1845, Wilhelm Greisinger’s (1817–1868) adage “Geistenskrankheiten sind Gehirnkrankheiten” (mental diseases are brain diseases) had resounded in medical circles (Greisinger, 1861), so the reformed psychiatric institutions that took shape after 1884 often had laboratory facilities where the neuropathological substrates of psychiatric diseases could be studied. In this way, psychiatrically interested physicians developed above-average knowledge of the structure and function of the nervous system, and became interested in neurological disorders as well. In 1876, Thorbecke drafted a new law on Higher Education that aimed at reorganizing the university faculties. Henceforth, a medical department not only had teaching obligations, but was also responsible for scientific research in its respective fields. Also, for the first time, this law announced the intention of the government to establish a chair of psychiatry in one of the three universities in the northern Netherlands. Due to the efforts of Professor Franciscus Cornelis Donders (1818–1889), who was a student of Schroeder Van der Kolk’s, and who became famous because of his ophthalmological research, the first chair of psychiatry was established in Utrecht. Cornelis Winkler (1855–1941) was invited to fill the position, but at first was reluctant to accept the invitation to lecture on what he called “such a philosophical subject.” Only after a round of visits with such specialists as Theodor Meynert (1833–1892) and Obersteiner in Vienna, Leydersdorf, and Wagner Von Jauregg (1857–1940) did he become more enthusiastic about teaching psychiatry on a physiological and neurological basis. In particular, his discussions with Wagner Von Jauregg induced him, after his return to the Netherlands, to pursue an academic career in which he would study both neurology and psychiatry, so as to further the mutual development of these specialties. With the intervention of Professors Pekelharing and Donders,

Winkler’s nomination as lector of psychiatry was effectuated. His appointment followed in May 1885. In 1893, Winkler was promoted to full professor of psychiatry in Utrecht, with the promise that a modern clinic would be built for up-to-date care of patients, as well as facilities for teaching psychiatry and neurology. Nevertheless, Winkler resigned in 1896 because of lack of cooperation from the university board. In the same year he was appointed Professor of Psychiatry and Neurology at Amsterdam Municipal University, where he remained active until 1915. Prior to Winkler’s appointment in Amsterdam, neurology had been mainly taken care of by the collaborators of Professor Pieter Klazes Pel in the department of internal medicine. Between 1887 and 1915, Pel contributed about 60 publications on neurological subjects. During the period from 1874 to 1893, the physicians in charge of the neurological patients were G. Waller and C.C. Delprat. At the time of his appointment to the chair of psychiatry, Winkler closely cooperated with Johannes K.A. Wertheim Salomonson (1864–1922), who was a physician in Pel’s department. He was involved in the neurological consultation of patients, and in addition practiced “electrotherapy” in his outpatient clinic, which he had taken over from Delprat in 1893. Winkler saw to it that Wertheim Salomonson was appointed as Extraordinary Professor in Neurology, Electroneurology, and Radiology in 1900 (Winkler, 1947). The second chair of psychiatry in the Netherlands was established at Leiden University in 1899, with the appointment of Gerbrandus Jelgersma (1859–1942). Jelgersma was interested in both neurology and psychiatry. His publishing interests included the structure and function of the cerebellum in mammals and man, and he prepared a very complete series of sections of the whole human brain for study under the microscope. The latter work was published only after his retirement in 1931. Jelgersma taught both psychiatry and neurology, but later on he became more interested in psychotherapeutic possibilities for psychiatric patients. He was instrumental in the acceptance of psychoanalysis in the Netherlands, which was the subject of his rectorial oration in 1917. After 1919 he left neurological teaching to his cooperator Ernst De Vries (1883–1976), who handled this responsibility until he moved to Peking in 1925 as an extraordinary professor of neurology (Bouman, 1921; Winkler, 1921).

Belgium Although psychiatry was already blossoming in early19th-century Belgium, neurology only germinated very gradually. Ze´non Glorieux established the first outpatient clinic for neurological diseases in Brussels in 1888. Jean J. Crocq (1868–1925) headed a neurological service within the internal medicine department of the

THE DEVELOPMENT OF NEUROLOGY IN THE LOW COUNTRIES 695 Molenbeek Hospital, also in Brussels, in the same perphysicians and only military surgeons were trained iod. Further, Arthur Van Gehuchten (1861–1914), who for the campaigns and battles of the French armies. earlier himself had acquired a broad neuromorphologiIn 1815, the battle of Waterloo was fought on Belgian cal basis in neuroanatomy in Louvain, and who was soil and countless injured had to be cared for. During already a professor of neuroanatomy, had his first the Franco-Prussian War (1870–1871), thousands of experiences in clinical neurology in Brussels. Later on casualties were transported to Belgium for medical he would amplify his activities and become the founder and surgical treatment. And during World War I, the of the Louvain School of Neurology. bloody battle of the Yzer once again challenged the The development of neurology led to the establishknowledge and skills of the Belgian surgeons. ment of the Belgium Neurological Society in 1896 by During World War I, a large field hospital was estab19 physicians interested in the field of neurology. lished in De Panne called L’Oce´an, and it became a wellBut, during World War I, the development of scientific known center for the treatment of war casualties. Dr. and medical research came to a standstill in Belgium. Antoine Depage (1862–1925) played a central role in The disastrous fire of Louvain not only destroyed practhe surgical care in this hospital. Neurological injuries tically the whole exceptional university library, but also were frequent, and Depage developed a method to cut out the heart of academic Belgium. remove corpora aliena from the brain, employing a parDuring the interbellum, Belgian neurology was ticular type of hand-served electromagnet. His organizaactive in the field of patient care, and its practitioners tion of this field hospital served as an exemplary model produced mainly case reports. An organized structure for casualty surgery and was successfully copied all of a national systematic research program of neurolalong the French front (Sondervorst, 1981). ogy, as well as powerful research institutions, was Harvey Cushing (1869–1939) worked at the Oce´an Hoslacking, with the exceptions of the Bunge Institute of pital as an American army surgeon, as did George DebaiLudo Van Bogaert (1897–1989) and the Louvain Group sieux (1882–1956), the future chief of the Surgery around Paul Van Gehuchten (son of Arthur). Department of Leuven University. Debaisieux’s interest Twenty-two years after World War I, in 1940, in neurosurgery dated from this period. Before this time, Belgium was once again crushed by the German occuin Leuven, he had already performed daring operations pation and most academic activities were halted for 5 under the guidance of Arthur Van Gehuchten on the triyears. But, even after World War II, neurology as a geminal ganglion and on cases of spinal cord compression. specialty did not receive the support from the academic In 1925, he sent his resident Jean Morelle to Boston, in authorities that it deserved. order to specialize in neurosurgery under Cushing. After The first university where the specialties of neurolreturning to Leuven in 1927, Morelle and Paul Van ogy and neurosurgery were recognized was Louvain, Gehuchten established a neurosurgical center in Leuven when in 1952 an Institute of Neurology and Neurosurand, in 1931, Morelle became head of the Neurosurgical gery was created. Here, at the retirement of Paul Van Department within the Department of General Surgery. Gehuchten in 1964, two combined departments (one Paul Martin (1891–1968) also trained under Cushing in francophone and one Dutch language) of neurology Boston and set up a neurosurgical center in Brussels. In and neurosurgery were established. 1925, together with Ludo Van Bogaert, he founded the Yet, as late as 1970, on the occasion of the 75th anniGroupement Oto-Neuro-Ophthalmologique (ONO) as a versary of the Belgian Society of Neurology, its presicommon study group for those specialists who often dent, C. Coers, still lamented that Belgian neurology had to deal with patients with complex disorders (vide remained the poor child of the medical faculties and that infra). In the opinion of some, Paul Martin therefore “the individualization of the teaching and of the research may be considered the person who gave neurosurgery of neurology often are met with suspicion,” and “the its place in the larger world of Belgian health care. He planning of independent neurological departments still was named the first chair of neurosurgery in Brussels is eliciting sarcasm and hostility” (Coers, 1970). This state (1941). After the end of World War II, he became the of affairs, however, has ameliorated since that time. acting head of the Institute Bordet in Brussels. In the Netherlands the first neurosurgical procedures were performed in Utrecht by the surgeon J.A. GuldeRELATIONSHIP OF NEUROLOGY narm (1852–1905), who at Winkler’s request performed TO NEUROSURGERY trepanations for the evacuation of brain abscesses. In In Belgium, the specialty of surgery expanded earlier 1889, they operated on their first patients suffering from and farther than elsewhere in the Low Countries. brain tumors. In 1893, Von Eiselsberg was appointed to Several factors played a role. First, during French and the chair of surgery at Utrecht and he too operated on Napoleonic times in the southern Netherlands, no brain tumors (Von Eiselsberg and Ranzi, 1913).

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When Von Eiselsberg left Utrecht because the facilities that had been promised to him failed to materialize, Winkler left for Amsterdam. There, as chair of Neurology and Psychiatry, he stimulated the neurologist L.J.J. Muskens (1872–1937) to specialize in neurosurgery. Muskens trained for 20 months with Victor Horsley in London and thereafter started his own private practice in Amsterdam and continued to operate for at least 25 years. In the meantime, Winkler cooperated intensively with the general surgeons Korteweg and Rotgans. Several theses on neurosurgery were published around the turn of the century (Eijk, 1897; Eberson, 1898). During the first three decades of the 20th century in the Netherlands, no systematic and structured neurosurgical services, however, were developed, and neurosurgical procedures were performed on an ad hoc basis by general surgeons in cooperation with the neurologist requesting the operation. After his appointment to the chair of neurology in Amsterdam in 1923, Bernardus Brouwer (1881–1949) made a lecture tour in the United States and visited Walter Dandy (1886–1946) in Baltimore and Cushing in Boston. He was impressed by the results that had been achieved. In 1927 he sent Ignaz Oljenick (1888–1981) to Boston, where he was trained by Cushing and Hugh Cairns. After his return to Amsterdam, Oljenick became the first full-time neurosurgeon in the Netherlands and had at his disposal a neurosurgical unit within Brouwer’s neurological department (Van Alphen, 2002). Thus, it can be concluded that the early development of neurosurgery in Belgium originated mainly in the surgical departments, with neurologists participating, whilst in the Netherlands neurosurgery’s cradle stood in the neurological departments of Utrecht and Amsterdam. In both countries, neurosurgery and neurology were closely linked.

reviewed the past history of the Society. In addition to its 19 founding fathers, there were 140 members by 1944, of whom 82 were still active. Ley (1948) noted that neurological teaching was provided on a structured basis in only one of the four Belgian universities (Louvain). Even in 1970, on the occasion of the 75th anniversary of the Society, the paradox continued that, although Belgian neurology had an excellent international record, on the national level it remained the Cinderella of the medical faculties. Eventually, in 1996, on the occasion of the 100th birthday of the Society, note was taken of the fact that almost all medical faculties in Belgium had an independent department of neurology with its own responsibility for teaching, research, and patient care. That year, the Belgian Neurological Society counted about 350 members. It continues to be the national neurological association and is affiliated with the World Federation of Neurology (WFN). Ludo Van Bogaert acted as the first president of the WFN from 1957 to 1965, and during that period its secretariat was located in the Bunge Institute in Belgium. Even before the founding of the Belgian Neurological Society in 1896, a Journal de Neurologie was established by J. Crocq and X. Francotte. Later on, this journal merged with the Bulletin of the Socie´te´ de Me´decine Mentale. In 1945, the Journal was the common voice of the Belgian Neurological Society, the Society of Mental Medicine, the “Groupement ONO et Neurochirurgical (NC),” and the Belgian Congresses of Neurology and Psychiatry. In 1956 the Journal was renamed Acta Neurologica Belgica. It still has a considerable readership in both Belgium and the Netherlands, and its papers are published in English, French, and Dutch.

SOCIETIES, JOURNALS, AND INSTITUTES

Up to the year 1962, two professional societies promoted the scientific and societal interest of Belgian neurologists and psychiatrists. Both societies at that time were exclusively francophonic. The Socie´te´ Belge de Neurologie, mentioned earlier, was the association of neurologists; the Socie´te´ Belge de Me´decine Mentale was the association of psychiatrists. The fact that both associations were francophone was a considerable drawback for Dutch-speaking Flemish neuropsychiatrists, and a reason for their poor attendance at the scientific and social activities of these societies. In order to break this relative isolation, a group of Flemish neuropsychiatrists formed the Association of Flemish Neuropsychiatrists in 1962. This new association was not intended as an alternative to the Belgian Society of Neurology but, it was hoped, would result in an intensification of the mutual contacts

The Belgian Neurological Society The Belgian Neurological Society was established in Brussels in 1896 for the study of anatomy, physiology, and pathology of the nervous system. It was the first of its kind exclusively devoted to the neurological profession, although it was also open to neurosurgeons. The Socie´te´ de Neurologie in France was established several years later. As a national society, it had to integrate multiple communities with different languages and cultural backgrounds. Therefore, the society often witnessed differences of opinion (De Haene, 1996). On the occasion of the 50th anniversary of the Society’s foundation, under the presidency of Louis Christoph, neurosurgeon in Lie`ge, R.A. Ley of Brussels

The Flemish Society of Neuropsychiatrists

THE DEVELOPMENT OF NEUROLOGY IN THE LOW COUNTRIES between Flemish neuropsychiatrists. It would raise their self-confidence and stimulate their activity on the national scene. The board of the Association consisted of two neurologists and two psychiatrists, and the presidency alternated between a neurologist and a psychiatrist for 2-year terms. Its first president was Professor Raymond Van den Bergh (Louvain). That the Association met a long-felt need appears from the fact that its membership in 1973 numbered 250 and increased to 500 in 1981, when it was decided to form two separate scientific secretariats within this association, one for neurology and one for psychiatry (Van den Bergh, personal communication). The ever-advancing differentiation of the various professions, however, led to increasingly independent groups within the association. Since 2005, the common board of the Association of Flemish Neuropsychiatrists served three independent societies, the Flemish Society of Neurology, the Flemish Society of Psychiatry, and the Belgian Society of Neurosurgeons. The latter is bilingual (French and Dutch).

The Netherlands Society of Neurology In 1871, the Netherlands Society of Psychiatry was founded by psychiatrist J.N. Ramaer (1817–1887), who became its first chairman. The Society was very active in defending an appropriate level of patient care and reasonable remuneration for psychiatrists. It was instrumental in getting the government to pass the second law on the insane in 1884, which regulated state supervision of the mental health system and brought further improvements to the care of institutionalized patients. In 1885, C. Winkler and G. Jelgersma were admitted as members of the Society. The first had just been appointed lecturer in psychiatry in Utrecht; the latter was prosector in the psychiatric hospital Meerenberg, near Haarlem. As mostly psychiatrists were interested in the correlation of behavioral disturbances and morphological lesions in the brain, they were generally neuropsychiatrists. Gradually, however, it became apparent that neuropathological disturbances often manifested themselves essentially in neurological symptoms and signs. Those physicians especially interested in the latter field criticized the lack of attention to these subjects and threatened to split off into an independent society. Therefore, in 1895, the name of the Society was changed to the Netherlands Society of Psychiatry and Neurology and the subject of neurological disturbances was placed higher on the agenda of the meetings. In 1931 an official registry of specialists was established by the Dutch Medical Association, and from

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1934 onward physicians registering in the specialty of neuropsychiatry had to indicate the field of their main activity, i.e., either neurology or psychiatry. The training, however, continued to be for both disciplines. In 1962 two separate departments were established within the Society for Psychiatry and Neurology, and, finally, in 1972, both Neurology and Psychiatry were acknowledged as specialties in their own right (Keyser, 2003). In 1974 a separate Society of Neurology was founded, “ending more than one hundred years of joint participation of psychiatrists and neurologists in a single association” (Schulte and Endtz, 1977). The Netherlands Society of Neurology is affiliated with the World Federation of Neurology. A Dutch journal provided a forum for members of the Netherlands Society for Psychiatry and Neurology. From 1871 until 1897, a journal of psychiatry was published and, in 1897, it was renamed Psychiatrische en Neurologische Bladen (Journal of Psychiatry and Neurology). The journal was in the Dutch language, which limited the distribution of Dutch scientific findings outside the region. Therefore, from 1948 on, more papers were published in English and the journal’s title was changed to Folia Psychiatrica, Neurologica et Neurochirurgica. When the Netherlands Society of Psychiatry and Neurology split in 1974, the Netherlands Society of Neurology continued with the journal under the title Clinical Neurology and Neurosurgery (CNN). In 1971 the Netherlands Society of Psychiatry, together with the Flemish Society of Neuropsychiatrists, had started the Tijdschrift voor Psychiatrie (Journal of Psychiatry). This journal published psychiatric papers in the Dutch language and continues to do so. The neurological CNN failed to obtain adequate subscriptions, got a low citation rating, and had a disappointingly small readership beyond the automatic subscription for the membership of the Netherlands and Flemish Neurological Societies. A suggested merger with Acta Neurologica Belgica in 1986 failed, mainly because the Belgians wanted the French language. So, at the close of 2001, CNN was discontinued, George Bruyn having been its last editor from 1990 onward. Since the beginning of 1998, the new Nederlands Tijdschrift voor Neurologie has met the needs of the Netherlands Society of Neurology for a national forum (Koehler et al., 1998).

The 1907 Congress The first International Congress for Psychiatry, Neurology, Psychology, and Care for Lunatics was held in Amsterdam in 1907. The event was organized by Winkler, Van Wayenburg, and Wertheim Salomonson.

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G. Jelgersma from Leiden was the Congress’s president and acted as its chairman. It was attended by over 800 participants, amongst whom there were many famous neurologists: Babinski, Bechterew, Pick, Vogt, Oppenheim, Westphal, Von Monakow, Weir Mitchell, Marie, Lombroso, Marinesco, Van Gehuchten, and Liepmann. In addition, psychiatrists and neuropsychiatrists from 22 countries took part in the discussions. Jelgersma contributed a demonstration of the first series of brain preparations, which would be published as his Atlas Anatomicum Cerebri Humani in 1931. Also at this congress, C.U. Arie¨ns Kappers read his first paper on the newly formulated theory of neurobiotaxis. The wide-ranging influence that this comprehensive Congress had on the development of Dutch neurology may be deduced from the fact that it prepared the ground for the establishment (2 years later) of two institutions that were to shape the direction of the future development of neurology in the Netherlands, i.e., the Central Institute for Brain Research in Amsterdam and the Amsterdam Society of Neurologists.

Central Institute for Brain Research (Amsterdam) The Central Institute for Brain Research was inaugurated in 1909 under the auspices of the Dutch Royal Academy of Sciences. In 1901, at the meeting of the International Association of Academies in Paris, Wilhelm His (1831–1904) spoke out for the creation of a global League of Institutes with a communal brain research program and an equitable distribution of research projects. This resulted in the formation of the “Brain Commission.” Winkler and the anatomist Bolk, after drawing up an official report for the Dutch Royal Academy of Sciences, managed to obtain agreements from the Academy and from the Amsterdam Municipal authorities and Dutch government to found the Central Institute for Brain Research, to be housed next to the Laboratory for Anatomy of Amsterdam University. The Institute had a major influence on neurological research activities in the Netherlands. Its first director, C.U. Arie¨ns Kappers (1877–1946), developed a 40-year program of comparative neuroanatomical research. It resulted in the 1936 textbook The Comparative Anatomy of the Nervous System of Vertebrates including Man, which for the next 50 years was a leading reference in its field (Arie¨ns Kappers et al., 1936). This book was extended by Rudolf Nieuwenhuys, H.J. ten Donkelaar, and C. Nicholson into the monumental three-volume textbook, The Central Nervous System of Vertebrates, (Nieuwenhuys et al., 1998). Important neurobiological concepts that germinated in the Central Institute for

Brain Research were the neurobiotaxis principle formulated by Arie¨ns Kappers (1908), and the fetalization or retardation theory of Bolk (1866–1930) that explained a number of features of human (neuro-) ontogenesis (Bolk, 1918). After the death of Arie¨ns Kappers in 1946, Brouwer became director of the Institute and the research emphasis was modified to include neuropathology. Brouwer’s successor, S.T. Bok (1892–1964), was director of the Central Institute for Brain Research from 1953 until his retirement in 1962. He introduced statistical and stereological methods in neuroanatomy and advocated a quantification of the cerebral cortex, for instance in his book Histonomy of the Cerebral Cortex (Bok, 1959). J. Arie¨ns Kappers, a nephew of C.U. Arie¨ns Kappers, was director from 1962 to 1975, and began a fertile research program on the pineal gland and the circumventricular organs and hypothalamus, resulting in no less than 19 theses. The name of the Institute was changed to the Netherlands Institute for Brain Research in 1976. J. Arie¨ns Kappers’ student and successor, Dick Swaab, subsequently extended the research program to include the structural, ultrastructural, and neurochemical aspects of the hypothalamic nuclei and the cerebral cortex. His findings on the sexual dimorphism of a particular hypothalamic nucleus created a stir with a broader public (Swaab and Fliers, 1985; Swaab and Hofman, 1990; Zhou et al., 1995). In 1985, Swaab, together with F.C. Stam, founded a brain bank for neuropathological research into a variety of disorders, including Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. The close ties with the University of Amsterdam that had existed from the beginning resulted in the Central Brain Institute’s move, along with the Medical Faculty, into an annex at the newly built Amsterdam Medical Center in 1984.

The Society of Amsterdam Neurologists (1909) The Society of Amsterdam Neurologists was founded in 1909 by Van London, Van Valkenburg, Arie¨ns Kappers, Winkler, Wertheim Salomonson, De Vries, Merkus, and K.H. Bouman. The birth of this Society of Amsterdam Neurologists was a reaction to the lack of time available to discuss neurological subjects during the meetings of the Dutch Society of Psychiatry and Neurology, and therefore the expressed aim was to provide a forum exclusively restricted to neurology. Undoubtedly it was the enthusiasm and inspiration generated by the 1907 International Congress in Amsterdam that had sparked the initiative to establish this society.

THE DEVELOPMENT OF NEUROLOGY IN THE LOW COUNTRIES During Winkler’s tenure in Amsterdam as the Chair of Psychiatry and Neurology, i.e., up to 1915, he was the driving force behind the organization of the Society’s meetings. After he left for Utrecht in 1915, B. Brouwer took over as secretary, and an actively contributing membership furthered the flourishing of the Society. After World War II, A. Biemond was president twice and participated actively in the meetings. The Society meets according to a monthly schedule and the sessions are hosted alternately by one of the training hospital neurological departments in the Amsterdam region. The meetings are attended by neurologists and residents and have a function in the teaching and tuition of the trainees. The Society has been and still is instrumental in forming a strong “Amsterdam School” in neurology, and is an influential platform for the neurological sciences in the Netherlands.

The Oto-Neuro-Ophthalmological Group in Belgium During World War I, the usefulness of close collaboration between ENT surgeons, neurologists, and ophthalmologists had been demonstrated in the neurological centers caring for the wounded soldiers. This resulted in the establishment of Oto-Neuro-Ophthalmological Study Groups that functioned as forums for the exchange of ideas and practical experiences, where scientific medical subjects could be discussed. The first such group functioned under Barre´ in Strassburg, France. In Belgium, in 1925, Paul Martin, a neurosurgeon in Brussels, and Ludo Van Bogaert, from Antwerp, took the initiative and, together with Henry Coppes (an ophthalmologist) and E. Buys and C. Hennebert (ENT surgeons), founded the Groupement ONO et Neurochirurgical (NC). They persuaded Jean Crocq, secretary of the Belgian Society of Neurology, to have four sessions of the Neurological Society a year devoted to subjects put forward by members of the Groupement ONO et Neurochirurgical. Paul Martin became the secretary of the group, and for years he was the initiator and energizer of its activities. Members of the group often contributed to the International ONO Congresses, for instance the ones of 1932 in Montpellier (France) and of 1937 in Geneva.

The Netherlands Study Club for Neurosurgery In 1936, F.A. Verbeek, then working as a neurosurgeon in Groningen, took the initiative with B. Brouwer, the Amsterdam neurologist and godfather of Dutch neurosurgery, to start a Netherlands Study Club for Neurosurgery. Co-founders were Ignaz Oljenick (Amsterdam), Arnoud C. De Vet (Wassenaar), and C.H. Lenshoek

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(Utrecht). The objective of the newly established group was “the promotion of neurosurgery” among its members. In addition to neurosurgeons, a limited number of neurologists joined as associate members. The frequency of the meetings initially was four times a year, on a rotational basis in each of the (then) four neurosurgical centers. Often they consisted of a business meeting (concerning subjects like training programs and the planning of new neurosurgical units) and a scientific meeting, where case reports and papers on neurosurgical and neurological subjects were presented. Bernard Brouwer remained president of the Study Club until his death in 1949, and Verbeek was secretary from 1936 until his death in 1958. After Brouwer, the presidency and vice-presidency were alternately fulfilled by a neurosurgeon and a neurologist. Following the founding of a Netherlands Society of Neurosurgeons in 1952, the neurologists became ordinary voting members of the Study Club, and the membership was extended to two neurosurgeons and two neurologists from each center, while the frequency of the meetings was reduced to twice yearly. Today the Netherlands Study Club for Neurosurgery still remains a unifying factor in the Netherlands, with the active participation of neurosurgeons and neurologists from all over the country.

The Bunge Institute in Antwerp In 1927, the Bunge Foundation was established in memory of Eduard Bunge (1851–1927), a wealthy industrialist from Antwerp. The aim was to found a center of medical and surgical research. Therefore a new clinic was to be built in Antwerp/Berghem that, according to the wish of the founder, could have at its disposal laboratory facilities for experimental, physiological, and pathological studies of diseases. The Bunge Institute opened in 1934. Ludo Van Bogaert became the head of the Department of Internal Medicine and Neurology, and he transferred his anatomopathological laboratory from the Stuyvenberg Hospital to the Bunge Institute. This was the beginning of a 40-year-long period during which Van Bogaert, with a large number of collaborators, produced an impressive number of publications in clinical neurology. The funding of the research activities needed an additional financial input, and this was provided by the Born family of Antwerp in 1938. Accordingly the foundation went under the name Born–Bunge Foundation, although the hospital retained its name as Bunge Institute. In 1957, the first International Congress of Neurological Sciences (ICNS) was held in Brussels with Ludo Van Bogaert as secretary general. This activity resulted in the foundation of the World Federation of Neurology (WFN), with Ludo Van Bogaert as its first president.

700 A. KEYSER During the subsequent 8 years (1957 to 1965), Van Haller, to Edinburgh by Monro, to Sweden by Bogaert remained in charge, and the Bunge Institute Linnaeus, to Vienna by Van Swieten, and to Russia became the center for the WFN, where numerous conby his nephew Herman Kauw Boerhaave, who became gresses and international workshops were organized. court physician in Moscow. Especially influential was The WFN’s journal World Neurology, later renamed Gerard Van Swieten (1700–1772), the court physician Journal of Neurological Sciences, had its office in the who founded the Viennese School of Medicine and Bunge Institute during that period. reorganized medical care and teaching throughout In 1977 the comprehensive laboratories financed by Austria-Hungary and in the Austrian Netherlands. the Born–Bunge Foundation were transferred to the In modern times, neurology developed in Leiden campus of the Universitaire Instelling Antwerpen. after a chair of psychiatry was established in 1889, Two years later, the Neurological Department of the because psychiatric research in those years consisted Bunge Institute was incorporated into the newly built of neuroanatomy and neuropathology, which meant University Hospital Antwerp (Martin and Martin, that neurological teaching was included. Gerbrandus 1990, 1996; Baeck, 2005). Jelgersma was appointed professor. He had a lifelong interest in neuroanatomy and was interested in functional neuroses (he published a number of textbooks The Belgian Neurological Institute on psychiatric diseases). In 1935 Le´on Laruelle, working in Brussels, founded the After 1912, Jelgersma left neurology teaching to his Centre Neurologique, a neurological center, which later collaborator Ernst De Vries, who had written a thesis was renamed Institute Neurologique Belge (Belgian Neuon neuroglia under Constantin Von Monakow in Zurrological Institute). Its aim was to study patients from ich and became lecturer in neurology in 1913. When clinical, biological, and histological perspectives, and to De Vries left for China in 1925, Abraham Gans took collect and save all data in order to guarantee in-depth over his teaching duties (Rooijmans, 1998). analyses. With this initiative, Laruelle created a precursor The university had decided to create a chair of of the neurological research units that sprang up later on neurology prior to World War II, but it was not until and nowadays are allied to many university departments 1946, when Gans resigned, that G.G.J. Rademaker of clinical neurology. After the death of Laruelle, Andre´ (1887–1957) was appointed to the chair of neurology. Balisaux took over the directorate with the collaboration In 1958, Rademaker was succeeded by W.J.C. Verhaart of the neurosurgeon Fonsette and, later on, physicians (1904–1983) who was mainly interested in comparative Nols, De Baets, and Brasseur. anatomy, especially of the pyramidal tract. He succeeded in unifying the departments of neurology, DUTCH UNIVERSITIES neuroanatomy, neurosurgery, neuropathology, and clinical neurology into one single structural organizaThe University of Leiden tion, the Leiden Institute of Neurological Sciences. The University of Leiden was founded in 1573 by WilAfter Verhaart left in 1970, A. Verjaal (1910–1973) took liam (the Taciturn) of Orange as a reward for the heroic over. His thesis (Verjaal, 1938) had been on memory defiresistance of its population against the Spanish. During cits after head injury and in 1950 he had published a textthe 17th century, Franciscus De La Boe Sylvius (1614– book for students on agnosia, aphasia and apraxia. 1672) was professor of the practice of medicine in LeiVerjaal was an excellent teacher, but died suddenly in 1973. den. Renier De Graaf and Niels Stensen were among George W. Bruyn (1928–2002) was now appointed his pupils, as was Jan Swammerdam. Sylvius gave many to the chair of neurology. He had been trained in accurate descriptions of the nervous system and his Utrecht and had an encyclopedic knowledge of neurolname still remains connected to the aquaductus cerebri ogy. Together with Pierre Vinken he started and edited and the fissura lateralis. He founded the first chemical the Handbook of Clinical Neurology for years (Vinken laboratory in a university, but believed bed-side teaching and Bruyn, 1968–2003). Bruyn introduced his interest was the most important part of medical education. in migraine pathophysiology to Leiden. Hereditary Herman Boerhaave (1668–1738), during the later amyloid angiopathy, which frequently occurs in the part of his professorship, lectured extensively on nerNorth Sea fishing village of Katwijk, near Leiden, also vous diseases and adhered to the iatrochemical school held his interest, as did the pathophysiology and the of medicine. He consolidated the method of bed-side mode of inheritance of Huntington’s disease. After teaching in Leiden that had been introduced by Sylvius. his retirement in 1992, his successors amplified these Boerhaave had many eminent pupils who disseminated fruitful lines of research: M. Ferrari (b. 1954) analyzed his ideas throughout Europe: to Go¨ttingen by Von the genetics of hemiplegic migraine, and Raymond

THE DEVELOPMENT OF NEUROLOGY IN THE LOW COUNTRIES 701 A.C. Roos (b. 1954), who was appointed chair in 1993, After Winkler’s retirement in 1925, Leendert Boucontinued the study of movement disorders. man (1869–1936) took over. He had been professor Dr. Axel Wintzen (b. 1937), who had been a staff at the Vrije Universiteit of Amsterdam from 1907 member since the time of Verjaal, and who had been until now, where he held a chair in Theoretical in charge of the clinical department prior to the appointBiology, Neurology, and Psychiatry. In contrast to ment of Bruyn, later on became head of the outpatient Winkler, Bouman was inclined to give psychoanalysis department of neurology. He had an interest in neuroand phenomenology a role in the care of psychiatric muscular diseases and was appointed to the chair for patients. Thus, a new approach developed over neuromuscular diseases in 1995 (he left in 2002). the years, with less emphasis on neuropathological findings. After Bouman died in 1936, the chair was split and University of Utrecht H. Ru¨mke (1893–1967) was appointed in psychiatry The State University of Utrecht was founded in 1636. and W.H. Sillevis Smitt (1894–1985) in neurology. SilleJ.C. Schroeder van der Kolk and F.C. Donders were vis Smitt developed an interest in the so-called dysraphic the two protagonists of the teaching of neuropsychiastate and stigmata degenerationis that in many patients tric subjects here during the 19th century. may be accompanied by a dysfunction of the nervous Schroeder van der Kolk was professor of anatomy system – and he intended to prove a correlation between and physiology, but also was involved in the care of these phenomena. In this context, he frequently lectured the insane (as described above). Schroeder van der Kolk on his findings in patients suffering from phakomatoses became Inspector General of Public Health Care and that were supposed to be derived from a disordered contributed much to the amelioration of the care of neuroectodermal germinal layer (Sillevis Smitt, 1951). institutionalized psychiatric patients. In addition he pubA number of scientific publications resulted, e.g., Bijl’s lished research papers on the function of the spinal cord thesis on the “Status Dysraphicus” (Bijl, 1956) and and the brainstem, and on epilepsy (Schroeder van der Keuter’s publication on the prognostic value of these Kolk, 1858). His ideas on the function of the central phenomena as to the risk of post-vaccinal encephalitis nervous system in relation to the mind were published in military recruits. He also was interested in the correposthumously (Schroeder van der Kolk, 1863, 1870). lation between psychological processes and biological He was succeeded by F.C. Donders, who became phenomena at the level of the autonomic nervous syswell known because of his investigations within the tem, and tried to attribute psychosomatic dysfunction field of ophthalmology. As to psychiatry, he was to “diencephalic” constitutional deviations. In Sillevis instrumental in the institution of a chair of psychiatry Smitt’s time, close cooperation existed between the neuin the university, in order to guarantee the teaching rological department and Professor Henk Verbiest of psychiatry for medical students. (1909–1997), the neurosurgeon. In 1885 Cornelis Winkler was appointed lecturer in Professor A. Kemp (1909–2003) succeeded Sillevis psychiatry. He was predominantly interested in neuroSmitt in 1965. From 1938 on, Kemp had been associate anatomical research, but taught psychiatry all the professor and head of the clinical department of neusame. In 1893 he was appointed to the newly created rology. He excelled in teaching neurology. Some of chair of psychiatry and neurology. Because of lack of his scientific publications concerned the diagnosis and facilities, he left for Amsterdam in 1896. treatment of the cerebello-pontine angle tumors and From 1900 until 1903 Theodor Ziehen (1862–1950) of myotonia dystrophica. Under his guidance, the neuroJena occupied the chair. Another German, Karl Heilpathological laboratory that had been neglected since bronner (1869–1914), succeeded him in 1904. Under his Winkler’s time was revitalized by Ernst De Vries, guidance a new clinic was completed in 1912. In 1914, who had by now returned to the Netherlands. In 1960 at the beginning of the Great War, Heilbronner suddenly J.J. Van Rossum took over and in 1989 his neuropathodied. Winkler now returned to Utrecht and continued his logical department was incorporated in the Department activities in neurology and psychiatry. He adhered to the of Pathology. position that psychiatry should be approached neurobioKemp was also instrumental in developing neuromuslogically. In addition, he performed neuro-anatomical cular research in Utrecht. He sent Frans G.I. Jennekens studies. His Handbook of Neurology contains the results (b. 1931) in 1969 to John Walton (then in Newcastle upon of his research on rabbits, cats, and dogs. During the Tyne, UK), who had international renown in the field of same period, Magnus, De Kleyn, and Rademaker, and neuromuscular diseases. Back in Utrecht, Jennekens also Stenvers, developed their important research into established a laboratory of neuromuscular diseases and the pathophysiology of posture and stance and into the was later named Extraordinary Professor of Neuromyoloptic motor reactions (Magnus, 1924; Rademaker, 1931). ogy. The eventual development of the Utrecht clinic as a

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national reference center for neurosurgery for epileptic disorders was also the fruit of Kemp’s early initiatives. In 1980 an illness abruptly forced Kemp to step down, and in 1983 J. Van Gijn (b. 1942) became chair of neurology. He developed an interest in the clinimetric analysis of drug effects and promoted “evidence-based medicine.” He organized several international trials on the efficacy of drugs employed for the secondary prevention of thromboembolic stroke (Jovanovic et al., 2004).

University of Groningen The State University of Groningen was founded in 1614. It obtained some renown early in the 19th century from the spinal cord studies published by Professor of Physiology Isaac Van Deen (1805–1869). He studied the transmission of nervous impulses and reflexes in animals after partial transections of the spinal cord. In this way he showed that the dorsal columns of the spinal cord convey sensory impulses and the anterior columns motor impulses. His data were explicitly cited by Brown-Se´quard in his well-known studies in humans (Van Deen, 1841; Koehler, 1989). The first chair of psychiatry in Groningen was established in 1903 when a new academic hospital was opened including a psychiatric department. In 1876, the medical faculty had been asked by the provincial authorities to provide for a facility for teaching psychiatry, but this request had been rejected. In 1896, Dr. Enno Dirk Wiersma (1858–1940) started a private clinic in the city and in 1897 was asked to teach psychiatry as a private lecturer. Dr. Wiersma was appointed chair of psychiatry in 1903. He closely cooperated with Professor G. Heymans, who was the first professor of psychology in the Netherlands. Together they studied the physiological consequences of emotional states. In 1912 Wiersma was also charged with neurology, and in 1916 a new clinic for neurology and psychiatry was built. After his retirement in 1928, Wiersma was succeeded by W.M. Van der Scheer (1881–1957), who continued to teach both neurology and psychiatry. His main interest, however, was in psychiatry. He introduced occupational therapy and other modalities of active treatment in the wards. After his retirement in 1949, the chair was split and J. Droogleever Fortuyn (1906–1999) was appointed to the chair of neurology, while E. Kraus was appointed to the one in psychiatry. During the 1970s, the neurological department was reorganized. The classical neuroanatomical orientation was redirected into a more neurobiochemical direction. Work groups on neurotraumatology, movement disorders, and multiple sclerosis were formed. The intensive care unit for assisted ventilation, dating from 1955, and

initiated by Droogleever Fortuyn, became a nucleus of activity for the neurotrauma group, where, together with anesthesiology and pulmonology, new procedures were developed for the treatment of head trauma (Droogleever Fortuyn, 1991). In 1974 J. Minderhoud (b. 1932), who was especially interested in this treatment of brain injury, succeeded Droogleever Fortuyn. Together with the neuropsychologists Deelman and Van Zomeren, he published many studies on the cognitive sequelae of head trauma (Minderhoud and Van Zomeren, 1984). H. Oosterhuis (1932–2002), who was appointed in 1976, wrote several textbooks on neurology for medical students and residents, and contributed much to the teaching of neurology, not only at the local level in Groningen but also at postgraduate courses for Dutch neurologists in general. He was an international authority in the field of diagnosis and treatment of myasthenia gravis and headed the Groningen Neuromuscular Workgroup (Oosterhuis, 1997). J.P.W.F. Lakke (1928–2001) was given a special chair for movement disorders in 1987 and became an authority in the treatment of parkinsonism. In 1995 J.H.A. De Keyser from the Vrije Universiteit Brussels was appointed head of the department of neurology and succeeded to the chair of neurology.

Free University of Amsterdam The Calvinist Free University of Amsterdam was founded in 1880 by Abraham Kuyper for the training and tuition of orthodox Protestant ministers. It was not until 1950 that an official Medical Faculty was established. In 1907, when the first International Congress of Psychiatry, Neurology, Psychology, and Care for the Insane was organized in Amsterdam, the Association for Christian Care of Insane and Nervous Patients (1884) in the Netherlands founded a chair for Theoretical Biology, Neurology, and Psychiatry. Leendert Bouman was appointed and he also became head of the Valerius Clinic for Neurology and Psychiatry, which opened in 1910. Bouman was an inspiring leader who organized monthly seminars in the Valerius Clinic. These seminars developed into an unofficial interdisciplinary forum where many people met and exchanged ideas, among them F.J.J. Buytendijk (1887–1974), Bok, Ru¨mke, and Sillevis Smitt. Nevertheless, the contrast between the reality of neuropsychiatric patient care and the requirements of the association to defend a more anthropologically oriented Protestant orthodox psychiatry in the Valerius Clinic resulted in key departures. Bouman left for Utrecht in 1925, and Ru¨mke and Sillevis Smitt later on joined him.

THE DEVELOPMENT OF NEUROLOGY IN THE LOW COUNTRIES 703 In 1928 Lammert Van der Horst (1893–1978) was Frederik Ruysch (1638–1731) was both a medical appointed in both neurology and psychiatry at the Free practitioner and a professor of anatomy and botany. University. In psychiatry, he developed an anthropoloHis injection preparations that visualized the blood vesgical and phenomenological approach that could be sels in great detail became famous. He demonstrated brought in harmony with the Protestant Christian the existence of the arachnoid as separate from the tradition. Van der Horst furthered the development pia mater of the brain. of neurology too. He initiated the first electroIn 1851 Gustaaf Eduard Voorhelm Schneevoogt encephalographic unit in the Netherlands within the (1814–1871) was appointed to teach “Neuropathology Valerius Clinic. In 1945 a separate neurological unit in connection with the doctrine of insanity.” was created. The internist professor P.K. Pel was very active in the In 1950 the Medical Faculty of the Free University field of neurology. He organized an outpatient clinic of Amsterdam was officially established, but the that was run by his residents G. Waller (from 1874 to Department of Neurology and Psychiatry remained in 1883) and C.C. Delprat (from 1874 until 1893); Delprat the Valerius Clinic. J.F. Folkerts (1912–1977) was also became a lecturer in neurology in 1886. appointed Chair of Neurology in 1961. Folkerts was In 1896, a chair of psychiatry and neurology mainly interested in cerebrovascular diseases, and was founded in Amsterdam and C. Winkler was together with Professor Raymond Van den Bergh (Louappointed. Johannes Wertheim Salomonson had taken vain) he edited the first Dutch multi-authored textbook charge of the neurological outpatient department of for students and residents (Van den Bergh and FolkC.C. Delprat within Pel’s department in 1893. Winkler erts, 1972). In 1974, a section of neurological and neuchose to cooperate with him and saw to it that he was rosurgical sciences was created within the medical appointed extraordinary professor of neurology faculty of the Free University. and electrotherapy in 1899. Because of Wertheim Folkerts was succeeded by J.H.A. Van der Drift Salomonson’s vivid interest in the recently discovered (b. 1922) in 1977, who was mainly interested in cerebroX-rays of Konrad Ro¨ntgen, radiology was added in vascular diseases and in teaching. Johan C. Koetsier 1900. (b. 1936) took over the chair of neurology in 1977. Up When Winkler left to return to Utrecht in 1916, K.H. to that time, the Department of Neurology had been Bouman (1874–1947) was appointed for psychiatry and located within the Valerius Clinic; it was moved to neurology, but after Wertheim’s death in 1922 the chair the University Hospital of the Free University of of psychiatry and neurology was split into one for neuAmsterdam in 1985. Koetsier had an interest in multirology and one for psychiatry. ple sclerosis, was volume editor of the Handbook of In 1923, Bernardus Brouwer was appointed for neuClinical Neurology, volume 47 on demyelinating disrology and remained in that position till 1946. It can be eases (Koetsier, 1985), and initiated a Centre of Multistated that, with the chair of Brouwer, neurology came ple Sclerosis in Amsterdam with brain-bank facilities of age in the Netherlands. Trained by Winkler and (in cooperation with the Central Institute of Brain Wertheim, Brouwer in turn trained a good number of Research). neurologists who later were appointed to chairs of neuIn 1998 Koetsier retired and J.J. Heimans (b. 1950) rology in the Netherlands. became chair of neurology and head of the departA. Biemond (1902–1973) was professor of neurolment. He developed the specialty of neuro-oncology ogy from 1947 to 1971. Like Brouwer, Biemond comin cooperation with the nearby Antoni Van Leeuwenbined a vivid interest in clinical neurology with hoek Hospital. several lines of basic research. As a teacher he was unrivaled, and he wrote several textbooks based on large series of personal cases with autopsies (BieThe Municipal University of Amsterdam mond, 1946, 1954). After Biemond, W.A. Den Hartog The Municipal University of Amsterdam was founded Jager (1914–1993) held the chair until 1980. He was in 1877. It was the first non-state university within the especially interested in neuromuscular disorders and Netherlands. Prior to this event, a medical school had in amyotrophic lateral sclerosis. In 1977 he presided already been established under the name of Atheover the 11th International Congress of Neurology, naeum Illustre (1632), and a hospice had opened partly held that year in Amsterdam. H. Van Crevel (1932– for teaching purposes (in 1669). 2002), who had trained in Rotterdam, was appointed In 1641, Nicolaas Tulp described the anatomy of in 1980 and retired in 1991. Marinus Vermeulen developmental malformations of the brain. He was (b. 1946) next served as chair for neurology and mainly interested in the cerebellum, but also published Jan Stam (b. 1949) fulfilled the function of teaching on six cases of spina bifida. professor of neurology in 1993.

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University of Nijmegen The University of Nijmegen was founded in 1923 by Dutch Catholic bishops, in order to stimulate the emancipation of the Catholic part of the population. Dutch Catholics had been in a disadvantageous position since the 16th-century revolt against Spain, and had no entry into the higher administrative and governmental functions. At the start, the university consisted only of faculties of law, letters, philosophy, and theology. In 1951 a medical faculty was established to train Catholic physicians, so they could assist patients in morally adequate ways in decisions of health, life, and death. J.J.G. Prick (1909–1978), who had trained with Brouwer in Amsterdam, was appointed to the combined chair of neurology, psychiatry, and psychology in 1953. Together with his colleague and close friend F.J.J. Buytendijk, Prick defended the principle that the holistic and anthropological approach to the patient would ensure the good and complete understanding of the function of the human nervous system (Prick, 1971). In addition to publications on this subject, he composed a handbook of poliomyelitis during the last epidemics of this disease in the Netherlands in the 1950s (Prick, 1961). In addition, experimental neurological research in epilepsy and clinical research into multiple sclerosis was organized by Otto Hommes, whereas metabolic disorders of the central nervous system in childhood were studied by Fons Gabree¨ls at this time. In 1971 the chair was split and Prick continued in the chair of neurology up to his death in 1978. He was succeeded by professor Bento P.M. Schulte (1928–1991). His thesis (Schulte, 1959) on the Praelectiones de Morbis Nervorum 17301735, a manuscript of 206 lectures by Herman Boerhaave (1668–1738) as noted by his pupils Van Eems and Von Swieten, revealed his strong interest in medical history. While practicing in Tilburg from 1960 to 1980, he organized the comprehensive Tilburg Stroke Study. In Nijmegen he and Bruce Scho¨nberg were instrumental in initiating neuroepidemiological research courses. He also contributed to the study of aphasia in cooperation with the local Max Planck Institute for Linguistics, and he furthered the development of geriatric neurology. Schulte was succeeded by George W.A.M. Padberg in 1994, who organized the research lines of the department of neurology into a neuromuscular work group, a research group of neurodegenerative diseases, a research group for movement disorders, and a neuro-oncology unit.

Rotterdam University Although Erasmus of Rotterdam (1469–1536) for centuries had given the name of Rotterdam an intellectual aura, the Erasmus University of Rotterdam was only

founded in 1973. J.W.G. Ter Braak (1903–1971) was appointed in neurology in 1961. He was especially interested in eye movements. Arthur Staal succeeded Ter Braak in 1970. H. Van Crevel, who remained lecturer under Staal until 1980, was one of the first Dutch neurologists to initiate a multicenter double-blind controlled study on the effectiveness of pharmacotherapy in a neurologic disorder. The efficacy of the administration of the pro-coagulant tranexaminic acid for the prevention of rebleeds in subarachnoid hemorrhage patients was the object of his study. Herman Busch discovered the effectivity of treatment of immunological neuromuscular disease by means of plasma exchange and plasma infusion in the early 1980s. It was Marinus Vermeulen who, in 1985, published the first results from gammaglobuline infusion in a patient with chronic inflammatory demyelinating polyneuropathy (Van Doorn and Vermeulen, 1987). Later on, this line of research was amplified in a large multicenter study of Guillain–Barre´ syndrome by Professors Frans Van der Meche´ and Pieter Van Doorn (Van der Meche´ et al., 1988). Until 1991 Staal trained a good number of students and residents in the Dijkzigt Hospital department, many of whom became professors of neurology elsewhere in the Netherlands, among them P. Van der Lugt (Maastricht, 1979); J. Van Gijn (Utrecht, 1983); and M. Vermeulen (Amsterdam, 1991). In 1991 Frans Van der Meche´ succeeded Staal as head of the department.

State University of Maastricht The University of Maastricht was founded in 1976. Its medical faculty was the first in the Netherlands to adopt a problem-centered way of teaching (McMaster method), and its success inspired other medical faculties in the country to model their medical teaching along the same lines. In 1979 Paul Van der Lugt (1936–1990) was appointed chair of neurology. He was especially interested in epilepsy. This line of research led to the establishment of facilities for the neurosurgical treatment of epilepsy and was continued by the neurologist Dr. M. De Krom (b. 1948) and psychologist A. Aldenkamp. Dr. Chris Ho¨weler from Maastricht made an important contribution to the study of myotonic dystrophy by demonstrating the phenomenon of anticipation in subsequent generations of families with this inherited neuromuscular disease (Ho¨weler et al., 1980). In 1994 Albert Twijnstra (b. 1944), neuro-oncologist, organized the first meeting of the European Association of Neuro-Oncology in Maastricht.

THE DEVELOPMENT OF NEUROLOGY IN THE LOW COUNTRIES 705 J. Troost (b. 1936) was head of the Department of During the 17th and 18th centuries, the University Neurology from 1992 until 2001. He was trained in of Louvain remained an intellectual unifying factor Utrecht and specialized in child neurology. He was sucfor the southern (Austrian) Netherlands. During the ceeded in 2002 by Professor M. Van Limburg (b. 1956) middle years of the 18th century, medical teaching who, in cooperation with J. Lodder (b. 1948), concenwas reformatted along the lines that were developed trated on the epidemiology and treatment of cerebroin Austria-Hungary by Gerard Van Swieten (who stuvascular disease. died in Louvain in 1714). In 1754, a decree was issued The medium-care stroke unit that was established in in Vienna for the installation of a permanent royal Maastricht was the first facility in the Netherlands to commission for Louvain University, with the tasks of integrate intravenous thrombolysis into regular care. monitoring affairs at the university and promoting A program was recently developed for neuroendovasthe sciences. De Ney formed the trait d’union between cular interventions and clinical research changed from the Viennese commission and the local authorities in observational studies to preventive trials on various the Austrian Netherlands. aspects of cerebral small vessel disease. In the second half of the 18th century, the University of Louvain was moved to Brussels by Maria BELGIAN UNIVERSITIES Theresa’s successor, Jozef II (1765–1790), who as an enlightened ruler tried to curtail the influence of the The University of Louvain church. The Brabant Revolution (1787) was induced The University of Louvain was founded in 1425 by Jean by Jozef’s harsh administrative measures, which failed IV, Duke of Brabant, with papal approval in order to to acknowledge the feelings and sentiments of the establish the possibility of a studium generale for the eduvarious strata of the population. Later on, Emperors cation of students who up to that time had to go abroad. Leopold II (1790–1792) and Frans II were forced In 1426, a medical faculty was inaugurated after the to reinstate the former institutions, but strong antimodel of medical faculties of Cologne, Paris, and Vienna. clerical and anti-intellectual feelings gained momenTeaching consisted of the writings on anatomy and phytum. Eventually, in 1797, after more than 350 years, siology by Galen, and on diseases by Hippocrates, Avithe first University of Louvain was abolished. cenna, and Rhazes. A baccalaureate was awarded after The second University of Louvain was established 2 years of successful studies and the candidate was licenby royal decree of William I of the Kingdom of the tiated and ready to practice after 3 years (and an addiNetherlands in 1816 and opened its doors in 1817 as a tional exam). To become a doctor medicinae required state university. Although William I trod carefully, additional studies and considerable costs. The thorough the church and the traditional Catholic institutions felt organization and quality of its professors made the Unifrustrated. In 1835, this State University of Louvain versity of Louvain attractive to students, and before the was closed down. end of the 15th century it could compete with the famous In 1834, before this happened, the Belgian bishops universities in central and northern Europe. had decided to establish a new Catholic University, in The most illustrious alumnus of the university was reaction to the foundation of the Free (liberal) UniverAndreas Vesalius (1514–1564), who was born in Brussity in Brussels that same year. It began in Mechelen, sels and entered the Collegium Trilingue in Louvain but in 1835 the university was moved to Louvain in 1531. After his basic years he went to Paris, where and was installed in the former State University of he studied medicine under Jacobus Sylvius (1478– Louvain’s old buildings. This francophone Catholic 1555). Back in Louvain in 1536 and 1537, he finished University of Louvain lasted from 1834 until 1968, his baccalaureate thesis and then went to Padua, Italy. when a restructuring of the university system took There he was granted the degree of doctor medicinae place. The Flemish Dutch part of the university and nominated (by the “Illustrious Senate of Venice”) remained in Louvain as the Katholieke Universiteit professor of surgery. This meant that he also was Leuven, but the francophone part moved to Ottignies, charged with the teaching of anatomy. In 1543, where the Universite´ Catholique de Louvain (UCL) Vesalius published his De Humani Corporis Fabrica was established. The medical faculty of UCL was to (Vesalius, 1543). In the 7th book of the Fabrica, he have its hospital in Voluwe/Brussels (Hoˆpital St. Luc), described the anatomy of the human brain in a surprisand moved there in 1976. ingly modern fashion. He also did away with a large The development of neurology at the medical number of errors in human anatomy made by Galen faculty of Louvain University started with the activities and his followers, who had dissected animals, not of Arthur Van Gehuchten, who first studied the anathumans. After the publication of the Fabrica, Vesalius omy and histology of the nervous system and then entered the service of Charles V as imperial physician. neuropathology and clinical neurology. A chair of

706 A. KEYSER neuropathology was established in 1906, and Van to the chair of neurosurgery. Laterre established a Gehuchten was officially charged with the teaching of laboratory for the analysis of the cerebrospinal fluid and neurology at Louvain in 1912. Several young scientists inaugurated a research line on inflammatory neurological who worked with him went on to play important roles disorders, in particular multiple sclerosis. During the in Belgian neurology. 1980s, Peter Van den Bergh (b. 1954) developed a national In 1927, the first francophone chair of neurology in neuromuscular reference center within the Department Belgium was founded in Louvain, and it was awarded of Neurology to incorporate clinical, neurophysiological, to Arthur’s son, Paul Van Gehuchten (in 1935 he was genetic, neurological, and biochemical data for neuroalso entrusted with the newly established Dutch chair muscular patients. In 1998, Laterre was succeeded by of neurology). Although Paul Van Gehuchten was the Christian Sindic (b. 1949), who extended the research proacting head of the clinical neurology service, this sergram in neuroimmunology. vice remained embedded in the Department of Internal Medicine and General Surgery until 1952. Up to his The University of Ghent retirement in 1964, he would remain pivotal in clinical The University of Ghent was founded by William I of neurological activities. the Netherlands in 1817. Earlier, in 1804, a medical In 1952, independent departments were formed and school had been established by Jan Karel Van Rottera new neurological institute was built. The Institute of dam (1759–1834) on the instigation of the prefect of Neurology consisted of an integrated organization the De´partement in that French-dominated period. comprising services for neurology, neurosurgery, neuVan Rotterdam was appointed surgeon to the municiroradiology, clinical neurophysiology, neuropathology, pal hospital. J.F. Kluyskens (1771–1843) was a surgeon and neurochemistry. In 1964, when Paul Van Gehuchat the Bijloke Hospital in Ghent and was charged with ten retired, this neurological institute was split into the surgical courses, and J.E. Verbeek (1789–1848) the francophone Clinique de Neurologie et de Neurotaught anatomy. Van Rotterdam became the first Recchirurgie under the direction of Professor Dereymaetor of the newly founded university in 1817, and the ker and the Dutch-language Kliniek voor Neurologie medical faculty can be considered as the continuation en Neurochirurgie under the direction of Professor of the earlier medical school. Raymond Van den Bergh. The University of Ghent in its early years was a bulIn 1976 the francophone department was moved to wark of Orangist and even Calvinist academicians. It a new location in Voluwe (University Hospital Saint lost a lot of its prestige in Belgium after the 1830 uprisLuc) on the outskirts of Brussels, where the Universite´ ing against the northern Netherlands. But in 1835, after Catholique de Louvain La Neuve was established. The the establishment of a new State University, things Dutch-language part remained in Louvain in the Instiimproved significantly. tute of Neurology and Neurosurgery. In the meantime, Jozef Guislain (1797–1860) strove for better psychiatric care in Ghent. Guislain’s crusade Universite´ Catholique de Louvain La Neuve resulted in important improvements in the care of the Albert Dereymaeker (1916–1988) headed the clinical insane in Belgium and in reform of the psychiatric departments of neurology and neurosurgery at the Uniinstitutions. At the university, he organized a course versite´ Catholique de Louvain La Neuve. He was interon psychiatry and became known internationally ested in the diagnosis and treatment of cervical because of his textbooks and treatises on psychiatric spondylogenic myelopathy, and the development of illness. In Ghent, a hospital was named after him (Instisurgical treatment of movement disorders was a main tute Guislain) and a statue commemorates his activtopic in the department. ities. The first Belgian Child Neurology Department was During World War I, the Germans proposed to initially under Demeyer (1927–1999), and later run by establish a Flemish (Dutch) language subdivision of Gilbert Lyon (1921–1991) and Philippe Evrard (1942– the University of Ghent, an initiative that was viewed 1997). The William Lennox Center of Epilepsy was also by the majority of the Flemish population as a poisoassociated with the university. This Center developed nous gift. In 1918, King Albert proposed to establish into a more comprehensive facility for the rehabilitaa Flemish university in Ghent. It took until 1930 before tion of neurological patients under the leadership of this intention was realized, and from then onward all Professor Thierry De Barsy. of the University of Ghent used Dutch. In 1979, Dereymaeker was succeeded by E. Christian From 1920 to 1939, Professor Hector De Stella Laterre (b. 1933) as chair of neurology and head of the (1869–1955) of the Department of Internal Medicine clinic. Professor Guy Stroobandt (b. 1933) was appointed was responsible for teaching neurology. He published

THE DEVELOPMENT OF NEUROLOGY IN THE LOW COUNTRIES clinical and experimental studies on the cerebellum and on the vestibular system. Jean Crocq, who practiced neurology at the St. Jans Molebeek Hospital in Brussels, joined the University of Ghent in 1922 to teach psychiatry. He regularly organized clinical demonstrations in the Guislain Institute and reportedly died of a central encephalitis lethargica, contracted while caring for one of his patients. He was succeeded by Professor Maurice Hamelinck (1882–1934), who continued to extend the psychiatric teaching facilities in conjunction with the Guislain Institute, next to which a psychiatric outpatient clinic was constructed in 1930. Neurology teaching in Ghent became connected with psychiatry after World War II. In 1946, Jacques De Busscher (1902–1966) was appointed chair of psychiatry. In 1949, neurology was added to his chair. He contributed much to the study of neurological problems, his department grew with a facility for clinical neurophysiology, and he was instrumental in establishing an autonomous department of neurosurgery. The new chair of neurosurgery was occupied by Professor J. Caemaert. Prior to this time, Fritz De Beule (1880–1949) had been the head of the Department of General Surgery. Before, in Louvain, he had joined forces with Arthur Van Gehuchten to develop a retrogasserian neurotomy for the treatment of trigeminal neuralgia. He had also been one of the first to perform spinal decompression in patients with a cord compression. From 1925 onward he worked in Ghent and was appointed as the chair of surgery in 1930. He retired in 1949. The chair of neurosurgery was consecutively occupied by Professor G. Hoffmann (1970–1978), Professor L. Calliauw (1979–1995), and Professor J. Camaert until the present. Professor De Busscher was succeeded in 1967 by Professor Henri Van der Eecken (b. 1920), who had specialized in neurology and psychiatry in Louvain before going to the Salpeˆtrie`re for a year, and then to Harvard on a research fellowship in neurology and neuropathology under Denny-Brown. Subsequently he worked in the laboratory of human anatomy in Ghent, mainly studying the vascularization of the human brain. This work resulted in a number of publications on anastomoses between the leptomeningeal arteries of the brain (Van der Eecken and Adams, 1953). From 1955 onward he was charged with the teaching of neurology. In 1970 an autonomous chair of neurology was established in Ghent and Professor Van der Eecken was the first to be appointed to this position. Van der Eecken was succeeded by De Reuck in 1987, and De Reuck was succeeded by Paul Boon in 2004. Boon had an interest in epileptology and, in cooperation with the neurosurgical department, established facilities for epilepsy surgery and neurostimulation.

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The University of Lie`ge One of the earliest signs of scientific revival during the Napoleonic period in Lie`ge was the establishment of the Socie´te´ Libre des Sciences Physiques et Me´dicales in 1806. Earlier, J.N. Comhaire (1778–1837), who had studied in Paris, had been allowed to lecture on anatomy in an improvised amphitheater in the St. Clemens Church. During this time, N.G.A.J. Ansiaux (1780– 1834) gave surgical courses and physiological lectures. In 1812, a school of medicine was founded with the approbation of the Chancellor of the Imperial Academy. Here a Cours de Clinique was offered. In 1817, both activities, i.e., the anatomical course of Comhaire and the clinical course of Ansiaux, formed the nucleus of the Medical Faculty of Lie`ge founded by William I of the Kingdom of the Netherlands in 1817. T.D. Sauveur (1766–1838), a physician of the Sint Abraham Hospital in Lie`ge, joined the two professors named above and was the first Dean of the newly erected University of Lie`ge. In 1825, V. Folman (1794–1837) was appointed the fourth professor. He taught anatomy. Other medical teachers of that time were H.M. Gae¨de (1795–1834), Ch. Moonen (1807–1837), F.C.E. Votten (1801–1888), N.J.V. Ansiaux Jr., and H. Sauveur Jr. After the Revolution of 1830, resulting in the independence of Belgium, the State University of Lie`ge was installed by the law on higher education of 1835. In the surge of new scientific activities, the Socie´te´ de Me´decine de Lie`ge was founded in 1847. During the second half of the 19th century, the University of Lie`ge attracted mainly students from the region, but quality of medical teaching and tuition could compete with the best medical faculties in the country. Joseph A. Spring (1814–1872) was one of the first professors of medicine in Belgium who, from his experiences in Munich and Paris, introduced a critical approach and taught his students to base their diagnoses on facts, not theories. After Spring, Voltaire Massius (1836–1912) took over and together with Constant Van Lair (1839–1914) played an important role in the reformation of the medical sciences and medical teaching not only locally, but in Belgium at large. Eventually Van Lair became professor of pathological anatomy, and he published on the histopathology of nerve sutures. In 1845 Theodor Schwann (1810–1882), a student of Johannes Mu¨ller, came to Lie`ge, after first having taught in Louvain. He was an originator of cell theory, an idea that reshaped biological and medical research. L. Frederique (1851–1935) lectured on physiology and remained well known for his experiments on crossed cerebral circulation. Both Hyacinthe Sauveur and Charles Frankinet taught neurology.

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Xavier Francotte (1854–1921) became interested in psychiatric diseases, contributed regularly to the Journal Belge de Neurologie and to the Bulletin of the Socie´te´ de Me´decine Mentale de Belgique, and published a short manual of neuropathology used by medical students. This neuropathological tradition was continued by Paul Divry (1889–1967), who held the chair of psychiatry and was interested in neuropathology. In 1927, he became one of the first to use histochemical techniques in the analysis of senile plaques and to study the pathophysiology of nervous system disorders. In 1933 a chair of neurosurgery was established, still within the Department of General Surgery, and Louis Christophe was the first neurosurgeon to occupy it. From 1929 onward, he had been a member of the Belgian Society of Neurology, and he contributed many lectures to the meetings of the Socie´te´ de Neurologie before passing away in 1959. In 1964 an autonomous chair of neurosurgery was established for Professor Bonnal, who came from Marseille. Bonnal also had an important role in the training of neurologists. Michel Gerebtzoff (1913–2003) later on was the director of the Laboratory of Neuroanatomy, and he was internationally recognized for his work on the histochemistry of the nervous system (his publications on acetylcholinesterases still are a major reference; Gerebtzoff, 1959). The teaching of clinical neurology, however, remained embedded in the Department of Internal Medicine. In the 1970s, two major groups developed clinical neurology and research at the Lie`ge University. One was led by Paul J. Delwaide, who introduced clinical neurophysiology and became known for his work on spasticity and extrapyramidal disorders. The other was headed by Georges Franck, who was mainly interested in central nervous system biochemistry and epilepsy. There was now explosive growth in the neurosciences at Lie`ge, attested to by the fact that several pupils from the neurology school chaired scientific societies internationally (European Society of Clinical Neuropharmacology, Professor Delwaide; International Headache Society, J. Schoenen; European Neurological Society, G. Franck) and nationally (Belgian Neurological Society, M. Gerebtzoff, G. Franck, G. Moonen, J. Schoenen; Belgian Brain Council, J. Schoenen). In the mid-1980s, George Franck became the first Professor of Neurology (and Psychiatry), and, at the end of the 1990s, Gustave Moonen became the first full Professor of Neurology. Administratively Neurology had two autonomous clinical departments, one at the Centre Hospitalie`re Universitaire and the other at the Citadelle Hospital. These departments were part of the Department of Internal Medicine.

University of Brussels The University of Brussels was established in 1834 by free-thinkers and was officially named Universite´ Libre de Bruxelles (Free University of Brussels). The preexisting school of medicine, which had been created in Brussels during the French occupation, and which had continued ever since, formed the nucleus of the medical faculty. In the Sint Pieters Hospital, clinical courses had been organized and also autopsies had been performed. The comprehensive network of clinical facilities in Brussels facilitated the organization of the clinical training for medical students. L. Seutin (1793–1852) was appointed head surgeon in the Sint Pieters Hospital in 1823, and became professor of the newly established chair of surgery in Brussels. He contributed much to the development of the Brussels school of surgery. Ze´non Glorieux, in 1888, opened the first outpatient clinic for nervous diseases in the Rue des Epe´roniers in Brussels; J.-J. Crocq (1824–1889) established a neurological service in the Molenbeek Hospital, where he lectured during clinical conferences; and P. Spehl provided clinical lessons in the Sint Pieters Hospital. The teaching of clinical neurology at the Universite´ Libre de Bruxelles remained incorporated within the Department of Internal Medicine. Le´on Laruelle (1886–1960) worked in Brussels as a neurologist. Because autonomous positions for neurological teaching and research facilities were both lacking in the university, he founded the Centre Neurologique of Brussels in 1935. It was later called the Institute Neurologique Belge. Here patients could be studied in depth under all possible aspects with the most up-to-date techniques. This initiative sparked a new enthusiasm for research in Belgium. Laruelle cooperated with surgeon Paul Martin, and their cooperation resulted in the establishment of a neurosurgical center and the founding of the chair of neurosurgery. In his Belgian Neurological Institute, Laruelle developed a procedure for ventriculography by means of the lumbar approach. He studied poliomyelitis, and his institute was the first to provide respiratory assistance for affected patients. His scientific research concerned the vegetative centers of the diencephalon, and some of his work was published in the Revue Neurologique in 1933 and 1934. The Laboratory of Clinical Neurophysiology, under the direction of Fre´de´ric Bremer (1892–1982), became widely known in the neurological world because of the quality, scope, and depth of its investigations. After studies on the physiology and pathophysiology of the pituitary gland, publications on the inhibitory function of

THE DEVELOPMENT OF NEUROLOGY IN THE LOW COUNTRIES the paleocerebellum appeared. The example of Dusser De Barenne was followed by P. Rijland in Brussels with his study of the effects of strychninization on nerve excitability, while J. Titeca studied the effects of curare. The neurophysiology of muscular tone and the influence of the summation of afferent impulses on muscle contraction was reported in a number of papers. The isolated brain preparation (cerveau isolé) was a model to study sleep–wake cyclic activities and their influence in the electrical activity of the cerebral cortex. The discovery by Berger in 1930 of the electrogenesis of the cortical activity and its clinical application inspired Bremer to start an additional line of investigations on the various types of epilepsy. J. Desmedt succeeded Bremer. He applied himself to the study of the neuromuscular transmission and myasthenia gravis, and he studied the central auditory pathways. Neurosurgery in Brussels was performed by Antoine Depage (1862–1925) and his collaborators after World War I. The Brussels school of surgery at that time had become a center of excellence in Belgium. In 1941, a chair of neurosurgery was established for Paul Martin. His background consisted of a thorough grounding in general surgery and good training in neurology (with Cushing, among others). The Universite´ Libre de Bruxelles is francophone and its first chair of neurology was occupied by J. Hildebrand.

The University of Antwerp The University of Antwerp is of recent origin. In 1959, a preclinical course in medicine was established by the Catholic Church (University Faculty St. Ignatius, Antwerp) and in 1964 a state university was founded (Rijks Universitair Centrum Antwerpen, RUCA). In addition, in 1971 a Universitaire Instelling Antwerpen (UIA) was established. Finally, in 2003, these three precursor institutes were unified into one academic institution: the University of Antwerp. Within the city of Antwerp, however, a tradition of high-level medical practice had prevailed for centuries. A first organizing structure for the medical profession was established in 1620 with the founding of the Collegium Medicum Antwerp, which remained active until 1805. During the 17th century, a School of Surgeons existed and autopsies were performed in “De Waag.” In the 19th century, a number of physicians practiced in Antwerp with great skill. J.P. Hoylarts (1754–1831) worked at St. Elisabeth Hospital and later in the Minniemen Hospital. Surgeon L.H.J. Vrancken (1770–1853), who introduced vaccination against smallpox in 1800, organized the care for the casualties of the battle of Waterloo (1815) and, in 1832, during the Belgian revolution

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and the siege of the Citadel of Antwerp by the French, was again active in the care for the wounded. L.H. Leroy (1755–1826), who had studied anatomy and surgery in Amsterdam, taught surgery at the school of the Collegium. Also J.J.J. Van Haesendonck (1769–1808) was active in this field. Claude Louis Somme´ (1772–1855) was head of St. Elisabeth Hospital, and in 1834 a Socie´te´ de Me´decine d’Anvers was established in Antwerp. During the first half of the 20th century, Antwerp became well known in the neurological world because of the activities of Ludo Van Bogaert, who had studied medicine in Brussels and had specialized in neurology with Pierre Marie (La Salpeˆtrie`re) and Marcel Labbe´ (Hoˆpital de la Charite´) in Paris. He first volunteered in St. Elisabeth Hospital in 1923 and was appointed at Stuyvenberg Hospital in that same year; from 1934 until 1949, he acted as head of the Department of Internal Medicine. From 1934 until his retirement in 1981, Van Bogaert also was the director of the Bunge Institute with its Department of Neurology and of the Born–Bunge Foundation that eventually comprised eight laboratories with exceptional research facilities. Van Bogaert and his colleagues produced more than 700 scientific publications on a great variety of neurological subjects, and Van Bogaert can be considered the founding father of Antwerp neurology (Martin and Martin, 1990; Baeck, 2005). In the meantime, the Universitaire Instelling Antwerpen was established and a new University Hospital was built in Edegem/Antwerp in 1971. In that same year the Born–Bunge Laboratories were transferred to the university’s premises in Wilrijk/Antwerp and remained there as an autonomous organization. The Department of Clinical Neurology of the Bunge Institute was integrated in the University Hospital at Edegem/Antwerp and the Bunge Institute Hospital closed in 1979. Professor J.J. Martin, who acquired a broad mastery of neurology and neuropathology while cooperating for years with Ludo Van Bogaert in the Bunge Institute, was the head of the Department of Neurology at the University Hospital from 1980 until 2000.

LUXEMBURG History The Grand Duchy of Luxemburg was part of the Kingdom of the Netherlands as conceived in 1815. After the Belgian revolt of 1830 and subsequent secession in 1839, King William of the Netherlands remained Grand Duke of Luxemburg. Today Luxemburg is an independent state with a small (2586 km2) territory and a population of about 450000, one third of them foreigners. Around

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100000 of its inhabitants live in or near the capital of the same name. There is not much to report on neurology in Luxemburg before the 20th century. A number of medical doctors who worked elsewhere in Europe, however, were of Luxemburg extraction. One was Be´ne´dictAugustin Morel (1809–1873), the famous psychiatrist who started his medical training in Paris and who became well known for his degeneration theory. The Neuropsychiatric Medical Center of Ettelbruck in northern Luxemburg was founded in 1855. Pierre Schmit was the first physician connected to what was originally the Hospice Central of Ettelbruck, but Adolphe Buffet was the medical director who, between 1902 and 1910, inaugurated the new building that was to form the nucleus for the Neuropsychiatric Center. Under Buffet’s directorate, this psychiatric hospital provided considerable neuropsychiatric care in Luxemburg. Its 300 beds made possible the institutionalization of psychiatric patients, and its laboratory was, and still is, a facility for brain research. Since the 1950s the number of beds in Ettelbruck Psychiatric Hospital has gradually declined and an independent general hospital with a department of neurology now functions nearby.

Neurological services During the 1950s, George Muller (b. 1930) started his practice of neuropsychiatry. He developed an interest in neurotraumatology and initiated a call for the organization of a European Center of Neurotrauma (Cite´ du Cerveau Hochfelden). The neurosurgeon Roilgen established a neurosurgical service in the Foundation Norbert Metz (Clinique d’Eich) in the mid-1950s. He was assisted in his efforts to develop neurological and neurosurgical patient care by Henri Metz (b. 1932). He practiced in Luxemburg from 1964 onward, and was the head of the neurology department of the Centre Hospitalier de Luxembourg and presided over the birth of the unit of pediatric neurology at the children’s hospital. Nowadays the neurological activities in Luxemburg City are concentrated in three hospitals, of which the Centre Hospitalier Luxembourgeois, with four fulltime neurologists, performs at an academic level, with neurophysiological, neuroradiological, and neurosurgical facilities available. In Esch, the second city of the Grand Duchy, neurological and neurosurgical services are also available.

Professional organizations During the 20th century, the Socie´te´ Luxembourgeoise de Neurologie, Neuropsychiatrie et Electroencephalographie (SLNNE) was established to discuss scientific and

professional subjects. In 1987, the more specialized Socie´te´ Luxembourgeoise de Neurologie (SLN) was founded, which in 2006 listed about 40 neurologists, but also had neurosurgeons and neuroradiologists as members. The former SLNNE continued its activities, but its membership now consists mostly of psychiatrists. In Luxemburg there is no full medical faculty. A first year of training in medicine can be provided, but after that students most go elsewhere. Formerly, most went to France, but now increasing numbers go to university hospitals in Belgium and Germany.

BIOGRAPHICAL SKETCHES Over the years, the practice of neurology and its professional organization have changed considerably. Nowadays the landscape of clinical neurology consists of departments of neurology in almost every hospital, staffed with cooperating teams of specialists, who individually focus their attention on ever-smaller segments of neurology. In the beginning, however, neurology was dominated by a small number of physicians of strong character who tenaciously pursued the development of a body of knowledge on the relationship between diseases of the nervous system and their expression in the form of behavioral disturbances and clinical symptoms and signs. They provided the lighthouses that enabled their successors to steer a stable course on the high seas of human pathology. It therefore seems appropriate to provide short neurologically oriented biographies of some of the giants who figured so prominently in the development of neurology in the Low Countries.

Cornelis Winkler (1855–1941) Cornelis Winkler (Fig. 43.2) may be considered the godfather of Dutch neurology. After his medical studies in Utrecht (1873–1879), he became resident in the Municipal Hospital in The Hague, but soon returned to Utrecht because he felt more attracted to research. He was invited to become lecturer in psychiatry in Utrecht by F.C. Donders, who taught physiology and ophthalmology there, but Winkler declined the offer because he considered psychiatry too heavily based on philosophy and inexact psychology. After traveling to Vienna, where he met with Theodor Meynert and Julian Wagner Von Jauregg, he developed the idea of studying psychiatry from a physiological and a neurological point of view, and discussed this with Donders. In 1885 he became reader in psychiatry in Utrecht. Toward the end of the 1880s, Winkler was a member of a commission that traveled to the Dutch East Indies in order to analyze the cause and find a possible treatment for beriberi. Later on this activity eventually

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Utrecht a new psychiatric-neurological clinic with a laboratory for experimental work, and Winkler continued his scientific activities there for 10 more years, until he resigned in 1925 at the age of 70. His numerous publications were collected into a nine-volume Opera Omnia. In his Handbook of Neurology: The Structure of the Nervous System (Winkler, 1917–1933), he published the results of his experimental work on the mammalian nervous system. Winkler laid the foundations for the academic practice of neurology (and psychiatry) in both Utrecht and Amsterdam, and left a lasting heritage for future generations of Dutch physicians (Winkler, 1947).

Gerbrandus Jelgersma (1859–1942) Jelgersma (Fig. 43.3) studied medicine in Amsterdam from 1878 to 1885. He acquired his psychiatric and neurological knowledge as a prosector in the Meerenburg psychiatric institute, where he also became skilled in performing autopsies and preparing nervous tissue for microscopic examination. From 1892 on, he became interested in forensic psychiatry, a subject that in those days was studied intensely along the lines of the “degeneration hypothesis,” as formulated by Lombroso. Fig. 43.2. C. Winkler (1855–1941).

would result in the discovery of vitamin B1 as the deficient factor, by Christian Eykman (1858–1930) and Gerrit Grijns (1865–1944). Upon returning to the Netherlands, Winkler was nominated professor of psychiatry and neurology in Utrecht (1893) — the first such chair installed in the Netherlands. But in 1896 he resigned because of a lack of teaching facilities and because the university board had promised a new clinic that did not materialize. He now accepted the new chair of psychiatry and neurology at the University of Amsterdam, where he took charge of a neurological clinic at the Binnengasthuis and a psychiatric clinic at the Buitengasthuis. Together with his Leiden colleague Jelgersma, in 1907 he organized the International Congress for Neurology, Psychiatry, and Mental Care in Amsterdam. Further, with the anatomist Bolk, he promoted the founding of the Central Brain Institute, and in 1909 was one of the founding fathers of the Society of Amsterdam Neurologists. In that same period he planned the construction of a new neurological and psychiatric clinic at the site of the future Wilhelmina Gasthuis, but these plans were postponed because of the onset of World War I. In 1915 he returned to Utrecht to succeed Heilbronner, who had suddenly died at the beginning of the war. Heilbronner in the meantime had constructed in

Fig. 43.3. G. Jelgersma (1859–1942).

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In 1894 he was appointed Privatdozent in criminal anthropology and forensic psychiatry at Amsterdam University. In addition, he became director of a clinic for mental patients in Arnhem. In 1899, he was appointed to the chair of psychiatry, which had recently been founded at Leiden University, and he remained in this position until 1930. Jelgersma published mostly on neuroanatomical subjects, especially on the cerebellum. His 1917 monograph was titled The Physiological Function of the Cerebellum, and an important additional paper came forth in 1918. His psychiatric teachings resulted in a textbook on functional neuroses (Jelgersma, 1897) and in a handbook of psychiatry (Jelgersma, 1911). In 1907 he presided over the First International Congress for Psychiatry, Neurology, Psychology, and Care for Lunatics, where among other subjects the Freudian approach to neurosis was discussed. In 1914, he devoted his rectorial address to the university to the psychoanalytical method, helping to make psychoanalysis an acceptable method in Dutch psychiatry. From the beginning of his professional activities, neurology was included in his teaching duties, but he preferred to leave the lecturing to others (e.g., Ernst De Vries, Abraham Gans). Jelgersma was succeeded in psychiatry by E.A.D.E. Carp in 1930. After his retirement, he completed his opus magnum, the Atlas Anatomicum Cerebri Humani, an endeavor he had started on in 1906 but would not publish until 1931 (Jelgersma, 1931).

Arthur Van Gehuchten (1861–1914) Arthur Van Gehuchten (Fig. 43.4) was born in Antwerp in 1861, and began his studies in Leuven in 1881. During his early years there, he worked as a student in the laboratory of cytology of J.B. Carnoy. He made an educational tour of neurological departments in Germany and visited Ludwig Edinger’s lab in Frankfurt am Main, where he became acquainted with comparative neurological studies and with Karl Weigert’s experiments. His training in biological research was completed in 1886, and he received a Leuven doctorate in the Natural Sciences. In the meantime, he started his medical studies. In 1887, at age 26, he returned to Leuven and 2 years later was appointed Chair of Anatomy at the Catholic University, before even being licensed as a physician. His first publication (in 1890) concerned the histology of the olfactory mucosa in mammals and involved the Golgi method. His microscopical investigations enabled him to support the new neuron doctrine, and he corresponded regularly with Santiago Ramo´n y Cajal, then at Barcelona and later in Madrid. These developments led Van Gehuchten to formulate

Fig. 43.4. A. Van Gehuchten (1861–1914).

his theory of the dynamic polarization of neurons, later confirmed neurophysiologically by Sherrington. Van Gehuchten obtained his MD in 1893, and in the same year published the collected results of his neuroanatomical investigations as Le Système Nerveux de l‘Homme (Van Gehuchten, 1893). He now applied himself more to the study of neurological diseases. He took his first steps in clinical neurology under the guidance of Ze´non Glorieux, who in 1888 had installed an outpatient clinic for neurological patients in Brussels’ Rue des Epe´ronniers. Van Gehuchten became one of the founders of the Belgian Association of Neurologists in 1896. His activities in the borderlands of neuroanatomy and clinical neurology resulted in the founding of the first chair of neuropathology in Louvain for Van Gehuchten (in 1906). In 1908 a Department of Neurology was established, reflecting the respect that his work had generated. Knowledgeable about photography and cinematography, Van Gehuchten applied these new tools in pioneering ways to his teaching and research (Aubert, 2002, 2007). As early as 1905, he was collecting a large number of cinematographic images of neurological disorders for teaching, and in 1912 he was officially charged with teaching neurology in Louvain (Godderis, 2002). Van Gehuchten’s exceptional medical career came to an end in 1914, with the German invasion of Belgium and their burning of Louvain University. Van Gehuchten lost most of his personal and scientific belongings

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and fled to England, where he was welcomed at Cambridge University. Here he apparently took up his activities in order to complete a textbook of neurology that he had almost finished and saved from the blaze in Louvain. He died in 1914.

Paul Van Gehuchten (1893–1989) The development of neurology at Louvain University that had been initiated by Arthur Van Gehuchten was continued by his son, Paul Van Gehuchten. The latter started his studies in 1910 at the Louvain Medical Faculty but, because of the war, did not complete his medical education until 1919. Paul Van Gehuchten took it upon himself to edit the textbook Les Maladies Nerveuses, which his father had almost finished, and published it (Van Gehuchten, 1920). This textbook was to be repeatedly reprinted and translated. Paul Van Gehuchten went to Paris to train further in neurology and neuropathology under Pierre Marie at the Salpeˆtrie`re Hospital. From 1927 on, he taught neurology in Louvain, and in 1929 was appointed chair of neurology. Neurology at that time was part of the University Department of Internal Medicine in the Sint Pieters Gasthuis and it was taught in French. Like his father, Paul Van Gehuchten remained interested in both clinical neurology and neuropathology. In addition, he stimulated the development of a neurosurgical service in cooperation with Debaisieux and Morelle. In the 1950s, he was instrumental in founding the Institute of Neurology in Louvain that marked the emancipation of neurological science at the academic level. At his retirement in 1964, the institute was split into two departments, the Dutch-language Kliniek voor Neurologie en Neurochirurgie, and the French-language Clinique de Neurologie et de Neurochirurgie. Paul Van Gehuchten’s scientific work centered on infectious diseases of the central nervous system, brain tumors, and the vestibular nuclei. He was a natural educator and his book Neurologie du Medecin Practicien (Van Gehuchten, 1963) reflected his pedagogical gifts. Like his father, Paul Van Gehuchten left a lasting imprint on Belgian neurology (Van Gehuchten, 1970).

Ludo Van Bogaert (1897–1989) Ludo Van Bogaert (Fig. 43.5) was one of the most productive and renowned 20th-century Belgian neurologists. He published 753 scientific papers, books, and articles on a wide variety of subjects. He also helped create the Bunge Institute in Antwerp, which became a leading center for the study of clinical neurology. The son of a physician, Van Bogaert intended to study medicine, but the outbreak of World War I

Fig. 43.5. L. Van Bogaert (1897–1989).

precluded his studies and he joined the Belgian Army. In 1918, he was wounded by a machine gun bullet that caused a temporary paralysis of his legs. He was hospitalized in the field hospital L’Oce´an in De Panne. Here his neurological interests were aroused and, after a protracted period of recovery, he enrolled at the Brussels Free University, where he obtained his medical degree in 1922. He went to Paris to train under Pierre Marie and later Guillain at the Salpeˆtrie`re, and with Labbe´ at the Hoˆpital de la Charite´. On his travels, he also visited Von Economo in Vienna, the Vogts in Berlin, Jakob in Hamburg, and other leading figures. Returning to Brussels, he completed his thesis on cerebral lesions in amyotrophic lateral sclerosis in 1925. Van Bogaert was appointed Associate Professor in the Medical Faculty of the Free University of Brussels in 1927. Since 1923, he had worked at the Internal Medicine Department in the Stuyvenberg Hospital in Antwerp, where he established a histopathological laboratory in the basement. Ten years later he became head of the Department of Internal Medicine of the Antwerp Stuyvenberg Hospital (1934) and remained in that position until 1949.

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During these years, Ludo Van Bogaert got involved in the foundation of the Bunge Institute in Berghem/ Antwerp. The Stuyvenberg histopathology laboratory was moved to this new institute, the official opening of which took place in 1934. Van Bogaert and his collaborators in the Bunge Institute published a large number of papers and trained numerous young neurologists in neuropathology. Throughout his career, he integrated clinical findings with post-mortem neuropathological data, following Charcot’s anatomo-clinical method. His special focus was a group of the heredodegenerative disorders of the central nervous system. In 1945 he published a series of five cases of subacute sclerosing panencephalitis (SSPE), a disorder that often goes by the name of Van Bogaert’s disease (Van Bogaert, 1945). In 1946 (with Divry) he published on a familial disorder consisting of diffuse corticomeningeal angiomatosis combined with a progressive demyelination of the white matter, since known as Divry–Van Bogaert syndrome (Divry and Van Bogaert, 1946). And in 1949 (with Bertrand), he described a syndrome with familial idiocy and spongiform degeneration of the central nervous system, a disease now called Canavan’s disease in some countries (Van Bogaert and Bertrand, 1949). Fig. 43.6. B. Brouwer (1881–1949).

Bernardus Brouwer (1881–1949) Brouwer (Fig. 43.6) was born in Amsterdam and studied medicine at the Municipal University there. He was inspired by Winkler and Wertheim Salomonson and, after his MD, worked under Constantin Von Monakow in Zurich. After his return from Switzerland, he became an assistant to Salomonson and Winkler. In 1909 he defended his doctoral thesis, Deaf Mutism and Acoustic Tracts, a comparative study of the brain of a deaf mute and a normal brain (Brouwer, 1909). This thesis was a continuation of previous work done by Winkler on the auditory nerve. In 1913, Brouwer was appointed vice-chairman of the recently founded Central Institution for Brain Research under Arie¨ns Kappers. Later on he did ablation experiments on animals with W.P.C. Zeeman (1879–1960) to determine the central representation of the retina, and also studied the topographic relationships of the oculomotor nerve subnuclei. In 1923, he became the first full professor of neurology in the Netherlands, and he remained the head of the Amsterdam University Neurology Department until 1945. Brouwer made two lecture tours to the USA, the first in 1926 and the second in 1933. These trips enabled him to become better acquainted with the American way of studying neuroscience, which he characterized as

putting more emphasis on experimental techniques and being driven by practical results. He was particularly impressed by the neurosurgical techniques that had been developed by Harvey Cushing and by Walter Dandy in the field of brain tumor surgery, viz., ventriculography. This stimulated him to strive for a strong neurosurgical unit within his own department, and in 1927 he sent Ignaz Oljenick to Cushing for 2 years to learn neurosurgery. Two years later, Oljenick became the first neurosurgeon in the newly opened neurological institute in Amsterdam. From thence onward, Brouwer continued to foster neurosurgery as a discipline in its own right throughout the Netherlands. Brouwer took an active part in the Amsterdam Society of Neurologists, serving as its president for two terms. The same can be said of the Neurosurgical Study Circle that he founded with the neurosurgeon Verbeek in 1936, over which he presided up to his death in 1949. During World War II Brouwer remained head of his neurology department, and also acted as rector of the university for 2 years. He was criticized for continuing the rectorate under the Germans, and the Amsterdam Municipal Council chose to suspend him after the liberation, although his patriotism remained unquestioned.

THE DEVELOPMENT OF NEUROLOGY IN THE LOW COUNTRIES In 1947, Brouwer succeeded Arie¨ns Kappers as director of the Central Institute for Brain Research. He died 2 years later (Bruyn and Koehler, 2002).

A. Biemond (1902–1973) After his medical studies in Amsterdam, Biemond (Fig. 43.7) was trained in neurology by Brouwer, first in the Binnengasthuis and then in the Wilhelmina Gasthuis in Amsterdam. In 1929, he became chef de clinique, and in 1947 succeeded Brouwer as the chair of neurology at the University of Amsterdam. He retired in 1970 and died 3 years later. In addition to some 150 publications in Dutch and international journals, he published two textbooks, one being Brain Diseases (Biemond, 1946) and another on Diseases of the Spinal Cord and the Peripheral Nervous System (Biemond, 1954). He was a great defender of the clinical method, contending that meticulous history taking and systematic neurological examinations should be the primary points of departure for the clinician, to be subsequently complemented by means of additional technical investigations. The cases reported in his textbooks (partly based on some 1000 necropsy reports) illustrated this method convincingly. Bedside neurology was the hallmark of Biemond’s approach.

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Biemond’s publications on disorders that he had been the first to describe earned him lasting fame. One such disorder was the disturbance of potassium metabolism in familial periodic paralysis. “Biemond’s disease” is an autosomally dominantly inherited degeneration of the posterior columns with ataxia. A specific type of congenital familial analgesia and several more disorders also bear his eponym. After World War II, Biemond stimulated the subspecialization of his staff members, and this initiative resulted in an exemplary diversification of knowledge and skills within his neurological department. In the 1977 commemorative booklet on the occasion of the 11th World Congress of Neurology in Amsterdam, Schulte and Endtz wrote: “Most of the neurologists now practicing in the Netherlands are scientific descendants in the first, second or even third degree of the Amsterdam Neurological School,” (Schulte and Endtz, 1977) thus confirming Biemond’s own dictum that “Amsterdam is not only the capital of the country, it has from the very beginning been the center of the Netherlands’ neurological science” (Biemond, 1971).

ACKNOWLEDGMENT The author thanks the following persons for their kind cooperation: R. Van den Berghe (Leuven); P. Boon (Ghent); J.J. Martin (Antwerp); Mme G. Aubert (Brussels); F.G.I. Jennekens (Utrecht); A. Twijnstra (Maastricht); J. Schoenen (Lie`ge); A. Wintzen (Leiden); I. De Haene (Bruges); R. Metz (Luxemburg). Professor G. Janssens, PhD, revised the manuscript.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 44

History of neurology in Italy MARINA BENTIVOGLIO 1 * AND PAOLO MAZZARELLO 2, 3 Department of Morphological and Biomedical Sciences, Faculty of Medicine, University of Verona, Verona, Italy 2 Department of Experimental Medicine, University of Pavia 3 Museum for the History of the University of Pavia, Pavia, Italy

1

INTRODUCTION In Italy, neurology acquired the status of clinical discipline (as “clinic of mental diseases”) after the national reunification (which was officially declared in 1861, but was completed much later) and became a clinical specialization (as “clinic of nervous and mental diseases”) at the beginning of the 20th century. Until then, neurological diseases were considered the domain of internal medicine or psychiatry. Medical history sources and reports of neurological diseases indicate, however, that the origins of Italian neurology can be traced back several centuries. This chapter summarizes the history of neurology in Italy starting from the Renaissance. The country had a long tradition of medical studies even before then. In the Middle Ages, the Medical School of Salerno (a coastal southern city) was the most important source of medical knowledge in Europe at the time. Salernitan masters also speculated about natural philosophy, especially on Aristotle’s views of nature (physis), contributing to the labeling of medicine as physica or “physick,” from which the term “physician” derives. Universities also have a long history and tradition in Italy: the University of Bologna was founded in 1088, the University of Padua was officially founded in 1222, and the University of Pavia in 1361. In order to place events in the Italian peninsula in a historical context, it is also worth recalling that the country has been, over the centuries, solidly placed in an international context due to its geopolitical situation. At the crossroad between the West and the East (Venice and Genoa controlled European trade with Asia) and with a strategic location in the Mediterranean basin, in the mid-16th century most of Italy came under the influence of the Spanish Habsburgs and subsequently of the Aus-

*

trian Habsburgs in northern Italy. Napoleon then conquered much of Italy and established republics and sovereignty under his influence. Following Napoleon’s defeat, the North of Italy was largely under the Austrian Empire and the South under the Bourbons (the Kingdom of the two Sicilies, comprising Naples besides Sicily). The independence wars started in the mid-19th century. Our chapter ends in the early 1960s, i.e., the period that marks, from several points of view, the transition from history to contemporary chronicle. The last four decades of the 20th century also witnessed, in Italy as elsewhere, a remarkable development of neurology that is still ongoing. This occurred in parallel with the parcellation of neurology in many different subfields, which are difficult to view in a synthetic unitary manner and with the required historiographical detachment. Our story is, therefore, forced to end shortly after the mid20th century.

THE ORIGINS OF “CLINICAL NEUROLOGY” IN THE ITALIAN PENINSULA During the Renaissance, treatises of nervous system physiopathology and descriptions of neurological diseases still followed Hippocratic and Galenic “humoral” theories, which were flourishing at that time. Neurological diseases are repeatedly mentioned in the works of Gerolamo Cardano (1501–1576), a medical doctor whose consultations were requested all over Europe. He was so famous that he was requested in 1552 to cure the archbishop John Hamilton, primate of Scotland, who suffered from a mysterious disease that probably had a nervous component. After a difficult journey, Cardano at last reached Edinburgh. The therapy he recommended to the archbishop,

Correspondence to: Marina Bentivoglio, Department of Morphological and Biomedical Sciences, Faculty of Medicine, Strada Le Grazie 8, 37134 Verona, Italy. E-mail: [email protected], Tel: +39-045-8027-158, Fax: +39-045-8027-163.

720 M. BENTIVOGLIO AND P. MAZZARELLO based on a healthy regime for daily life, was so beneficial were published in the 1538 opus, Tabulae anatomicae to his patient that Cardano’s prestige in the European medsex, and in his monumental opus De Humani Corporis ical community greatly increased. Fabrica Libri Septem (1543), which represented a breakIn 1588 David de Pomis (1525–1576) authored the through in knowledge of the nervous system (see Ch. 12). book Enarratio Brevis de Senum Affectibus PraecavenNeurological diseases, and in particular headache as dis atque Curandis, printed in Venice, in which he occupational disease, are mentioned in the treatise De focuses on vertigo and apoplexy in the elderly. The Morbum Artificum (1700), written by Bernardino physician Epifanio Ferdinando (1569–1638), from the Ramazzini (1633–1714), professor at the University of southern Italian area of Salento, provided in 1621 accuPadua. This is the first text focusing specifically on rate descriptions of patients affected by different occupational diseases (Zanchin et al., 1996). neurological diseases, including a case of apoplexy with A theoretical and practical turning point in the a positive outcome. development of clinical neurology occurred in Italy, Italian physicians and surgeons also contributed to as elsewhere in Europe, in the 18th century, when the theories on the active contraction and relaxation of old Greco-Roman concepts of humoral pathology were the brain, as described by Galen, which were debated abandoned. Until that time, physicians had interpreted during the Middle Ages and Renaissance (Manzoni, the protean manifestations of neurological diseases as 1998). In a treatise that appeared in 1559 Realdo based on the imbalance of the four body humors Colombo (who died in the same year) stated that the (blood, phlegm, yellow bile, and black bile). In the space between the brain and the dura mater accommo18th century, the concept of humoral pathology was dates the brain’s “systolic and diastolic” movements, gradually replaced by the concept of pathology of analogous to the space between the heart and pericarorgans. This evolution was largely due to Giambattista dium. This conjecture also supported the popular belief Morgagni (1682–1771) and greatly influenced medical that brain movements could be influenced by the knowledge throughout Europe. Morgagni, who was phases of the moon (the origin of the words “lunacy” professor of medicine and anatomy at the Universities and “lunatic”). During the full moon, it was thought, of Padua and Bologna, also worked as a hospital docthe brain expands. This idea can also be found in the tor (Giordano, 1941; Belloni, 1990b). In his book De earlier treatise, printed in 1480, on skull fractures by Sedibus et Causis Morborum per Anatomen Indagatis, Pietro de Argellata (who died in 1423), a part of his which appeared in 1761, Morgagni developed the idea Cyrurgia (Manzoni, 1998). that careful annotation and classification of patients’ The idea of brain contractions was also followed symptoms was of utmost importance. He also stressed by Marcello Malpighi (1628–1694), whose pioneering recording the outcome and, in fatal cases, performing works on microscopy became rapidly known all over autopsies to correlate the pathology with clinical sympEurope. He ascribed nervous function to a glandular toms. With this approach, Morgagni wished to estabconglomeration (the cerebral cortex), excreting nervous lish a relationship between ante-mortem and postspirits or juices into brain fibers, under constant conmortem findings. He is, therefore, regarded as the traction, with waves deriving from external objects founder of modern pathology. via the sense organs. In terms of the neurological Many of the numerous diseases studied by Morgagni implications of this theory, Malpighi proposed that epiaffected the nervous system, some being hydrocephalus, lepsy is due to an alteration of this mechanism, with cerebral tumors, cerebral palsy in children, cerebral toxic particles affecting the nervous juice and irritating abscesses, and cerebral apoplexy. For the latter, he brain fibers (Temkin, 1994). Importantly, Malpighi, showed that hemorrhagic lesions of the cerebral parenchfocusing attention on environmental stimuli, discovyma are contralateral to the impaired part of the body. ered that the “extremities of the nerves” have the funcAlthough still linked to Hippocratic principles, tions of tactile and taste sensory receptors. Andrea Comparetti (1745–1801), a pioneer of neurology Malpighi’s disciple, Anton Maria Valsalva (1666– who was a disciple of Morgagni, wrote the opus Occur1726), professor at the University of Bologna, observed sus Medici de Vaga Aegritudine Infirmitatis Nervorum. similar “receptor extremities” for hearing. In the acoustic Antonio Molinetti, who also studied at the University nerve, he noted four terminal processes (“cordelline,” of Padua, is the author of a treatise on the physiology thin threads), one with a spiral shape and the other three and pathology of sensory functions. Molinetti underforming ansae, housed in the semicircular canals (Belloni, stood that different facets of language could be disso1990a). ciated after brain lesions. This led Giambattista Vico These investigations flourished on the fertile soil of the (1688–1744), a renowned Neapolitan philosopher, to a studies made at the University of Padua by the Flemish remarkable neuropsychological finding. Vico (1744) Andreas Vesalius (1514–1564). His main contributions described the case of a man who, after suffering from

HISTORY OF NEUROLOGY IN ITALY severe apoplexy, remembered nouns but forgot verbs (see also Grossi and Boller, 1996). Neuropsychiatric cases started to be included in medical treatises printed in Italy, such as those of Giacomo Bartolomeo Beccari (1682–1766), a colleague of Morgagni at the University of Bologna and author of “Medical consultations.” More than 200 of these consultations were published posthumously, and included cases of vertigo, hemiplegia, sciatic pain, depression, and convulsions (Marri Malacrida, 1990). Morgagni also influenced Giovanni Battista Borsieri (1725–1785), professor of internal medicine at the University of Pavia, who authored Institutiones Medicinae Practicae. In this text, Borsieri dealt extensively with neuropsychiatric diseases, with special reference to headache, apoplexy, epilepsy, tetanus and vertigo. Another disciple of Morgagni was Antonio Scarpa (1752–1832), whose studies contributed to the development of clinical neurology. Anatomist and surgeon in Modena and Pavia, Scarpa established important scientific relationships throughout Europe, especially in France, England and central Europe (Franceschini, 1963). In his investigations of the ear, Scarpa described the bipartition of the acoustic nerve into cochlear and vestibular nerves, and made several other contributions to the anatomical basis of clinical symptoms. In his opus, Tabulae Nevrologicae, published in 1794, Scarpa illustrated the course of some cranial nerves and the innervation of the heart in humans (see Ch. 12). A colleague of Scarpa at the University of Pavia and a pioneer of social medicine, Johann Peter Frank (1745– 1821), identified diabetes insipidus and also focused attention on diseases of the spinal cord, emphasizing their importance. The same topic was examined in greater depth a few years later in Pavia by Vincenzo Racchetti (1777–1819), in his opus Della Struttura, delle Funzioni e delle Malattie della Midolla Spinale (“On the structure, functions and diseases of the spinal cord,” 1816). A pioneer of Italian neurology was also Vincenzo Malacarne (1744–1816), who identified the “basilar artery imprint” in the skull, around the contour of the occipital foramen, in his studies on clinical neurology and neuropathology. During the second half of the 18th century, the Neapolitan Domenico Cotugno (1736–1822) (Fig. 44.1) made important contributions to neurology. In his De Acquaeductibus Auris Humanae Internae, Cotugno (1761) described the cochlea and the fluid in the labyrinth. He proposed that hearing is due to hydrodynamic properties, contrary to the old Aristotelian concept of aer ingenitus within the ear as a basis for sound perception. Cotugno’s De Ischiade Nervosa Commentarius, published in 1764, is famous for its description of the cerebrospinal fluid and the clinical study of “nervous

721

Fig. 44.1. Domenico Cotugno (1736–1822), who provided remarkable contributions to neurology, including the description of the cerebrospinal fluid and pioneering studies on sciatic pain.

sciatica” (Belloni, 1963, 1990c). In the latter domain, Cotugno distinguished between two types of sciatic pain: “arthritic sciatica,” due to lesions of the coxo-femoral joint, and “nervous sciatica,” resulting from lesions of the sciatic nerve. He thus differentiated hip pain from nerve lesions characterized by pain diffusion along nerve trunks with muscular leg impairment (limping, semi-paralysis). The recognition of the site of origin of sciatic pain suited Morgagni’s approach well, i.e., the need for a specific localization of a given disease to be correlated with clinical symptoms. In the second half of the 18th century and first half of the 19th century, Italian neurology was influenced by three theoretical and experimental trends largely debated throughout Europe: Hallerian irritability, animal electricity as proposed by Luigi Galvani (1737–1798), and the doctrines of Franz Joseph Gall (1758–1828) on organology, which is usually referred to as phrenology. Concerning the first, Albrecht von Haller (1708–1777) presented his ideas on irritability to the Royal Society of Sciences in Go¨ttingen in 1752. He referred to irritability as an autonomous and independent property of the muscle fiber, which causes it to contract (vis contractilis musculis insita). In contrast, nerves are characterized by sensibility, e.g., the capability to trigger a pain sensation in response to a stimulus. These ideas raised great interest in the scientific community of the Italian peninsula, and led to a heated debate between supporters and detractors of Hallerian theories, stimulating an experimental approach to neural functions. This experimental orientation represented a turning point in Europe

722 M. BENTIVOGLIO AND P. MAZZARELLO for neurology, neurophysiology, and neuropathology stimulation,” implying the use of “vomitories,” laxa(Bonuzzi, 1990; Ongaro, 1990). Besides debates on irrittives, and especially bleeding. Other diseases may be ability, which ascribed muscle motion to a force reladue instead to inadequate stimulation, and can be tively independent from the action of the nerve, Haller treated with stimulants (e.g., wine, laudanum, cinchona and his followers raised objections against the idea that bark) (Cosmacini, 2002). electricity could be involved in body functions. This At the beginning of the 19th century, the physician opposition was mostly based on the conductive nature and anatomist Luigi Rolando (1733–1831) provided of body fluids, which, degrading any electric “disequilisome major contributions to experimental and clinical brium,” would not allow the isolated transmission of neurology (Castellani, 1974), besides his contributions body signals. An important aspect of this scientific to the anatomical foundations of neurology (see debate concerned the efficacy of the application of elecCh. 12). In his investigations on the ablation of the paltricity to medical treatments (Piccolino and Bresadola, lium in birds, Rolando obtained a state of rest (“Rolan2003). dic sleep”), and hypothesized that cerebral functions This debate had a significant echo also in Bologna, are localized in specific parts of the brain. In the same leading Galvani to explore experimentally the possible era, Francesco Saverio Verson (1805–1849), a professor involvement of electricity in neuromuscular physiolof internal medicine in Padua, presented his anatomoogy, in order to assess also a rationale for medical clinical systematic classification of neurological disapplications of electricity. Galvani thus pursued in eases (Premuda, 1992). the 1780s his experiments on frogs and other experiThe anatomist Bartolomeo Panizza (1785–1867), a mental animals. In a crucial experiment in 1786, professor in Pavia, provided, among other findings, Galvani obtained muscle contractions by simply conthe first clinical description of ataxia due to posterior necting the nerve and muscle of a frog with a metallic root lesion, and discovered the gustatory and sensorybody in the absence of external electricity. After a motor functions of different nerves (Berlucchi and long series of experiments with metallic conductors Taraschi, 1963; Mazzarello and Della Sala, 1993; and conductors of other kinds, Galvani reached the Manni and Petrosini, 1994). Panizza also described conclusions that electricity is intrinsic to the animal’s the case of a malformed newborn, who had survived body (“animal electricity”), and that electric “disequi18 h after birth with normal vital parameters (e.g., librium” exists between the interior and the exterior respiration, circulation, swallowing, suction, defecaof the muscle fiber as in a “minute Leyden jar.” tion and bladder function), and whose autopsy had Galvani formulated this hypothesis in a scientific shown aplasia of the cerebral hemispheres, cerebelmemoir entitled De Viribus Electricitatis in Motu lum, and a large part of the brain stem. Panizza’s Musculari, published in 1791, in which he effectively main contribution was, however, the discovery of overthrew the concept of animal spirits. The impact the center of vision in the occipital cortex (see of Galvani’s work on the neurological sciences Ch. 12; see also the translation of the original Panizza included calls for therapeutic electricity to treat neuarticle in Colombo et al., 2002). His disciple, Alfonso rological diseases, the development of neurophysiolCorti (1822–1876), described the acoustic receptor ogy, and, later on, electrodiagnostics (Piccolino and apparatus, now called the organ of Corti (Iurato, Bresadola, 2003). 1963; Hintzsche, 1971; Grmek, 1983). On an entirely different horizon, Gall’s phrenology In the meantime, pioneering contributions were achieved popularity in Italy. Phrenological skulls flourishing in Italy in other areas of the neurological became part of the paraphernalia of doctors and sciences, and neuropsychology in particular. A remarkcharlatans alike, as many people gravitated to his sysable contribution oriented toward neuropsychology tem delineating special cortical organs for different was provided in 1867 by Antonio Quaglino (1817– functions. 1894), professor of ophthalmology in Pavia, who, in Toward the end of the 18th century, the medical syscollaboration with Giovanni Borelli, described for the tem elaborated by the Scottish physician John Brown first time a patient with color blindness and prosopag(1735–1788), and divulgated by Pietro Moscati (1739– nosia (Quaglino and Borelli, 1867; Benton, 1990). In a 1824) and especially by Giovanni Rasori (1766–1837), paper presented to the Academy of Sciences of became very popular in Italy. Brownism was a reducBologna in 1866, Giovanni Brugnoli (1814–1874), tionist medical approach that ascribed to excitability, professor of clinical medicine at the University of as a driving force in living organisms, the physiopatholBologna, discussed, for the first time in Italy, the corogy and symptomatology of diseases. According to tical localization of the speech center and presented Rasori, some diseases are due to an excess of “stimulaseven cases of acquired aphasia (Cubelli and Nichelli, tion,” hence their treatment has to be based on “counter1990).

HISTORY OF NEUROLOGY IN ITALY 723 beginning of the 20th century. Nevertheless, “neurolAFTER THE BIRTH OF ITALY AS NATION ogists” were not officially recognized as such. In the 1860s, there were 17 state universities in Italy, Given the social relevance of lunacy, on one hand spe1 institute for higher education (in Florence), and 4 free cialists of “nervous” diseases were frequently in universities administered by the municipality or the charge of psychiatric patients and, on the other province. With national reunification, the discipline hand, neurological diseases (such as dementia) were “clinic of mental diseases” was officially introduced long considered the domain of psychiatric diseases in the universities of the Kingdom of Italy. The head (Schiffer, 2005). physician of the hospital department or asylum (where Andrea Verga (1811–1895) was one of the most illusmany neurological patients were admitted) was often trious figures of this period. Both psychiatrist and anaappointed to the post of university professor. Other tomist, Verga had been a disciple of Panizza and neurological patients were admitted to medical departbecame director of the asylum of San Celso, and then ments, and professors of internal medicine sometimes of the above-mentioned Senavra Hospital as well as of gave university courses in neurology. The textbooks the Ospedale Maggiore in Milan. Typical of Verga on neuropsychiatry were frequently authored by proand other psychiatrists, general practitioners, or patholfessors in internal medicine. Neurology was, in genogists of those times was the interpretation of psychiaeral, considered closer to internal medicine than to tric diseases on the basis of organic lesions of the psychiatry. nervous system. When Italy was united into one nation, “clinic of A great impulse to clinical neurology was given, in mental diseases” courses were initiated or continued the Lombardy region, by Serafino Biffi (1822–1899), throughout the country, in the North and center (Pavia, Cesare Lombroso (1835–1909), and Paolo Mantegazza Turin, Bologna, Modena, Florence, Genoa), in the (1831–1910). Biffi established a long-lasting collaboraSouth (Naples), and on the island of Sardinia (Cagliari tion with Verga, and pursued neurological studies and Sassari) (Dro¨scher, 2002). In the 1870s and 1880s, stemming from his dissertation on the sympathetic the discipline was sometimes denominated “clinic of and parasympathetic innervations of the eye, which psychiatric diseases” and was implemented in some continued with studies on the innervation of the tonuniversities (e.g., Turin, Rome, Naples, as well as gue. Biffi could thus demonstrate the gustatory funcPalermo on Sicily) by courses closely related to neuroltion of the lingual nerve. He also described the ogy (dealing, for example, with electrotherapy or “clinmandibular branch of the trigeminal nerve and the ical neuropathology”). In the 20th century, this function of the glossopharyngeal nerve. In addition, discipline changed to “clinic of nervous and mental disBiffi investigated some endemic diseases, such as creeases,” thus explicitly including neurological diseases. tinism and pellagra, with a sociological orientation The asylums, which were frequently old institutions, (Coari, 1968; Zerbi, 1988). Both Mantegazza and Lomwere disseminated throughout the national territory broso published books on pain and its objective meaand generally included a special section for epileptic surement (“algometry”) and debated this topic at the patients. Some of the asylums became important cenIstituto Lombardo di Scienze e Lettere (the Academy ters of clinical and neuropathological research (such of Sciences of Lombardy). as the Pia Casa della Senavra in Milan, and the asylum Lombroso is internationally renowned as the founof Collegno, which was equipped with an active neuroder of a new discipline – criminal anthropology – pathological laboratory). devoted to the identification in somatic features of Large neuropsychiatric hospitals were scientifically the “degenerative” stigmata of criminals (Zambianchi, related to university centers, and physicians in these 1963). His studies on “criminal woman” (Lombroso hospitals sometimes conducted research at very high and Ferrero, 2004) and “criminal man” (Lombroso, levels. For example, the San Lazzaro Hospital of 2006) are well known and available in modern English Reggio Emilia became a main center of neuropsychiatranslations. Interestingly, Lombroso believed that gentric investigations. Directed by the psychiatrist Carlo ius is closely related to madness (Mazzarello, 2001). In Livi (1823–1877), this hospital hosted, as will be preaddition, Lombroso’s school was the first to document sented further on, a large number of Italian neuropsycortical malformations within the neuropathological chiatrists who gave a great impulse to neurological picture of the developmental disorder currently called sciences all over the country and entertained internaTaylor’s dysplasia (Chio` et al., 2003). Lombroso also tional relationships. described pellagra in detail, and the first paper pubAs dealt with in detail in the next section, hospitals lished by Camillo Golgi (1843–1926) was focused on entirely dedicated to neurological and neuropathologithis disease and was written under his mentorship cal investigations started to appear in Italy at the (Mazzarello, 2006, 2009).

724 M. BENTIVOGLIO AND P. MAZZARELLO Besides his remarkable contributions to the discovMunich with Alois Alzheimer (1864–1915) at the Instiery of the organization of the nervous system (see tute directed by the renowned psychiatrist Emil Ch. 12), Golgi exerted an influence on clinical neurolKraepelin (1856–1926). After the first report of ogy through his disciples (see further), and also con“Alzheimer’s disease” in 1906, Perusini studied other tributed himself to knowledge of neurological cases and provided a clear description of the clinical diseases. While working as a physician in the Pia Casa and neuropathological hallmarks of the disease. Alzdegli Incurabili (“Hospital for the Chronically Ill”) in heimer repeatedly quoted “Perusini’s cases” in his last Abbiategrasso, near Milan, Golgi (1874) described a work, dated 1911 (Pomponi and Marta, 1993; Macchi case of chorea (probably Huntington’s chorea). The et al., 1997; Lucci, 1998). The Institute directed by autopsy examination revealed neuronal loss and reacKraepelin also hosted Francesco Bonfiglio (1883– tive gliosis in the corpus striatum and frontal cortex. 1966) who was also involved in the early studies on By correlating the clinical symptoms with neuropathoAlzheimer’s disease (Bick et al., 1988). Other Italian logical findings, his investigation pioneered the study neurologists who were active in the Institute directed of brain lesions in neurodegenerative diseases. by Kraepelin were Ugo Cerletti (1877–1963), and OttorAnother relevant contribution to neurology was given ino Rossi (1877–1936), who, as presented further on in by Giuseppe Giannuzzi (1839–1876), who was especially detail, played key roles in Italian neurology. This also interested in bladder innervation and elucidated in part documents the tradition of “training abroad” young its mechanisms of contraction. Clodomiro Bonfigli Italian investigators and the exchanges with institutions (1838–1919), director of the asylum of Ferrara and then in other European countries. of Rome, and associate professor of psychiatry, actually After rigorous neuroanatomical training under Golfocused on neurological disorders, providing interesting gi’s mentorship, Casimiro Mondino (1859–1924) contributions on mental retardation in children. became professor of histology and of psychiatry at the University of Palermo, and at the end of the 19th century was appointed to the chair of psychiatry at FROM THE 19TH TO THE 20TH CENTURY the University of Pavia. At the beginning of the 20th At the end of the 19th and at the beginning of the 20th century Mondino founded in Pavia the Istituto Neurocentury, a group of eminent figures of Italian neuropatologico (Neuropathological Institute) for the study psychiatry, though mainly interested in the psychiatric of the organic basis of nervous and mental diseases. aspects of “nervous and mental” diseases, played As will also be emphasized further on, the term “neuimportant roles in clinical neurology and introduced ropathology” was used at that time to designate nernovel trends of research in the neurological sciences. vous system diseases (i.e., it was a synonym of Among these, Ernesto Belmondo (1863–1939), proneurology in its modern use). Mondino left his wealth fessor at Padua, investigated diverse problems, includto this institute, which was subsequently named after ing the alterations of the spinal cord in pellagra, him – Istituto Neurologico C. Mondino (Mazzarello cocaine-induced cortical excitability, and the pathogenand Calligaro, 1999). esis of muscular dystrophy and hypotrophy (Schergna, Eugenio Tanzi (1856–1934), another member of the 1990). Enrico Morselli (1852–1929), who had worked in San Lazzaro Hospital team, was professor at Palermo the above-mentioned San Lazzaro Hospital in Reggio and Florence. He was probably the first Italian scienEmilia and was then professor at Genoa, contributed tist, along with his disciple Ernesto Lugaro (1870– studies on epilepsy and on the function of the sympa1940), to embrace the neuronal doctrine diffused by thetic system. Augusto Tamburini (1848–1919), who Santiago Ramo´n y Cajal (1852–1934) and opposed by was Livi’s successor at the San Lazzaro Hospital, was Golgi (see Ch. 12). Tanzi proposed a synaptic theory professor at Pavia, Modena, Florence, and Rome. He of learning and memory based on the neuronal docrapidly became a leading figure in Italian neuropsytrine. He postulated that practice and experience foster chiatry, animating and organizing research groups with neuronal growth and can decrease the space between considerable “managerial” talent (Babini, 2002). Durassociated neurons, thus enhancing functional commuing his direction (starting in 1877) of the San Lazzaro nication between them (Tanzi, 1893; Buchtel and Asylum, this hospital became a “center of excellence” Berlucchi, 1977; Berlucchi, 2002). Lugaro published for work on neurological diseases. Tamburini himself important psychiatric, neurological, and neuroanatomicontributed studies on progressive paralysis, localizacal papers. He co-authored with Tanzi a highly tion of neural functions, aphasia, and hallucinations. regarded textbook (Trattato delle Malattie Mentali), Tamburini’s disciple, Gaetano Perusini (1879–1915), and described the cerebellar cells since named after who died prematurely during World War I, contributed him. Moreover, Lugaro introduced in 1893 the term to the neuropathological study of dementia, working in “plasticity” in the neurosciences, employing this term

HISTORY OF NEUROLOGY IN ITALY 725 for the first time to denote neural modifiability of the temporal lobe” includes a constellation of symp(Berlucchi, 2002). He also had amazing intuitions on toms, namely transient hemiplegia, hemianesthesia, the chemical nature of synaptic transmission, and was astereognosia, agraphia, alexia, transient verbal deafthe first to distinguish “nervous conduction” (intraness, hemianopsia, mental impairment and confusion. neuronal) and “nervous transmission” (interneuronal), Bianchi’s experimental and clinical studies on the according to their modern meanings (Berlucchi, frontal lobe provided a basis for the development of 2002). Furthermore, Lugaro (1907) formulated pioneerpsychosurgery pursued by Egas Moniz (1874–1955). ing theories on the function of glia. Frontal lobectomy was pioneered in Italy by Adamo Lugaro’s disciple Bernardino (Dino) Bolsi (1896– Mario Fiamberti (1894–1970) through a transorbital 1972), who succeeded him to the chair of clinic of nerroute, using a “leucotome” he had designed himself. vous and mental diseases at the University of Turin, His technique, which was introduced in 1937 at the developed methods to stain microglia, and made same time as that of the American neurosurgeon Walremarkable pioneering observations on the migration ter Freeman (1895–1972), avoided an “open” neurosurof microglial cells into the central nervous system durgical operation. Fiamberti’s practice was then adopted ing development, as well as on microglial activation by others in Italy and abroad (Ferraro, 1953a; Zanobio, around senile plaques (Bolsi, 1927, 1930). 1990; Armocida, 2007). His proposal of an “ice pick Also of special relevance are the contributions to lobotomy,” as it came to be known, was soon, howneurology made by Leonardo Bianchi (1848–1927) ever, considered dangerous and abandoned, given the (Santoro and Gencarelli, 1968; Grossi and Boller, damage it produced in many cases. 1996; Traykov and Boller, 1997). After obtaining his Another important and stimulating figure in Italian MD degree at the University of Naples, Bianchi qualineurology between the 19th and 20th centuries was Giofied for university teaching in electrotherapy (1876), vanni Mingazzini (1859–1929) (Ferraro, 1953b; Ferro internal medicine (1877) and clinical practice (1878). In et al., 1990). Professor of “neuropathology” since 1897, 1890, he was appointed to the University of Naples, and then director of the clinic of nervous and mental diswhere he fused the chairs of psychiatry and “neuroeases of the University of Rome, Mingazzini promoted an pathology” (the term used, as mentioned above, to desanatomo-clinical approach to the interpretation of neural ignate nervous system diseases). Interested in the study and psychic functions. He authored the volumes Anatoof the cerebral localization of psychic functions, Bianmia Clinica dei Centri Nervosi (“Clinical anatomy of nerchi performed experimental studies with monkeys. By vous centers”) and Il Cervello in Relazione con i means of selective cortical ablations, he observed that Fenomeni Psichici: Studio sulla Morfologia degli Emismonkeys did not show impairments of voluntary moveferi Cerebrali dell’Uomo (“The relationship of the brain ments or sensory deficits after bilateral frontal lobecwith psychic phenomena: study of the morphology of certomies, but instead exhibited cognitive impairments ebral hemispheres in Man”). Mingazzini’s approach was (e.g., memory deficits) and behavioral disturbances. adopted by Alf Brodal (1910–1988) in his Neurological In 1894, he presented his data at the International ConAnatomy in Relation to Clinical Medicine, which gress of Medicine in Rome, where he was severely criappeared in 1948. Mingazzini’s name also remains assoticized by some people. Nevertheless, Tamburini ciated with a sign that indicates pyramidal dysfunction. supported Bianchi’s frontal lobe findings at the same Furthermore, neurology was intensely cultivated in meeting by showing that this lobe is markedly affected Italy by professors of general pathology, physiology in cases of progressive paralysis, a disease marked by and internal medicine. Important representatives of psychic and behavioral changes. This stimulated Bianthis period are Achille De Giovanni (1838–1916), Ettore chi to investigate the clinical outcome of brain lesions Marchiafava (1847–1935), and Luigi Luciani (1840– further, especially among the wounded during World 1919), who, as presented below, provide further examWar I. He could thus document that, after frontal lobe ples of the contributions given to clinical neurology lesions, many patients exhibited impaired concentraby professors of other disciplines. tion capacity, mental performance, and problemAfter obtaining his MD degree at the University of solving abilities. Bianchi’s doctrine on the frontal lobe Pavia in 1862, where he had been a student of Bartolomeo as site of higher mental functions (integrating affecPanizza, Achille De Giovanni became professor of gentive, psychic, and intellectual activities with the inforeral pathology at the same university and then of internal mation provided by cortical sensory areas) was thus medicine at the University of Padua. Soon after his delineated (Lambiase et al., 1990a, b). Bianchi also condegree, De Giovanni started to investigate neurological tributed to the anatomy of cortical association pathdiseases and in particular alterations of the sympathetic ways, such as the fronto-occipital, arcuate, and system. In 1876, he published a book titled Patologia temporo-frontal bundles. The “Bianchi deep syndrome del Simpatico (“Pathology of the sympathetic system,”

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“pathology” being used here to indicate “diseases”), in which he proposed that altered autonomic functions could predispose people to neurological diseases. Ettore Marchiafava was professor of pathology (until 1917) and then of internal medicine at the University of Rome. His contributions to neurology focused on infectious and degenerative brain disorders. In 1897, Marchiafava described a primary degeneration of the corpus callosum in the brain of an alcoholic. This observation was developed and completed in 1903, when Marchiafava and Amico Bignami (1862–1929) published their findings of necrosis of the middle portion of the corpus callosum in three alcoholics, all having died after repeated seizures and coma (Marchiafava and Bignami, 1903). In 1907, Bignami described another case with alterations of the corpus callosum accompanied by a similar lesion in the central portion of the anterior commissure. Approximately 40 cases of “Marchiafava– Bignami disease,” all alcoholic patients, had been described by 1931. The disease was first described outside Italy by King and Meehan (1936), and was then reported in many countries, dispelling the idea prevailing at the time of a racial (genetic) predisposition. Initial hypotheses, which implicated low-quality wine in the etiology of the disease, were then discredited; in rare cases, the disease was also observed in people without alcoholism, and the etiology is still unknown. The Marchiafava–Bignami disease is currently regarded as a rare and severe complication of chronic alcoholism, whose hallmark is acute demyelination and necrosis of the corpus callosum preceded by edematous swelling of this commissure. The diagnosis, which previously could only be ascertained by autopsy, can now be made in vivo with neuroimaging techniques, and magnetic resonance imaging in particular, which have thus revived interest in this disease (see, for example, Heinrich et al., 2004; Me´ne´gon et al., 2005). The physiologist Luigi Luciani gave remarkable contributions to neurology with his investigations on cortical localization and cerebellar functions (Bock Berti, 2006). After his studies at the Universities of Naples and Bologna, where he graduated in medicine in 1868, Luciani was appointed assistant professor in physiology. From March 1872 to November 1873, he worked in Leipzig in Carl Ludwig’s (1816–1895) laboratory, where he focused on heart physiology (Schadewaldt, 1990; Upshaw and Silverman, 2000). Upon his return to Italy, Luciani was appointed professor of general pathology (at Bologna and Parma) and of physiology (at Siena and Florence, and, after 1893, in Rome). In Parma he collaborated with clinicians Giuseppe Seppilli and Augusto Tamburini, who were at the San Lazzaro Hospital in Reggio Emilia, in the study of the localization of neural

functions. This collaboration resulted in several publications, including a volume (co-authored by Seppilli) on Le Localizzazioni Funzionali del Cervello (“The functional localizations in the brain”) (Tagliavini, 1982; Morabito, 2000). Luciani’s studies exerted a profound influence on clinical neurology, combining experimental analysis of the effects of selective ablation of different brain areas with clinical and autoptic findings. His investigations on the cerebellum as an integrative center for the control of voluntary movements and posture were performed in 1882 and 1883, first in Florence and then in Rome. The doctrine elaborated by Luciani on cerebellar functions helped to guide the clinical interpretation of cerebellar syndromes and disorders (Crepax, 1963; Manni and Petrosini, 1997). Of particular interest also is the activity of Sante De Sanctis (1862–1935), at the crossroad between different disciplines that had to find their own individuality in Europe. During his training abroad, De Sanctis investigated hypnotism in Zurich with August Forel (1848– 1931), who was also a pioneer of the neuron theory (see Ch. 12). In Italy, De Sanctis had been a student of Luciani, as well as of Mingazzini and Marchiafava, in Rome. De Sanctis focused on experimental psychology, and he is considered one of the founders of this discipline in Italy; he also contributed to neuroanatomy, clinical neurology (and in particular epilepsy), and psychiatry (Cazzullo, 1953; Fiasconaro, 1991; Lombardo and Cicciola, 2006; Lombardo and Foschi, 2008). Among the guests at Golgi’s laboratory was the neuropsychiatrist Vittorio Marchi (1851–1908). Marchi was a student of Luciani in Florence, a disciple of Tamburini in the San Lazzaro Asylum, and then of Golgi in Pavia (Roizin, 1953; Belloni, 1974; Rizzoli, 1990; Mazzarello, 2006). His name remains attached to the method of staining degenerating myelin sheaths, which had a significant impact on experimental tract tracing of neural circuits (see Ch. 12).

BETWEEN NEUROLOGY AND PSYCHIATRY Since medical history is obviously intertwined with political history, it has to be recalled here that the history of neurology in Italy during the first half of the 20th century was dominated not only by World Wars I and II but also by the fascist regime (from 1922 to World War II). World War I gave an impulse to Italian neurology by stimulating studies on the wounded, as mentioned above in the case of Leonardo Bianchi, and as will be presented below concerning other neuropsychiatrists. As also presented above, it had been preceded in Italy by remarkable scientific activity in the field of

HISTORY OF NEUROLOGY IN ITALY neurology, within and outside academia. In contrast, during fascism, Italian neurology became, with a few exceptions, rather provincial and autarchic, with limited flow of information and limited exchanges with foreign institutions, as required by fascist policy. A new impulse to neurology in Italy had to wait, as outlined below, until the end of World War II, when modern neurology and its distinction from psychiatry were finally promoted. The Kingdom of Italy became a republic in 1946. The beginning of the 20th century continued the cultural stimuli of the end of the 19th century, and several leading neurologists were trained in clinical and academic institutions. The San Lazzaro Asylum, repeatedly mentioned above as the “cradle” of numerous Italian neuropsychiatrists, also hosted Carlo Ceni (1866–1965). A physician internationally known for his studies on epilepsy, Ceni, who became professor at Cagliari, on Sardinia, and then at Bologna, was also a pioneer of neuroendocrinology (Canestrelli, 1979). In the Italian academic tradition, the newly appointed young professors often started their careers on the islands of Sardinia or Sicily. This happened not only in cases mentioned previously and in Ceni’s career, but also in the academic career of another brilliant neurologist, Carlo Besta (1876–1940), in addition to many others. Besta (Fig. 44.2) also worked in the

Fig. 44.2. Carlo Besta (1860–1940), who founded a hospital in Milan entirely dedicated to neurological diseases, named after him – Carlo Besta National Neurological Institute.

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San Lazzaro Asylum. He graduated in medicine from the University of Pavia in 1900, and was a professor at the University of Messina, on Sicily, before he moved to the newly founded University of Milan, becoming its first professor of “clinic of nervous and mental diseases” (from 1925 to 1940). During World War I, Besta was a neurological consultant at the Military Hopital of St. Ambrose, in Milan, and set up a center in Milan (the Institute for Head Wound Casualties), where he studied brain-damaged war veterans. He described focal syndromes caused by injuries to different areas of the cerebral cortex and traumatic epilepsy. His institute was moved to the campus of the University of Milan and a new hospital was inaugurated in 1932 under the patronage of the King of Italy. This institute was initially named Istituto Neurologico Vittorio Emanuele III, and later named Istituto Neurologico Carlo Besta (Arosio, 2000). This and the Mondino Institute in Pavia are the first hospitals in Italy, and among the first in Europe, entirely dedicated to neurological diseases and research, a health policy which has been, therefore, pioneered in Italy. Besta was a pioneer in diagnostic neuroradiology and in epilepsy caused by cortical lesions. Besides numerous clinical investigations, he provided seminal contributions on the “perineuronal net.” This neuronal envelope had been discovered by Golgi in 1898, and Besta investigated and described both its normal and pathological features, an area that has again become of scientific interest (Spreafico et al., 1999). In line with the interest of clinicians in basic neuroscience are the contributions of Arturo Donaggio (1868–1942), another disciple of Tamburini. He graduated in Modena and became an assistant in the San Lazzaro Hospital. After qualifying for teaching in neuropsychiatry in 1901, Donaggio was appointed full professor at Modena and ended his career at the University of Bologna. He introduced a histological method to stain neurofibrils and provided important contributions on extrapyramidal disorders and on epilepsy, reaching such a high reputation in neuropsychiatry that he was nominated for the Nobel prize in 1924 (Fiasconaro, 1992). Sadly, in 1938, at the age of 70, he was one of the 10 Italian professors who signed the “Manifesto della razza,” the racial laws promulgated by the fascist regime against the Jews. The neuropsychiatry clinic San Salvi in Florence, directed by Tanzi, was another “center of excellence” for neurological training. Ernesto Lugaro, whose work was mentioned above, Ottorino Rossi (mentioned previously in relation to his training in Kraepelin’s Institute in Munich) and Vito Maria Buscaino (1887– 1978) were residents at this clinic. Buscaino, who was

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then appointed to the chair of “clinic of nervous and mental diseases” at the University of Catania, on Sicily, and later moved on to Naples, is renowned for his studies on the physiopathology of sensation and emotion. He has also promoted editorial initiatives (see further). The Institute of General Pathology of the University of Pavia, directed by Camillo Golgi, was associated, as mentioned above, with many neurological studies. The students and interns were stimulated to perform rigorous histopathological investigations of the nervous system, which could be useful in clinical practice (Bentivoglio and Mazzarello, 1999; Mazzarello, 2003, 2006, 2009). In addition to Mondino, Marchi, Besta and Ceni (mentioned previously), the neurologists Ottorino Rossi, Guido Sala (1877–1939), Eugenio Medea (1873–1967), and Rosolino Colella (1864–1940) started their scientific careers in Pavia and exerted a high influence on Italian neurology fostering research. Ottorino Rossi (Fig. 44.3) graduated in medicine from Pavia (Ferraro, 1953c; Mazzarello, 1996) and was an intern in Golgi’s laboratory. After his internship in Munich, Rossi became an assistant to Eugenio Tanzi in Florence, and was part of the editorial staff of the journal Rivista di Patologia Nervosa e Mentale (see further). He became a professor at Siena and Sassari, and succeeded to Mondino after his death in 1924. Rossi provided contributions to neuroanatomy,

Fig. 44.3. Ottorino Rossi (1877–1936), leading neurologist who succeeded Casimiro Mondino at the University of Pavia, and provided seminal experimental and clinical contributions.

neuropathology, neurophysiopathology, and clinical neurology. On the basis of his studies on the trigeminal nucleus, Rossi (1907) was able to provide an explanation for the “syringomyelitic dissociation of sensitivity.” He also analyzed the afferent fibers associated with the Meissner and Auerbach plexuses, which were later implicated in the physiopathology of Hirschsprung’s disease (a congenital impairment of the large intestine smooth muscle contraction due to improper muscle innervation), and he engaged in the study of glucose in the cerebrospinal fluid, as well as of peripheral nerve regeneration. The latter area of investigation was pioneered experimentally by Aldo Perroncito (1882–1929) in Golgi’s laboratory. Furthermore, Rossi provided noteworthy contributions to the neurotraumatology of the wounded during the war, on the corpus callosum of alcoholics, on neuroimmunopathology and on cerebrovascular diseases. Of relevance are his descriptions of the cerebellar symptoms called “primary asymmetries of position.” Some of Rossi’s disciples became esteemed professors of neurology, including Giuseppe Carlo Riquier (1886–1962) at Padua, Milan and Pavia, who was a pioneer of neurorehabilitation, and Carlo Berlucchi (1897–1992) at Padua and Pavia, renowned for his investigations of alcoholism, hallucinations (in particular the “chronic hallucinatory psychosis”) and psychopathology (Savoldi, 1992). Guido Sala was also important in Italian neurology, although he did not become a full professor because of quarrels with his mentor, Mondino. Sala studied traumatic injuries of peripheral nerves during World War I in the military hospital “Collegio Borromeo” of Pavia, then directed by Golgi (Pensa, 1939; Savoldi, 1990). Camillo Negro (1861–1927) graduated from Turin in 1884 and was further trained by Wilhelm Erb at the University of Heidelberg. Negro was appointed to the chair of neuropathology (i.e., neurology) at the University of Turin in 1910. In collaboration with the physiologist Zaccaria Treves, Negro described the cogwheel phenomenon, or “Negro’s sign,” in Parkinson’s disease, at the Fifth International Congress of Physiology, held in Turin in 1901. He then published this work in the Archives Italiennes de Biologie (Negro and Treves, 1901; Ghiglione et al., 2005). We owe to Eugenio Fazio (1849–1902) another eponym in clinical neurology. It is Fazio–Londe’s disease, or infantile progressive bulbar paralysis. The French pathologist Paul F.L. Londe (1864–1944) also contributed to it, and therefore shares the eponym. The most renowned representative of Italian neuropsychiatry in the mid-20th century was probably Ugo Cerletti, who graduated in Rome in 1901. During an internship in the laboratory of Franz Nissl (1860– 1919) in the psychiatric clinic of the University of

HISTORY OF NEUROLOGY IN ITALY 729 Heidelberg, Cerletti was trained in the histopathology trical current (Linington and Harris, 1988). The of the central nervous system. After his MD degree, history of ECT from there on is well known and Cerletti became a resident of the Paris institute directhe technique rapidly diffused internationally. ted by Pierre Marie (1853–1940) and, as mentioned Trained in the Padua psychiatric and “neuropathopreviously, at the Deutsche Forschungsanstalt fu¨r logical” institute directed by Ernesto Belmondo, Psychiatrie, directed by Kraepelin in Munich. After Cerletti’s successor Lionello De Lisi (1885–1957) also qualifying for university teaching in 1906, Cerletti exerted a remarkable influence on Italian neurology. worked in Rome with Augusto Tamburini publishing De Lisi worked first in Padua (in the internal medicine histopathological studies. Of special relevance are his clinic directed by Achille De Giovanni), and then at observations on the luetic brain, in which he detected the civil hospital of Venice. He qualified in Cagliari features of active inflammation. His observations led as professor of the clinic of nervous and mental dishim to state (in 1910) that the alterations are due to eases, and succeeded Ugo Cerletti, who had moved the presence of a microbe, contrary to Kraepelin’s to Rome, at the neuropsychiatric clinic of Genoa, in opinion. Two years later, the Treponema was found 1935. De Lisi provided the first description of myocloin nervous tissue affected by neurosyphilis, thus connus during sleep and made additional contributions in firming Cerletti’s views. the areas of stroke and Wilson’s disease (De Lisi, Cerletti also published studies on cerebral malaria 1929). He founded an important neurological school and atherosclerosis. He traveled through many Alpine in Genoa, which was subsequently developed by his valleys with his friend Gaetano Perusini (whose work main disciples, Cornelio Fazio (1910–1997) and Carlo on Alzheimer’s disease has been presented in the preLoeb (1921–2005), internationally regarded for their vious section). They visited almost every cottage and studies on cerebrovascular diseases (Vinci, 2004; collected a large series of cases of endemic goitre creFavale, 2005). tinism, a problem solved only later by the distribution Another bridge between psychiatry and neurology, of iodate salt. Cerletti became professor of neuropsyas well as between these disciplines and psychoanalychiatry in the newly founded University of Bari (1924) sis, was built by Marco Levi Bianchini (1875–1961), also in southern Italy, and moved then to Genoa (1928), on the basis of his editorial initiatives (see further). initiating in this university the “clinic of nervous and After graduating in medicine from Padua in 1899, Levi mental diseases,” and finally to Rome (1935). Bianchini worked with Tanzi and Lugaro in Florence, Cerletti is best remembered today for having introand then in the Congo in 1901 (Cappelli, 2000). He then duced electroconvulsive shock therapy (ECT) for psybecame director of the asylum of Teramo and of chiatric diseases. He collaborated with his assistant Nocera Inferiore. An eclectic scholar especially interLucio Bini (1908–1964) in this domain, and he was ested in epilepsy and hysteria, Levi Bianchini had wide twice nominated for the Nobel prize for his contribuneurological and psychiatric interests (Ceccarelli, tions. Cerletti and Bini first applied their electrical 2006). He was also the first translator of the works treatments for mental illness to a patient suffering of Sigmund Freud (1856–1939) from German to Italian, from paranoid schizophrenia, this being in April and he met Freud, who greatly appreciated his transla1938 (Novelletto, 1979; Guarnieri, 1991; Pallanti, 1999; tions and support. Levi Bianchini founded the Italian Passione, 2004; Mula et al., 2006). Historically, Society of Psychoanalysis in 1925 with Edoardo Weiss their new therapy followed two other recently intro(Guarnieri, 1991; Lisciani Petrini and Oneroso, 2006). duced shock treatments: insulin shock therapy, After World War II, bridging neurology and psyintroduced in 1934 by Manfred Sakel (1900–1957), chiatry and the expanding field of the neurosciences and cardiazol therapy, pioneered in the same year was also a goal of Hrayr Terzian (1925–1988). In by Ladislav von Meduna (1896–1964). Cerletti 1948, upon graduating in medicine from Padua, he thought to replace these problematic methods with spent 2 years at the Institute of Physiology directed electrical treatments, based on evidence in animals by Giuseppe Moruzzi in Pisa. Terzian became professhowing that cranial electric shocks, which are more sor of the clinic of nervous and mental diseases in easily controlled, can also cause transient unconCagliari and then in Verona. Besides his studies on episciousness for anesthetic purposes, and that they lepsy and drug abuse, his main scientific contribution leave animals healthy. Prior to treating their first is his pioneering report with neurosurgeon Dalle Ore patient, Cerletti and Bini established that the passage on the severe consequences of bilateral temporal of electrical current with certain parameters and lobectomy for intractable epilepsy, “a dramatic confirwith bitemporal electrodes was safe and predictable. mation of the experimental studies of Klu¨ver and Bucy They visited the slaughterhouse and found that aniin monkeys” (Terzian and Dalle Ore, 1955). This study mals were not killed, but only stunned, by the elecis still cited as a seminal contribution to the field

730 M. BENTIVOGLIO AND P. MAZZARELLO (Fountas and Smith, 2007). Terzian, very interested “Statistical-Historical-Medical Journal of the Kingin public health, was also a main supporter of the dom of Two Sicilies”), considered the first journal important reform in the Italian mental health system of Italian neuropsychiatry. (“Law 180,” promulgated in 1978), which abolished In view of growing interest in the nervous system, the asylums and was promoted by psychiatrist in 1864 Andrea Verga and Serafino Biffi gave a new Franco Basaglia (1924–1980), Terzian’s close friend. editorial impulse to these studies and transformed the As recalled by the neurologist and neuropathologist “Psychiatric Appendix” into a new journal, the ArchiDavide Schiffer (at present professor emeritus at the vio Italiano per le Malattie Nervose e piu` particolarUniversity of Turin) in his biographical memoirs, neumente per le Alienazioni Mentali (“Italian Archives rological patients with mental alterations (due, for of Nervous Diseases and especially Mental Alienaexample, to dementia) could still be found in the asytion”). Verga and Biffi also promoted a new society, lums in those times (Schiffer, 2005). the Societa` Freniatrica Italiana (“Italian Phreniatric Clinical neurophysiology developed in Italy after the Society”), which was founded in Rome in 1873. Verga war, with Paolo Pinelli (still active; professor emeritus was elected president, Biffi secretary-treasurer. The at the University of Milan) and Lodovico Bergamini “Archives” became the official journal of the Society. (1921–1996), who specialized in Denmark at the laboraTwo years later, Carlo Livi, in Reggio Emilia, tory of Fritz Buchtal (1907–2003) and was one of the piofounded another journal, the Rivista Sperimentale di neers of the field. In terms of clinical neurophysiology it Freniatria e Medicina Legale (“Experimental Review is also worth recalling the work of Elio Lugaresi (still of Phreniatry and Forensic Medicine”). It soon active; professor emeritus at the University of Bologna), attracted the best Italian contributions to anatomy, who has focused on sleep physiopathology and provided physiology, and pathology of the nervous system. Golthe first description of “fatal familial insomnia” (Lugargi’s main neuroanatomical studies, and Luciani’s and esi et al., 1986). This rare hereditary prion disease, hallTamburini’s studies on cortical localization of psychic marked by loss of sleep and other neurological functions, were published in this journal. alterations, has raised considerable interest for its impliIn 1871, Paolo Mantegazza, in Florence, founded the cations in sleep neurobiology and pathology, and conArchivio per l’Antropologia e la Etnologia (“Archives cerning the potential biological function of the prion of Anthropology and Ethnology”). It was the official protein (Montagna, 2005). organ of the Societa di Antropologia, Etnologia e Psicologia Comparata (“Society of Anthropology, Ethnology and Comparative Psychology”), which also had NEUROLOGY AS AN AUTONOMOUS been founded by Mantegazza. It too published studies DISCIPLINE IN ITALY: SCIENTIFIC on clinical neurology. SOCIETIES AND JOURNALS Giuseppe Buonuomo, director of the Naples Asylum, In 1852, Andrea Verga founded the Appendice Psiand Leonardo Bianchi, who was at that time director chiatrica (“Psychiatric Appendix”) of the Gazzetta of the psychiatric clinic in Palermo, launched the Medica Italiana (“Italian Medical Gazette”), directed journal La Psichiatria, la Neurologia e le Scienze by Bartolomeo Panizza. In the foreword to the first Affini (“Psychiatry, Neurology, and Related Sciences”) issue, Verga stated that the journal was “supporting in 1883. Francesco Vizioli (1834–1898), in Naples, the importance of the union of psychiatry with neurofounded in 1883 and published in 1885 the first periodpathology,” providing a tool for exchanges and comical dedicated to neurological diseases, the Giornale di munications from all physicians interested in diseases Neuropatologia (“Journal of Neuropathology,” with of the nervous system. the term being used as synonym for “neurology”). The need for a scientific society manifested in At the 7th Congress of the Societa` Freniatrica Italia1861, when Biagio Gioacchino Miraglia (1814–1885) na, which was held in Milan in 1891, the Archivio Itafounded the Societa` Frenopatica Italiana (“Italian liano per le Malattie Nervose e piu particolarmente Society of Phrenopathy”), in the asylum of Aversa per le Alienazioni Mentali was merged with the Rivista (near Naples), aiming to promote research on the Sperimentale di Freniatria in order to collect all releanatomy, physiology, and pathology of the nervous vant work in the field of neuropsychiatry. The editorial system. This society gathered members (alienists and initiatives underwent further development in the folscholars of different disciplines) from all over Italy lowing years. In 1896, Tanzi, Morselli and Tamburini and its official journal was the Annali Frenopatici founded the Rivista di Patologia Nervosa e Mentale Italiani (“Italian Phrenopathic Annals”). In 1843 Mir(“Journal of Nervous and Mental Pathology”), edited aglia had founded a scientific journal (Giornale Medby the psychiatric clinic of Florence. In 1906 Lugaro ico-Storico-Statistico del Regno delle Due Sicilie; became director of this journal, which soon developed

HISTORY OF NEUROLOGY IN ITALY as the main organ for the dissemination of neurological studies in Italy. In the following year, Ezio Sciamanna (1850–1905), director of the psychiatric clinic of Rome, and anthropologist Giuseppe Sergi (1841– 1936) founded the Rivista Quindicinale di Psicologia, Psichiatria, Neuropatologia (“Fortnightly Journal of Psychology, Psychiatry and Neuropathology,” the latter term still used to indicate “neurology”). In the meantime, neurological studies were becoming increasingly independent from psychiatric ones, both in the congresses of the Societa` di Freniatria and in neuropsychiatric journals. In 1907, neurology finally became an autonomous discipline, marked by the founding of the Societa` Italiana di Neurologia, or SIN (“Italian Society of Neurology”). Begun in Rome, this society held its first congress in Naples in 1908, with an opening lecture by its first president, Leonardo Bianchi (Salomone et al., 1996). Many of the scientists mentioned in this chapter were among the founders, including, besides Bianchi: Morselli (vice-president), Mingazzini (vice-president), Tanzi (secretary-general), Belmondo, Besta, Ceni, Colella, Donaggio, Golgi, Lombroso, Lugaro, Mondino, Negro, Roncoroni, Tamburini, and De Sanctis. The second congress was held in Genoa the following year, and Morselli was elected president. Congresses in several other Italian cities followed. In 1932, during fascism, the 9th SIN congress was held in Modena and the Society then entered a period of inactivity. In April 1946, a meeting defined as “congresso straordinario” (i.e., outside the regular sequence) marked the reconstruction of SIN under the leadership of De Lisi, who was its president until 1949. The program of the SIN annual congresses was reinstated with the 10th SIN congress, which was held in Milan (Bonavita, 1999). From an academic point of view, however, neurology was still taught together with psychiatry under “clinic of nervous and mental diseases.” Groups with specific interests developed within the SIN and Terzian was the initiator of the study group on the history of neurology within this society. Among other groups focusing on research on nervous system diseases, it is worth recalling the Italian Association of Neuropathology, which was officially founded in 1966 by a group of neurologists with training in pathology. This initiative also finally solved the equivocal use, in Italy, of the term “neuropathology,” which from then had, at last, its modern meaning (Schiffer, 2005). Giorgio Macchi (1919–1999), a professor in Perugia and then at the Catholic University in Rome, was the main promoter of the foundation of the Italian Association of Neuropathology. His research in neuroanatomy and neuropathology had helped to bridge, in Italy, the basic and clinical neurosciences, as he

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strongly advocated (Macchi, 1988). Macchi is especially renowned for his studies on the organization of the thalamocortical system (Jones, 2007). In 1960, a group of neurologists working in various hospitals decided to separate from academia and founded the Societa` dei Neurologi Ospedalieri (SNO), which is still very active and probably represents a unique initiative in the context of European neurology. As for editorial initiatives, new journals dedicated to neurology appeared in Italy during the 20th century. In 1920, Marco Levi Bianchini (1875–1961) founded the Archivio Generale di Neurologia, Psichiatria e Psicoanalisi (“General Archives of Neurology, Psychiatry and Psychoanalysis”). In 1938, this journal merged with the Archivio di Psicologia, Neurologia, Psichiatria e Psicoterapia (“Archives of Psychology, Neurology, Psychiatry and Psychotherapy”) of Agostino Gemelli (1878–1959); the journal then became the Archivio di Psicologia, Neurologia e Psichiatria (“Archives of Psychology, Neurology and Psychiatry”). In 1946 Vito Maria Buscaino founded in Naples the journal Acta Neurologica, which published papers written in the main European languages. In the second half of the 20th century, foreign journals, mostly published in English, rose in international prominence. Some of the Italian journals now began to publish in English and established international editorial boards. In 1979 Renato Boeri (1922–1994), who was a director of the Neurological Institute Carlo Besta, founded the Italian Journal of Neurological Sciences, the official journal of the SIN. In 2000, it changed its name to Neurological Sciences. The journal Functional Neurology was founded at the Mondino Neurological Institute. A leading journal in neuropsychology is Cortex, and the first editor of this journal was Gildo Gastaldi (1907–1973), professor of the clinic of nervous and mental diseases in Milan. However, the real initiator and active promoter of the journal was, from its beginning, Ennio De Renzi (still active; professor emeritus at the University of Modena), who was also the main driving force for the development of neuropsychology in Italy from the 1960s.

CONCLUDING REMARKS The SIN congress held in 1971, when Mario Gozzano (1898–1986) was president of the society, promoted the division of psychiatry and neurology into two different disciplines in Italy, and emphasized the affinity of neurology with internal medicine. This view, shared by psychiatrists, was accepted by Italian legislators, and the two disciplines became divided in academia. In more recent years, with the development of new diagnostic

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techniques, such as neuroimaging approaches, genetic studies, and all of the unique challenges of the postgenomic era, both neurology and psychiatry can be seen as falling under the common umbrella of the neurosciences, and have become closer, from the cultural point of view, in the Italian community.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 45

A history of Russian and Soviet neuro(patho)logy BOLESLAV LICHTERMAN * Department of the History of Medicine, Research Institute for the History of Medicine of Russian Academy of Medical Sciences, Moscow, Russia

INTRODUCTION Christianity was adopted in Russia in 988 in its Byzantine or Orthodox version. From the 13th to the 15th centuries Mongolian hordes occupied most of the country. These two factors contributed to a prolonged isolation of Russia from the mainstream of European civilization. At the turn of the 18th century, czar (and first Russian emperor) Peter the Great (1672–1725) “cut opened window into Europe.” This was the beginning of the Westernization and modernization of the patriarchal lifestyle of Russia. Hundreds of foreign specialists and consultants were invited into the country, including medical doctors. Under Peter’s decree, the first school for feldshery (physician’s assistants) was created at the Moscow military hospital in 1707, under the directorship of a Dutch physician, Nicolas Bidloo (c. 1670–1735). The first Russian university, which opened in Moscow in 1755, had a medical faculty, but for several decades its graduates had to continue their studies abroad to get diplomas to be eligible for licenses to practice medicine in the Russian Empire. There appeared to be no major differences between medical practice in Russia and in other European states during the early-19th century, because most medical practitioners in Russia were Europeans. One of the first Russian professors of medicine was Matvei Yakovlevich Mudrov (1772–1831) who had the chair of pathology, therapy and clinics at Imperial Moscow University. In 1819, he opened the Clinical Institute with 32 beds for bedside teaching of medical students. From 1820 it included a special ward “for nervous diseases and insanity of mind” (Yudin, 1951, p. 50). From 1831 (after Mudrov’s death from cholera) to 1835 Justinus Djadkowsky (1784–1841) had the chair. He wrote

*

that the “nervous system governs all other systems, organs and parts” (cited by Mikulinsky, 1951, p. 53). This idea of supremacy of the nervous system (“nervism”) was later developed by Sechenov and Pavlov (see below). Djadkowsky suggested a new theory of pathogenesis, according to which the development of disease process is determined by the state of the nervous system. He classified all diseases into two groups: (1) febrile (when the nervous system is excited) and (2) not-febrile (when the nervous system is inhibited). Nervous diseases belonged to the second group and were subdivided into five orders (diseases of sensations, of incentives, of mind, of movements, and of forces). There was a further division into 13 families, which included more than 30 disease entities (falling sickness, dementia, hysteria, tetanus, hydrophobia, paralyses, lethargy, etc.). In 1835, emperor Nikolas I (1796–1855) issued a special decree aimed at increasing the number of Russian physicians. Russia became isolated from Western Europe under this emperor, and the tradition of sending young scientists abroad for postgraduate training was interrupted. After the French Revolution of 1848, almost all faculties of Moscow University were either closed or significantly reduced in order to suppress liberal political movements, with the exception of the medical faculty. According to the university bylaws of 1835, the department of pathology, therapy and clinics was divided into the department of special pathology and therapy, and the clinic of internal medicine. Nervous diseases were included in the program of special pathology and therapy, whereas psychiatry had to be taught by a professor of the clinic of internal medicine (Lisitsyn, 1961). With the teaching program of 1850, nervous diseases were singled out in a separate class and divided

Correspondence to: Dr. Boleslav Lichterman, Department of the History of Medicine, Research Institute for the History of Medicine of Russian Academy of Medical Sciences, Frunzenskaya nab. 46–75, Moscow 119270, Russia. E-mail: [email protected], Tel: +7(916)9141409, Fax: +7-495-608-86-95.

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into four types: (1) impairments of sensations, mainly pain (neuralgias); (2) impairments of movements – (a) convulsions and (b) paralyses; (3) impairments of movements and sensations (falling sickness, frenzy, quinsy, etc.); and (4) nervous diseases specific to certain organs (organs of respiration, organs of blood circulation, stomach, sexual organs). By 1860, nervous and psychiatric patients comprised about 10% of all patients at clinics of internal medicine of Imperial Moscow University (Lisitsyn, 1955). Nikolas I, who died in 1855, was succeeded by a liberal emperor, Alexander II (1818–1881), who began what came to be known as the “epoch of Great Reforms.” Krepostnoe pravo (serfdom of peasants) was abolished in 1861. This change had a major impact, in as much as 90% of the country’s population was rural. During the last quarter of the 19th century “the river of European civilization seemed rather definitely to shift its flow toward the countries of Central Europe. Those on the periphery of the cultural watershed also fed generously their youthful, creative energies into that common stream” (Yakovlev, 1970, p. 167).

CLINICAL NEURO(PATHO)LOGY IN IMPERIAL RUSSIA The idea of localization, which was claimed by Virchow as a principal feature of modern medicine, had a profound impact on Russian neurology. Most Russian academic medical doctors were either the pupils of Virchow or the pupils of his pupils (Lichterman, 2003). Russian neurologists were interested in the pathology of the nervous system and were neuropathologists as well. This tradition is felt even today, especially by the lay public in Russia, who call neurologists nevropatologi (neuropathologists). Additionally, the most important Russian neurological periodical was named Voprosy nevropatologii i psikhiatrii (“Problems in Neuropathology and Psychiatry”) until recently, when “Neuropathology” was replaced by “Neurology.” In the Russian medical literature, the term “neurology” is considered to be related to basic neuroscience, whereas a clinical neurologist is called nevropatolog (neuropathologist). Pathologists who study the anatomy of the nervous system in health and disease are called neiromorphologi (neuromorphologists). Clinical neuro(patho)logy as a specialty emerged in Imperial Russia in the second half of the 19th century and was represented by two schools – one in Moscow and another in St. Petersburg. They will be examined in turn.

The Moscow School of Neuro(patho)logy Alexei Yakovlevich Kozhevnikov (1836–1902) is considered the father of Russian neuro(patho)logy (Fig. 45.1). He graduated from Imperial Moscow University in

Fig. 45.1. Alexei Yakovlevich Kozhevnikov (photograph c. 1898).

1858 and initially worked as an obstetrician. Then Kozhevnikov became an assistant professor at the clinic of internal medicine. In 1865 he defended his doctorate thesis on Duchenne’s disease (Ataxia locomotrice progressive) and in the next year was sent abroad to study nervous diseases and psychiatry, “with special reference to the subjects that are closely related to them: psychology, physiology, special pathology and therapy, etc.” (Lisitsyn, 1961, p. 60). Kozhevnikov received a broad education in Germany. He worked in the laboratory of the anatomist and physiologist Albert Ritter von Koelliker (1817–1905) in Wu¨rzburg, as well as in the laboratories of anatomist-pathologist Virchow and physiologist Emil du Bois-Reymond (1818–1896) in Berlin. In du Bois-Reymond’s laboratory, he studied the projections of sensory fibers in the spinal cord of the frog. In Koelliker’s laboratory, he investigated histological relationships of cortical pyramidal cells and Purkinje cerebellar cells with nervous fibers. On his return, Kozhevnikov organized the first Russian neurological clinic, which was opened on 15 September 1869 in Novo-Ekaterininskaya bol’nitsa (New Catherine’s Hospital) in Moscow. There were

A HISTORY OF RUSSIAN AND SOVIET NEURO(PATHO)LOGY 19 beds, including beds for “non-agitated” psychiatric patients. These neurological beds were taken out of the surgery and internal medicine university clinics. The new clinic was aimed at teaching neurology and psychiatry to medical students. Kozhevnikov was a dozent (associate professor) for nervous diseases and psychiatry, which belonged to the chair of special pathology and therapy. There was also one assistant at the clinic. In October 1870, Kozhevnikov was elected to the chair of special pathology and therapy (until 1884). According to the new university bylaws, the first chair of nervous and mental diseases at Imperial Moscow University was inaugurated in 1884 (Arkhangel’sky, 1965). Kozhevnikov was appointed professor of neurology and psychiatry (this joint chair of nervous and mental diseases was divided into two chairs, one of neurology and another of psychiatry, only after the October Revolution of 1917). The neurological clinic was enlarged to 25 beds and received a second assistant. In 1887, a special building with 50 beds was erected for the psychiatry clinic, and 5 years later Sergei Korsakov (see below) became the clinic director. A new building for the nervous clinic was built in 1890 (Fig. 45.2). It had 44 beds and included an auditorium for 250 students (Bobrova, 1955). In 1891, an infirmary for 30 chronic neurological patients was opened. There

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was also an outpatient neurological clinic. Kozhevnikov’s idea was to demonstrate all stages of nervous diseases to the medical students, using both outpatients and the infirmary. Kozhevnikov had a collector’s talent. In 1892, he created a “neurological museum” with some 400 neurological specimens. The museum was aimed at providing the necessary materials for studying the nervous system in health and disease, as well as for teaching. The museum collections were divided into several sections: (1) normal human anatomy; (2) history of the development of the central nervous system; (3) comparative anatomy of the nervous system; (4) anthropology; (5) pathological anatomy; and (6) clinical. By 1902, the number of specimens reached 1500 (excluding microscopic specimens, photographs and pictures; see Bobrova, 1955). Kozhevnikov’s colleagues donated a brain of a Caspian seal, skulls from people of different nationalities, and an Egyptian mummy (Lisitsyn, 1961). Kozhevnikov was the author of the first Russian textbook, Nervnye bolezni I psikhiarija (“Nervous Diseases and Psychiatry”; Kozhevnikov, 1883). All nervous diseases were divided into two main groups, (a) organic and (b) functional (neuroses), when pathological changes in the nervous system were not detected. The latter group included epilepsy, chorea, catalepsy, the shaking palsy, neurasthenia and hysteria.

Fig. 45.2. A photograph from 1898 of a new building of the nervous clinic of Moscow University (courtesy of Museum of the Sechenov Medical Academy, Moscow).

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Almost every disease was viewed as a reaction, due to molecular or anatomical lesions, of the nervous centers. Nervous diseases were considered diseases of the whole body. As for the etiology of nervous diseases, their causes were divided into predisposing (age, gender, social status, heredity, nationality) and producing (injuries of the nervous system, cold, infections and intoxications, syphilis, alcoholism, rheumatism, psychic factors, etc.). The latter were divided into molecular (psychotrauma and malnutrition) and anatomical (compression, inflammation, rupture) varieties. In 1874 Kozhevnikov published a paper “Aphasia and Central Organ of Speech” where suggested that “central organ of speech is located in the cortex of left hemisphere around the Sylvian fissure (in righthanded persons) (Kozhevnikov, 1874). “Both third frontal gyrus and insula Reili are equally responsible for the ability to speak,” he wrote (cited by Lisitsyn, 1955, p. 219). He also wrote, “movements of blood vessels are controlled by special nerves called vasomotor nerves. Their higher centers are located in cortex” (cited by Lisitsyn, 1955, p. 169). According to Kozhevnikov, cortical vasomotor centers are located near centers of voluntary movements. Body temperature is also controlled by special nervous centers. In 1894, Kozhevnikov described four cases of a new form of epilepsy called epilepsia corticalis sive partialis continua, which nowadays is considered a result of tick-borne encephalitis (Kozhevnikov’s epilepsia partialis continua was later described in English literature as “Rasmussen’s encephalitis”; Kozhevnikov, 1894; He´caen and Dereux, 1956). For the treatment of nervous diseases, Kozhevnikov liberally practiced bloodletting, leeching (3–4 leeches behind the ears and on the bridge of the nose), cauterization along the nerve passage, and zavoloka (or seton) – a skein of cotton or silk passed below the skin of the neck with an end protruding to promote inflammation and suppuration for the sake of counterattraction (Lisitsyn, 1955). By the late 1880s, there were more than 30 physicians in Moscow interested in nervous and mental diseases. In 1890, Kozhevnikov organized the Obshestvo nevropatologov I psikhiatrov pri Imperatorskom Moskovskom Universitete (Society of Neuro(patho)logists and Psychiatrists at Imperial Moscow University). Apart from scientific problems, the Society discussed organizational issues, such as construction plans of psychiatry hospitals. Brief accounts of the Society meetings were published in two foreign journals, Archives de Neurologie and Neurologisches Zentralblatt. The Society was named after Kozhevnikov after his death (until 1932, when his name was erased for ideological reasons).

Well known at home and in other places, Kozhevnikov became an honorary member of 17 learned societies in Russia and abroad. Kozhevnikov’s most important and long-lasting contribution to neurology might well be the Moscow neurological school that he created. His pupils included five professors of neurology (Vladimir Roth, Lazar’ Minor, Grigory Rossolimo, Vladimir Muratov and Livery Darkshevich) and one professor of psychiatry (Sergei Korsakov). Among these men, Sergei Korsakov (Korsakoff; 1854–1900) is particularly famous for his description of a syndrome of alcoholic polyneuritis combined with memory impairments (Korsakoff’s syndrome) (Fig. 45.3). His famous article on the syndrome was translated into English and commented on by Maurice Victor and Paul Yakovlev (1955). Beginning in 1890, Korsakov headed the psychiatry clinic of Moscow University. Vladimir Karlovich Roth (1848–1916) succeeded Kozhevnikov as a chairman of the chair of nervous and mental diseases at Moscow University (from 1902 to 1911) (Fig. 45.4). In 1895, Roth described 14 cases of a special form of isolated neuritis of the external femoral nerve and named it meralgia paresthetica. It was

Fig. 45.3. Sergei Sergeevich Korsakov.

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Fig. 45.4. Vladimir Karlovich Roth.

Fig. 45.5. Vladimir Aleksandrovich Muratov (photograph c. 1915).

described at the same time by Bernhardt, and hence has become known as Roth–Bernhardt’s syndrome (Shenderovich, 1962). Roth also created the Kozhevnikov Neurological Institute. In 1911, Roth, along with 130 other professors and teachers, left the Moscow University in protest against the reactionary politics of the minister of education. Vladimir Aleksandrovich Muratov (1865–1916) agreed to become the chair of nervous and mental diseases at Moscow University after Roth’s retirement (Fig. 45.5). Muratov published more than 100 works on neurology and psychiatry. His dissertation was dedicated to secondary degeneration after focal motor cortical lesions (1893). He distinguished seizures from involuntary subcortical movements (chorea and athetosis). “We consider any epilepsy as a suffering of cerebral cortex,” Muratov wrote (cited by Lisitsyn, 1961, p. 302). In his Klinicheskie lektsii po nervnym I dushevnym boleznyam (“Clinical Lectures on Nervous and Mental Diseases”; Muratov, 1899) he described encephalitis. He was a pioneer of pediatric neurology. In 1898 he published Klinicheskie lektsii po nervnym

boleznyam detskogo vozrasta (“Clinical Lectures on Nervous Diseases of Children”). After Kozhevnikov’s death in 1902, the Moscow Society of Neuro(patho)logists and Psychiatrists proposed naming the street where the neurology clinic stands after Kozhevnikov. Ironically, this street was named several decades later after his pupil Grigory Ivanovich Rossolimo (1860–1928), who had the chair of nervous diseases at Moscow University from 1917 to 1928 (Fig. 45.6). In 1889, he singled out recurrent hypertrophic polyneuritis in children. In 1902, he described a sign – percussion of the plantar surface of the 2nd to 5th toes cause their flexion – that still bears his name (Rossolimo’s reflex). Like Babinski’s sign, this reflex is exaggerated by pyramidal tract lesions. Rossolimo was a founder of Russian pediatric neurology. In 1911 he established the Institut detskoi nevrologii I psikhologii (Institute for Pediatric Neurology and Psychology), and in 1917 he organized a 30-bed department for children with nervous diseases at the university clinic (instead of the infirmary for chronic

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Fig. 45.6. Grigory Ivanovich Rossolimo (photograph c. 1925).

patients – see above). This was the first pediatric neurological department in Europe and perhaps in the world (Tsuker, 1967). Throughout his life, Rossolimo was also interested in psychology. He created a method for obtaining individual psychological profiles, which was based on answers to 10 questions. The data obtained were evaluated using a 10-point score and were presented graphically. Also interested in surgical neurology, Rossolimo first introduced lumbar puncture in Moscow and modified Zernov’s encephalometer (Lichterman, 1998). In 1893, Rossolimo referred one of his patients to a surgeon (Professor K.F. Klein), who opened a cerebral cyst. Rossolimo designed many devices for neurological practice: a dynamometer for measuring the strength of hand compression (1894), a clonograph for registration of hand hyperkinesias (1893), an analgesimeter for measuring pain intensity (1902), a synergometer for investigation of adiadochokinesis, an orthostasiometer for measuring instability in Romberg’s test, an optokimometer for defining the degree of impairment of coordination in hands and legs, a prozometer for

determining the degree of face distortion in facial nerve paralysis and for tongue deviation in hypoglossal nerve paralysis, and a dematographometer for measuring intensity of irritation and degree of response. Lazar’ Solomonovich Minor (1855–1942) was one of the brightest representatives of the Moscow neurological school (Fig. 45.7). He described central hematomyelia, familiar hereditary tremor, “seating symptom” in sciatica (Minor’s phenomenon), and epiconus syndrome (spinal cord lesions at L5-S2 levels). Livery Osipovich Darkshevich (1858–1925), another of Kozhevnikov’s pupils, established the neurology school in Kazan (Fig. 45.8). Upon graduation from Moscow University, he spent more than 3 years in Western Europe, working in the laboratories and clinics of Meynert, Flechsig, Holtz, Charcot, and others. From 1892 to 1917, he held the chair of nervous diseases at Kazan University, where he established an operating room, laboratory, and museum. He described the upper oculomotor nucleus that was later named after him (Darkshevich’s nucleus) and wrote many works on neuroanatomy and neurophysiology. His 3-volume Kurs nervnykh boleznei (“A Manual on Nervous Diseases”) dates from 1904 to 1917 (Popelyansky, 1976). An X-ray cabinet was installed at the clinic of nervous diseases of Moscow University in 1908. X-rays were used not only for diagnostics but also for the treatment of syringomyelia. The first cerebrospinal fluid analysis was performed at this clinic in 1914. After the start of World War I, the clinic and Neurological Institute were transformed into a military hospital with 100 beds.

The St. Petersburg School of Psychoneurology According to Shenderovich, “contrary to St. Petersburg School of Psychoneurology, the founders of Moscow School of Neuro(patho)logy were primarily clinicians rather than experimentalists” (Shenderovich, 1956, p. 390). In 1857 it was decided to teach psychiatry as a separate specialty at the Medico-Surgical Academy in St. Petersburg (later renamed the Imperial Military Medical Academy). In 1859, Ivan Mikhailovich Balinsky (1824–1902) opened the first Russian psychiatry clinic here and started to teach this subject to the students. The next year he was appointed a professor of a chair of nervous and mental diseases. Balinsky believed that mental diseases are nervous diseases, and therefore that “success in treatment of mental diseases depends on further study of anatomy and physiology of nervous system” (cited by Balinsky, 1958).

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Fig. 45.7. Lazar’ Solomonovich Minor, Mikhail Borisovich Krol’ and Vasily Vasil’evich Kramer (from left to right) studying brain anatomy (photograph c. 1910, courtesy of Museum of the Sechenov Medical Academy, Moscow).

After Balinsky’s retirement in 1875, he was succeeded by his pupil Ivan Pavlovich Merzheevsky (1838–1908) – a psychiatrist who was interested in experimental physiology (Fig. 45.9). In 1880 six beds for neurological patients were installed at the psychiatry clinic. This was the beginning of clinical neurology

in St. Petersburg. Starting in 1883, Merzheevsky edited Vestnik klinicheskoi I sudebnoi psikhiatrii I nevropatologii (“Herald of Clinical and Forensic Psychiatry and Neuro(patho)logy”). Out of 26 dissertations from Merzheevsky’s clinic, 19 were experimental works.

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Fig. 45.9. Ivan Pavlovich Merzheevsky (photograph c. 1880). Fig. 45.8. Livery Osipovich Darkshevich.

The most outstanding representative of his school was Vladimir Mikhailovich Bekhterev (1857–1927) (Fig. 45.10). This neurological giant had more than 600 publications, including 170 books and papers on neurology and psychiatry. He described more than 15 new reflexes, 10 signs, and 10 new disease entities (Shenderovich, 1956). He designed several devices including a reflexometer (for measuring the angle of shin deviation when examining the knee reflex), an algesimeter (for measurement of pain sensation), etc. His name is also immortalized in Bekhterev’s mixture (a mixture of bromides, Adonis vernalis and codeine for treatment of epilepsy), which is still included in the Russian pharmacopoeia. At the age of 16, when Bekhterev was a first-year student at the Medico-Surgical Academy (which was later renamed the Imperial Military Medical Academy) he was hospitalized in a psychiatry clinic of the academy with acute hallucinations, which might explain his decision to become a neuropsychiatrist. These hallucinations (auditory and visual) were attributed to overstrain. Bekhterev spent almost a month in the clinic. He was diagnosed “Hallucinationes exaltatii manica”

(which would probably be equivalent to “Acute polymorphous psychotic disorder without schizophrenic symptoms” in DSM-IV) (Kuznetsov, 1995). Bekhterev graduated from the Academy in 1878 at the age of 21. Five years later he had published 50 scientific works in national and international periodicals and was sent to Germany and France for 2 years of postgraduate training (Platonov, 1928). Upon his return at the age of 27, Bekhterev was appointed to the chair of nervous and mental diseases in Kazan, where he established neurology and psychiatry departments, and histological, physiological and psychophysiological laboratories. Additionally, he founded the “Society of Neurologists and Psychiatrists” and the journal Nevrologichesky Vestnik (“Neurological Bulletin”; see below) in 1892. In 1894, he was appointed a chairman of the chair of nervous and mental diseases at the Imperial Medical Military Academy in St. Petersburg (after Merzheevsky’s retirement). This period of Bekhterev’s career was later called “anatomical” (Pines, 1935), and results of his work were published in his twovolume book, Provodyatschie puti spinnogo I golovnogo mozga (“Conductive Ways of Spinal Cord and Brain”), in 1877 and 1888. There were two German editions of this book (von Bechterew, 1894) published

A HISTORY OF RUSSIAN AND SOVIET NEURO(PATHO)LOGY

Fig. 45.10. Vladimir Mikhailovich Bekhterev (photograph c. 1890).

under the influence of brain anatomist Paul Flechsig (1847–1929). In this work, Bekhterev described 12 methods of morphological investigation of the nervous system, with special reference to the myelogenetic method associated with Flechsig. Nevertheless, Bekhterev was fairly critical of Flechsig’s doctrine of Associationszentrum (association center). Bekhterev, in fact, questioned the strict isolation of cortical centers. The next period of Bekhterev’s scientific career can be called “physiological.” The results were laid down in his multivolume monograph Osnovy uchenija o mozgovykh funktsiyakh (“Basics of Cerebral Functions Doctrine,” 1907), which was also translated into German (von Bechterew, 1908–1911) and French. Bekhterev regarded Gustav Fritsch (1838–1927) and Edward Hitzig (1838–1907) as his teachers in physiology. In this phase, Bekhterev gave up his research on static brainmorphology and abandoned the myelogenetic method. He turned exclusively to the field of experimental pathology, using the methods of irritation and extirpation. The central problem addressed in his book on brain functions is localization of higher functions. Bekhterev now tried to discover precise cortical areas for com-

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plex cerebral function, underestimating brain functioning as a whole. His experimental methods of irritation and extirpation were now directly related to normal functioning: “Every region on the cerebral surface, irritation of which causes this or that movement of a member, is considered to be the centre, responsible for the movement of that member,” Bekhterev wrote. All types of functions were subsequently distributed to specific parts of the roof brain. For example, he localized the perception of bitter, salt, acid and sweet in different parts of what he believed was the gustatory cortex. One of Bekhterev’s critics compared every center with a box located near similar boxes, making the cerebral cortex a collection of such boxes. Centers, Bekhterev concluded, must be distinct from one another. It should be noted that Bekhterev was a fierce opponent of Ivan Petrovich Pavlov (1849–1936). Instead of Pavlov’s notion of “conditioned reflex,” Bekhterev used the term sochetatel’ny refleks (“combinative reflex”): “Formation of such artificial combinative reflexes was achieved in I.P.Pavlov’s laboratory for salivary discharge. But inapplicability of salivary combinative reflex for human investigation forced us to search possibilities for formation of combinative motor reflexes for experimental studies, which was finally achieved” (Bekhterev, 1909, p.1107, transl. B. Lichterman). The last period of Bekhterev’s career can be described as “reflexological.” The most characteristic works of this period, associated with post-revolutionary Russia, are his books Ob’jektivnaya Psikhologiya (“Objective Psychology”) and Kollektivnaya Refleksologiya (“Collective Reflexology”) (Bekhterev, 1921, 1928). The word “psychology” was gradually replaced by “reflexology,” and all central nervous system activity was envisioned in terms of reflexes. The brain itself now became an energy accumulator. As the neuro(patho)logist Lev Yakovlevich Pines (1895–1951) wrote in 1935: Remove brain and replace it with an energy accumulator – nothing will change in this concept. Complex neurophysiological processes are reduced to physical ones, to energy circulation through ingoing and outgoing transformers. Morphology disappeared; brain (which underwent a long period of development) is absent. That is why there is no principal difference between functioning of brain and that of a cell: both are energy accumulators. (Pines, 1935, p. 29, transl. B. Lichterman) This remark leads one back to the German influences on Russian neuro(patho)logy in the 19th and early20th centuries, and to the work of Rudolf Virchow, and his emphasis on cellular pathology. Moreover, like

746 B. LICHTERMAN Virchow, Bekhterev was involved in politics and social 1939, 8th edition) and edited Rukovodstvo po voennoi matters. He had been very critical of the Tsarist regime nevropatologii (“A Manual on Military Neuro(patho) and had enthusiastically greeted the October Revolulogy”) (Astvatsaturov, 1935). And as a researcher, he tion of 1917. described the nasolabial and axial reflexes, an epilepBekhterev’s last papers revived the idea taken togenic zone in the temporal lobe, the significance of from German neuropathologists that outstanding peonegative repercussion, the role of the thalamus in the ple must possess special brains. Bekhterev suggested pathogenesis of causalgia, strial contractures, and akito collect the brains of celebrities, “to reveal the nature nesias and various methods for alleviating these conof genius and talent.” The anatomical basis of giftedditions. ness, he believed, could be revealed by the careful Astvatsaturov developed courses and gave lectures investigation of numerous brains of politicians, poets, on “thalamic” emotions and psychosomatic relations. artists, etc. The enigma of genius could, in fact, be Some movement disorders after cerebral lesions were solved by creating a “brain pantheon” (Bekhterev, explained by Darwin’s evolutionary theory, an 1927a, b). Ironically, Bekhterev’s own brain was the approach that was called biogenetic or historical. He first in this collection of 1500 brains (Shenderovich, claimed that during the evolution of the nervous sys1956). tem, its higher forms of organization emerged as A similar “pantheon” was also created in Moscow, superstructures over the more ancient ones. The latter where a special institute had been founded for studybecome hidden, but can still reveal themselves after ing Lenin’s brain (Institut mozga – “The Institute of cortical lesions. For example, man and ape originated Brain”). Oscar Vogt (1870–1959) and his wife Ce´cile from a common ancestor whose upper and lower extre(1875–1962) were invited to participate in this endeavor mities had prehensile functions. For this reason, abnorin 1925. mal plantar reflexes (Babinski’s sign, Rossolimo’s sign, Bekhterev is rightfully considered one of the fathers Mendel–Bekhterev’s sign, Zhukovsky’s sign, etc.) after of Russian neurosurgery. He encouraged one of pyramidal system lesions can be viewed as rudiments his pupils Lyudvig Martynovich Pussep (1875–1941) of the prehensile activities of distant ancestors. In a to become an early Russian surgical neurologist way, Astvatsaturov constructed a bridge between (Lichterman, 1998). In 1897, Bekhterev established an anthropology and neurology. Pyramidal signs, as he operating room in a new building of the neurological envisioned them, might be compared to paleontological clinic at Imperial Military Medical Academy. In 1907 artifacts (Razdol’sky, 1949). For Astvatsaturov, comhe founded Psikhonevrologichesky institut (Institute parative anatomy and physiology were keys for the for Psychoneurology) – “a research and teaching instituanalyses of clinical symptoms. Clinical phenomena tion aimed at development and dissemination of knowlcould also be helpful for elucidating general biological edge in psychology and neurology, and their bordering problems. sciences.” It was the first private university in Imperial Apart from Bekhterev, there were other famous Russia. There Pussep became a professor of surgical pupils of Merzheevsky – professors Blumenau, Shcherneuro(patho)logy in 1910 – the first professor of neurobak and Chizh. Leonid Vasil’evich Blumenau (1862– surgery in the world. 1931) wrote his doctoral thesis K ucheniyu o davlenii Another of Bekhterev’s pupils was Alexei Molotkov na mozg (“Towards Teaching on Pressure on Brain”) in (1874–1950), who organized the Institut khirurgicheskoi 1889. In order to clarify differences of opinion between nevropatologii (Institute for Surgical Neuro(patho) von Bergmann and Adamkiewicz (see below) on the logy) in Leningrad in 1926 (Lichterman, 1998). pathogenesis of elevated intracranial pressure and cereIn 1916, the joint chair of nervous and mental disbral compression, Blumenau carried out his experimeneases at the Imperial Military Medical Academy was tal work on rabbits and dogs. He became a chairman divided into two departments (a chair of nervous disof a chair of nervous diseases of Eleninsky institut usoeases and a chair of psychiatry). Mikhail Ivanovich vershenstvovanija vrachei (Eleninsky Postgraduate Astvatsaturov (1877–1936), also a pupil of Bekhterev, Medical Institute) in St. Petersburg in 1903. His main was elected to a chair of nervous diseases of the Acadwork was Mozg Cheloveka (“Human Brain”; 2nd edn.; emy in 1916, a position he occupied until his death. Five Blumenau, 1925). Blumenau tried to adapt Pavlov’s of the first seven chairs of nervous diseases in Leninideas to clinical practice. He called Pavlov’s works on grad (St. Petersburg was renamed Petrograd in 1914 higher nervous activity “a bridge over an abyss” (he and then Leningrad in 1924) were headed by Astvatsameant bridging mind and body). In his work Isteriya I turov’s coworkers and pupils. ee patogenez (“Hysteria and its Pathogenesis”), BlumeAstvatsaturov also authored a textbook of nervous disnau viewed the problem of hysteria from a reflex standeases, which went through eight editions, (Astvatsaturov, point (as prevalence of cortical inhibition). Beginning

A HISTORY OF RUSSIAN AND SOVIET NEURO(PATHO)LOGY in October 1926, Blumenau was a consultant neurologist at the Institute of Surgical Neuro(patho)logy. Alexander Efimovich Shcherbak (1863–1934) is considered a founder of Soviet physiotherapy (Likhterman, 1963) (Fig. 45.11). He graduated from the Imperial Military Medical Academy in 1883 and started to work at Merzheevsky’s clinic. In 1890, he defended his dissertation “On Dependence of Phosphor Metabolism on Increased and Weakened Brain Activity.” Afterwards he was sent abroad for several years and worked in the laboratories and clinics of du BoisReymond, Flechsig, Wundt, Charcot, etc. On his return he was elected to the chair of nervous and mental diseases at Warsaw University. In 1910 he retired from the university and in the next year moved to Sebastopol. In 1914 he became a director of a newly founded Institut fizicheskikh metodov lecheniya (Institute for Physical Therapy) in Sebastopol, which he headed until his death. In 1921 this institute was named after Ivan Mikhailovich Sechenov (1829–1905) – a Russian physiologist whose ideas Shcherbak applied to physical therapy. In

Fig. 45.11. Alexander Efimovich Shcherbak (photograph c. 1930).

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1863, Sechenov published his famous popular book Reflexy golovnogo mozga (“Reflexes of the Brain”) and was accused of propagating nihilism (initially Sechenov named his book Popytka vvesti fiziologicheskie osnovy v psikhicheskie protsessy, meaning “An Attempt to Introduce Physiological Foundations into Psychic Processes,” but due to censorship pressure the title was changed to “Reflexes of the Brain”). As Shcherbak wrote in 1921: As we know, Sechenov’s “brain reflexes” and “centers of inhibition” became popular among the lay public and even have become household words. Nevertheless the idea of “reflex nature” of higher psychic activity in the 1860s seemed seditious. It was viewed as a blow to the officially approved Weltanschauung (world outlook). This was the main reason why Sechenov was persecuted. As always happens, persecutions could not abolish the idea. On the contrary, it flourished in the works of other Russian scientists: the greatest modern physiologist I.P.Pavlov and his school, and also the greatest neurologist V.M.Bekhterev and his pupils (Shcherbak, 1927, p. 15; also cited by Likhterman, 1963, p. 387). Shcherbak put forward two hypotheses to explain the actions of different physical factors on the human body – an hypothesis of biological resonance and an hypothesis of reflex action. The first hypothesis tried to explain the elective action of different physical factors. He suggested that “biological resonance” might be a mechanism of adjustment of an organism to environment. According to Shcherbak only such an energy that evokes a resonance might be absorbed by a body. This might explain electivity of all agents of physical therapy. Those physiological systems and tissues, whose resonances coincide with oscillations of external stimuli, become a target for elective (preferential) action. The idea was to explain how physical therapy triggers regulatory physiological systems. Unfortunately the hypothesis of biological resonance was not tested experimentally (Likhterman, 1963). Perhaps it may serve as an example of an idea ahead of its time. The hypothesis of reflex action implied that different physical agents provoke reflexes by irritation of nervous endings in different tissues (skin, mucosa, vascular walls, etc.). Shcherbak discovered the importance of some skin zones. Irritating these areas elicits a marked reflex response from certain inner organs. He described two special functional systems, which were called “cervical vegetative apparatus” and “lumbosacral vegetative apparatus.” His last monograph was dedicated to the role of vegetative neurology for physiotherapy (in the

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English literature, the term “autonomous nervous system” is used instead of “vegetative nervous system”). Shcherbak’s ideas were further developed at the Sechenov Institute for Physical Therapy (which moved to Yalta in 1945) by his pupils, including Professor Boleslav Vladimirovich Likhterman (1902–1967) who headed the neurological clinic at this institution (Fig. 45.12). One of the streets in Sebastopol is named after Shcherbak. Another pupil of Merzheevsky was Vladimir Fedorovich Chizh (1855–1922?), who became a chairman of a chair of nervous and mental diseases of Yurjev (now Tartu, Estonia) University in 1891. He is known for his works on neurasthenia and for his pathobiographies of Russian writers Nikolay Gogol and Fedor Dostoevsky (Sirotkina, 2002). Some Russian doctors who were non-neurologists also contributed to clinical neurology. For example Dr. Vladimir Kernig (1840–1917), an internist from St. Petersburg, described a test known as Kernig’s sign. A patient lies supine with his thigh flexed, so that it is at a right angle to the trunk. If the leg cannot be completely extended at the knee joint due to pain, this is Kernig’s sign. It is a characteristic of meningitis.

Neurological chairs, periodicals and meetings prior to 1917 There were 16 chairs for nervous and mental diseases in Russia before the October Revolution of 1917, in Kazan, Kiev, Kharkov (two chairs), Moscow (two chairs), Tomsk, Odessa, Perm’, St. Petersburg (four chairs), Saratov, Warsaw (the Warsaw University was evacuated to Rostov-on-Don during World War I), and Yurjev (the Yurjev University was evacuated to Voronezh during World War I). There were about 300 neurologists and 1000 neurological beds in 1916 (Khoroshko, 1947).

Eight neuropsychiatry periodicals were published in Imperial Russia: 1. Arkhiv psikhiatrii, nevrologii i sudebnoi psikhopatologii (“Archive of Psychiatry, Neurology and Forensic Psychopathology”) (Kharkov, 1883–1899). 2. Nevrologichesky Vestnik (“Neurological Herald”) (Kazan, 1893–1918). 3. Vestnik klinicheskoi I sudebnoi psikhiatrii I nevropatologii (“Herald of Clinical and Forensic Psychiatry and Neuro(patho)logy”) (St. Petersburg, 1883–1899). 4. Voprosy nervno-psikhicheskoi meditsyny (“Problems of Neuropsychiatry Medicine”) (Kiev, 1896–1905). 5. Obozrenie psikhiatrii, nevrologii I eksperimental’noi psikhologii (“A Review of Psychiatry, Neurology and Experimental Psychology”) (St. Petersburg, 1896–1916). 6. Zhurnal nevropatologii in psikhiatrii im. S.S. Korsakova (“The S.S. Korsakov Journal of Neuro (patho)logy and Psychiatry”) (Moscow, 1901– 1917; the publication resumed in the 1920s but the name of Korsakov was deleted from the journal title for ideological reasons in 1931 and was returned to the journal two decades later). 7. Voprosy psikhiatrii I nevrologii (“Problems in Psychiatry and Neurology”) (Moscow, 1912– 1914). 8. Psikhiatricheskaya Gazeta (“Psychiatric Newspaper”) (Petrograd, 1914–1918). The first congress of Russian psychiatrists took place in Moscow in 1887. In 1911, the First Congress of the Russian Union of Psychiatrists and Neuro(patho) logists, presided over by V.K. Roth, gathered in Moscow. There were 280 participants.

Polish neurology

Fig. 45.12. Boleslav Vladimirovich Likhterman (photograph c. 1940).

At the end of the 18th century, Poland was divided between Austria, Prussia, and Russia. Polish and Russian neurology were closely related, and many Polish neurologists trained and worked in the Russian Empire. The history of Polish neurology was reviewed by Eufemiusz Herman (1975). An interested reader will find a detailed account of Polish neurological schools, societies, and congresses in Herman’s book. The author also describes the development of other neurosciences in Poland, including neuroanatomy, neurophysiology, neurogenetics, general and pediatric neurology, and neurosurgery. In addition, more than half of this book is dedicated to biographies of famous Polish neurologists of the 19th and 20th centuries.

A HISTORY OF RUSSIAN AND SOVIET NEURO(PATHO)LOGY 749 One of the most important Polish neurological conThe growth of neurological care tributions was made by Albert Adamkiewicz (1850– By 1940, the number of neurologists had increased 1921), who worked at Jagellonian University in almost 10-fold from the pre-revolutionary period. StaKrakow. In his study, Die Blutgefasse des menschlitistics from 1940 show there were 3213 neurologists in chen Ruckenmarke (“Blood Vessels of Human Spinal the USSR at that time (Brusilovsky and Davidenkov, Cord”), which was published in two parts in 1881– 1961), along with 8549 neurological beds (Khoroshko, 1882, he gave descriptions of spinal cord blood vessels, 1947). There were more than 100 neurological clinics anastomoses, aneurisms, vertebral fractures, and disloand hospital departments in 1947 (Khoroshko, 1947). cations (Adamkiewicz 1881, 1882). He showed spinal By 1957, there were 87 chairs of neurology – 76 at cord vascularization in a memorable series of colored medical institutes (medical faculties of universities anatomical plates. Adamkiewicz demonstrated the became independent medical institutes around 1930), reduction in radicular arteries by injecting colored soluand 11 chairs at postgraduate medical institutes (Kholotions into the vessels. He named them aa. spinales, and denko, 1958). By 1959, the number of neurologists had gave a detailed description of anterior and posterior risen to 9850 (2.6% of the total number of Soviet phyradicular arteries. The number of aa. spinales antesicians; see Brusilovsky and Davidenkov, 1961). riores varied from 3 to 13. He always noted one large Several research neuropsychiatry institutes were vessel in the lower part of the spinal cord, and he organized in the 1920s and 1930s. These included the called it arteria magna spinalis. It is this artery that Bekhterev Psychoneurology Institute and the Institute was later named after Adamkiewicz in French literafor Surgical Neurology in Leningrad, the Institute of ture (Lichterman, 2000). Brain, the Institute of Higher Nervous Activity of the Communist Academy, the Central Research Institute SOVIET NEURO(PATHO)LOGY for Neurosurgery, and the Neurology Department of The year 1917 was a turning point in Russian and world the All-Union Institute of Experimental Medicine (the history. Two revolutions occurred within the year. On department was transformed in 1944 into the Institute 27 February 1917 (12 March on the Gregorian calendar), of Neurology) in Moscow, the Ukranian PsychoneurolCzar Nicolas II (1868–1918) abdicated the throne and ogy Academy in Kharkov, and the Sechenov Institute Russia was proclaimed a republic. Then, on 25 October for Physical Therapy in Sebastopol (see above). Addi(7 November on the Gregorian calendar), the power tionally, more than 200 neurological books were pubwas seized by bol’sheviki, led by Lenin (Vladimir Il’ich lished during the 25-year period from 1917 to 1942 Ul’yanov, 1870–1924) and Leo Trotsky (Lev Davidovich (Propper-Grastchenkov, 1942). Bronstein, 1879–1940). The First All-Union Congress of Neuropathologists Despite hunger, civil war, and economic collapse, and Psychiatrists took place in Moscow in December there were revolutionary changes made in all spheres 1927. It gathered about 750 participants (288 neuroloof life. In 1918, Narodny commissariat zdravookhranegists and 475 psychiatrists). The main topics included nija RSFSR (The Ministry of Health of the Russian prophylactics and organization of neurological care, Soviet Federal Socialist Republic) was established. It exogenous nervous and mental diseases, neurosyphilis, was headed by Lenin’s ally, Nikolai Semashko (1874– epilepsy, and visceral signs of organic neuropsychiatry 1949). For the first time in the Western world, both diseases. It was decided to form local commissions to abortions (in 1920) and active euthanasia (physicianfight against epilepsy. assisted suicide; in 1922) were legalized. Problems with neurological care are revealed in The number of medical doctors increased five-fold unpublished records of the Second All-Union Conduring the 20-year period from 1917 to 1937. The Union gress of Neurologists and Psychiatrists, which took of Soviet Socialist Republics (USSR) soon became the place in Moscow in December 1936 and was attended country with the second-largest number of physicians by 1800 specialists (Gosudarsvenny arkhiv Possiiskoi in the world, exceeded only by the United States. In Federatsii [State Archive of Russian Federation; the second half of the 20th century, the USSR would GARF], Fond 8009, opis 1, delo no. 47, list 119). There become the world leader for the number of medical were four main topics: (a) organization of neuropsypractitioners. In 1986, it boasted 1 202 000 physicians chiatric care, (b) neurotrauma, (c) brain tumors, and and 3 227 000 nurses. The medical doctors were now (d) diagnosis and treatment of schizophrenia. It was mostly women. Before the October Revolution of decided that neurology should be taught to the 1917, female doctors comprised about 10% of the total fourth-year medical students (60 h of introduction to number of physicians; by 1937 their share had increased clinical neurology) and fifth-year medical students to almost half (Strashun, 1937). (10 h of clinical neurology).

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According to the Ministry of Health, neurological care was insufficient. There were 4237 neurological beds in the Russian Federation, which comprised only 2% of the total number of hospital beds. Almost half of them were concentrated in the Moscow and Leningrad regions. There were 1158 neurologists in the Russian Federation in 1936 – a 3-fold increase compared to 309 specialists in the Russian Empire in 1916. But this number was still seen as inadequate (GARF, Fond 8009, opis 1, delo no. 47, list 157). During the interwar period, neurology itself was fragmented into “daughter specialties.” These subspecialties included neurosurgery, pediatric neurology, occupational neurology, neuromorphology, vegetoneurology, etc. Hereditary disorders of the nervous system were investigated by Sergei Nikolaevich Davidenkov (1880– 1961), who published a first book on this subject in 1925 and created a school of genetic neurologists. In his book, Evolutsionno-geneticheskie problemy v nevropatologii (“Problems of Evolution and Genetics in Neuro(patho)logy”; Davidenkov, 1947), Davidenkov described symptoms of hereditary diseases, scapuloperoneal amyotrophy, a painful form of hypertrophic neuritis, latent forms of myopathy, Friedreich’s ataxia, etc. He recommended treatment of myopathy by X-ray irradiation. Davidenkov organized medico-genetic consultations in Leningrad. However, his research was severely criticized when genetics was declared a “bourgeois pseudoscience” and officially prohibited after a special session of the Academy of Agricultural Sciences of USSR in 1948. All activity in the field of medical genetics was halted until the 1960s. Nikolai Vasil’evich Konovalov (1900–1966) investigated clinics, pathogenesis and treatment of hepatolenticular degeneration (Wilson–Konovalov disease in Russian literature). Neurosurgery had a strong impact on the development of Soviet neurology (Propper-Grastchenkov, 1942). The problem of brain tumors also stimulated interest among those investigating cerebral localization. Two pupils of Lazar’ Minor (see above), Mikhail Borisovich Krol’ (1879–1939) and Vasily Vasil’evich Kramer (1876–1935) (see Fig. 45.6), helped to advance the field. Krol’ described semiology of aphasias, agnosias, and apraxias, whereas Kramer published a book, Uchenie o lokalizatsiyakh: Golovnoi mozg (“Teaching on Localizations: Brain”) (Kramer, 1929). Infections of the nervous system were among the key problems in the 1920s and 1930s. There was a burst of epidemic encephalitis during the Civil War of 1918– 1920. The clinical picture, pathology, and sequelae (postencephalitic parkinsonism and dystonias) of epidemic encephalitis were investigated by Soviet

neurologists. These neurologists were cut off from foreign neurological literature and had to work independently of their Western European colleagues. In 1935 a neurologist, A.G. Panov, described a specific infection among those who worked in coniferous forest taiga in the Russian Far East (seasonal or taiga encephalitis). This encephalitis had a seasonal character (new cases appeared mainly in May and June). Within 5 years, the joint efforts of clinicians, pathologists, parasitologists, and virologists resulted in considerable knowledge about the clinical picture. They made advances in the diagnosis, pathology, epidemiology, therapy, and even immunization against a new disease, one now called “tick-borne encephalitis” (Davidenkov, 1942). Occupational disorders of the nervous system and neurotoxicity were studied by several Soviet neurologists. Vegetative disorders (autonomous dysfunctions) also attracted considerable attention. Alexander Mikhailovich Grinshtein (1881–1960) described cortical centers of the vegetative (autonomous) nervous system in his seminal book Puti I tsenry nervnoi sistemy (“Pathways and Centers of Nervous System”) (Grinshtein, 1946). He studied causalgia and reflex traumatic syndromes and suggested treating these disorders with preganglionic sympathectomy. In 1944, the All-Union Neurosurgical Council recommended this method as the best way to treat severe causalgia. He also described a sudden feeling of hunger as a possible epileptic aura. In his laboratory, he further showed that experimental lesions in the hypothalamic region could result either in hyperthermia or hypothermia, depending on the lesion location. This was later confirmed by John Fulton in the United States.

Neurology in the Great Patriotic War (1941–1945) Neurological activity during the Great Patriotic World War II was almost totally dedicated to neurotrauma. It included the timing of surgeries for peripheral nerve injuries, managing open head injuries, intracarotid injections of penicillin in post-traumatic cerebral infections, indications for closure of traumatic skull defects, and surgical treatment of causalgia, etc. (Grinshtein, 1946; Khodos, 1965). The wartime neurological experience was summarized in four volumes (vols. 4, 5, 11 and 26) of the 35-volume edition of the Opyt sovetskoi meditsyny v Velikoi Otechestvennoi voine 1941–1945 godov (“Experience of Soviet Medicine in Great Patriotic War 1941–1945”; 1951–1953) and in many monographs. During the war and immediate post-war period neuropsychology became an independent branch of

A HISTORY OF RUSSIAN AND SOVIET NEURO(PATHO)LOGY psychology (Luria, 1979). Alexander Romanovich Luria (1902–1977), who is considered by many to be one of the founders of neuropsychology, authored two books based on wartime experiences. One was Travmaticheskaya afazia (“Traumatic Aphasia”; 1947, English edition, 1970), and the other was Vosstanovlenie funktsy posle voennoi travmy (“Restoration of Brian Functions after War Trauma”; 1948, English edition, 1964). Throughout his life Luria developed the ideas of his teacher Lev Semenovich Vygotsky (1896–1934) (Luria, 1979; Homskaya, 2001). Vygotsky wrote that “Marxist psychology is a synonym of scientific psychology in general” (Arkhiv RAN [Archive of Russian Academy of Science], Fond 350, opis 2, delo no. 337, list 71). According to Loren R. Graham, Vygotsky’s effort to show the importance of sociocultural context for a theory of mind was based on the Marxist concept that ‘being determines consciousness’ [. . .] He advanced a brilliant theory of psychology in which social influences, and, particularly, the theories of Marxism, played central roles. This fact is a valuable antidote to the common Western view that the influence of Marxism on Soviet science has been uniformly destructive (Graham, 1993, p. 104 and p. 108). Disintegration of higher psychic functions due to head injuries demonstrated interplay of biological and social factors and enabled Luria to explain basic mechanisms of cerebral organization of human behavior.

The Pavlovian session of the two academies (1950): impact on clinical neurology The idea of nervism was already popular in Russian physiology and medicine in the 19th century (see above). According to Pavlov, who introduced this term in 1884, nervism is “a direction in physiology which tends to extend the influence of the nervous system upon the maximum number of activities of the organism” (Pavlov, 1951, p. 197, translated by Boleslav Lichterman). According to Minor, “the impact of the nervous system on the whole organism is so great that any disease is a nervous disease at the same time” (cited by Bobrova, 1955, p. 10, transl. B. Lichterman). The concept of nervism was fitted to Communist Party ideology – in fact, the very idea of the nervous system regulating all body functions was similar to how communism was penetrating all aspects of Soviet society. At the same time (late 1940s–early 1950s), Virchow’s cellular theory was severely criticized in the USSR. It was claimed that Virchow struggled throughout his life against the idea of subordination of cells

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and tissues to the nervous system, calling such ideas “oligarchic” (Lichterman, 2003). In the early 1950s, Virchow’s cellular theory was declared antiscientific, metaphysical, and even anti-Pavlovian. The more “democratic” ideas of cellular theory would not be tolerated in the Soviet totalitarian state. A “Scientific Session, Dedicated to the Problems of the Physiological Teaching of Academician I.P. Pavlov,” was organized by the Academy of Sciences of the USSR and the Academy of Medical Sciences of the USSR under the initiative of Stalin (Grigor’yan, 1999). It took place from 28 June to 4 July 1950 in Moscow. Many physiologists (L.O. Orbeli, L.S. Shtern, I.S. Beritashvili [J. Beritoff], P.K. Anokhin, etc.) and some neuropsychiatrists (A.S. Shmaryan) were severely criticized for their “anti-Pavlovian” views. These “renegades” were fired from their high-ranking positions after the session. Soviet neurophysiology was firmly set against capitalist models. For example, the theory of chemical conduction of nervous impulses (developed by Dale, Loewi, Nachmanson, and others) was branded a “reactionary theory that needs to be smashed up” (Grigor’yan, 1999). In October 1951, there was a joint meeting of the presidium of the Academy of Medical Sciences of the USSR and plenum of the board of the All-Union Society of Neuro(patho)logists and Psychiatrists to examine the fulfillment of recommendations of the Pavlovian session. Their recommendation was to treat nervous diseases (including organic cases and head injury) by prolonged sleep (for “protective inhibition of reflexes”). Sadly, many head-injured patients died of undiagnosed intracranial hematomas as a result of such “treatments.” The Pavlovian session that took place at the height of the Cold War clearly led to the further isolation of Russian neurology. “The river of European civilization” shifted westward again.

Neurological textbooks and societies There were many textbooks on nervous diseases published during the Soviet era. They include a textbook edited by G.I. Rossolimo (1930, 3rd ed), a two-volume textbook by M.B. Krol’, M.S. Margulis and N.I. Propper-Grastchenkov (1939), a textbook by M.I. Astvatsaturov (1939), one by E.K. Sepp, M.B. Tsuker and E.V. Schmidt (1950), and one by Kh.G. Khodos (1948). In addition, a Mnogotomnoe rukovodstvo po nevrologii (Multivolume Manual on Neurology, 1955–1962) was published in eight volumes between 1957 and 1963. Today there are two major neurological periodicals in Russia: Zhurnal nevrologii in psikhiatrii im. S.S. Korsakova (published monthly) and Nevrologichesky zhurnal (6 issues per year).

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The All-Union Society of Neuro(patho)logists and Psychiatrists was established in 1936. In the early 1990s, it was split into two separate societies, one for neurologists and the other for psychiatrists. The former launched the Vserossiiskoe obshestvo nevrologov (VON) (All-Russian Society of Neurologists), which today has 74 branches and about 7000 members. The total number of neurologists in Russia is about 20 000. In 2001, the number of inpatient neurological beds was 80 394 (Lichterman, 2001). VON organizes congresses every 5 years. The 9th All-Russian Neurological Congress took place in Yaroslavl’ in May–June 2006, and had about 2000 participants (Lichterman, 2006). Within the framework of VON there are several specialized societies. Among them are the National Association Against Stroke, the Russian League Against Epilepsy, the Russian Society Against Headache, and the Society for Sleep Studies. Licenses for practicing neurology are not issued by these neurological societies. Instead, they are granted by the Russian healthcare authorities. The majority of Russian neurologists now work in state-run hospitals and outpatient clinics, and are not required to obtain individual licenses. Medical graduates must have a 1-year internatura (internship) in neurology, in order to obtain their certificates to practice as neurologists. Neurological residency programs are still non-existent.

SUMMARY This synopsis of Russian neurology is obviously not exhaustive. It was not written to examine the final decades of the Soviet Union in detail, but rather to concentrate on the earlier, more formative years of the discipline in Russia and the Soviet Union, including some of the most influential figures of those times. As the reader has seen, neurology has had a colorful history in this part of the world, which has produced some of the internationally recognized giants in this field. It is hoped that this part of the world will be viewed as fertile ground for more detailed studies, both of the people and institutions that have played significant roles in the region’s neurology, and of the political, cultural and social conditions behind the neurological sciences and medical care.

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T.II [Voprosy obshei I klinicheskoi nevropatologii. Trudy nevropatologov Leningrada. T.II ¼ Problems of General and Clinical Neuro(patho)logy. Proceedings of Leningrad Neuro(patho)logists. Vol. 2]. Gosudarstvenny institut usovershenstvovanija vrachei im. S.M. Kirova, Leningrad, pp. 362–368. Poccoлимo ГИ (Peд.) [Rossolimo GI (Ed.)] (1930). Кypc нepвньIx бoлeзнeй [Kurs nervnykh boleznei ¼ The Course of Nervous Diseases]. 3rd edn. Gosizdat, Moscow – Leningrad. Ceпп EК, Цyкep MБ, Щмидт EB [Sepp EK, Tsuker MB, Schmidt EV] (1950). HepвньIe бoлeзни. Yчeбник [Nervnye bolezni. Uchebnik ¼ Nervous Diseases. A Textbook]. 4th edn. Medgiz, Moscow. Шepбaк AE [Shcherbak AE] (1927). O peфлeкcax гoлoвнoгo мoзгa и эндoгeнньIx oшyшeнияx [O refleksakh golovnogo mozga I endogennykh oshsheniyakh ¼ On Brain Reflexes and Endogenous Perceptions]. Izvestiya Gos. Inst. Fizich. Metodov Lechehniya im. Sechenova, Sebastopol, Vol. 1:15–42. Шeндepoвич ЛM [Shenderovich LM] (1956). MaтepиaльI к иcтopии oтeчecтвeннoй нeвpoпaтoлoгии [Materialy k istorii otechestvennoi nevropatologii ¼ Materials for a History of Russian Neuro(patho)logy]. Arkhangelsk. A manuscript of a habilitation thesis at the Central Medical Library, Moscow. Шeндepoвич ЛM [Shenderovich LM] (1962). Oчepки paзвития oтeчecтвeннoй нeвpoпaтoлoгии [Ocherki razvitija otechestvennoi nevropatologii ¼ Sketches of Development of Russian Neuro(patho)logy]. Krasnoyarskoe knizhnoe izdatel’stvo, Krasnoyarsk. Sirotkina I (2002). Diagnosing Literary Genius: A Cultural History of Psychiatry in Russia, 1880–1930. Johns Hopkins University Press, Baltimore, MD, pp. 23–35. Cтpaшyн ИД [Strashun ID] (1937). Coвeтcкий вpaч [Sovetsky vrach ¼ A Soviet Physician]. Profizdat, Moscow. Цyкep MБ [Tsuker MB] (1967). Paзвитиe дeтcкoй нeвpoлoгии в CCCP [Razvitie detskoi nevrologii v SSSR ¼ Development of pediatric neurology in the USSR]. Zh Nevropato Psikhiatr 67: 1650–1652. Victor M, Yakovlev PI (1955). S.S. Korsakoff’s psychic disorder in conjunction with peripheral neuritis. Neurology 5: 394–406. von Bechterew W (1894). Die Leitungsbahnen in Gehirn und Ru¨ckenmark. Besold, Leipzig. von Bechterew W (1908–1911). Die Funktionen der Nervencentra. Bd. 1–3. Fischer, Jena. Yakovlev PI (1970). Vladimir Bekhterev. In: W Haymaker, F Schiller (Eds.), The Founders of Neurology. CC Thomas, Springfield, IL, pp. 167–171. Юдин TИ [Yudin TI] (1951). Oчepки пo иcтopии oтeчecтвeннoй пcиxиaтpии [Ocherki po Istorii Otechestvennoi Psikhiatrii ¼ Sketches of a History of Russian Psychiatry]. Medgiz, Moscow.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 46

Neurology and traditional Chinese medicine NAI-SHIN CHU * Department of Neurology, Chang Gung Memorial Hospital and Chang Gung University, Taipei, Taiwan

INTRODUCTION Traditional Chinese medicine has a history as ancient as Ayurvedic medicine in India, dating back to around 3000 BC, when Shen Nung (the Divine Husbandman) and Huang Di (the Yellow Emperor) were reputed to have established the ancient medicine of China (Wong and Wu, 1936; Chen, 1937; Lee, 1940; Shi, 1984). The historical events attributed to these two figures are considered legendary or symbolic. Shen Nung taught his people to cultivate crops and he tasted hundreds of plants, and even got intoxicated several times a day, in order to find those suitable for medicinal use. Consequently, Shen Nung has been worshiped as the founder of Chinese medicine. The Yellow Emperor’s name was associated with the earliest Chinese medical classic, Huang Di Nei Ching (Yellow Emperor’s Classic of Internal Medicine or Canon of Medicine). It was a collective work of the physicians of the Warring States (401–250 BC), using the Emperor’s name to enhance the authority of the book (Nei Ching, c. 300 BC). Huang Di Nei Ching or Nei Ching had a profound influence on the medical thought and attitude of traditional Chinese medicine. Nei Ching consists of two parts: one is Su Wen (Plain Questions), comprising questions and answers between the Yellow Emperor and his minister, Chi Po, whose conversations involved health and disease, more philosophical than medical; another is Ling Shu (Mystical Gate), which mainly dealt with acupuncture, but also covered anatomy, physiology and pathology. Nei Ching is considered the Bible of traditional Chinese medicine. Despite its antiquity, its concepts of health and disease are today still revered and followed by physicians of Chinese medicine. One characteristic of traditional Chinese medicine is that it is organ-oriented (Li, 1575; Wong and Wu, 1936).

*

The organs of main concern are the heart, liver, spleen, lungs, and kidneys. The brain was not considered an organ, but as atypical hollow viscera called the “sea of the marrow” (Wong and Wu, 1936; Chen, 1937; Shi, 1984). The nerves were not identified and muscle was considered a tissue. Consequently, five main organs took over the functions of the brain. Hence, the history of neurology in Chinese medicine is unusual and different from Western medicine. Nevertheless, it is interesting to explore the long history of Chinese medicine to see how brain functions were perceived and where they were placed, as well as to see how some neurological diseases could be identified and even successfully treated, with the nervous system basically ignored. Equally interesting is the history of how the rich Chinese materia medica contributed to neuropharmacology.

TRADITIONAL CHINESE MEDICINE The foundations of Chinese medicine were laid down at about the times of Hippocrates and Aristotle in Ancient Greece, approximately a few hundred years before the time of Christ (Table 46.1). When Chinese medicine was at its zenith in the Han dynasty, Galen, who lived in the second century, was dominating Western medicine. The most important works in Chinese medicine were completed shortly after the end of the Han dynasty. These works include Nei Ching (Nei Ching, c. 300 BC), Treatise on Febrile Diseases (204 AD) by Chang Chung-ching, Pulse Classic (265 AD) by Wang Shu-ho, and Systematic Manual of Acupuncture (259 AD) by Huang Fu-mi (Wong and Wu, 1936; Lee, 1953a, b; Shi, 1984). Chinese medicine gradually began to decline after the so-called Golden Age, dating from the Han dynasty to the Tang dynasty. The last great work was Pen Tsþo Kang Mu (The Great Herbal ), by

Correspondence to: Nai-Shin Chu MD, Department of Neurology, Chang Gung Memorial Hospital, 199 Tung-Hwa N Road, Taipei 10591, Taiwan. E-mail: [email protected], Tel: þ886-3-3281200, ext 8417, Fax: þ886-3-3287226.

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Table 46.1 Outline of Chinese dynasty in relation to important figures of Chinese medicine and Western medicine Year

Dynasty

2800 BC 2200–1100 BC 1027–771 BC 770–402 BC 401–256 BC 221–206 BC 206 BC–220 AD

Xia, Shang Chou Spring & Autumn Warring States Ch’in Han

265–419

Wei, Chin

420–589 581–618 618–907 960–1279 1271–1368 1368–1644 1644–1911

North and South Sui Tang Sung Yuan (Mongol) Ming Ch’ing

Chinese medicine

Western medicine

Shen Nung (Founder of medicine)

Confucius Yellow Emperor’s Canon Pien Chı´ao (God of medicine) Pen Tsa´o (The Herbal) Chang Chung-ching (Chinese Hippocrates) Hua To (God of surgery) Wang Shu-ho (Pulse classic) Huang Fu-mi (Acupuncture classic)

Li Shih-chen (The Great Herbal)

Hippocrates Aristotle Dioscorides* (materia medica) Galen

Vesalius

*Pedanius Dioscorides (c. 40–90) was an Ancient Greek physician, pharmacologist and botanist. He wrote a five-volume De Materia Medica, which is a precursor to all modern pharmacopeias and one of the most influential herbal books in history.

Li Shih-chen (1578), a contemporary of Vesalius, the great medical figure of the Western Renaissance. The foundations of traditional Chinese medicine are based on the principle of Yin and Yang, the Doctrine of Five Elements, the theory of correspondence between microcosm and macrocosm, and the concept of Qi, the vital energy (Nei Ching, c. 300 BC; Wong and Wu, 1936; Chen, 1937; Shi, 1984). Each deserves mention. The principle of Yin and Yang indicates that the human body, like the universe, consists of a positive force (Yang) and a negative force (Yin). These two forces will confront as well as complement each other. This principle applies not only to anatomy and physiology, but also to symptoms and treatment of diseases. The Doctrine of Five Elements proposes that everything in the human body and in nature belongs to one of the five elements, which are represented by metal, wood, water, fire, and earth. From this doctrine evolved the five organs (heart, liver, spleen, lungs, and kidneys), five emotions (joy, anger, sorrow, worry, and fear), five climatic factors (heat, wind, humidity, dryness, and cold), and so forth (Table 46.2). It should be noted that the five organs govern some brain functions, such as emotions and perception. Health or disease depends upon the complex synergism and antagonism of five elements and their representations.

The idea of correspondence between microcosm and macrocosm holds that human beings are also governed by the rules that govern nature. Therefore, the phenomena occurring inside man can be understood in terms of the phenomena occurring in nature. The cause of disease was categorized into an external cause, i.e., climatic factors of wind, cold, heat, humidity, and dryness; and an internal cause, i.e., emotional factors of joy, anger, worry, sorrow, and fear. Neurological diseases were often considered wind maladies. The concept of Qi and the meridian system proposes that the meridian system carrying Qi and blood has connections with internal organs, and along their courses there are 365 points for acupuncture. Life is maintained by Qi: if Qi is disturbed, disease appears; if Qi is stopped, it is death. Qi may be disturbed by external evil Qi invading the meridian system, or by internal bad Qi, produced by organs. Traditional Chinese medicine is strongly organoriented (Nei Ching, c. 300 BC; Wong and Wu, 1936). The functions of different organs are organized like a government. The heart is the emperor of the body and the seat of vital spirit; the lungs are the ministers; the liver is the general; the pericardium is the ambassador, etc. The five organs control five senses and all parts of the body. For example, the liver has the eye

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Table 46.2 Five organs and their relationships with nature and body functions. Modified from History of Chinese Medicine (Wong and Wu, 1936, p. 20)

Element Planet Climate Emotion Vocalization Taste Odor Color

Heart

Liver

Spleen

Lungs

Kidneys

Fire Mars Heat Joy Laugh Bitter Burned Red

Wood Jupiter Wind Anger Shout Sour Stinking Green

Earth Saturn Humidity Sorrow Sing Sweet Fragrant Yellow

Metal Venus Dryness Worry Weep Pungent Fishy White

Water Mercury Cold Fear Groan Salty Putrid Black

for an opening, and converts the fluid into tears; the heart has the tongue for its opening, and converts the fluid into perspiration.

VIEWS OF THE BRAIN AND NERVOUS SYSTEM IN CHINESE MEDICINE The nervous system was almost completely ignored in traditional Chinese medicine. The brain within the skull was thought of as a reservoir of bone marrow (Fig. 46.1). When it is full, the body feels light and strong, but when it is deficient, symptoms of dizziness, tinnitus, limb aching, blurred vision and tired feelings develop (Nei Ching, c. 300 BC). This orthodox view on the functions of the brain seemed to be related to body energy. In this respect, the brain has functions similar to the kidney, which is the seat of vigor and strength. The spinal cord was considered no more than a canal, and the nerves were not mentioned at all. In contrast, Taoism viewed the brain as an organ with other functions. It is the palace of “nirvana” and the source of seminal essence (Yin, 1615) (Fig. 46.2). Taoism in its original form was pure philosophy and had an influence on the doctrines of traditional Chinese medicine, particularly Yin/Yang and the Five Elements (Wong and Wu, 1936; Chen, 1937; Lee, 1940; Shi, 1984). Some members later ventured into mysticism, occultism, and alchemy. One group of Taoism used charms to cure diseases or to expel demons. Another group studied alchemy and developed ways of cultivating health and prolonging life. Some famous physicians of traditional Chinese medicine were also devoted Taoists, e.g., Ko Hung (281–341 AD) and Sun Si-miao (590–682 AD). The Taoistic art of healing was especially popular in folk medicine. Wang Ching-Jen (1768–1831) of the Ch’ing dynasty had another, different view. He was a physician of Chinese medicine. His anatomical knowledge came from observing the dead bodies torn open by wild dogs

during an epidemic (Wang, 1830). Based upon this observation, he wrote a book called Errors of Medicine Corrected, criticizing the inaccuracy of previous anatomical studies. His criticism earned him the sobriquet “reformer of Chinese medicine” (Chen, 1937; Shi, 1984). In a strict sense, he was not an anatomist, and his anatomical drawings were also plagued by errors and lack of details. Although he did not study the brain, he advocated that the seat of memory and cognition was in the brain, not in the heart (Wang, 1830). His view of the brain is likely to reflect the view of Liu Chi, a Muslim scholar who knew Arabian medicine (Sharpiro, 2003), or the view of Chin Sen, a Catholic Chinese scholar who learned Western medicine from Catholic missionaries (Shi, 1984; Chen, 1992a). Surprisingly, he still considered the brain as the “sea of marrow,” but the marrow came from the purest Qi.

ANATOMICAL DISSECTION IN CHINESE MEDICINE In the long history of Chinese medicine, there were only a few anatomical dissections. Furthermore, postmortem autopsy was practically unheard of. The earliest record of dissection was mentioned in the Ling Shu part of Nei Ching (Huang Di, c. 300 BC, p. 47). It states: It is beyond human ability to measure the height of the sky or the width of the earth. But for an eight feet person it is not difficult to do the surface measurements. After death the body may be dissected and a general idea can be obtained about the consistency, size and capacity of the viscera, the length of the blood vessels, the condition of the blood, and the amount of Qi within the meridian system. It has been noted, however, that the appearances of the organs in the anatomical charts of Ling Shu did not appear to be those of humans, raising the possibility

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that the charts were based on animal dissection, similar to Galen’s anatomical work (Lee, 1940). Although dissection was attempted in ancient times, it was suppressed when Confucianism became dominant in the Han dynasty. The next reference to human dissection occurred in 16 AD, when the Emperor Wang

A

Mang ordered the court physician and a skillful butcher to dissect the body of a political rebel, Wang Sun-ching, after his execution (Wong and Wu, 1936; Lee, 1953b; Chen, 1992b). Measurements were made of the internal organs and bamboo rods were inserted into the blood vessels to ascertain their beginnings

B

Fig. 46.1. Anatomical charts showing the interior view of the human body. (A) An ancient anatomical chart from the book History of Chinese Medicine (Wong and Wu, 1936). The arrow indicates Ming Mon (gate of life), which has connections to the heart, kidneys, and brain. (B) An illustration in the book Yang I Ta Chuan (A Complete Work of Surgery, 1773) by Ku Su-chen of the Ch’ing dynasty (Ku Su-chen, 1773). Continued

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Fig. 46.1 Cont’d. (C) An illustration from the Sung dynasty that was included in the book Complete Medical Works of Library Collections, Ancient and Modern (1726) of the Ch’ing dynasty. These anatomical illustrations are basically similar and were based on the Atlas of Truth, which was compiled by Yang Chien in 1106. The brain was a reservoir of bone marrow called “sea of marrow,” and the spinal cord was a canal.

and ends. Although some have said that the purpose of the dissection was to learn how to “cure diseases,” an alternative explanation is that Emperor Wang Mang ordered it as an additional punishment to the rebel, because mutilating the dead body of an opponent was considered the cruelest of insults in China.

One thousand years passed before another human dissection was recorded, and again on some political rebels, Ou Hsi-fan and his followers (Wong and Wu, 1936; Lee, 1940; Shi, 1984; Chen, 1992b). After these rebels were executed, their abdomens were opened and their kidneys and intestines were cut out. The

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A

B

Fig. 46.2. Anatomical charts from the classic Taoist work Shing Ming Kuei Chi (Supreme Aim of Life, 1615), showing the interior view of the human body. In Taoism, the brain is the palace of Ni Huan, a Chinese translation of the Sanskrit “nirvana.” The brain is also the source of seminal essence. The spinal cord is the channel linking the cavity of the “sea of marrow” with Ming Mon (gate of life) (see arrow), which is situated between the kidneys. The kidneys are organs of vital energy and also genital organs.

doctor and artist examined the body and drew pictures of the organs. A total of 56 persons were examined in 2 days! These dissections resulted in the book Ou Hsi-fan’s Anatomical Pictures, which appeared in 1045. Another occasion for dissection occurred in 1104, when several bandits were executed. The anatomical drawings of this dissection were later edited by an eminent physician, Yang Chieh, who found the anatomical drawings varied only a little from ancient books. Yang Chieh later published the edited drawings as his Atlas of Truth in 1106 (Lee, 1940; Shi, 1984; Chen, 1992b). The anatomical drawings from the earlier three human dissections were lost. Only the Atlas of Truth was preserved, and it became the standard reference of human anatomy, because anatomical dissection was not attempted after the Sung dynasty.

The main reasons for ignoring dissection and anatomy in China are probably: (1) Confucian teachings dictate that the body comes from the parents, and shall not be mutilated, so therefore human dissection is a gross violation of filial piety and is strongly discouraged; and (2) out of respect to ancestors and authority, Chinese physicians were afraid or reluctant to challenge the ancient teachings.

ANATOMY BOOKS IN CHINESE The first human anatomy book in Chinese was written by Jesuit Father Johann Terrenz (1576–1630) in 1597, during the Ming dynasty (Wong and Wu, 1936; Chu, 1996; Sharpiro, 2003). Terrenz was an accomplished chemist, astronomer, and physician. He was a colleague

NEUROLOGY AND TRADITIONAL CHINESE MEDICINE of Galileo, whom he knew from Padua. The book was given the title A Treatise on the Human Body, and was the Chinese translation of the 1597 anatomical text by Casper Bauhin (1560–1624), who wrote in Latin. The book was later edited by Chinese scholar Bi Gongchen and published as Western Views of the Human Body in 1634 (Chu, 1996; Sharpiro, 2003). This book, however, had almost no influence on Chinese medicine. Another attempt at a translation was made by Jesuit Father Dominique Parrenin (1665–1741) during the Ch’ing dynasty (Wong and Wu, 1936; Saunders and Lee, 1981; Chen, 1992a). The famous Emperor Kang Hsi had gathered Catholic missionaries around him because they had cured his malaria and a cardiac palpitation, which the imperial physicians had been unable to do. Emperor Kang Hsi therefore became more interested in Western medicine, and Father Parrenin was offered the honor of teaching Western medicine to the Emperor. He began by teaching anatomy, with an emphasis on the brain and the nervous system. His anatomical lectures were based

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on the French text by Pierre Dionis (1643–1718) titled L’anatomie de l’homme suivant la circulation du sang et les nouvelles decouvertes. Parrenin then decided to translate this text into the Manchu dialect of the ruling class. After five years’ labor, he finished the task and submitted his manuscript to the aged Emperor (Fig. 46.3) (Saunders and Lee, 1981; Chen, 1992a). The work drew opposition from the court physicians and was never printed. The early medical activities of the Jesuits left few permanent traces on traditional Chinese medicine, reflecting how reluctant Chinese physicians were to adopt the principles of European medicine. The medical activities of the Jesuits were also cut short by the dissolution of the Society of Jesus in 1778. After the Opium Wars, the Christian medical missionaries were much more successful than the Catholic missionaries. They established hospitals and even medical schools (Wong and Wu, 1936; Chen, 1992a). One Protestant medical missionary, Dr. Benjamin Hobson (1816–1873), wrote a series of medical textbooks in

Fig. 46.3. Manchu anatomy by Jesuit Dominique Parrenin (1665–1741) who completed the work in 1722. The anatomical work was written in the Manchu dialect of the Ch’ing ruling class (Saunders and Lee, 1981). Although the work was commissioned by the great Emperor Kang Hsi who was interested in Western medicine, it was never printed by the Imperial Press for scientific collections.

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Chinese. His first book was Outline of Anatomy and Physiology (1850). In the foreword, he stated that the anatomical charts of Chinese medicine were grossly inaccurate; if the medical missionaries wanted to introduce Western medicine to China, the first subject should be anatomy. Hobson also contended that the Chinese were wholly ignorant of the nervous system. He was called the first “modern anatomist” in China and his book became so popular that it was reissued several times and even pirated. During the second half of the 19th century, the brain and the nervous system finally became known in China.

NEUROLOGICAL DISEASES IN CHINESE MEDICINE In the early medical treatises, external factors called evil Qi were considered the dominant causes of disease (Nei Ching, c. 300 BC; Shi, 1984). They were wind, cold, heat, humidity, dryness, and fire. Among them, wind was regarded as the major cause of disease, probably because the ancient center of Chinese civilization was in the windswept Yellow River region. This may explain the fact that “wind” maladies were the earliest diseases found in the oracle bones of the Shang dynasty in the 14th century (Lee et al., 1962). Among the earliest wind diseases were some affecting the nervous system. For example, one record showed that King Wu Ting sought oracular guidance for the treatment of his headache. In general, nervous and mental diseases were classified as wind malady in traditional Chinese medicine (Chen, 1937; Shi, 1984). Stroke as Chung Feng was also mentioned in the ancient books. Chung Feng literally means “succumbed to wind,” or “attacked by wind” (Lee et al., 1962). Nervous and mental diseases are prominent in Nei Ching. There are chapters on headache, dizziness, epilepsy, psychosis, delirium, numbness, paralysis, syncope, significance of pain, theory of dreams, and physiology of emotion (Nei Ching, c. 300 BC). Although neurological diseases showed an early prominence, they seemed to fade into minor diseases later, probably because the brain and the nervous system were not really recognized. Still, despite continuing ignorance of the nervous system, several neurological diseases were described. Of these, some were briefly presented, but others were more extensively studied. Contributions to these disorders also came from Chinese materia medica.

Metal and carbon monoxide poisoning Metal and carbon monoxide poisonings were briefly described. An observation in the Sung dynasty reported that workers engaging in plating gold and silver suffered

from shaking of head and hands (Chen, 1937; Shi, 1984). This condition, which was related to occupation, seems compatible with mercury poisoning. A second possibility is lead poisoning, a condition long known to affect metal workers. Carbon monoxide intoxication was reported by Chang Ching-yua, a famous physician of the Ch’ing dynasty, who mentioned that, because of a bitterly cold winter in the capital, charcoal burning in the center of the house with the windows tightly closed often resulted in death (Chang, 1624). The smaller the house and the tighter the windows were closed, the more people would die. If there was a small opening in the roof, or if the windows were not so tightly closed, such tragedies might be prevented.

Tetanus The Chinese word for tetanus is Po Shang Feng, meaning “wind breaks into an open wound.” Tetanus as a disease was already described in Nei Ching and, as the name implies, was definitely a wind disease (Yu, 1930; Chen, 1937; Shi, 1984). The described symptoms of tetanus included fever, headache, neck stiffness, inability to lie down, convulsion, muscular atrophy, and numbness. Chang Chung-ching (160–219 AD), the so-called Chinese Hippocrates, observed that the patient had fever over the whole body except the feet; the pulse was weak and slow; the neck was stiff; the jaw was locked so that the patient was unable to speak; the body was arched backward so that it was impossible for the patient to lie on his back; the wound was very hard to cure; and the longer the wait the more incurable it became, because there was more chance for the wind to penetrate it (Yu, 1930). Physicians of the later Sung dynasty believed that tetanus was caused by poisons, for which they urged the use of lizards, scorpions, silkworms, and horns of antelope (Yu, 1930). They also observed that infants and women after delivery were very susceptible to the disease (Chu, 1280). On account of the good description of this disease in Chinese medicine, Po Shang Feng has become the formal medical term for Western medicine in China and also in Japan.

Epilepsy Epilepsy was also one of the neurological diseases described in Nei Ching. The Chinese translation of epilepsy is Dian, meaning falling sickness, and the epileptic attack is Xian, meaning convulsion (Wang, 1589). However, Dian could also mean psychosis without excitation. Psychosis with excitation is Kwan, meaning madness.

NEUROLOGY AND TRADITIONAL CHINESE MEDICINE The seizures mentioned in most medical books are of the grand mal type. The attacks consist of generalized convulsions with loss of consciousness, frothing of mouth, and vocalization (Wang, 1589; Lee et al., 1962; Lai and Lai, 1991). Compatible with modern definitions of epilepsy, which state that it should be recurrent, Su Wen (Nei Ching, c. 300 BC, p. 395) had the following observation: In the disease of falling sickness (Dian), the attack initially occurs once a year; If not treated, it will occur once a month; If again not treated, then four or five times a month. Status epilepticus was reported by Shen Jin-ao in 1773 as follows: During the attacks, the patient makes unusual noises, and froths at the month. When the patient is about to awaken, the attack begins again, and the cycle occurs again and again and never stops. (Shen, 1773, p. 541) Focal seizure was not recognized. Moreover, the proposed etiologies and mechanisms for seizures were often based upon the doctrines of traditional Chinese medicine: stagnation of phlegm, invasion of evil wind, insufficiency of blood or vital energy, kidney weakness, and, for infants, emotional shock of the mother during her pregnancy (Lai and Lai, 1991).

Leprosy Although a passage in Su Wen has been thought to be leprosy (Wong, 1930), a more likely description of leprosy was given by Ko Hung (283–343) in his book Prescriptions for Emergencies (319 AD, p. 38), which has: The first symptoms of Lai Ping (leprous disease) are numbness of the skin, intolerable itching, or a sensation like worms creeping. The eyesight is blurred, and there are dark scaly skin patches. In Chao’s treatise (610 AD, pp. 10–11), the symptoms were further elaborated: Symptoms of Lai Ping are loss of sensation, absence of sweating, loss of hair and eyebrows, perforating skin ulcers, hoarseness of voice, nasal deformity, distorted ears, deformed fingers, disfigured face, etc. (Fig. 46.4) Further development was noted in the 12th century, when Chen Yeng (1174) proposed that the causes of the disease are: first, wind poison; second, damp poison; and third, infection. His idea of infection was vague, stating that disease is transmitted by blood and Qi. This

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idea seemed to lead, at least eventually, to the popular belief that leprosy could be sexually transmitted. It is interesting to note that the majority of British medical missionaries in China during the 1860s and 1870s still considered leprosy a hereditary disease, doubting the popular Chinese belief that leprosy is contagious (Wong, 1930; Wong and Wu, 1936). A breakthrough in the treatment of leprosy was the introduction of chaulmoogra oil (Li, 1578; Leung, 1999). It was first tried by Chu Tan-chi in the 13th century, who disapproved of this remedy on account of severe side-effects (Chu, 1280). However, the use of chaulmoogra oil became popular in the late Yuan dynasty. Ma Feng, the Chinese name for leprosy, appeared in the early Ming dynasty and was accepted as a proper medical term in the Ch’ing dynasty (Leung, 1999). Ma Feng was categorized as the “disease of surgery” because skin infections, such as abscess and ulcer, were traditionally treated by surgeons.

Beri-beri Jiao Qi disease, the Chinese name for beri-beri, was an endemic disease of the South in the Chinese medieval time (25–900 AD) (Chen, 1992b; Fan, 1995, 2004). Jiao Qi literally means that the symptom starts from foot (Jiao) due to invasion of evil wet wind (Qi). The symptoms of Jiao Qi disease were well described by Chao Yen-feng (610 AD, pp. 58–59) as follows: Jiao Qi disease is caused by poisonous wind. The symptoms start from foot to knee and include numbness, weakness, discomfort sensation like worms creeping; legs are weak and unable to walk, mildly swollen, cold, painful, or difficult to move around. There is difficulty swallowing, vomiting on looking at food, or intolerable of the smell of food. Sometimes, a sensation of gas ascends toward the heart. There is pain of the body and the limbs, hot sensation and headache, or palpitation. There are abdominal pain and diarrhea. There are forgetfulness and non-sense speech. There are mental dullness and blurred vision. If not treated, the disease will ascend to abdomen causing swelling. If the disease ascends to the chest, death may occur. The symptoms described above indicate involvement not only of the legs, but also of the abdomen, heart, and even brain. The mental symptoms resemble those of Wernicke–Korsakoff syndrome.

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A

B

Fig. 46.4. Leprosy patients as depicted in traditional Chinese medicine. (A) A patient taken from a surgery book of the Sung dynasty that was included in Four Literary Treasuries (1772), the famous encyclopedia of the Ch’ing dynasty. The patient shows skin lesions, red eyes, loss of eyebrows, ulcers on the fingers, knees and legs, and loss of fingernails. (B) A patient taken from Yang I Ta Chuan (A Complete Work of Surgery, 1773) of the Ch’ing dynasty. Besides skin lesions, the patient has nasal deformity, blindness, loss of eyebrows, upwarding of lips, and loss of fingernails and toenails. In Chinese medicine, skin disease was often included in surgery books.

By the Ming dynasty, Jiao Qi was recognized to have wet and dry forms (Chen, 1992b). In the wet form, the legs are edematous, and may have ulcers. In the dry form, the legs have spasms and pain, and waste without edema. Although the real cause of this disease was then unknown, the herbs to treat Jiao Qi often contained vitamin B1 (Chen, 1992b). Sun Si-miao (652, 656 AD) recorded that Jiao Qi could be avoided if rice bran was eaten frequently. He also advocated drinking cow’s milk and eating beans. Following these mea-

sures, Jiao Qi was no longer a fatal illness or an endemic disease by the Sung dynasty (Chen, 1992b; Fan, 1995).

ANESTHETICS AND MEDICATIONS General anesthesia A revered story in Chinese medicine had to do with the open abdominal surgery performed by Hwa To under general anesthesia in the 2nd century (Wong, 1927; Chu, 2004). The operations included dissection of

NEUROLOGY AND TRADITIONAL CHINESE MEDICINE 765 gangrenous intestines. Before the surgery, Hwa To disthe influence of Arabian medicine, which excelled in this solved an anesthetic called Ma Fu San (foamy narcotic field. With the collapse of the Yuan dynasty, surgery powder) in wine, which the patient then drank to and orthopedic surgery in particular deteriorated. become “drunk, numb and insensible.” Unfortunately, the composition of the anesthetic powder was not menEphedrine tioned and still remains a mystery. The discovery of ephedrine constitutes one of the The story of Hwa To’s use of Ma Fu San was menmost interesting chapters of modern pharmacology. tioned in two historical books, Chronicle of the Three Ma Huang (Ephedra sinica), a perennial shrub growKingdoms (270 AD) and Annals of the Late Han ing abundantly along the Great Wall of China, had Dynasty (430 AD), but not in the medical books been known in China as a medicinal herb for over (Chu, 2004). Therefore, the reliability of this piece of 4000 years. It was used as a diaphoretic and an medical history has been questioned (Lee, 1940; Lang, antipyretic, and prescribed for fever, cough, influ1982; Chu, 2004). Further, Hwa To has been worshiped enza, and post-partum difficulties (Li, 1578). It was as the god of surgery, largely because of the fabulous the favored herb of Chang Chung-ching (204 AD) to surgical stories in the popular historical novel, treat fever. Romance of the Three Kingdoms (Lee, 1940; Chu, Ephedrine is the principal alkaloid of Ma Huang. 2004). It was isolated in 1887 by Nagai, a Japanese pharmaMore reliable descriptions of general anesthesia cologist of Tokyo University, who named it ephedrine were documented in the medical treatise Effective Pre(Nagai, 1887). In 1923, Chen and Schmidt of the scriptions from Physicians of a Distinguished Medical Peking Union Medical College in Beijing began a Lineage (1337) by Wei Y-lin, a famous orthopedic surmore thorough biomedical investigation, first by geon in the Yuan dynasty (Lee, 1955; Miyasita, 1973; isolating the active compound of Ma Huang, apparShi, 1984). The book contains special chapters on orthoently unaware of Nagai’s work, and then carrying pedics and arrow wounds. In the section on “Method out a series of physiological and pharmacological of administration of an anesthetic” (Wei, 1337, experiments (Chen and Schmidt, 1924). Their results p. 827), we find: indicated that the various effects of ephedrine were When the patient suffers from severe pain due to analogous to those of epinephrine and reminiscent bone fracture and the fracture can not be set, first of the classic, early-20th-century work of the Nobel give him one dose of anesthetic. Wait until he can prize-winning, English pharmacologist, Sir Henry no longer feel pain before performing the operaDale, on the sympathetic amines (Barger and Dale, tion. If the patient still does not lose consciousness, 1910; Chen, 1974). another dose of white datura flower and aconite The work of Chen and Schmidt took North America mixed with good wine should be administered and Europe by storm, because they demonstrated the slowly. If the patient appears intoxicated, stop the fruitful cooperation between empirical Chinese knowladministration. The quantity of white datura and edge on materia medica and Western scientific techaconite should be adjusted to age, state of physical nology (Chen and Schmidt, 1926; Wong and Wu, debilitation, and amount of blood loss. 1936). Furthermore, when compared to epinephrine, ephedrine has three distinct advantages for clinical The above description shows that during the Yuan use: (1) it is orally effective; (2) it has a long duration dynasty general anesthesia was used in the surgical of action; and (3) it has lower toxicity. Subsequently, treatment of bone fractures. General anesthesia was a large amount of Ma Huang was shipped to the US induced by narcotic wine and the anesthetics included for extraction of ephedrine. The demand for Ma white datura flowers, aconite roots, rhododendron Huang was so great as to cause real concern among flowers, and roots of scopolia (Wei, 1337; Lee, 1955; the Chinese about the possible depletion of the plant Miyasita, 1973; Chu, 2004). White datura flower is (Chen, 1974). Fortunately, ephedrine was successfully called Man To Lo Hua (mandrake, mandala flower) synthesized in 1927. in China. It contains scopolamine and a small amount In retrospect, ephedrine, from the Chinese herb of hyoscyamine and atropine. Ma Huang, is one of the drugs that have influenced For surgery under general anesthesia, Chinese medimodern concepts in neuropharmacology. The rise of cine seemed to be ahead of Western medicine by five Ma Huang from obscurity to its present status took litcenturies (Nuland, 1995). Unfortunately, orthopedic surerally the span of Chinese medical history. Ephedrine gery under general anesthesia did not prosper afterhas become one of the most popular sympathomimetic wards in China (Lee, 1955). It was thought that drugs. orthopedic surgery during the Yuan dynasty was under

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NEUROLOGY IN MODERN CHINA Neurology as a branch of medicine was not recognized until after the collapse of the Ch’ing dynasty in 1911. The new specialty of neurology had an early start in China. The first department of neurology was established in Peking Union Medical College Hospital, Beijing, in 1921 (Feng, 1959). However, the development of neurology in other parts of China was slow, beginning in 1933. The Chinese Society of Neurology and Psychiatry was organized in 1952, followed by launching of the Chinese Journal of Neurology and Psychiatry in 1955. During this period, the numbers of physicians engaged in neurology and beds for neurological care had increased several fold (Feng, 1959; Chao, 1965). The period from 1960 to 1976 witnessed the abolition of neurology as an independent department in many hospitals. After 1976, neurology resumed its development, and in the 1980s the tendency to separate neurology from psychiatry became strong, just as was true in the West (Wang, 1995). The Chinese Society of Neurology was finally established in 1993 and the specialized Chinese Journal of Neurology was issued in 1994. Current health policy in China incorporates modern Western medicine and traditional Chinese medicine into a newer system of thought and practice (Kao, 1973). Special attention is paid to medical care in rural areas, occupational diseases, nutritional problems, and parasitic diseases, for reasons that are self-explanatory. In neurology, efforts are directed to handle common neurological diseases, to emphasize preventive medicine through epidemiological investigations, and to grow scientifically by specializing in various neurological fields (Wang, 1995).

CONCLUSIONS Traditional Chinese medicine had ignored the brain from the beginning, and continued to do so for over 2000 years, until Christian medical missionaries succeeded in establishing Western medicine in China after the Opium Wars. Early attempts by the Catholic missionaries to introduce Western medicine, particularly anatomy and physiology, left few permanent traces. Knowledge of the nervous system is minimal and erroneous in traditional Chinese medicine. The brain is a reservoir of bone marrow, the spinal cord a canal, and the nerves unidentified. This lack of knowledge about the nervous system stemmed largely from the fact that dissection of the human body was not emphasized and was even discouraged. Nevertheless, traditional Chinese medicine made several contributions to neurology, mainly the identification of some neurological diseases and the discovery

of drugs from the rich Chinese materia medica. Among neurological diseases, leprosy and beri-beri were beautifully described and effectively treated. Further, general anesthesia was used in orthopedic surgery in the 14th century, and ephedrine was isolated from the Chinese herb Ma Huang and opened a new perspective for neuropharmacology. In modern China, neurology as a medical specialty was established in 1921. The health policy of the government has largely been to integrate modern Western medicine and traditional Chinese medicine. The new combined approach is interesting and important, and should be closely followed by historians of medicine and practitioners of the art.

REFERENCES Barger G, Dale HH (1910). Chemical structure and sympathomimetic action of amines. J Physiol 41: 19–59. Chang CC (204). Shang Han Lum (Treatise on Febrile Diseases). Commercial Press, Shanghai, 1955. Chang CY (1624). Ching Yueh Chuan Shu (Ching Yueh’s Complete Work). Shanghai Science & Technology Publishing House, Shanghai, 1991. Chao YC (1965). Neurology, neurosurgery and psychiatry in new China. Chin Med J 84: 714–742. Chao YF (610). Chu Ping Yuan Hou Lum (General Treatise on the Causes and Symptoms of Diseases). National Research Institute of Chinese Medicine, Taipei, 1981. Chen KK (1974). Half a century of ephedrine. Am J Chin Med 2: 359–365. Chen KK, Schmidt CF (1924). The action of ephedrine – the active principle of the Chinese drug, Ma Huang. J Pharmacol Exp Ther 24: 339–357. Chen KK, Schmidt CF (1926). The action and clinical use of ephedrine. JAMA 87: 836–841. Chen PS (1937). Chung Kuo I Xue Shi (History of Chinese Medicine). Commercial Press, Shanghai. Chen SK (1992a). Jin Dai I Xue Zai Chong Kuo (Modern Medicine in China). Ju Jing Culture Enterprise Co., Taipei. Chen SK (1992b). Chong Kuo Chuan Tung I Xue Shi (History of Traditional Chinese Medicine). Ju Jing Culture Enterprise Co., Taipei. Chen Y (1174). San Chi In Ping Chen Fang Lum (Treatise on Three Etiologies of Diseases). Commercial Press, Taipei, 1983. Chu NS (2004). Legendary Hwa Tuo’s surgery under general anesthesia in the second century China. Acta Neurol Taiwan 13: 211–216 (in Chinese with English summary). Chu PY (1996). The flesh, the soul and the Lord: Jesuit discourse of the body in seventeenth century China. New Hist 7: 47–98 (in Chinese with English summary). Chu TS (1280). Mai Yin Cheng Chih (Pulse Diagnosis of Diseases). Shanghai Health Publishing House, Shanghai, 1958.

NEUROLOGY AND TRADITIONAL CHINESE MEDICINE Fan KW (1995). On beri-beri from the Eastern Chin dynasty to the Sung dynasty. New Hist 6: 155–177 (in Chinese with English summary). Fan KW (2004). Jiao Qi disease in medieval China. Am J Chin Med 3: 699–1011. Feng YK (1959). Neurology in new China. Chin Med J 79: 398–408. Huang Di Nei Ching c. 300 BC (Yellow Emperor’s Classic of Internal Medicine). Hebei Science & Technology Publishing House, Hebei, China, 1994. Huang FM (259). Jia Yi Ching (Systemic Manual of Acupuncture). People’s Health Publishing House, Beijing, 1962. Kao FF (1973). China, Chinese medicine, and the Chinese medical system. Am J Chin Med 1: 1–59. Ko H (319). Chou Hou Pei Chi Fang (Prescriptions for Emergencies). People’s Health Publishing House, Beijing, 1963. Ku Chin Tu Shu Chi Cheng I Pu Chuan Lu (1726). Complete Medical Works of Library Collections, Ancient and Modern. Chinese Publishing House, Shanghai, 1959. Ku SC (1773). Yang I Ta Chuan (A Complete Work of Surgery). Chinese Traditional Medicine and Medicinal Herbs Publishing House, Beijing, 1994. Lai CW, Lai YHC (1991). History of epilepsy in Chinese traditional medicine. Epilepsia 32: 299–302. Lang XC (1986). An inquiry into Ma Fu San and another discussion of Hua Tuo’s nationality. Chin J Med Hist 16: 88–72 (in Chinese). Lee T (1940). I Xue Shi Kang (An Outline of the History of Medicine). Chinese Medical Association, Beijing. Lee T (1953a). Achievements of Chinese medicine in the Sui (589–617 AD) and Tang (618–907 AD) dynasties. Chin Med J 71: 301–320. Lee T (1953b). Achievements of Chinese medicine in the Ch’in (221–207 BC) and Han (206 BC–219 AD) dynasties. Chin Med J 71: 380–396. Lee T (1955). Chinese medicine during the Chin (1127– 1234) and Yuan (1234–1368) eras. Chin Med J 73: 241–258. Lee T, Cheng CF, Chang CS (1962). Some early records of nervous and mental diseases in traditional Chinese medicine. Chin Med J 81: 55–59. Leung KC (1999). The historical nosology of Li/Lai in China. Proceeding of the Institute of History and Philology, Academia Sinica, Taipei 70: 399–438 (in Chinese with English summary). Li SC (1578). Pen Tsao Kang Mu (Great Herbal, or Great Pharmacopoeia). Institute of Chinese Medicine, Taipei, 1994. Li T (1575). I Xue Ru Mom (Introduction to Medicine). Chinese Medicine and Herb Publishing House, Beijing, 1995. Miyasita S (1973). A neglected source for the early history of anesthesia in China and Japan. In: S Nakayama, N

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Sivin (Eds.), Exploration of an Ancient Tradition. MIT Press, Cambridge, MA, pp. 273–278. Nagai N (1887). Ephedrin. Pharm Zeit 32: 700. Nuland SB (1995). Surgery without pain. The origin of general anesthesia. In: SB Nuland, Doctors. The Biography of Medicine. Vintage Books, New York, pp. 263–303. Saunders JB, Lee FR (1981). The Manchu Anatomy and Its Historical Origin. Li Ming Culture Enterprise Co., Taipei. Sharpiro H (2003). Interpreting the idea of nerves in nineteenth century China. Symposium on the History of Medicine in Asia: Past Achievements, Current Research and Future Directions. Institute of History and Philology, Academia Sinica, Taipei, pp. 473–482. Shen JA (1773). Shen Shi Chun Shen Shu (Shen’s Book of Respect for Life). Hubei Chinese Culture Publishing House, Hubei, China, 1874. Shi CH (1984). Chong Kuo I Xue Shi (History of Chinese Medicine). National Institute for Compilation and Translation, Taipei. Sun SM (652). Chian Chin Yao Fang (A Thousand Golden Remedies). People’s Health Publishing House, Beijing, 1995. Sun SM (656). Bei Chi Chian Chin Yao Fang (Invaluable Prescriptions for Ready Reference). People’s Health Publishing House, Beijing, 1987. Wang CJ (1830). I Lin Kai Cho (Errors of Medicine Corrected). Shanghai Ancient Book Publishing House, Shanghai, 1997. Wang KT (1589). Cheng Chi Chun Sheng (Principles and Practice of Medicine). Shanghai Science & Technology Publishing House, Shanghai, 1962. Wang SH (265). Mai Ching (Pulse Classic). Shanghai Health Publishing House, Shanghai, 1957. Wang ST (1995). Development of modern neurology in China. In: XS Chen, SH Chen (Eds.), Chong Kuo Shian Dai Shen Jing Jing Shen Bing Xue Fa Jan Gai Kuang (Development of Modern Neurology and Psychiatry in China). Chinese Science and Technology Publishing House, Beijing, pp. 1–5 (in Chinese). Wei YL (1337). Shih I Teh Hsiao Fang (Effective Prescriptions from Physicians of a Distinguished Medical Lineage). Shanghai Science & Technology Publishing House, Shanghai, 1964. Wong KC (1927). Hua To – the god of surgery. Chin Med J 41: 695–698. Wong KC (1930). The early history of leprosy in China. Chin Med J 44: 737–743. Wong KC, Wu L-T (1936). History of Chinese Medicine. 2nd ed. National Quarantine Service, Shanghai. Yin CJ (1615). Shing Ming Kuei Chi (Supreme Aim of Life). Education & Science Publishing House, Beijing, 1993. Yu H (1930). Tetanus in ancient Chinese medical literature. Nat Med J Chin 16: 297–300.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 47

History of clinical neurology in Japan AKIRA TAKAHASHI * Department of Neurology, School of Medicine, Nagoya University, Gifu, Japan

INTRODUCTION OF CHINESE MEDICINE TOGETHER WITH BUDDHISM TO JAPAN Buddhism was first introduced to Japan in 538 AD. The Chinese priest Ganjin Daiwajoˆ (688–763) arrived in Japan in February 753, upon receiving an invitation from the court of Japan. In 759 he founded the Toˆshoˆdaiji Temple as a school for the study of Buddhist precepts in Heijyoˆ-kyoˆ (present-day Nara City), where he devoted himself to teaching Chinese medicine. Thereafter Chinese medicine spread gradually throughout the country together with Buddhism, and played an important role in mainstream Japanese medicine until modern times. In 984, the Ishimpo was published in 30 volumes as a set of Chinese medicine books. This is the oldest historical document on the subject in Japan.

INITIAL CONTACT WITH EUROPEAN CULTURE In 1543, a storm drove a Portuguese trading vessel headed for China ashore on the small island of Tanegashima, off the southern tip of Kyushu. This was the first arrival of the Europeans. Japan was carrying on a brisk trade with China at that time. Six years later, a vessel that included Francisco Xavier (1506–1552) among its passengers arrived at Kagoshima. There followed a century of contact with the Portuguese, and later the Spanish, who had trade and the establishment of Christian missions as their principal aims. At this time, medical initiatives were quite limited. The first practitioner of Western medicine in Japan was a Portuguese Father, Luis d’Almeida (1525–1583). He was born in Lisbon, studied surgery, and became a medical missionary for the Society of Jesus. Almeida undertook the care of many patients, including the *

lepers, and in 1557 opened a hospital, Cole´gio Sociedade Iesu in Funai, in Iapone in Bungo (present Oita), Kyushu. This was the first Western-style hospital in Japan, but it burned down in 1589, during a civil war. The Dutch first reached Japan in 1600, drifting ashore on the surviving ship, the Liefde, which had encountered violent storms when traversing the Strait of Magellan. Ieyasu Tokugawa (1542–1616), the founder of the Edo shogunate, began with hopes of extending Japanese trade and commerce. Gradually fears of Christian subversion outweighed his desires for trade. He put a ban on Christianity and issued an edict for all missionaries to leave in 1614. Twenty years later, the third shogun, Iemitu Tokugawa, decided to isolate the remaining Portuguese inhabitants in one place at Nagasaki, the westernmost district of Japan. In 1636, they were moved to Dejima, a man-made island in Nagasaki, but 2 years later were expelled from Japan. Because the Dutch avoided missionary activity and concentrated on trade, unlike the Portuguese, their trade was still permitted in Japan. They were moved to Dejima in 1841 to have more access to trade. Trade with the Dutch, through the small window of Dejima, continued for more than 250 years, until the end of the Edo era.

JAPANESE INTEREST IN DUTCH MEDICINE After permitting the Dutch to stay in Nagasaki, the Japanese interest in foreign medicine shifted from the Chinese and Portuguese to the Dutch. The Dutch Commerce House was built in Dejima, and medical doctors always stayed there. At that time, there were a few Dutch interpreters in Nagasaki. Some of them took the opportunity to learn Western medicine, especially surgery from the Dutch doctors. The Japanese named the

Correspondence to: Akira Takahashi, 126, 4-chome, Momoyama-cho, Obu, Aichi, 474-0026 Japan, or c/o Tokai Central Hosp., 4, Sohara-Higashijima machi, Kakamigahara, Gifu, 504-8601 Japan. Fax: +81-583-82-1762.

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science through the Dutch language Rangaku and the Dutch medicine K om o-Igaku (Dutch-style medicine). Interest grew in Western medicine, particularly after a human dissection on 4 March 1771 established the accuracy of a Western treatise on anatomy. On this occasion, two shogunate physicians, Ryoˆtaku Maeno (1723–1803) and Gempaku Sugita (1733–1817), had their copies of Ontleedkundige Tafelen, which was the Dutch translation (3rd edn., Amsterdam, 1734) of the original German anatomical atlas and text, Anatomische Tabellen, written by Johann Adam Kulmus (1689–1745) and published in Danzig in 1722. They compared what they saw with the illustrations in the Dutch book and were struck by the accuracy of the illustrations. As they returned home from the execution grounds, Maeno and Sugita decided to translate Kulmus’s text. By obtaining the cooperation of an additional three physicians, and with great effort for 4 years, their translation into Chinese was completed. The entire five volumes of the book, titled Kaitai-Shinsho, were published in 1774. Because the Kaitai-Shinsho showed that Western medicine was superior to and more precise than Chinese medicine, Dutch language, and the study of Dutch Sciences (Rangaku) proved crucial for the advancement of Western medicine in Japan (Bowers, 1970; Aki, 1982; Nagayo, 1991). Genzui Udagawa (1755–1797) was one of the students of Sugita. He translated a medical book written by Johannes de Gorter (1689–1762), one of the important disciples of Herman Boerhaave (1668–1738), and published it under the title of Seisetu-Naika-Sen’yo in (1793–1810). His magnum opus of 18 volumes increased knowledge of neurological diseases in Japan.

SIEBOLD’S VISIT TO JAPAN In 1824, a German medical doctor, Philipp Franz von Siebold (1796–1866) (Fig. 47.1), came to the Dutch Commerce House in Nagasaki. He graduated from Wu¨rzburg and came from a distinguished family in that German city: his grandfather was one of the best surgeons in Europe and his father was professor of physiology at Wu¨rzburg. Siebold showed untiring zeal in studying the culture of Japan and he taught Dutch, natural history, and medicine. He was the first foreigner to teach and demonstrate Western medical, surgical, and obstetric procedures in Japan in a systematic way. Siebold had some talented students, and one of them, Choˆei Takano (1804–1850), published the first modern physiology textbook in Japan, Igen Sûyô, in 1832. Gemboku Itoˆ was born a poor farmer’s son. He learned Dutch, Dutch medicine, and vaccination in Nagasaki. In 1833, Itoˆ established a private medical

Fig. 47.1. Philipp Franz von Siebold (1796–1866).

school in Edo (Tokyo), and in 1858 was promoted to court physician of the Tokugawa shogunate. This was the highest medical position at that time. During the summer of 1858, Itoˆ set up at Otamagaike an institution for vaccination in Edo, the Otamagaike-Shutoˆsho. It was the predecessor of the present Medical Faculty of the University of Tokyo.

ESTABLISHMENT OF MODERN MEDICAL EDUCATION BY A DUTCH NAVAL SURGEON In 1853, the arrival of a US mission commanded by Matthew Calbraith Perry startled the Japanese. The Tokugawa shogunate recognized that Japan at the time was defenseless against foreign invaders by sea. It quickly founded a naval military school in Nagasaki in 1855. J.L.C. Pompe van Meerdervoort (1829–1908) (Fig. 47.2) arrived there in 1857 as a Dutch naval surgeon, and he hoped to establish a Western-style system of medical practice and education. Pompe van Meerdervoort began a series of lectures on modern medicine on 12 November 1857 (this date is considered the birth date of the Nagasaki University Medical School). He applied himself to his work for 5 years with the cooperation of two Japanese students, Ryoˆjun Matsumoto and Ryoˆkai Shiba. In all, it is estimated that 133 medical students attended his numerous lectures in

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Tsunatume Hashimoto (1845–1909), another of his students, was the founder of the Red Cross Society of Japan. He studied medicine in Berlin, Wu¨rzburg, and Wien, and published a paper, “Ueber Pseudomuskelhypertrophie,” in a German journal in 1886. This was the first neurological publication by a Japanese physician in a Western medical periodical. Ryoˆjun Matsumoto was one of Pompe van Meerdervoort’s best pupils. By this time, the OtamagaikeShutoˆsho had changed its name to Seiyoˆ-Igakusho (Institution for Western Medical Education) and then to Igakusho. In 1862, Matsumoto assumed the directorship of the Igakusho.

INTRODUCTION OF GERMAN MEDICINE Decision to introduce German medicine to Japan

Fig. 47.2. Johannes Lydius Meerdervoort (1829–1908).

Cartherinus

Pompe

van

basic and clinical medicine, and that he treated more than 10000 patients (Pompe van Meerdervoort, 1867). One event is worthy of additional attention, and it relates to neurology. In 1859, Pompe van Meerdervoort dissected an executed criminal in the presence of 21 of his pupils. He exhibited the brain and the peripheral nerves to them. This was the first systematic dissection of a human body and the first neuroanatomy lecturedemonstration in Japan. Many of Pompe van Meerdervoort’s students became leaders of medicine in Japan during the closing days of the Tokugawa shogunate and into the Meiji Restoration. Several deserve mention because of their work on neurological subjects. Ryoˆkai Shiba (1839–1879) was exceptional at acquiring foreign languages, and he was the only pupil really able to understand correctly the medical content of Pompe van Meerdervoort’s lectures. In 1862, he published the first Japanese textbook on medical therapeutics, Shichi-shin-yaku (Seven New Medicaments), in which he concisely described the essence of medicaments for a variety of diseases, including epilepsy, neuralgias, choreic movement, and palsy (Takahashi, 1998). Shiba conducted a post-mortem examination in 1876 in a lonely village in Aichi Prefecture, in order to study the pathological anatomy. This was the first time this had been undertaken in Japan.

In November 1867, the Tokugawa Shogun resigned his shogunate and the Emperor Meiji was restored to a position of true prestige. Edo was renamed Tokyo. The East College of the University now entrusted its administration to two physicians: Tomoyasu Sagara and Jun Iwasa. These men decided to introduce Westernstyle medicine from Germany into Japan, because Germany was viewed as the leader of the medical world in the latter half of the 19th century. They transmitted an official request to the German government, inviting German professors to teach at the college. Prussian military physician Theodore Hoffmann (1837–1894) and surgeon Leopold Mu¨ller (1822–1893) arrived in Japan on 23 August 1871. They devoted their energies to promoting German-style medicine in Japan and, after 4 years, academics at the medical school were elevated (Kraas and Hiki, 1992).

Erwin von Baelz Between 1871 and 1881, a total of 13 German-speaking medical teachers came to Japan. Physician Erwin Otto Eduard von Baelz (1849–1913) (Fig. 47.3) was the most meritorious among them. He was born in Bietigheim in Germany. After completing his medical courses in Tu¨bingen, he took a doctorate in medicine in 1872 at Leipzig (Dissertation: Zur progressive Bulbärparalyse), and qualified himself to give lectures at the university level. He worked as an assistant in Prof. Wunderlich’s Department of Internal Medicine, where he befriended the young neurologist Adolf Stru¨mpell (1853–1925). Five days after arriving in Tokyo in 1876, Baelz began a series of lectures on physiology at Tokyo Medical School, and he would exert his influence on medical students of the Imperial University of Tokyo for more than 25 years. Soon after beginning his

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Fig. 47.3. Erwin Otto Eduard von Baelz (1849–1913).

physiology lectures, he also began to lecture on internal medicine. His lectures ranged from psychiatry, gynecology, obstetrics, etc. Baelz delivered the first series of Western-style lectures on neurological topics in Japan. His lectures were published both in Japanese (Naika-Byôron, 1882; Baelz’s Naika-Gaku, 1893) and in German in 1900–1901. In them, various neurological diseases were systematically described. Baelz’s medical textbooks were well received, and went through several editions in Japan (Kraas and Hiki, 1992).

TWO PIONEERS IN NEUROLOGY Hiroshi Kawahara (1858–1918) ˆ mura, a neighboring Kawahara (Fig. 47.4) was born in O town of Nagasaki. In 1871, he started his medical studies in the Nagasaki Medical School, which had been established under the guidance of Pompe van Meerdervoort. In 1874, when the school was closed for political reasons, he transferred to the Tokyo Medical School, the predecessor of the present Faculty of Medicine of the University of Tokyo, where he was strongly influenced by Erwin Baelz. Soon after graduation, Kawahara was appointed to a professorship of internal medicine at the Aichi Medical School (now, the Nagoya University School

Fig. 47.4. Hiroshi Kawahara (1858–1918).

of Medicine). His masterpiece in neurology is the first description anywhere of X-linked muscular atrophy (bulbo-spinal muscular atrophy). In 1953, Takikawa described three patients affected with this disease in one family, and deduced that the disease was inherited as a sex-linked recessive trait. Kawahara’s greatest contribution to Japanese neurology in and of itself is the publication of the first textbook of clinical neurology written in Japanese, and it appeared in 1897b (Takahashi, 2001).

Kinnosuke Miura (1864–1950) After completing his medical studies at the Faculty of Medicine of the University of Tokyo, Miura turned to Baelz to learn more about neurology. In 1889, he accepted an opportunity to visit Europe. While there, he studied clinical neurology under Carl Gerhardt and Hermann Oppenheim in Berlin, Felix Marchan in Marburg, and Wilhelm Heinrich Erb in Heidelberg, and then Jean-Martin Charcot in Paris. Because of the strong influence French neurology had on him, Miura introduced it into Japan (Iwata, 2000). In 1894, he became Professor of Internal Medicine at the University of Tokyo, and nurtured many young promising physicians. Of these, many became

HISTORY OF CLINICAL NEUROLOGY IN JAPAN 773 leading professors, including Seizoˆ Katsunuma, Ken had previously been noted by Rudolph Albert von Ko¨lKure, and Shigeo Okinaka. liker (1817–1905), the Swiss-born professor of anatomy In 1902, Miura and Shuzoˆ Kure founded the Japanese and physiology at Wu¨rzburg (1896). Neither Ko¨lliker Society of Neuro-Psychiatry. In the first issue of the nor Fuse had given the nucleus an anatomical name, Society’s official journal, Shinkeigaku Zasshi (Journal of but today the nucleus is called by the eponym, the Neurology), Miura (1902) reported a clinico-pathological “Ko¨lliker–Fuse nucleus.” It is now known to be one study of amyotrophic lateral sclerosis in Japan. of the brainstem regulatory centers for both the respiratory system and the cardiovascular system. JAPANESE CONTRIBUTIONS TO Yas Kuno (1882–1977) elaborated on the physiology NEUROLOGY: 1900^1945 of human perspiration. His most important book, The Physiology of Human Perspiration, was published in After closing the Tokugawa shogunate and the Meiji Great Britain in 1934, and it had a revised edition in Restoration, Japan made major efforts to adopt 1956 in the United States. aspects of Western culture. In 1877, the University of Tokyo was founded as the first Imperial University. CONTRIBUTIONS TO NEUROLOGY: Unfortunately militarism soon began to grow, and aca1945^2000 demic investigations were increasingly restricted. World War II made a shambles of Japan in all respects. Extraction of adrenaline, thiamine and The country lost many research institutes, scientists, “cerebral sleep substance” and students of ability. But Japan’s scientific research grew at an extraordinary rate after the war, when it Jokichi Takamine (1854–1922) and his assistant Keizoˆ actively adopted American culture in addition to that Uenaka succeeded in crystallizing and isolating the active of Western Europe. principle of the suprarenal gland in 1900. In the next year, Takamine marketed the agent under the name “adrenalin” and presented it to the world (Takamine, 1901). Umetaroˆ Suzuki (1874–1943) refined thiamine (Vitamin B1) and named it “oryzanine.” He also disclosed its intimate relationship to beri-beri, a disorder caused by inadequate amounts of the B vitamin (Suzuki and Shimamura, 1911). In 1909, Kuniomi Ishimori (1874–1955) extracted a so-called sleep substance from the brain of dogs. His experiments forced the dogs to stay awake for prolonged periods of time.

Detection of pathogenic agents from brain and spinal cord Hideyo Noguchi (1876–1928) graduated from Saiseigakusha, a private medical school, in Tokyo in 1897, and 2 years later emigrated to the United States. In 1904, he went to the Rockefeller Institute for Medical Research in New York City. Noguchi and Moore (1913) were the first to demonstrate Treponema pallidum in the central nervous systems of patients dying of general paresis and tabes dorsalis, thereby proving the syphilitic origins of these diseases. Kaneko and Aoki (1928) distinguished Japanese encephalitis from encephalitis lethargica, and 8 years later Taniguchi, Hosokawa and Kuga (1936) isolated the virus.

Neuroanatomy and neurophysiology Gennosuke Fuse (1880–1946) conducted his research on neuroanatomy under Constantin von Monakow (1853– 1930) in Zu¨rich. In 1913, he described a nucleus that

Degenerative diseases of the CNS DEMENTIA

WITH MOTOR NEURON DISEASE

Hirano and his associates (1961) described “Parkinsonism-dementia complex” as an endemic disease confined to the Chamorro population of Guam, one of the Mariana Islands. It seemed to be associated with amyotrophic lateral sclerosis in many patients. The main pathological findings were cortical atrophy, loss of pigment from the substantia nigra and locus ceruleus, and numerous intra-neural neurofibrillary tangles in degenerated areas of the cerebral cortex, thalamus, and brainstem – yet not associated with senile plaques. In a study of the disease, Hirano et al. (1966) found unique structures in the pyramidal cells of the hippocampus. They are now called Hirano bodies or eosinophilic rod-like structures. This disease is regarded as a distinct endemic disease entity at present, and is also found in Japan (Kuzuhara et al., 1996; Konagaya et al., 1999). Yuasa (1964) reported on an autopsied man who suffered from amyotrophic lateral sclerosis (ALS) with organic dementia. The initial symptoms were intellectual deterioration and personality changes. Eight months later, he developed bulbar signs, after which ALS symptoms and signs reflected a faster spiral downward. Mitsuyama and Takamiya (1979) described the neuropathologic features of dementia with motor neuron disease as a distinct clinicopathological entity. More than

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100 cases have been reported in Japan since 1964. Mitsuyama (2000) characterized the clinical features of this disease as follows: the initial symptom is fronto-temporal dementia, neurological symptoms usually develop 6–12 months after the onset of psychiatric symptoms, bulbar symptoms become evident, lower motor neuron signs are predominant, and pyramidal signs are rare. Pathologically, it is characterized by atrophy in the frontal lobes and hippocampus, cortical microvacuolation limited to the superficial cortical layer II, neuronal loss of the hypoglossal nuclei and anterior horn cells in the cervical and thoracic cord, presence of Bunina bodies, and little degeneration of the corticospinal tracts.

BULBOSPINAL

MUSCLE ATROPHY

Kawahara (1897a) first described cases of progressive bulbar palsy affecting two brothers. Takikawa (1953), as noted in the previous section on Hiroshi Kawahara, disclosed the sex-linked, recessive inheritance in this disease. Sobue et al. (1989) performed neuropathological and neurophysiological studies and concluded that lower motor and primary sensory neuropathy were major neurological manifestations of this disease. Since the discoveries of androgen receptor gene mutation by La Spada et al. (1991), and nuclear inclusions of the androgen receptor protein in the lesions by Li et al. (1998), it has been suggested that estrogen plays a possible pathogenetic role and that hormonal and gene therapy may be potential tools for controlling this disease.

HEREDITARY DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY (H-DRPLA) H-DRPLA is an autosomal-dominant, hereditary, neurodegenerative disorder, characterized clinically by myoclonus epilepsy, cerebellar ataxia, choreoathetosis, dementia in the elderly, and mental retardation in children. It is characterized anatomically by concurrent degeneration of the dentatorubral and pallidoluysian systems. Naito et al. (1972) first described this disease as a degenerative type of myoclonus epilepsy in two families. Oyanagi et al. (1976) reported prominent degeneration of the pallidoluysian system in addition to that of the dentatorubral system. Naito and Oyanagi (1982) established this hereditary system-degeneration of the central nervous system (CNS) as a distinct clinico-pathological entity under the name of “hereditary dentatorubral-pallidoluysian atrophy.” Phenotypic variation is extensive, but the clinical diagnosis is not always difficult. More recently, Ikeuchi et al. (1995) disclosed a close relation of CAG repeat expansions with a wide spectrum of clinical presentation and prominent anticipation.

SPINOCEREBELLAR

ATAXIA TYPE

1 (SCA1)

Among the autosomally dominant cerebellar ataxias, Yakura et al. (1974) first disclosed the gene locus on chromosome 6p22–p23. Clinically, ataxic gait and speech are the typical onset signs, usually showing in the twenties. Ophthalmoplegia, optic atrophy, pyramidal and extrapyramidal signs, peripheral sensorimotor neuropathy, mild dementia, and amyotrophy follow. Expansion of the CAG repeat was reported by Orr et al. (1993) and Kameya et al. (1995).

MULTIPLE

SYSTEM ATROPHY

(MSA)

In 1969, Graham and Oppenheimer first introduced the umbrella term “MSA.” Independently, Takahashi et al. (1969) reported an intimate relationship among olivopontocerebellar atrophy (OPCA), Shy–Drager syndrome (SDS) and striatonigral degeneration (SND). Recently, the terms OPCA, SDS and SND have been jettisoned in favor of describing cases of MSA according to their predominant motor disorder: cerebellar (MSA-C) or parkinsonism (MSA-P). Glial cytoplasmic inclusions (GCIs) were demonstrated in the CNS of MSA by Papp et al. (1989). Wakabayashi et al. (1998) reported the accumulation of a-synuclein/NACP in GCIs. Onufrowicz (calling himself Onuf) described a discrete group of small cells in the anterior horns of the sacral segments 2–4, and speculated that it might be the center of some of the striated muscles coordinating the acts of erection and ejaculation (Onuf, 1899, 1900). Mannen et al. (1977, 1979) found that the neurons in Onuf’s nucleus remain intact in ALS, but remarkably degenerate in MSA. Kihara et al. (1991) quantitatively studied sudomotor dysfunctions in MSA. They found that the main lesion responsible for them is in the intermediolateral column of the spinal cord, which begins in the lower extremities and expands upward, and that postganglionic pseudomotor dysfunction also develops as the illness progresses. Patients with MSA are not rare in Japan; MSA-C cases predominate, compared with MSA-P.

PARKINSON’S

DISEASE AND

LEWY

BODY DISEASE

The contributions of Prof. Isamu Sano to research and therapy of Parkinson’s disease are worth mentioning, because he and his associates disclosed depletion of dopamine in the brains of patients with Parkinson’s disease (Sano et al., 1959), and also were the first researchers in the world to show the efficacy of DOPA on the motor symptoms of this disease. They noted that both muscle rigidity and tremor dramatically

HISTORY OF CLINICAL NEUROLOGY IN JAPAN decreased 15–30 min after 200 mg of DOPA was given intravenously to patients with Parkinson’s disease. Sano concluded that DOPA is certainly effective but the intravenous administration is of little clinical use because the remission lasted only for several minutes (Sano, 1960). 123 I-metaiodobenzylguanidine (MIBG) is a physiological analogue of noradrenaline (NA) that traces the uptake and transport of NA in presynaptic nerve terminals and subsequent vesicular storage. Hakusui et al. (1994) reported that myocardial MIBG uptake is significantly reduced even without apparent autonomic failure in patients with idiopathic Parkinson’s disease. Orimo et al. (1999) proposed it as a useful diagnostic way of imaging the illness. In recent years, MIBG myocardial scintigraphy has been widely used, not only in Japan but also in other countries. Diffuse Lewy body disease (DLBD) has received more attention following a series of reports by Kosaka (1978) and Kosaka et al. (1984), who first described it in detail. Kosaka (2000) reviewed its frequency, clinical features, neuropathology and molecular biology.

AUTOSOMAL (AR-JP)

RECESSIVE JUVENILE PARKINSONISM

Type PARK2 of AR-JP is a distinct clinical and genetic entity. It is characterized by an early onset (before 40 years), mild dystonia, diurnal fluctuation, spontaneous improvement of movement disability after sleeping, a good response to levodopa, and less frequent resting tremor compared with sporadic Parkinson’s disease. This type of AR-JP was first described by Yamamura et al. (1973). Pathological changes include selective degeneration of pigmented neurons in the substantia nigra and locus ceruleus. But it is also characterized by an absence of Lewy bodies. Kitada et al. (1998) mapped the gene parkin for PARK2 to chromosome 6q25.2–q27, and identified a novel ubiquitin-like protein located in this region.

SEGAWA DISEASE (DOPAMINE-RESPONSIVE DYSTONIA, DRD; HEREDITARY PROGRESSIVE DYSTONIA WITH DIURNAL FLUCTUATION, HPD) Segawa et al. (1976) first described this illness, which is characterized by an inherited dystonia typically presenting in the first decade of life, diurnal fluctuations, exquisite responsiveness to levodopa, and mild parkinsonian features. Most cases have been reported from Japan and Southeast Asia. With increasing awareness of this condition, more cases are being reported in the world. Females are more involved than males. The most common presenting symptom is difficulty in walking. Typically the dystonia starts in one lower

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limb, resulting in a tip-toe walking pattern. Early in the disease course, patients are symptom free in the morning. Diurnal aggravation of symptoms depends more on the number of waking hours than on physical activity. The disease progresses markedly in the first 15 years. Progression slows in the third decade and plateaus thereafter (Segawa et al., 1986). In one autopsy case, the only neuropathologic finding was a decrease in melanin-pigmented neurons in the pars compacta of the substantia nigra. No inclusion bodies or gliosis was noted, and no evidence of a degenerative process in the striatum was observed. Tyrosine hydroxylase immunoactivity in the substantia nigra was normal (Rajput et al., 1994). The disease is caused by point mutation of the GTP cyclohydrase 1 gene (Ichinose et al., 1994).

Cerebrovascular diseases MOYAMOYA

DISEASE

Moyamoya is a Japanese word meaning “a cloud of smoke.” It has been used in recent years to refer to an “extensive basal cerebral rete mirabile” – a network of small anatomic vessels at the base of the brain around and distal to the circle of Willis, seen in carotid arteriograms, along with segmental stenosis or occlusion of the terminal parts of both internal carotid arteries. Opinion is divided as to whether the basal rete mirabile represents a congenital vascular malformation or a rich collateral vascularization, secondary to a congenital hypoplasia or acquired stenosis or occlusion of the internal carotid arteries early in life. This form of cerebrovascular disease was first described by Japanese neurosurgeons (Suzuki and Takaku in 1969). It is not limited to the Japanese (prevalence rate in 1994 being 3.16/105), but only a few patients have been reported from other parts of the world.

CEREBRAL

AUTOSOMAL RECESSIVE ARTERIOPATHY

WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY

(CARASIL)

Two inherited diseases similar to Binswanger leukoencephalopathy but without hypertension have been described: the dominant form being CADASIL (cerebral autosomal dominant arteriopathy with subcortial infarcts and leukoencephalopathy) from Europe, and the recessive one, CARASIL from Japan. Fukutake et al. (1985) and Fukutake and Hirayama (1995) described CARASIL as a new clinico-pathological entity distinct from Binswanger disease. They characterized it as a young-adult-onset arteriosclerotic leukoencephalopathy associated with lumbago/spondylosis deformans and diffuse baldness.

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Myelopathy JUVENILE

MUSCULAR ATROPHY OF DISTAL UPPER

EXTREMITY

(HIRAYAMA

DISEASE)

Hirayama et al. (1959) first reported 12 patients with this disease. Most cases are young men, insidiously developing muscle weakness and atrophy on one side of the hands and forearm. Sensory impairment and pyramidal tract signs are absent (Hirayama et al., 1963). Hirayama et al. (1987) published the first autopsied case and concluded that the pathogenesis is ischemia resulting from chronic antero-posterior compression. Mukai et al. (1985) reported dynamic changes of the cervical dural sac and spinal cord during anterior flexion of the neck, resulting in compressive postero-anterior flattening of the lower cervical dura and spinal cord. This disease is uncommon in Japan and few cases have been reported in the world. Neuropathological studies are currently needed.

COMPRESSIVE

MYELOPATHY SECONDARY TO

CALCIFIED LIGAMENTS IN THE SPINAL CANAL

In 1838, Key reported a case of paraplegia caused by disease of the ligaments within the spinal canal. For a long time neurologists showed little or no attention to this illness. Some Japanese physicians, however, have subsequently made noteworthy contributions to diseases of this kind. In 1938, Anzai reported an operated case of spinal root compression resulting from calcified ligamentum flavum. Tsukimoto (1960) reported an autopsy case of compressive cervical myelopathy in association with calcified posterior longitudinal ligament. Terayama and his associates (1964) described the symptoms and pathology based on an autopsy case and six patients suffering from cervical myelopathy associated with this disease under the name of ossification of posterior longitudinal ligament (OPLL). Since then, a number of reports have appeared. Although the incidence is rare among Caucasians, it is a significant cause of myelopathy in middleaged and older Japanese. The etiology remains obscure. Kameyama et al. (1995) demonstrated the pathologic characteristics as follows: indention and flattening of the cord due to anterior compression, gray matter destruction with neuronal loss and occasionally ischemic changes, white matter destruction with necrosis sparing the anterior columns, and secondary degeneration of the lateral and posterior columns.

SUBACUTE

MYELO-OPTIC-NEUROPATHY

(SMON)

Clioquinol (chinoform) was originally manufactured as a dusting powder for wounds and as an amoebicide. In Japan, it was put on the market in 1934. During

1937–1938, some patients who took Clioquinol by mouth seemed to develop SMON-like symptoms. A remarkable neurological syndrome following gastrointestinal complaints began to appear endemically in Japan in the mid-1950s. Tsubaki et al. (1964) reported the clinical and pathological characteristics under the newly coined name of subacute myelo-optic-neuropathy (SMON). A greenish coating of the tongue led pharmacologists to the discovery of Clioquinol metabolites in it. The sale of Clioquinol was immediately prohibited. The Japanese government estimated the SMON patients to be 12000 in total. SMON is characterized neuropathologically by combined degenerations of the posterior column, especially of Goll’s funiculus, corticospinal tracts, posterior spinal ganglia, posterior spinal roots, and the optic funiculus in its proximal portion, together with axonal and myelin sheath degeneration in the peripheral nerves. The cardinal neurological features comprise prominent paresthesis and mild muscular weakness in both legs of subacute onset following abdominal symptoms. Occasionally visual disorders and sphincter symptoms also appear (Sobue et al., 1971).

HTLV-I-ASSOCIATED SPASTIC PARAPARESIS

MYELOPATHY AND TROPICAL

(HAM/TSP)

Adult T-cell leukemia (ATL) was first recognized as a new disease entity in 1973 in Japan. In 1981, C-type retrovirus particles were found in an ATL cell line, and the structure of this virus, named ATLV, was determined in Japan. HTLV-I was isolated independently from a patient with cutaneous T-cell lymphoma in the USA. Later, it was confirmed that ATLV and HTLV-I were identical. Tropical spastic paraparesis (TSP) is an endemic neurological disorder found in many tropical and subtropical areas, such as the Caribbean Islands, southern United States, South America, and Africa. It had been considered to be degenerative in nature until 1986, when Gessain et al. found IgG antibodies to HTLV-I in the sera of the TSP patients in Martinique (Gessain et al., 1935). In the same year, Osame et al. noticed in Kagoshima, a temperate district of southern Japan, that some patients manifesting slowly progressive spastic paraparesis had antibodies against HTLV-I in both their serum and cerebrospinal fluid. In the next year, they proposed a term of HTLV-Iassociated myelopathy (HAM) as a new disease entity (Osame et al., 1986). HAM and TSP were later confirmed as a single entity and the name HAM/TSP was recommended by the World Health Organization (WHO). In 1989, Roma´n, Vernant and Osame compiled the fruits of years of research on HTLV-I and the nervous

HISTORY OF CLINICAL NEUROLOGY IN JAPAN system into a monograph. Ten years later, at the IX International Conference on HTLVs and Related Disorders (Kagoshima city in Japan, 1999), it was estimated that there were about 1200 patients with HAM/TSP in Japan and approximately 3000 in the world (Osame, 1999). Izumo et al. (2000) summarized the neuropathologic characteristics as follows. The spinal cord shows symmetrical atrophy, especially in the lateral column of the thoracic cord. Infiltration of mononuclear cells and degeneration of both myelin and axons are the essential findings, being most prominent in the lower thoracic cord. Severe and symmetrical degeneration of the anterolateral column and inner portion of the posterior column is common. They also suggest the topographical character may have some relation to hypoperfusion in the middle to lower thoracic cord.

Myopathies MUSCULAR

DYSTROPHY

Muscular dystrophy comprises a genetically heterogenous group of diseases. Since 1860, when Duchenne de Boulogne (1806–1875) described the pseudohypertrophic muscle atrophy of childhood that now bears his name, a number of subtypes have come to light. Some Japanese neurologists have described several novel types of muscular dystrophy. They include: Fukuyama-type congenital muscular dystrophy (Fukuyama et al., 1960), malignant limb-girdle muscular dystrophy (Miyoshi et al., 1974), oculopharyngodistal muscular dystrophy (Satoyoshi and Kinoshita, 1977), and Miyoshi distal muscular dystrophy (Miyoshi myopathy) (Miyoshi et al., 1986). A landmark of Japanese myology was the detection of elevated creatine phosphokinase (CPK; now known as creatine kinase or CK) in patients with Duchennetype muscular dystrophy and the development of a new method to determine the quantity of CK by Ebashi et al. in 1959. Okinaka and his associates (1961) disclosed marked elevation of serum CK level in Duchenne-type dystrophy. After identification of “dystrophin,” which is a gene DMD product and absent from DMD muscle, many Japanese myologists produced excellent studies of DMD and the variant subtypes. A pathogenic protein “fukutin” was identified by Toda et al. in 1993. At present, no therapy is established.

GLYCOGEN

STORAGE DISEASE

Up to the present, 10 types of glycogen storage disease have been recognized. Tarui et al. (1965) described muscle phosphofructose deficiency disease (glycogenosis type VII). It is characterized by recessive inheritance

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with young adult or late adult onset, proximal muscle atrophy and weakness, presenting with muscle pain and decreased exercise tolerance, increased serum creatine kinase levels, and absence of phosphofructokinase activity in muscles. Improvement has been reported after the administration of glucagons (Kono et al., 1984).

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 48

History of neurology in Australia and New Zealand 1

PAUL B. FOLEY 1 * AND CATHERINE E. STOREY 2 Prince of Wales Medical Research Institute, and Faculty of Medicine, University of New South Wales, Sydney, Australia 2 Department of Neurology, Royal North Shore Hospital, St. Leonards, Australia

INTRODUCTION In comparison with most Western countries, neurology as a recognized medical specialty has a relatively brief history in Australia: the national body for neurologists – the Australian Association of Neurologists (AAN) – was founded only in 1950. This late development can be explained by a number of factors, not least by the nature of Australia itself. The country is quite young, European colonization of the continent having commenced in 1788, initially as a British convict settlement. By the middle of the 19th century the transportation of prisoners to Australia had largely ceased, the original colony, New South Wales (NSW), had been granted self-government (1855), and a series of further, autonomous colonies had been established in Van Diemen’s Land (1826; now Tasmania), Western Australia (1829), South Australia (1836), Victoria (1851) and Queensland (1859). Each of these colonies was for the most part based on a single coastal city, separated from each other by distance and by sometimes fierce rivalries. Although achieved purely by democratic means, the creation of the Commonwealth of Australia on New Year’s Day 1901 was not achieved without considerable debate and some resistance, particularly with regard to freedom of interstate trade. Rivalry has particularly characterized the relationship between the two largest cities, Sydney (founded as a penal colony in 1788) and Melbourne (established in 1835 by free settlers). These metropolises not only accommodate about 40% of the national population (2006), but have historically played the roles of competing cultural centers with respect to many aspects of Australian life. The national capital, Canberra (founded 1913), was situated approximately halfway between the two state capitals in order to assuage suspicions that either should play the more dominant role in the new nation.

*

Full Australian sovereignty was not achieved until the adoption of the Statute of Westminster in 1942; Australian citizenship was introduced only in 1949; and the formal separation of the Australian and British legislative systems was not consummate until 1986. This historical background is essential for understanding the close ties between Australia and Britain, and between Australian and British medicine, including neurology, which persisted until the final third of the 20th century, even following the great influx of non-British migrants after Second World War. The other important feature in this regard was the isolation experienced in Australia, both before and after Federation. As the art and social critic Robert Hughes famously noted, the development of Australia since European colonization has been determined to a large degree by the “tyranny of distance.” Not only is the island nation geographically isolated from the rest of the Western world, to which it historically has felt more emotionally attached than to its more proximal northern neighbors, distances within the country are also massive by European standards: Perth on the west coast of the continent is as distant from Sydney as Moscow is from Madrid – with the difference that the two Australian cities are separated by thousands of kilometers of inhospitable desert. It is for this reason that Australia at the end of Second World War was home to less than 7.5 million people, and even today sustains a population of less than 21 million (90% European origin, 2% Aboriginal) on a landmass larger than Europe (without Russia); 91% live in urban areas. In summary, the difficulty of communications both within Australia and with the outside world, the concentration of a relatively small national population in

Correspondence to: Paul B. Foley, Prince of Wales Medical Research Institute, Barker Street, Randwick, Sydney NSW 2031, Australia. E-mail: [email protected], Tel: +61-2-9399-1092, Fax: +61-2-9399-1082.

782 P. FOLEY AND C. STOREY a handful of cities scattered along the coast, and the Country” are still cherished by many Australians. Only particular emphases demanded by life in isolated coloin 1938 was the Royal Australasian College of Physinial societies all hindered intellectual and cultural cians (RACP) founded as the body responsible for developments that might otherwise have been expected training, educating and examining Australian and in even a young “European” country. This has contribNew Zealand physicians, while the state branches of uted greatly to Australia not developing in a manner the British Medical Association (BMA) were the princimore closely resembling, for instance, the United pal professional organizations for physicians and stuStates of America. dents from the 1880s until the establishment of the New Zealand is even more isolated from the rest of Australian Medical Association (AMA) in 1962 the Western world. Slightly larger than Great Britain, (McGrath, 1975; Winton, 1988). These links were its population is about four million, 75% of which further enhanced by the fact that, then as now, English are Pakeha (of European heritage) and 15% Maori. was regarded by Australians as the sole language of New Zealand was originally part of the Colony of medical discourse. New South Wales; intensive European settlement Modern neuroscience can be traced at least as far began in 1839, and the islands were declared a separate back as the 17th century and to the man who coined colony in 1840. New Zealand declined to join the Comthe term “neurology,” Thomas Willis (1621–1675). Neumonwealth in 1901, becoming instead an equal Dominrology as a distinct branch of medicine, however, first ion in 1907; full sovereignty was achieved in 1987 via began to emerge in Europe with the establishment in the Constitution Act of 1986. 1860 of the National Hospital for (the Relief and Cure of) the Paralysed and Epileptic in Queen Square, London (from 1948: National Hospital for Nervous NEUROLOGY IN AUSTRALIA PRIOR Diseases, Queen Square; hereafter: Queen Square), TO WORLD WAR II and the appointment of Jean-Martin Charcot to the first The standards of Australian medical centers before chair in neurology in Paris in 1882, as well as with Second World War were generally modest in comparithe appearance of journals devoted to brain disease, son with their European and North American countersuch as Archiv für Psychiatrie und Nervenkrankheiten parts, and physicians were wholly dependent on (1868) and the Journal of Nervous and Mental Disease overseas specialist training and experience for expand(1876). It should be noted that physicians at Queen ing their skills and intellectual horizons. Medical speSquare were also expected (until the 1920s) to “be associalization of any kind was exceptional in Australia in ciated with the practice of general medicine or surgery the 19th and early 20th centuries, with the first speciain other institutions” (Holmes, 1954, p. 10); Kinnier lizations to emerge being gynecology, obstetrics and Wilson (1874–1937), junior neurologist at King’s College ophthalmology. There was also no unequivocal distincHospital from 1919, is generally regarded as being the tion between physicians and surgeons until the early first “pure neurologist.” Australian medical practi20th century (Power, 1935; Gandevia, 1971, p. 94). tioners were aware of overseas developments, as they The first Australian medical schools were established were also of the major neurological textbooks published in the mid-19th century: at the University of Sydney in by Romberg, Gowers and others in the 19th century, but 1856 (where actual teaching, however, did not comcircumstances at this point did not favor a focused mence until 1883) and at the University of Melbourne interest in neuroscience by antipodean physicians. in 1862. Prior to this, there had been limited local trainThis, of course, did not mean that neurological ing of “medical apprentices” in Sydney, most notably problems were unknown in Australia before 1950. by the former convict William Redfern (1774?–1833; Epidemiological studies suggest that the incidence of appointed assistant surgeon upon his emancipation in neurological disease in the non-Aboriginal population 1808) and later by the Sydney Infirmary (1849). Future of Australia is not significantly different to that in physicians were otherwise obliged to travel overseas, other Western nations, with the possible exception that usually to the United Kingdom, to pursue medical stuParkinson’s disease may be a little more common (for dies, and this applied especially to specialist training. example, Chan et al., 2005). It has indeed been reported Australian physicians were expected to be generalthat the first recorded neurological death in Australia, a ists, and any form of specialization was regarded with stroke fatality, may have occurred as early as 1791: suspicion. This was also a matter of practicality, as the Robert Hogg or Peter Hubbert, a convict attendrestricted opportunities offered by a small, young ing on Mr. White, in passing from his house to population militated against excessive specialization. the kitchen without any covering upon his head, Further, British medicine was regarded as the epitome of the art, while bonds of any kind with the “Mother received a stroke from a ray of the sun, which at

HISTORY OF NEUROLOGY IN AUSTRALIA AND NEW ZEALAND 783 the time deprived him of speech and motion, Smith (1871–1937). Elliot Smith graduated in medicine and in less than twenty-and-four hours, of his from Sydney University in 1892, where he also conlife. (Cited by Eadie, 2000a, p. 2) ducted research into the brains of non-placental mammals (for which he received his MD), before traThere was also awareness of even recently defined disveling to London in 1896 to study anatomy. He then orders. For example, Charcot published his clinicoaccepted the newly inaugurated chair of anatomy in pathological study of multiple sclerosis in 1868, and Cairo (1900–1909), marking the commencement of a Alfred Kingcombe Newman was evidently conversant varied and colorful career as anatomist, Egyptologist with this work when, in 1875, he discussed “insular and anthropologist. He prepared the first X-ray of a sclerosis of the brain and spinal cord.” The first clinimummy, promoted the “diffusionist” hypothesis of cally secure case of multiple sclerosis in Australia Egypt as the source of Western civilization, and played was identified in 1886 by James Jamieson (Frith, 1988). a role in the events of the Piltdown affair. After Given the lack of reliable testimony regarding the returning to the United Kingdom he made further conissue, it is difficult to address the question of whether tributions to neuroanatomy, particularly with regard to the Aboriginal inhabitants of Australia suffered particuthe corpus striatum, comparative anatomy, and the lar neurological diseases to any significant degree, evolution of the nervous system, initially at Manchealthough their lower life expectancy probably precluded ster (1910–1919) and then as professor of anatomy at the high incidence of those disorders associated with University College (until his death), where he revised advanced age. The young European population in 19ththe neuroanatomy section of Cunningham’s Textbook century Australia – in 1881, half the population was of Anatomy (Blunt, 1988). younger than 21 years (Gandevia, 1971, p. 82) – probably Two Australian anatomists with a particular interest also experienced a comparatively low incidence of in neuroanatomy studied with Elliot Smith at Univerage-related disease. sity College. Joseph Lexden Shellshear (1885–1958) Two major local medical journals published case developed an interest in both nervous system embryolreports and medical news, one each in Melbourne ogy and anthropology while working in Elliot Smith’s (Australian Medical Journal, 1856–1914; 1896–1909 as department after First World War. As Professor of Intercolonial Medical Journal of Australasia) and Anatomy in Hong Kong (1922–1936), he published Sydney (Australasian Medical Gazette, 1881–1914), many papers on the comparative morphology and before fusing in 1914 to form the Medical Journal of blood supply of the cerebrum, in which area he continAustralia. The review of neurological publications in ued to be productive after his return to Sydney, where these journals by Eadie (2000a, pp. 5–15) reveals that he also further pursued research into racial differences Australian physicians were working with concepts and in brain structure. He is remembered at Sydney by the definitions adopted from their British cousins, Shellshear Museum of Comparative Anatomy and although there were also examples of differences; for Physical Anthropology (Stone, 2002). example, Hughlings Jackson’s concepts of epilepsy Andrew Arthur Abbie (1905–1976) worked with were not generally embraced in Australia until the Elliot Smith a decade later, and was awarded his PhD early 20th century, with at least one Sydney physician in 1934 and the Johnston Symington Prize of the Anatoeven casting doubt on the nosological discreteness of mical Society of Great Britain and Ireland. He was the disorder (Money, 1896). awarded his DSc by Sydney University in 1941 for two Similarly, advances in neurological technology, such papers published in the Journal of Comparative Anatas lumbar puncture, cerebrospinal fluid analysis and omy, and as a teacher was long remembered by medical ventriculography, were, as a rule, adopted 5–10 years and science students for his stimulating neuroanatomical after their introduction in Europe or America. There demonstrations. Abbie was appointed to the chair of were also instances of overseas practice not being anatomy in Adelaide (1944) following a period of service adopted, perhaps the most peculiar being the fact that in the Australian Imperial Force, where he further puran extract of the Australian tree Duboisia myoporoides sued research in neuroanatomy and neuropathology, was widely employed from 1890 in Europe as an antiwith a particular interest in the corpus callosum, the parkinsonian agent and sedative, but was not used blood supply to the basal ganglia, and the nervous sysfor these purposes in its homeland. It was employed tems of Australian mammals. Like Shellshear, he was in Australia in ophthalmology, but even here it was also interested in anthropology, and from 1950 directed used alongside imported belladonna preparations the greater part of his attention to research into social (Foley, 2006). and physical characteristics of the Australian Aborigines The first major contributions by an Australian to (Elmslie and Nance, 1993; Bonnin, 1994). neuroscience were probably those of Grafton Elliot

784 P. FOLEY AND C. STOREY Other Australians who traveled to England in the during the acute phase, while Royle survived to course of their medical studies could not be persuaded exhibit initial signs of post-encephalitic parkinsonism to return. William John Adie (1886–1935) was born in in 1930. Royle, but not Hunter, therefore suffered the Victoria and studied medicine in Edinburgh, where he disappointment of seeing the premise underlying symgraduated in 1911. His attention turned early to neurolpathectomy for spastic paralysis gradually but decisiogy, and after postgraduate studies in German clinics vely refuted by a series of neurophysiological reports he was appointed resident medical officer at Queen during the following years, without, on the other Square. He served as physician and neurologist with hand, the relative success of the procedure ever being the British Army during First World War, following doubted or satisfactorily explained. which he added appointments at the Royal London Sympathectomy for spastic paralysis (and, to a Ophthalmologic (Moorfields) and Charing Cross Hosmore limited extent, for motor symptoms of encephapitals to his activities. His particular interest in neurololitis lethargica in children) is certainly not the only gical disease initially concerned narcolepsy (for his major neurosurgical technique to have enjoyed a period thesis on which the University of Edinburgh awarded of popularity before falling into disfavor. It was, in him their Gold Medal in 1925), but he also made signifany case, the first major neurological procedure to be icant contributions regarding the clinic of dystrophia developed in Australia, and the episode served to myotonica and disseminated sclerosis; he is best known enhance Australian consciousness of the potential of for his (admittedly not entirely original) 1931 descriplocal medical science. Hunter’s early death was a tration of the tonic pupil (“Adie’s syndrome”), where gedy that did nothing to reduce the awe with which response to light is poor but to accommodation somehe was regarded; Elliot Smith remarked that, “Had he what better. Adie was also esteemed as a fine teacher, lived, he might have become the foremost man of and, with James Collier (1870–1935), edited the highly science of the age” (Elliot Smith, 1924; see also Hooper regarded neurology section of Price’s Textbook of the et al., 1925). Practice of Medicine. He was also a founding member Another neurological disorder addressed by an of the Association of British Neurologists (1932) Australian, albeit no physician, in a manner that drew (Caughey, 1953). international attention was poliomyelitis (“infantile The first Australian neurological innovation that paralysis”). In the first half of the 20th century, there attracted international attention was the introduction was no effective treatment for the disorder, and nonby the young Sydney professor of anatomy John Irvine orthodox methods emerged in many parts of the world. Hunter (1898–1924) and the orthopedic surgeon NorIn Queensland, Elizabeth Kenny (1880–1952), better man Royle (1888–1944) of sympathectomy for the ameknown in Australia and the USA as “Sister Kenny,” lioration of spasticity. Hunter, who had been appointed replaced the standard serum and limb immobilization associate professor at the age of 22 years, introduced approaches with massage, heat application, and intense this novel approach in late 1923, following his return passive and active exercise regimes. Although confrom 3 years overseas studying under his mentor demned by medical authorities, her determined James Thomas Wilson (1861–1945; formerly professor approach won popular support, and clinics for her of anatomy at Sydney University) in Cambridge, Elliot method were established in some Queensland towns, Smith in London, and Arie¨ns Kappers in Amsterdam. and, on a much larger scale, in the USA, where she It had been hypothesized that skeletal muscular tone was also accorded the ultimate accolade of a Hollywood consisted of two elements, contractile tone and plastic film biography (featuring Rosalind Russell, 1946). As tone, and that these components were regulated by diswith the Hunter–Royle operation, her approach was tinct nerve fibers (“dual innervation”). The consebased on a false premise – the supposition of direct quences of disruption of nerve tracts from the muscular damage by the infectious agent of poliomyelianterior horn cells to muscle were well known (paralytis – but in practice the approach proved to be by no sis), but Hunter and Royle wondered whether symmeans inferior to standard interventions, and may even pathectomy might be of clinical value. Their have been more effective (Patrick, 1983). technique, promoted during a tour of the USA and It was also at about this time that a new and unusual the UK, was received with cautious acceptance by neurological disease was described in Australian leading international surgeons, including William journals: “X disease,” also known as the “mysterious Macewen (Glasgow) and William Mayo (Rochester, disease.” Outbreaks of this disorder occurred in various MN). During this journey both Australians fell ill, parts of rural NSW and Queensland in 1917, 1918 and Hunter died shortly thereafter. Unconfirmed and 1925. An acute, severe encephalitis (principally in reports suggest that both had contracted encephalitis children), the disease was characterized by high fever, lethargica in New York, with Hunter succumbing altered consciousness, signs of cerebrospinal irritation

HISTORY OF NEUROLOGY IN AUSTRALIA AND NEW ZEALAND and high mortality (c. 70%). It was initially thought to be a form of encephalitis lethargica, then making its first appearance in the Northern Hemisphere, but clinical and neuropathological differences were quickly noted. Research by Anton Breinl (1880–1944) at the Australian Institute of Tropical Medicine (Townsville), and by John Burton Cleland (1878–1971) and the neurologist Alfred Walter Campbell (more of whom below) for the Department of Public Health in Sydney, succeeded in demonstrating the transmissibility and viral nature of X disease, and elucidating its neuropathological consequences in various species; the responsible agent, however, could not be isolated. This was later accomplished following a further outbreak along the Murray River in 1951 (“Murray Valley encephalitis virus”). The disease is now recognized to belong to the family of arthropod-borne viral encephalitides which have since been identified around the world (such as Japanese and West Nile virus encephalitis) (Anderson, 1954).

NEUROPATHOLOGY Clinical neurology also began to emerge in Australia, albeit informally, in the 1920s, as certain physicians exhibited particular and sustained interest in neurological questions, particularly in the fields of neuroanatomy and neurophysiology. The most prominent was Oliver Latham (1877–1974; Pathology Laboratory, State Lunacy Department, Sydney), who has been described as the doyen of neuropathology in Australia. He contributed an extraordinary number of case reports on various neurological disorders, supplemented by superb neuropathological illustrations and descriptions. He conducted little original experimental work, but his morphological neuropathology provided the foundations of Australian neuropathology for half a century. Outliving not only most of his contemporaries but also most of his students, his career was unfortunately not adequately appreciated by a fitting obituary (cf. Noad, 1975; Burke, 1988a). One of Latham’s students, Brian Baxter Turner (1926–1974), traveled to Queen Square to work with Joseph Godwin Greenfield, before returning to Australia to establish the Oliver Latham Neuropathology Laboratory in Sydney. Here he investigated cerebellar degeneration in alcoholism, Parkinson’s disease, and congenital metabolic disorders; he also established the first chromosome laboratory in Australia, anticipating the emerging link between neuropathology and neurogenetics (Burke, 1988b). Other significant contributors to neuropathology in Australia have since included the Russian Jakob Mackiewicz (1887–1966), Ross Anderson (1923–1988), the Hungarian Istvan To¨rk (1939–1992) and Byron Kakulas (b. 1932), the first

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professor of neuropathology in Australia (at the University of Western Australia).

FORERUNNERS OF CLINICAL NEUROLOGY IN AUSTRALIA The title of “Honorary Neurologist” was borne by several physicians during the 1920s (including Hunter, at Lewisham Hospital, Sydney), but it did not imply the specific character that it does now, and in some cases was even used by psychiatrists. The first physician to have made neurology the focus of his career, interestingly, was never officially designated a “neurologist.” George Edward Rennie (1861–1923) studied medicine in London before returning to Sydney, where between 1894 and 1921 he occupied positions as Honorary Assistant Physician and Honorary Physician at the Royal Prince Alfred Hospital (RPA), then the leading teaching hospital in Sydney. Rennie devoted his professional attention primarily to clinical neurology, a field in which he was regarded as the leading expert in NSW. He contributed a number of papers on various neurological topics, including an interesting review of the pharmacological options then available for management of neurological disease, to the Australasian Medical Gazette, of which he was an editor. Like other physicians of his era, however, Rennie also published extensively on non-neurological matters (Finn, 1988; Eadie, 2000b). Two other physicians may also be regarded as significant pioneers of clinical neurology in Australia: ●

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Sidney Valentine Sewell (1880–1949): studied medicine in Melbourne, attended clinics at the National Hospital for the Paralysed and Epileptic in London, returned to Melbourne in 1910, opened private practice in Collins Street; brief tenure as neurologist and assistant pathologist at St. Vincent’s Hospital followed by appointment as physician at Melbourne Hospital, where he delivered a highly regarded series of lectures on neurology. His primary medical interest after First World War concerned pulmonary tuberculosis. His major medical influence was as a teacher (see Duffy, 1988; Hurley, 1988). James Froude Flashman (1870–1917): from 1900 inaugural director of the Pathology Laboratory of the NSW State Lunacy Department, where together with Latham he investigated the neuropathological basis of mental disease, including the first neuropathological confirmed case of multiple sclerosis in Australia (1915); from 1910 private practice in neurology and pathology; enlisted in the Army in 1915, organized medical facilities for Australian wounded; succumbed to pneumonia in France 1917 (obituary: Anonymous, 1917).

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ALFRED WALTER CAMPBELL The first Australian physician who unambiguously committed himself to neurology, however, was Alfred Walter Campbell (1868–1938; Fig. 48.1), a remarkable personality who established an imposing reputation both as neurocytologist and as neuropathologist. His most productive period was spent overseas. Following the completion of his medical studies in Edinburgh (1890), two years of postgraduate research in London, Vienna and Prague, and the award of his doctorate in medicine for his Alcoholic Neuritis, its Clinical Features and Pathology (1892), he assumed a position as resident medical officer and pathologist at Rainhill Asylum (near Liverpool). From there he published a number of significant neuropathological papers, including one with Henry Head that established the neurohistological basis of Head’s dermatomes, “On the pathology of herpes zoster and its bearing on sensory localisation” (Head and Campbell, 1900). Other research concerned senile brain changes, alcoholism, spinal tract degeneration and the neuromuscular effects of syphilis.

Fig. 48.1. Alfred Walter Campbell (1868–1938). From Eadie (2000a), p. 44.

Campbell’s most important work, however, evolved from his recognition that accurate descriptions of the cytoarchitecture of the mammalian cerebral cortex are crucial for the scientific advancement of neurology. On the basis of studies of normal human brains, various neurological disorders, and diverse animal species (including some monkeys from his collaboration with Sherrington and Gru¨nbaum) he accumulated a vast amount of valuable data. First introduced by Sherrington at the Royal Society in 1903, Campbell’s results were eventually published in 1905 with Royal Society financial support as Histological Studies on the Localisation of Cerebral Function. Although his topographical divisions of the cortex were not as fine as those published shortly afterward by Brodmann, the reliability of both his data and his conclusions was never contested, and his clear illustrations continued to be reproduced in textbooks for many years. His work was, in fact, highly valued by von Bonin, Fulton and Lorente de No´, who wrote: The only good [cytoarchitectonic pictures] are those of Campbell, who, let me put it in capital letters, HAS BEEN THE ONLY CYTOARCHITECTONIST WHO HAS DESCRIBED FACTS AND ONLY FACTS. The German architectonists have mixed facts with theories in such a manner that nobody can tell where facts end and theories begin . . . Campbell’s ink drawings, besides being good, are easily reproduced. (Lorente de No´, 1938; see also Fulton, 1938) Before this monograph had appeared, Campbell returned to Australia, where he practised as a neurologist (which is how Campbell described himself) and sometime neuropsychiatrist in Sydney until 1937, combining the two halves of nervous disease medicine, as was then customary in Europe. He also occupied positions as Honorary Neurologist at the Royal Alexandra Hospital for Children, the Coast Hospital and at the Department for Repatriation, but not at a University of Sydney teaching hospital. At the time of his return, Latham and Flashman were dominant in neuropathology, while Rennie was the leading voice in clinical neurology; all were based in Sydney, and this may have influenced Campbell’s perhaps curious decision to not resume full-time neuropathological research in Sydney. His daughter remembered that he was “frightfully shy and reserved, and loathed publicity” (Eadie, 2000a, p. 46), while an obituary recorded that lack of self-confidence precluded him from teaching (Parker, 1938). He may, however, have simply preferred the financial security of clinical practice, having married a childhood friend in 1906.

HISTORY OF NEUROLOGY IN AUSTRALIA AND NEW ZEALAND Campbell presented part of his investigation of the comparative anatomy of the cerebellum at the Australasian Medical Congress in 1911, but even this work was never published in full. His groundbreaking work of 1916 on the gorilla brain went unnoticed until its enthusiastic propagation by Fulton in 1938. As mentioned above, Campbell also investigated the nature of X disease after First World War, this work representing his last contribution to neurohistological research. Campbell served with the Australian Army Medical Corps at the 2nd Australian General Hospital in Cairo during 1915, where he oversaw the treatment of nerve injuries and mental traumata that resulted from the disastrous Gallipoli expedition. Upon his return to Australia he published in the Australian Medical Journal one of the first papers on “neuroses in war,” rather than “war neuroses” or “shell shock,” as in the title of Elliot Smith’s monograph (Smith and Pear, 1917): Campbell underscored the fact that the observed disorders were not essentially different from civilian neuroses, wherein he emphasized that cowardice played no role in disease presentation, but that a return to frontline service was nevertheless in most cases unlikely (Campbell, 1916). In his history of the Army Medical Services in First World War, Arthur Graham Butler extolled Campbell as “one of the most scientific, broad-minded, and able neurological specialists that the country has produced,” and specifically noted that “his appreciation of the medical, military and national problems” represented by the neuroses and psychoses of war “may be read today with interest and advantage” (Butler, 1943, pp. 81–82). Campbell continued to practise as a clinical neurologist until his death in 1937, the first Australian to devote himself exclusively to this field. However, he never occupied an academic or official teaching hospital position in Australia, and trained no students to further advance either his neuropathological work (which was, in any case, less recognized in his homeland than overseas) or the status of neurology as a medical specialty. Despite the limited impact of his contributions upon neurology in Australia, Campbell was nonetheless one of only two Australians selected for inclusion in Haymaker and Schiller’s second edition of The Founders of Neurology (1970), the other being Elliot Smith, whose scientific career, as noted above, unfolded almost entirely overseas (Ford, 1979; Eadie, 1981; for recent appreciation of the relevance of Campbell’s work, see Ffytche and Catani, 2005). Campbell is remembered today by the A.W. Campbell Award, with which the Australian Neuroscience Society (ANS) recognizes the most significant contribution to neuroscience by an ANS member during their first 5 postdoctoral years.

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DEREK DENNY-BROWN It is probable that one New Zealander, who similarly spent little time in the land of his birth, would have been included in The Founders of Neurology were he not alive at the time of its compilation. Derek Ernest Denny-Brown (1901–1981; Fig. 48.2) departed New Zealand after completing his medical degree at Otago University in 1925. Inspired by the work of Hunter and Royle, he aspired to a career in neurosurgery and traveled to England to study the physiology of posture and movement with Charles Sherrington in Oxford as a Beit Fellow (1925–1928), following a brief period as clerk at Queen Square. During this intensive period of research, DennyBrown investigated fundamental issues of neurophysiology, including the properties of white and red muscle, Sherrington’s model of the motor unit, the stretch reflex, and the nature of facilitation; he defined the subliminal fringe, and demonstrated the slow discharge of motor neurons in postural reflexes and the recruitment of single units. In 1932, he published with Creed, Eccles, Liddell and Sherrington the landmark Reflex Activity of the Spinal Cord. At the end of the fellowship that had facilitated this fruitful period, he accepted a position as House

Fig. 48.2. Derek Denny-Brown (1901–1981). Photograph courtesy of Joel Vilensky, Department of Anatomy and Cell Biology, Indiana University School of Medicine, Fort Wayne, IN, USA.

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Officer and Resident Physician at Queen Square. From 1931 he was registrar, and from 1935 to 1941 Assistant Physician at Queen Square and neurologist at St. Bartholomew’s Hospital, London. By this point DennyBrown had decided that his future lay with neurology rather than with neurosurgery. At Queen Square he had the opportunity to learn from, amongst others, Godwin Greenfield, Samuel Alexander Kinnier Wilson, and Macdonald Critchley, as well as Russell Brain at Maida Vale. His own contributions included the introduction to Queen Square of electromyography and muscle biopsy preparation, and he collaborated with Graeme Robertson (see below) in the investigation of sphincter reflexes. In 1941 he moved to Harvard as director of the Neurological Unit at Boston City Hospital, and in 1946 he was appointed Putnam professor of neurology at Harvard University. Throughout his career, Denny-Brown was a productive researcher, publishing on a broad range of neurological themes, but with a particular interest in neurotraumatology and movement disorders. He regarded neuropathology as “the essential science of neurology” and the neuropathology laboratory as the site of scientific progress (Kreutzberg, 1997). Also philosophically significant was his 1952 Shattuck Lecture to the Massachusetts Medical Society, “The Changing Pattern of Neurological Medicine,” in which he described a neurology as an autonomous medical specialty, but one to be considered in the context of its interactions with internal medicine, rather than with psychiatry. Denny-Brown’s research files, including both surgical records and film and photographic material, continue to be a valuable scientific resource. Although his career unfolded outside his homeland, his immense contributions to neurology ensure him a place in the history of Oceania neurology. Next to the physicist Ernest Rutherford (1871–1937), he is without doubt the most eminent scientist produced by New Zealand (Foley, 1982; Vilensky et al., 2004).

fact that his active career unfolded entirely outside Australia (Williams, 1979). Further, the interest in sympathectomy triggered by the work of Hunter and Royle attracted surgeons such as Albert Coates (1895–1977) to brain surgery. Neurosurgical units were established in several cities in the course of the 1930s: ●

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NEUROSURGERY PRIOR TO WORLD WAR II Neurosurgery, inspired by British pioneers such as Victor Horsley (1857–1916) and William Macewen (1848–1924), had been confidently pursued in Australia since the late19th century (McHill, 1903; Simpson and Dan, 2005). The Australian Hugh William Bell Cairns (1896–1952), who had studied with the influential American neurosurgeon Harvey Cushing (1869–1939), was the first to commit himself primarily to neurosurgery, and fostered a generation of Australian neurosurgeons, despite the

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In Melbourne, Albert Coates, who had been influenced by Sewell while a resident physician at Melbourne Hospital in 1925, founded a unit there in 1934, where in 1936 he introduced carotid angiography. Units were subsequently established at the Alfred and Austin Hospitals (under Hugh Trumble [1894–1962], who collaborated with his brother-inlaw Cox in work regarding blood vessel tumors) and St. Vincent’s Hospital (Frank Morgan, 1906–1988). In Adelaide, Henry Newland (1873–1969) and Leonard Lindon (1896–1978; who had trained in Boston with Harvey Cushing and had proposed a neurosurgical clinic for Adelaide in 1930) founded the Adelaide school of neurosurgery in 1936. In Sydney, Rex Money (1897–1984), after study in the UK and USA, had returned in 1938 to establish the first independent neurosurgical service at the RPA, where he was joined in the same year by Gilbert Phillips (1904–1952; see below). Douglas Miller, who, like Phillips, had studied with Hugh Cairns in London, returned to St. Vincent’s Hospital in 1939 and established a neurosurgical unit there. The Neurosurgical Unit at the Royal Perth Hospital was not established until 1950, by James Ainslie (1899–1973). Gerald Moss (see below) acted as neurologist to this unit until he departed in 1955 to Mental Health Services, although he did maintain an association with the Royal Perth. Prior to the establishment of this unit, neurosurgical emergencies were transferred to Sydney or Melbourne. In Brisbane, Geoff Toakley (1921–1999) was appointed neurosurgeon to the small Mater Hospital in 1954, and Kenneth Jamieson (1925–1976), who had trained with Trumble in Melbourne, to the Brisbane Hospital in 1956, where he established a neurosurgical unit in 1960 that evolved into the department of neurology and neurosurgery (1962). In New Zealand, Donald Mackenzie (1902–1974) was interested in neurosurgery from about 1937, but did not have access to a specialist neurosurgical unit at Auckland Hospital until after Second World War. He had trained in San Francisco in 1936 with the Cushing student Howard Naffziger (as had Rex Money), and had also worked in Queen Square (Sheehan et al., 2005).

HISTORY OF NEUROLOGY IN AUSTRALIA AND NEW ZEALAND Apart from Phillips, whose principal occupation had been in physiological laboratories before working with Hugh Cairns for 2 years, most of these men were more general surgeons with a particular interest in neurosurgery rather than specialist neurosurgeons. The establishment of an Australasian neurosurgical society was first proposed by Douglas Miller (1900– 1996) in 1939, and quickly realized: on 10 April 1940 eight Australian and New Zealand surgeons attended the inaugural meeting of the Society of Australasian Neurological Surgeons (from 1956: Neurosurgical Society of Australasia); two invited participants were prevented by military service from attending, but were accorded “founding member” status. There is little doubt that both the existence of this association and the natural professional interactions between neurologists and neurosurgeons were influential in the establishment of the AAN 10 years later. The first meeting of the Neurosurgical Society also included presentations on a broad range of neurological topics. Both Robertson and Cox, at that time the only two physicians officially designated clinical neurologists in Australia (see below), gave guest presentations (on encephalography and simulation of cranial tumor by Torula infection, respectively), as did the neuroanatomist Sunderland (on the hypothalamus) (Simpson et al., 1974; Curtis et al., 1980; Miller, 1985; Simpson and Dan, 2005). In Sydney, the contribution of the neurosurgeon Gilbert Edward Phillips to neurology in Australia was especially significant. During the early 1930s he had worked as research assistant to Sherrington at Oxford and Adrian at Cambridge, as clinical clerk at Queen Square and as assistant to Cairns. On his return to Sydney, he lectured in surgery, as well as on neurology, and applied neurophysiology in the anatomy department, where he inspired many of his students to take an interest in the neurological sciences. From 1937 to 1944, he was the highly regarded Honorary Assistant Neurosurgeon at RPA under the aegis of Harold Dew. During Second World War Phillips was a part-time consultant with the Royal Australian Air Force. He also returned to England in 1945 to undertake various short-term commissions, including officer-in-charge of the surgical division of the hospital for head injuries at St. Hugh’s College, Oxford. Phillips then returned to RPA as Honorary Neurosurgeon. From 1947 he worked to secure the support of the Returned Servicemen’s League (RSL) for the establishment of a center for the diagnosis of nervous diseases in ex-servicemen. These efforts led to the opening of the Northcott Neurological Diagnostic Centre in November 1951, the first independent unit in Australia for the study of neurological disease, and at a time when no Sydney hospital included a specialist neurological clinic (Lake, 2000).

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AUSTRALIAN NEUROLOGY IN 1939 When the Royal Australasian College of Physicians (RACP) was founded in March 1938, every physician was expected to have knowledge and experience in all branches of internal medicine. For the next 35 years specialization was not encouraged, and was even regarded with some suspicion. The conditions that prevail in a pioneer society – the physical hardships, the isolation, the youth of the population, limited resources – dictated that the 19th-century physician must become “jack-of-all-trades”; even the traditional distinction between physician and surgeon was blurred in Australia. Game noted as late as 1975: The emergence of neurology as a discipline in its own right has not been universally welcomed in some medical circles. There has long lingered a school of thought that general physicians should be all things to all men and that any declared specialisation beyond that represented a fragmentation of medicine to the detriment of the art . . . Some of our earlier Members had to expend a good deal of their endeavour in justifying their existence or attaining and maintaining their position as neurologists, and even now there are some institutions within the country which seek to make the neurologist subservient to the almost mythical figure of the complete general physician. (Game, 1975, p. 5) This situation, however, also contributed, at least until the middle of the 20th century, to the fact that the status of the general physician retained a relatively high level in comparison with non-specialists in Europe and North America. This also fueled the reluctance of medical authorities to condone a splintering of medical practice (Gandevia, 1971, pp. 93–94). The increasing complexity of modern medicine rendered specialization inevitable only in the final quarter of the 20th century. On the eve of Second World War there were only two full-time clinical neurologists in Australia, with a further three physicians who exhibited a particular interest in the field. ●

In Sydney, Kenneth Beeson (Bob) Noad (1900– 1987) promoted neurology as a specialty at Sydney Hospital and published a number of neurological papers, while Eric Leo (Gus) Susman (1896–1959) was de facto neurologist at RPA, although his official position, like that of Noad, was Honorary Physician. Susman also advised the Royal Alexandra Hospital for Children on neurological questions, and was later involved with the Northcott Neurological Centre. Both had trained at Queen Square in London (Selby, 1988a; Wolfenden, 1994).

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P. FOLEY AND C. STOREY In Perth, Gerald Carew Moss (1901–1972) was was directed toward the cellular organization of the first to cultivate clinical neurology in Western tumor cell colonies, pursuing the idea that they might Australia. He was a general physician at the Royal reproduce in 2-dimensional cell culture the characterisPerth Hospital, but interested in neurology long tic structures observed in vivo. His observation that before his appointment as senior neurologist upon tumor cells reproduced their original glial structure the opening of the Neurosurgical Unit in 1949. In raised questions concerning the validity of the prevail1955, he resigned his hospital appointments to ing embryogenetic brain tumor concept of Bailey and become neurologist to the Mental Health Services. Cushing; it is now recognized that gliomas derive from Moss also undertook university studies in the clasdifferentiated mature glial cells, confirming Cox’s sics, graduating with first class honors in classical cytogenetic model. Greek in 1960 (Sadka, 1988). Cox also studied disturbances of sleep and consciousness associated with particularly located basal These physicians were laying the foundation for tumors, whereby the absence of internal hydrocephalus the establishment of neurology in their respective indicated to him that cortical involvement in their cities, but progress was much more advanced at this effects was unlikely, a hitherto overlooked and subtle stage in Melbourne, with two physicians installed as point. This led him to suspect the existence of an alertHonorary Neurologists. Leonard Bell Cox (1894–1976; ing mechanism in the brainstem, foreshadowing the Fig. 48.3) had commenced practice as a neurological later identification by Magoun of the reticular formaconsultant in 1925, while conducting neuropathological tion as an activating brainstem system. Cox’ postulate, research at Melbourne University, the Baker Research however, did not receive major contemporary overseas Institute, and in his garage! In 1934, he was appointed attention (Schwieger, 1993, 1994; Wehner, 2004). Honorary Neurologist to the Alfred Hospital (where a Equally important was the fact that Cox served as Department of Neurology was established) and lecboth prototype and inspiration for the first generation turer in neuropathology at the University. of professional neurologists in Australia. The caliber Cox was interested in brain tumors and was one of of both his scientific work and his lectures, his unambigthe first to culture cerebral tumor tissue. His research uous enthusiasm for the specialty, and the organizational skills and drive crucial to the foundation of the AAN in 1950 ensured that his influence did not end with his death, as it had for Campbell in Sydney. It may be fairly asserted that a small Australian school of basic and clinical neuroscience was his heritage, including not only anatomists and clinical neurologists (such as Sydney Sunderland) but also neurosurgeons (Kenneth Jamieson) and neuropharmacologists (David Curtis). The second major figure in Melbourne neurology was Edward Graeme Robertson (1903–1975; Fig. 48.4). After 3 years at Melbourne Hospital (where he was influenced by Sewell), Robertson traveled to London in 1930 to work and study at Queen Square, collaborating with DennyBrown in the investigation of the neurophysiology of micturition and defecation. He then returned to Melbourne in 1934 and established himself as a consultant neurologist. Robertson had already been well established in London as a consulting neurologist, and his aim was to build a similar tradition in Australia. He had expected to be appointed as neurologist when he returned to Melbourne (such responsibilities having previously been the domain of psychiatrists), but he had to initially work as Honorary Physician in Outpatients at Melbourne Hospital; he was not appointed as Honorary Neurologist until 1944. In the following period he also received appointments as Honorary Neurologist to the Victorian Eye and Ear (1940), Children’s (1944) and Women’s Hospitals (1949), Fig. 48.3. Leonard Bell Cox (1894–1976). Photograph courtesy of Volkhard Wehner (Melbourne, Australia). as well as advising the Tasmanian Department of Public ●

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Fig. 48.4. Edward Graeme Robertson (1903–1975). From Eadie (2000a), p. 61.

Health and the Royal Australian Navy. Robertson’s newly officially sanctioned status as clinical neurologist and its context was thus a clear signal of the improved prospect for neurology as a recognized clinical discipline. Robertson was one of the leading authorities on the radiological examination of the brain, and was internationally recognized for his development of the now superseded technique of pneumoencephalography. John Fullarton Mackeddie (1868–1944), who had studied at Queen Square in 1923, had introduced diagnostic encephalography to Victoria in the mid-1920s. From 1935, Robertson contributed significantly to standardizing and improving the procedure. He published three monographs on the subject, Encephalography (1941; the 1967 revision is regarded as the classic tome on the subject), Further Studies in Encephalography (1946) and Pneumoencephalography (1957), as well as 66 scientific papers. One obituary recorded that Robertson “saw in the nervous system a complexity reduced to a perfection of orderliness which fascinated him” (Game, 1976). His international reputation contributed to elevating the profile of neurology in Australia and of Australian neurology overseas. The E. Graeme Robertson Lecture

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has been an important feature of AAN meetings since its inauguration in 1978 (Lance, 1988; Clark, 2002). (For further history of neuroradiology in Australia, see Sage [1995].) One of Cox’s scientific collaborators and colleagues at the Alfred Hospital was Sydney Sunderland (1910– 1993). Sunderland had been Honorary Assistant Neurologist at the Alfred for a brief period (1936–1937), but from 1938 (at the age of 27 years) to 1961 was professor of anatomy at the University of Melbourne, after returning from work on cortical neurophysiology with Le Gros Clark in Oxford and Wilder Penfield in Montreal. Sunderland’s long-term interest in the neurophysiology of peripheral nerve injury and surgical restoration of severed nerves (during the war he oversaw the armed forces’ Peripheral Nerve Injury Unit [PNIU] in Melbourne) would lead to two major textbooks, Nerve and Nerve Injuries (1968; based on his longitudinal study of more than 350 PNIU patients) and Nerve Injuries and their Repair: A Critical Approach (1991). Sunderland was internationally esteemed for his papers on the classification, diagnosis, therapy and prognosis of peripheral nervous system disorders. Although a clinical neurologist for only a short time, he contributed greatly to bridging the divide between clinical and experimental neurology (DarianSmith, 2005). Melbourne had thus become attractive to other prospective neurologists by the late 1940s. John Aylward Game (1913–1995) returned to Australia from Queen Square in 1950 to assume a consultant neurological position as junior to Cox at the Alfred Hospital. John Billings (1918–2007), perhaps better known since the 1960s for his promotion of a popular form of natural family planning, similarly returned to Melbourne from Queen Square in 1949 to a position as neurologist at St. Vincent’s Hospital (a position he retained until 1984) (Bladin, 2007). The number of physicians practising as clinical neurologists in Melbourne (and Australia) was thus increased to four. Game later recalled that this career choice represented “a slightly bold decision for the time” (Game, 1975, p. 2; Gilligan, 2005).

THE FOUNDATION OF THE AUSTRALIAN ASSOCIATION OF NEUROLOGISTS (AAN) The foundation of the Department of Neurology at the Royal Melbourne Hospital in 1944 marked the beginning of the establishment of Melbourne as the first center of Australian neurology, and it was in the southern capital that the idea of creating a professional organization for representing the interests of Australian neurologists was conceived during the immediate post-war years. The inaugural business meeting was held on 25 October 1950 in the Department of Anatomy at Melbourne University.

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The eight founding members included the principal motivating forces behind this move, Cox and Robertson, and the other two Melbourne neurologists (Game, Billings); their fellow Victorian Sunderland (described by Game [1975, p. 2] as providing “the first and lasting link between town and gown in our Association”); Noad (later President of the RACP) and Susman from Sydney; and Moss from Perth (who was unable to attend). Leonard Cox was appointed first president (1950– 1957), and Game honorary secretary (until 1965) and treasurer (until 1957). Game (1975) later described four central objectives of the new organization, as stipulated by its constitution, completed and adopted in 1954: 1. personal fellowship of all throughout Australia primarily interested in neurology; 2. scientific association and collaboration; 3. recognition and establishment of neurology in its broadest sense, bringing together both clinicians and others whose primary occupation was the study of the nervous system; 4. the establishment and maintenance of the highest possible standard of clinical neurology in Australia. (Game, 1975). The name selected for the association, the Australian Association of Neurologists, was chosen to identify its members geographically without limiting the breadth or scope of membership, which the alternative proposition, Association of Australian Neurologists, may have implied. It is significant that the association was designed as a national, not a state-based, organization, a decision reflecting the closer ties amongst Australians that had developed during the course of Second World War. This also applied to the men who initiated the association: most had served in some capacity with the armed services. New Zealand members were also welcome, despite the word Australian rather than Australasian being adopted for the name of the association, in contrast to the RACP and the corresponding neurosurgeons’ association. Two New Zealanders joined the AAN in 1962, and by 1988 the number had grown to 11. The New Zealanders for many years also supported their own association (New Zealand Association of Neurologists, NZAN), before the two national organizations merged to form the Australian and New Zealand Association of Neurologists (ANZAN) in 2006. The major discussion at the one-hour inaugural meeting concerned membership eligibility, and the “liberal view of including all physicians who had some interest in neurology was decided to be less important than the concept that we were seeking association of those who accepted occupation with the problems of

the nervous system as their primary interest” (Game, 1975, p. 2). The membership was thus restricted to those exclusively dedicated to clinical neurology. Initially this meant that new candidates were elected as “provisional members” for a period of 3 years, during which time they were to establish that their primary interest concerned neurology. This was later changed to provisionally accepting any medical graduate who held an MD or a Fellowship or Membership of the Royal College of Physicians in Australia (FRACP) or England (FRCP). A candidate with at least 3 years’ experience in clinical neurology and intending to maintain this occupation in the future qualified for ordinary membership. From 1975 a new category of “affiliatein-training” was introduced for medical practitioners undertaking specialist training as neurologists. Associate membership could be granted to nonneurologists with a professional involvement in medicine relevant to neurology, including radiologists, neuro-ophthalmologists and psychologists, or in the neurosciences, such as neurophysiology and neuropharmacology. Honorary membership has also been bestowed on outstanding international figures in the neurosciences, including John Eccles, Macdonald Critchley, Charles Symonds and Oliver Latham (Game, 1975; Selby, 1988b). The AAN was only 3 years old when it became a founding member of the World Federation of Neurology (WFN) in 1957. At this point the WFN, like many international scientific and medical associations, was perceived by many to be primarily an organization for Europe and North America. This made active participation difficult, especially given the problems of distance and the small local member base, but Australian delegates were nonetheless very active in the WFN from the beginning, and even provided two vice-presidents (Robertson, Game). William Carroll (Sir Charles Gairdner Hospital, Nedlands, Western Australia) is currently one of the elected trustees. Australia was also a founding member of the local division of the WFN, the Asian and Oceanic Association of Neurology (AOAN; 1960), and in 1967 hosted the second conference of the organization in Melbourne. Meetings of the AOAN are held every 4 years, between WFN congresses (most recently in 2008 in New Delhi).

NEUROLOGY IN NEW ZEALAND Ivan Macdonald “Dusty” Allen (1895–1962; Fig. 48.5) was the first New Zealand neurologist. He was initially a general physician, but traveled to the UK for postgraduate study in London at the West End Hospital for Nervous Diseases (where he worked with WorsterDrought) and Queen Square (1927–1931). Initially

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and worked to have a neurosurgeon appointed to Wellington. By 1967 he had achieved the establishment of a modern neurological department. Bergin operated a private practice that attracted patients from across the country, and was for a time visiting neurologist to Wanganui and Hawera Hospitals. Bergin was also active in the New Zealand Epilepsy Association and the Scientific Advisory Committee of the New Zealand Neurological Association, the foundation of which was largely due to his efforts, and was one of the first two New Zealand members of the AAN. Bergin also made major contributions to the education of both general medical staff and neurologists in neurology (Haas and Hornabrook, 2005).

EXPANSION OF CLINICAL NEUROLOGY IN AUSTRALIA

Fig. 48.5. Ivan Macdonald Allen (1895–1962). Photograph courtesy of the J.O. Mercer collection, Wellington Hospital photographic archives, New Zealand.

appointed on his return to New Zealand as Honorary Visiting Assistant Physician to Wellington Hospital in the national capital, his title was changed to Honorary Visiting Neurologist in 1937 and to Visiting Neurologist in 1940; from 1956 to 1962 he was Consulting Neurologist to Wellington Hospital. Despite his status as the then sole New Zealand neurologist, an impressive neurological publication record, and his status as foundation member of the RACP, he does not appear to have been invited to the inaugural meeting of the AAN, despite the fact that fellow countrymen were already members of the RACP (Bergin, 1988). John Daniel (Jack) Bergin (1921–1995) also practised neurology in Wellington. Bergin undertook postgraduate medical training at the Royal Post Graduate Medical School, Hammersmith, UK, following which he was appointed to Queen Square, the first New Zealander to be appointed to this institute after the war, from which point his professional life was committed to neurology. Bergin succeeded Allen at Wellington Hospital in 1956, but required tactful application of his intellectual faculty and clinical competence to overcome resistance to the idea of a specialist neurologist. He was instrumental in introducing a number of technological innovations to New Zealand, including neuroradiology and clinical neurophysiology (particularly electroencephalography),

Despite the ambitious hopes expressed by the founders of the AAN, clinical neurology grew slowly in the subsequent years; by 1962 there were still only 25 clinical neurologists practising in Australia. Nevertheless, the foundations for the future in Sydney had been laid in 1946 with the graduation of six physicians, all of them influenced by Gilbert Phillips, including William Burke (1923–1994) and George Selby (1922–1997). Burke was appointed Assistant Physician to the Neurosurgical Department of St. Vincent’s Hospital (Sydney) in 1951, where he developed a de facto neurological unit, which was, however, officially recognized as such only in 1962. George Selby had left for Europe in 1948, spending some time at Queen Square, before returning to consultant practice in Sydney. His hospital positions included his long period as physician at the Royal North Shore Hospital (RNS), where he also practised exclusively as a neurologist, and he was also for a time director of the Northcott Centre (O’Sullivan, 2005; Williamson, 2005). Notably, Selby has published on the history of neurology in Australia (for example, Selby, 1992). It would, however, require a great deal more time before formal neurological departments or consultant neurological posts would be established by the major University of Sydney teaching hospitals, principally for reasons of conservatism amongst other Sydney physicians and in the RACP. The first to be established was at the University of New South Wales (UNSW) teaching hospital, the Prince Henry, where in 1961 a Department of Neurology within the UNSW Division of Medicine was established under James Lance. The Neurological Unit at the RNS was established in 1964, under Selby. At the RPA, a Neurosurgical Unit had existed since the 1950s, but the Department of Neurology

794 P. FOLEY AND C. STOREY was inaugurated only in 1978, with John Allsop (also of physician’s intellect more than any other.” Basic the Gilbert Phillips school) being able to formalize the stainstruction in neurology was administered in Australia tus of his neurological practice at the hospital after almost via neuroanatomy and neurophysiology classes during 20 years (Allsop, 1994). the basic medical degree, after which the prospective Clinical neurology had also begun to establish itself neurologist was forced to seek further training overseas, in other states. In Brisbane, the first neurological usually at his own expense. The same problems, and in appointment was that of the late Peter James Landy, the ensuing period similar responses, applied to the who had trained in London, to the then relatively small training of neurosurgeons. There was no doubt, on the Mater Hospital in 1953. More important was the other hand, that the training received was of the highest appointment in 1960 of John Sutherland as senior visitquality, and the opportunity to meet and work with such ing neurologist to the Brisbane General Hospital. notable figures as Charles Symonds and Macdonald Shortly afterward, Mervyn Eadie was appointed as Critchley was in itself inspirational. Sutherland’s junior, and the two also advised the ChilSymbolic of the close ties between neurology in dren’s Hospital (Sutherland, 1994). Australia and Queen Square was the presentation to The Royal Adelaide Hospital had earlier appointed the AAN in 1954 by Macdonald Critchley (then Henry Kenneth Fry (1886–1959) as Honorary Assispresident of Section of Neurology, Royal Society of tant Physician in Neurology (1920–1924), but the Medicine) of a gavel. It was prepared from wood colappointment of John V. Gordon, after his return from lected from a bombed area of the National Hospital in Queen Square, as Physician and Clinical Assistant to Queen Square. As a mark of reciprocal appreciation, the Neurosurgical Unit (1953) represented the real the AAN later installed in the lecture theater of beginning of clinical neurology in South Australia; the National Hospital a plaque commemorating the his title was changed to Honorary Neurologist in late Francis Walshe (1886–1973), a doyen of British 1959. Richard Rischbeith, also returning from Queen neurology. Square, was appointed Consultant Neurologist to the The AAN nonetheless aimed to reach a situation Queen Elizabeth Hospital in 1958 (Burston, 1988; whereby Australian physicians could undertake speciaRischbeith, 1994; Jones, 1996). list neurological training in Australia, but without Marie (Mercy) Sadka (1923–2001) returned to Perth sacrificing the high standards and intellectual integrity in 1958 after postgraduate training at Queen Square that formed part of the heritage of the Queen Square and in Boston as Clinical Assistant Neurologist, the tradition. In 1966, the AAN proposed to the RACP that first female neurologist in Australia. Sadka played a plans be developed for instituting neurological training significant role in the development of neurology in in Australia, and in 1967 constituted a committee to Western Australia, introducing electroencephalography examine the facilities for undergraduate and graduate to the Royal Perth Hospital in 1959, and she was also training in the individual states. This committee passionately involved in rehabilitation services, foundreported in 1968 with plans for a course of training, ing the Stroke Rehabilitation Unit at the Royal Perth according to which students would be directed to insti(Rehabilitation) Hospital, also in 1959 (Gubbay, 2005). tutions within Australia offering appropriate facilities As AAN membership grew and began to establish and resources. its authority, it also expanded its role in the training By 1970 the RACP had also recognized that few phyof neurologists. As the biographies of many of those sicians would remain generalists in the future, and discussed above indicates, there was a great reliance initiated plans for both basic training in general medion Queen Square in London for specialist training. cine and for advanced specialist training, and thereby As early as 1908, Sid Sewell had been a clinical clerk formalised a pattern of medical subspecialty training. (and worked with Victor Horsley) at the revered center These plans were not entirely congruent with those of English neurology, but upon his return to Australia of the AAN, but agreements regarding co-existence of his appointments were as general physician. This was the two bodies’ aims were attained. It thus became posto be the rule until the final third of the 20th century: sible for Australian students to both learn neurology physicians traveled to London for their training, but from neurologists and to do so without the hitherto were unable to procure the title of “neurologist” on almost mandatory pilgrimage to London to benefit their return, no matter what the reality of their practice from the “perfection in the development of neurology might be. at Queen Square” (Game, 1976). Training posts are Selby (1988b) noted that neurology was regarded as still reserved for Australian trainee neurologists at the most complex branch of medicine; although there Queen Square and, more recently, at the Mayo Clinic was little the physician could do for his patients followin the USA (since 1977) and the Radcliffe Infirmary in ing diagnosis, “it was the specialty challenging the Oxford.

HISTORY OF NEUROLOGY IN AUSTRALIA AND NEW ZEALAND Further, it was proposed at the 1967 AOAN congress that Australia, without presuming to impinge upon the rights or aspirations of its Asian neighbors, should serve as the major center for neurology training in the Eastern Hemisphere. The AAN also sees itself as playing an important role in preventing “the separation of a race of ‘electricians’ from clinicians” (Selby, 1988b) through promotion of skilled history-taking and physical examination as being at least as important as the technological advances, including the possibilities for brain imaging which are now integral to clinical neurology (Game, 1975; Selby, 1988b).

AN INDEPENDENT EXISTENCE: AAN PUBLICATIONS The inaugural scientific meeting of the AAN followed the first business meeting in 1950. By 1958 the possibility and desirability of publishing the proceedings of these meetings were being discussed, as the Association had from the beginning set itself high scientific standards; despite limited resources, the papers presented compared “favourably with work done and papers produced in older and better endowed countries” (Game, 1975). The motivating force for the preparation of “a proper record” of these meetings was the second (1957–1965) AAN President, Graeme Robertson. The first volume of the Proceedings of the Australian Association of Neurologists was published in 1963, and included the scientific papers of the 11th Scientific Meeting (1962). Five hundred copies of this volume were printed and distributed with the financial support of four Swiss pharmaceutical firms (Ciba, Geigy, Roche, and Sandoz). Within a decade there had been a huge increase in the number of papers and breadth of scientific content. In 1977 the format changed to that of an annual journal, under the title Clinical and Experimental Neurology (ADIS Press, New York; Editor: 1977–1985, John Tyrer; 1985–1994, Mervyn Eadie). Neurologists were encouraged to publish their AAN meeting presentations in the journal, but this, perhaps ironically, became a problem as the international reputation of Australian neurology increased, so that it was not only desirable but also increasingly feasible to publish in international journals with a broader dissemination and which appeared more frequently. These limitations made attracting quality papers so difficult that the journal ceased publication in 1994. The Journal of Clinical Neuroscience had been launched that same year by the Neurosurgical Society of Australasia as its official publication. The AAN accepted the invitation of the editor, Andrew Kaye, to also designate the bi-monthly publication as its official journal.

795

The second volume of the Proceedings (1964) carried for the first time the official AAN insignia: the waratah (Telopea speciosissima) as depicted by James Sowerby (1757–1822) in the volume A Specimen of the Botany of New Holland (1793) by James Edward Smith (1759–1828). Sowerby’s drawing was based on sketches forwarded to England by Smith, who had assigned it the scientific designation Embothrium speciosissimum. At the suggestion of Robertson (1964), this image was adopted as the AAN emblem (Fig. 48.6) for a number of reasons. The first is that the waratah is “a distinguished Australian flower” (p. 3); it is, in fact, the floral emblem of NSW. Further, James Edward Smith was a botanist, an associate of Joseph Banks (who had visited Australia with Lt. James Cook) and founder of the Linnean Society (1788), but had also studied medicine in Edinburgh and London, so that there was a medical association. Finally, as Robertson wrote: It carries on a tradition established by a great hospital to which many of us owe a filial allegiance, for the rose, thistle, daffodil and shamrock form the emblem of the National Hospital for Nervous Diseases, Queen Square, London. (Robertson, 1964, p. 3)

Fig. 48.6. The depiction of the waratah in A Specimen of the Botany of New Holland (1793) by James Edward Smith, and adopted by the AAN as their insignia. Reproduced from the frontispiece to Robertson (1964).

796

P. FOLEY AND C. STOREY the discovery and investigation of electro-receptors in NEUROLOGY IN UNIVERSITIES the platypus and echidna (Proske, 2003). With the establishment of clinical neurology as a medThe founders of the AAN had harbored hopes that ical specialty, it was also possible and appropriate to an Australian Queen Square might become feasible at develop the standing of neurology in academic institusome time in the future, providing both the intellectual tions. Neurology had certainly maintained a certain climate and physical community and concentration of presence in Australian universities even before the facilities of the alma mater under southern skies. establishment of formal departments for the field, Academic status was initially not as attractive as might particularly in the form of neuroanatomy and neurobe expected; in 1950 there were only two full chairs of physiology. The Professor of Anatomy at Sydney medicine in Australia (Sydney and Adelaide; University in the 1920s, John Hunter, and his pure Melbourne had the quasi-professorial Stewart Lectureand applied research into the sympathetic nervous ship in Medicine, Brisbane a half-time chair), and the system, and the Professor of Anatomy and Histology principal functions of their holders were related to at Melbourne University, Sydney Sunderland, who their clinical and teaching roles, with research considachieved international recognition for his investigation ered quite subordinate to these other responsibilities. of peripheral nervous system injuries, have been Distance and a small population militated against the discussed above. realization of the ambition to establish a new Queen In a similar vein, John Carew Eccles (1903–1997) Square, so attention turned toward the institution of was from 1937 to 1943 Director of the Kanematsu one or more university chairs in neurology. Memorial Institute of Pathology in Sydney, having Until the 1960s, however, there were no specific acareturned from studying under Sherrington at Oxford demic appointments for clinical neurology in Australia. University, where he received his Doctor of Philosophy The establishment of the Australian Universities Comin 1929. The Kanematsu Institute, established in 1933 in mission in 1959 and the reforms it recommended led Sydney Hospital, was the first medical research instito a dramatic improvement in the state of the estabtute in NSW. During his tenure here Eccles, together lished universities as well as to the development of with Bernard Katz (1911–2003) and Stephen William new universities. This enabled research to flourish, parKuffler (1913–1980), analyzed neuromuscular junctions ticularly following the establishment of the Australian in cats and frogs, thereby commencing the fundamenResearch Grants Committee in 1965, which marked tal neurophysiological research which later brought the beginning of direct Government funding of higher Nobel prizes to Eccles in 1963 and Katz in 1970. education research, with an emphasis on basic research In 1952, Eccles moved as professor of physiology to and excellence (Molhuysen, 1966). the John Curtin School of Medical Research of the The new climate also permitted, though not immediAustralian National University (ANU) in Canberra, ately, the establishment of neurology departments in before leaving Australia for the United States in 1966 various universities. The first was the appointment in to escape mandatory age-based retirement. Although 1961 of James Waldo Lance (b. 1926), then neurological not appropriate for more extensive discussion here, consultant to Sydney Hospital, as senior lecturer in there is little doubt regarding the significance of the neurology at UNSW. Here a Department of Neurology contributions made by Eccles throughout his career to had been included in the new Faculty of Medicine from experimental neurophysiology, with respect to both its inception. Lance was outstanding in both his acaelectrical and chemical neurotransmission (Curtis, demic and research activities (he was particularly inter2005). ested in the neurophysiology of headache), as a result Similarly regarded as one of the founders of neuof which he received a personal chair in neurology in roscience in Australia was the physiologist Archibald 1975. By this time the Department of Neurology at Keverall McIntyre (1913–2002). McIntyre developed an UNSW was also making neurological appointments at interest in the neurosciences during his medical studies, the sub-professorial level. and met Eccles (and Katz and Kuffler) while he was Shortly afterward, the Bushell Chair of Neurology director of the Kanematsu Institute. During a varied was inaugurated at the older University of Sydney, career in various parts of the world, culminating in the with James Graham McLeod (b. 1932) its first occufoundation chair of physiology at Monash University pant. McLeod had been senior lecturer in the Departin Melbourne, McIntyre achieved international recogniment of Medicine since 1960, and had continued to tion for his investigations of the physiology of the practice as a clinical neurologist even after his appointnervous system, with particular focus on reflexes, senment as second professor in medicine some time later. sory receptors and plasticity and chromatolysis in spinal He combined this position with the Bushell chair to crecord pathways. In his retirement he also participated in ate the first permanent chair of neurology in Sydney.

HISTORY OF NEUROLOGY IN AUSTRALIA AND NEW ZEALAND 797 A year before, Mervyn John Eadie (b. 1932) had to be trained by experienced neurologists rather than been appointed to the chair of clinical neurology and by general physicians alone. Finally, the existence of neuropharmacology at the University of Queensland. Departments of Neurology in itself provides a context There had been earlier senior appointments of clinical for community amongst clinical neurologists, for neurologists in Brisbane: John Howard Tyrer (1920– fruitful interaction with the broader, non-hospital2006) had returned from London (where he had oriented neuroscientific community. worked with Russell Brain at London Hospital as traResearch has also played an important role in the veling fellow of the Royal Australasian College of Phyfunction of the AAN since its inception, and an assosicians) to occupy the chair of medicine at the ciation with the John Curtin School of Medical University of Queensland in 1954, but was prevented Research at ANU was established early. Peter Orlebar by the broader duties of his office from further pursuBishop (b. 1917) succeeded Eccles as director of the ing clinical neurology. Further, the Scotsman John institute in 1967, maintaining its high profile with Mackay Sutherland (1919–1995) had been appointed research in visual neurophysiology and encouraging half-time senior lecturer in 1956, but resigned after 3 young investigators of the next generation, including years to enter full-time consultant practice. the future professors of neurology James Lance Mervyn Eadie, however, was the first permanent (movement disorders) and James McLeod (peripheral appointment. He had succeeded Sutherland when he neuropathies) (Lance, 1987, 2002). resigned his lectureship, and had been upgraded to halfNon-neurologist members of the AAN have time reader in 1972 and half-time professorial fellow in included David Roderick Curtis (b. 1927), neurophyneurology and then to the full-time named chair in 1977. siologist and professor of neuropharmacology in CanEadie was particularly interested in neuropharmacology, berra (fellow of the Royal Society since 1968; but is also well known for his many publications on president of the Australian Academy of Science: the history of neurology in Australia, including the ency1986–1990), as well as the foundation member Sydney clopedic The Flowering of a Waratah. The History of Sutherland. Australian Neurology and of the Australian Association By the beginning of the 21st century, Australia was of Neurologists (2000). home to many internationally respected contributors to A fourth professorial appointment was made in the neurosciences. Neuroscientific research, both basic 1976 when Richard John Burns (b. 1935) received an and clinical, is undertaken in universities as well as in associate professorship in neurology at Flinders Uniinstitutions specifically devoted to neuroscientific stuversity in Adelaide. Frank Mastaglia was appointed dies, such as the Prince of Wales Medical Research by the University of Western Australia to a personal Institute in Sydney. The latter is an example of the chair in neurology (held at the Sir Charles Gairdner fruitful collaboration of neurologists, psychologists Hospital) in 1978. The 1980s then saw a rapid increase and biomedical scientists in the investigation of neuroin the number of academic appointments in all states, logical function and disease, and the communication probably at a greater rate than the expansion of the of basic information and research results to the general specialty itself. There are currently five academic posicommunity. tions in New Zealand, all in departments of internal A similar philosophy underlay the foundation of the medicine (Haas and Willoughby, 2002). Australian Neurological Foundation in 1970 at the instiSome disappointment has been expressed regarding gation of John Game and his neurosurgical colleague the fact that most professorial positions in more recent Keith Bradley. The Foundation was established by years have not been as permanent departmental heads, members of the AAN and the Neurosurgical Society but rather as personal or hospital-funded and hospitalof Australasia, under the patronage of Lord Casey based chairs, so that the autonomy and stability of such (then Governor-General and long-time supporter of positions are still perhaps less than ideal. As noted by Australian science), “to reduce the incidence and Eadie (2000a), the academic status of neurology in impact of disorders of the brain, spinal cord and nerAustralia and New Zealand may not be as secure as vous system through the provision of support, commufirst impressions suggest. nity education and research” (Brain Foundation: www. The prestige of neurology was nevertheless brainaustralia.org.au). The Australian Neurological enhanced by its formal academic institutionalization. Foundation thereby associated three distinct but related Further, the basic and clinical research of the appoinfields of activity, enabling it to address certain meditees and their departments has contributed much to cal, scientific and social aspects of neurological disease elevating the profile of Australian neurology internain a more coordinated manner than any single governtionally, as well as to growth in knowledge, which is ment bodies. One of the specific aims of the Brain its principal aim. It also allowed future neurologists Foundation was to alleviate chronic underfunding of

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neuroscientific research by governments by providing grants of up to AUS $ 40 000 (2008) to projects in the categories Parkinson’s disease; brain tumor, stroke, and headache and migraine; other research areas in neurosurgery, neurology and neuroscience; and general grants. The name of the Australian Neurological Foundation was changed to the more accessible Australian Brain Foundation in 1980, and finally to the Brain Foundation in 1997. The Neurological Foundation of New Zealand fulfills a similar function in that nation.

NEUROLOGY AND ANZAN IN 2006 Membership of the AAN has increased dramatically since the 1980s. By 1998 it had reached 300 (including 178 clinical neurologists practising in Australia or overseas), as well as 50 associate members; in 2006 the number of full members of ANZAN was 400, including 70 women and 38 New Zealanders. About half of those in clinical practice are private practitioners with parttime appointments at teaching hospitals, a quarter are salaried staff specialists, while a quarter are academic staff or private practitioners attached to district or private hospitals (Morris and Eadie, 1994; Hankey, 2001). Pediatric neurologists are confronted by issues different from those faced by colleagues treating adult patients, and a semi-formal pediatric neurology group has existed within the AAN for some time. It also holds its own scientific meetings. Ironic, in view of the earlier opposition to specialization has been the “sub-specialization” that has occurred in recent years, with the emergence of neurooncology, neuro-immunology, neuro-genetics and other fields of specific practice. Recognition of the maturity of neurology in Australia has also been marked by the increasing willingness of major international associations to stage their congresses there, a logistically difficult option for those based outside the region. The hosting of the 2005 Congress of the World Federation of Neurology by the AAN in Sydney was thus a significant milestone in the development of neurology in Australia, an encouraging vote of confidence in the local organization and members.

ACKNOWLEDGMENTS Professor Mervyn Eadie has published, in addition to the mentioned monograph, many papers on the history of neurology in Australia; his scholarship certainly made the preparation of this chapter easier, and interested readers are referred to The Flowering of a Waratah for further details and literature. Professor Eadie also read the manuscript and made many valuable corrections and suggestions. We also thank

Professor Malcolm Macmillan (Honorary Fellow, Department of Psychology, University of Melbourne) for reading the manuscript and making useful suggestions, particularly with regard to A.W. Campbell, and for drawing our attention to W.J. Adie. The figures for the current ANZAN membership were supplied by Mandy Jones, Executive Officer, ANZAN.

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Morris J (Comp.), Eadie M (Ed.), (1994). Neurology in Australia. Australian Association of Neurologists, Sydney. Newman AK (1875). On insular sclerosis of the brain and spinal cord. Aust Med J 20: 369–374. Noad K (1975). Oliver Latham. Med J Aust 2: 492. O’Sullivan DJ (2005). Burke, William John Gerard. Roll of the Royal Australasian College of Physicians. Available: http:// www.racp.edu.au/index.cfm?objectid=57D8BA7E-BBA85D39-133611C9100A5B6A&id=56; accessed 15 December 2008. Parker LR (1938). Alfred Walter Campbell. Med J Aust 1: 181–183. Patrick R (1983). Kenny, Elizabeth (1880–1952). Australian Dictionary of Biography. Vol. 9. Melbourne University Press, Melbourne, pp. 570–571. Power D (1935). How surgery came to Australasia. Aust NZ J Surgery 4: 368–383. Proske U (2003). Archie McIntyre (1913–2002). Clin Exp Pharmacol Physiol 30: 303–306. Rischbeith RH (1994). Neurology in South Australia. In: L Morris, MJ Eadie (Eds.), Neurology in Australia. Australian Association of Neurologists, Sydney, pp. 90–93. Robertson G (1964). The insigne of the Australian Association of Neurologists. Proc Aust Assoc Neurol 2: 2–3. Sadka M (1988). Moss, Gerald Carew. In: GL McDonald (Ed.), Roll of the Royal Australasian College of Physicians. Vol. 1. RACP, Sydney, pp. 217–218. Sage MR (1995). The history of neuroradiology: an Australian perspective. Aust J Neuroradiol 16: 1295–1302. Schwieger A (1993). Cox, Leonard Bell (1894–1976). Australian Dictionary of Biography. Vol. 13. Melbourne University Press, Melbourne, pp. 521–522. Schwieger AC (1994). Cox, Leonard Bell. In: JC Wiseman, RJ Mulhearn (Eds.), Roll of the Royal Australasian College of Physicians. Vol. 2. RACP, Sydney, pp. 67–69. Selby G (1988a). Susman, Eric Leo. In: GL McDonald (Ed.), Roll of the Royal Australasian College of Physicians. Vol. 1. RACP, Sydney, pp. 284–285. Selby G (1988b). The history of the Australian Association of Neurologists. In: JC Wiseman (Ed.), To Follow Knowledge. A History of Examinations, Continuing Education and Specialist Affiliations of the Royal Australasian College of Physicians. RACP, Sydney, pp. 105–114.

Selby G (1992). History of neurology in Australia. Clin Exp Neurol 29: 10–25. Sheehan JP, Sheehan JM, Ellegala DB, et al. (2005). Pioneers in the development of neurosurgical surgery in Auckland, New Zealand: Robertson, Wrightson, Mackenzie. Neurosurgery 57: 364–368. Simpson D, Dan N (2005). Australasia and the World Federation of Neurosurgical Societies. In: HA van Alphen (Ed.), World Federation of Neurosurgical Societies 1955–2005. A History. De Zaak Haes, Amstelveen, pp. 245–257. Simpson D, Jamieson KG, Morson SM (1974). The foundations of neurosurgery in Australia and New Zealand. Aust NZ J Surg 44: 215–227. Smith GE, Pear TH (1917). Shell Shock and its Lessons. University Press, Manchester, Longmans, London. Stone J (2002). Shellshear, Joseph Lexden (1885–1958). Australian Dictionary of Biography. Vol. 16. Melbourne University Press, Melbourne, pp. 228–229. Sutherland JM (1994). The development of neurology in Brisbane. In: L Morris, MJ Eadie (Ed.), Neurology in Australia. Australian Association of Neurologists, Sydney, pp. 55–61. Vilensky JA, Gilman S, Sinish PR (2004). Denny-Brown, Boston City Hospital, and the history of American neurology. Perspect Biol Med 47: 505–518. Wehner V (with Eadie MJ, Wehner MS) (2004). A Melbourne Doctor and His Generation. Leonard Bell Cox 1894–1976. Leddicott Press, Olinda, Victoria. Williams ET (1979). Cairns, Sir Hugh William Bell (1896–1952). Australian Dictionary of Biography. Vol. 7. Melbourne University Press, Melbourne, pp. 524–525. Williamson PM (2005). Selby, George Mor. Roll of the Royal Australasian College of Physicians. Available: http://www.racp.edu.au/index.cfm?objectid=57D8BA7EBBA8-5D39-133611C9100A5B6A&id=140; accessed 15 December 2008. Winton R (1988). Why the Pomegranate? A History of the Royal Australasian College of Physicians. RACP, Sydney. Wolfenden WH (1994). Noad, Sir Kenneth Beeson. In: JC Wiseman, RJ Mulhearn (Eds.), Roll of the Royal Australasian College of Physicians. Vol. 2. RACP, Sydney, pp. 241–244.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 49

Clinical neurology in Latin America RICARDO F. ALLEGRI * Services of Neurology & Neuropsychology (SIREN), Instituto Universitario CEMIC (Centro de Estudios Médicos e Investigaciones Clínicas); CONICET (Consejo Nacional de Investigaciones Científicas y Tecnológicas); Department of Neurology, Hospital Abel Zubizarreta, Gobierno de la Ciudad de Buenos Aires, Argentina

INTRODUCTION The history of neurology in Latin America developed in parallel with the leading European centers, most importantly in France and Germany, where most prominent Latin American neurologists were trained. Nevertheless, it is difficult to follow this puzzle of country-specific scattered data, which have hardly been included in international publications or were included in local journals without being referenced in bibliography indices. In fact, given lost records and the difficulties of publishing in Spanish in most international journals (Gibbs, 1995; Famulari, 2003) there are only limited data available on the history of neurology in some of these Latin American countries. Neurology in Latin America emerged toward the end of the 19th century, following the origin of the specialty in Europe and its official baptism with Charcot at the Salpeˆtrie`re Hospital in Paris. The first steps took place almost simultaneously in five countries: Argentina, Brazil, Uruguay, Chile, and Peru. In the other countries, the development of neurology took place later in the 20th century. In all cases, one can discern three fundamental stages: 1. Stage of neurology as part of internal medicine: doctoral theses and publications about neurological topics are found early in the history of medicine, but only within internal medicine. 2. Foundation stage of clinical neurology: under the typical European influence, mainly French, the first neurologists appear. With the founding of chairs of neurology, the birth of scientific societies, and specialized journals, clinical neurology consolidated. *

3. Stage of neurological sub-specialties: in the more recent North American-influenced years, there is a new paradigm favoring the atomization of the sciences. Specialists in epilepsy, headache, stroke, dementia, among others, appear.

SOUTH AMERICA Argentina The history of neurology in Argentina began in 1827 at the University of Buenos Aires School of Medicine (university names will be given in English throughout this chapter) with a doctoral thesis about epilepsy (Epilepsia: su naturaleza y curación) submitted by Martı´n Garcı´a (Bardeci, 1948). The foundation stage started in 1885, with the creation of the Hospital San Roque de Buenos Aires’ first nervous diseases ward. Its first chair, Jose´ Marı´a Ramos Mejı´a, had a solid humanistic education; he was a writer, a sociologist, a person of science, and an outstanding public man. His thesis was Apuntes clínicos sobre el traumatismo cerebral (Clinical Notes on Traumatic Brain Injury), including two reports on cranial trepanations. In 1887, only 5 years after Charcot was awarded the chair of neurology in Paris, Ramos Mejı´a became the first professor of neurology in South America, this being at the University of Buenos Aires. In his double capacity as chair and professor, he was a pioneer of neurology in Argentina (Somoza and Gualtieri, 1998). Ramos Mejı´a was the most important positivist in Argentina. His classical articles, more sociological and psychiatric than neurological, were La neurosis en los hombres públicos de la historia argentina

Correspondence to: Ricardo F. Allegri, MD, PhD, Servicios de Neurologı´a & Neuropsicologı´a (SIREN), CEMIC (Centro de Estudios Me´dicos e Investigaciones Clı´nicas), Galva´n 4102 (1431FWO), Buenos Aires, Argentina. E-mail: [email protected], Tel: +54-11-4546-8227, Fax: +54-11-4546-8293.

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(Neurosis in Public Men in the History of Argentina), Las multitudes argentinas (The Argentinian Masses) and Estudios clínicos sobre las enfermedades nerviosas y mentales (Clinical Studies on Mental and Nervous Diseases). In 1888, Federico Papi, an Italian neurologist and neuropathologist, took over the Department of Neurology at the University of Co´rdoba School of Medicine, which he headed until 1890, when he returned to Italy (Brunetti and Palacio, 1998). Three assistants collaborated with Ramos Mejı´a at the University of Buenos Aires and were essential for the development of neurology in Argentina. Christofredo Jakob specialized in neuropathology. He trained in Germany with Strumpell and published an atlas of the nervous system with him. Jakob is considered the founder of neuropathology in Argentina and was important in the systematization of brain slicing and for efforts to study the myelin sheath (Hano´n, 1956). Jose´ A. Este´vez, in contrast, favored a clinical approach. He was hired in 1913 and became known for his bedside clinical acumen. He published articles about facial progressive hemiatrophy, epidemic meningitis, Sydenham’s chorea, and hydatid cysts. Hydatid disease, endemic in South America, is a parasitic infestation caused by Echinococcus. Symptoms depend upon where hydatid cysts form in the brain. Seizures and headaches are common symptoms. The third important assistant was Jose´ Ingenieros, who made sociological contributions. In 1924, Mariano Alurralde succeeded Este´vez, and he gave his lectures an anatomo-pathologic orientation (Somoza and Gualtieri, 1998). Alurralde wrote articles about neurosyphilis. In Este´vez, Jakob and Alurralde’s times, the focus was on anatomy and histopathology; unsubstantiated opinions not backed by hard data were no longer as important as they had been in Ramos Mejı´a’s era (Somoza and Gualtieri, 1998). In 1941, Vicente Dimitri was designated professor of neurology at the University of Buenos Aires. Dimitri was the first physician with neuropathological and neurological training, which he acquired with Jakob and by visiting European hospitals. With Dimitri, neurology par excellence began (Figini, 1964). He greatly influenced those who surrounded him, including Jose´ Pereyra Ka¨fer, who became chairman of the Hospital Ramos Mejı´a Neurology Service (formerly Hospital San Roque) and then took over as professor of neurology at the University of Buenos Aires. In 1952, he founded the Sociedad Neurolo´gica de Buenos Aires, which later became the Sociedad Neurolo´gica Argentina (SNA), a part of the World Federation of Neurology (WFN). During the 1970s, the stage of neurological sub-specialties began, reflecting a greater North American influence (Somoza and Gualtieri, 1998). The new era

at the University of Buenos Aires Department of Neurology began with Roberto E.P. Sica, neurologist and neurophysiologist, whose most important articles were on motor neuron disease and on Chagas’ disease (also called American trypanosomiasis). The latter is a mammalian disease occurring only in the Americas. It is caused by the protozoan Trypanosoma cruzi, transmitted to humans in most cases by insects of the Triatominae subfamily, known in Argentina as “vinchuca.” Sica became chairman of the Hospital Ramos Mejı´a Neurology Service, the most recognized department of neurology in Argentina. FLENI (Fundacio´n para la Lucha contra las Enfermedades Neurolo´gicas de la Infancia) Neurological Institute in Buenos Aires dates back to 1959, when the creator Rau´l Carrea (a neurosurgeon) returned after several years in the US. The Centre for Neurological Research was the first scientific research laboratory to open in 1968 in the “Ricardo Gutierrez” children’s hospital, but it was closed in 1976. In 1978, Carrea opened the first Computed Tomography Center in Latin America at FLENI. At that point, he invited Ramo´n Leiguarda (a neurologist trained in London) to join him. In 1978 Carrea passed away unexpectedly and Leiguarda followed his work in maintaining and developing FLENI. Nowadays it is the most important non-profit neurological organization in Latin America, delivering preventive medicine, diagnostics, health care services, and research on neurological disease (www. fleni.org.ar). The first journal in Argentina was the Revista Neurológica de Buenos Aires created by Dimitri in 1936 (Fig. 49.1). In 1972, Pereyra Ka¨fer renamed it the Revista Neurológica Argentina with He´ctor Figini as its first editor. This journal is still published. Among the reviews and case studies in the early period of the journal, we find (in Spanish) Jakob’s “Contribution to pituitary neoplasm histogenesis” (Jakob, 1936), Dimitri’s “Retinal telangiectasis, angioma of the protuberance and cerebellum glioma” (Dimitri et al., 1936), and notices and summaries of international congresses and lectures. These notices and summaries were very important, since few physicians had a good command of non-Spanish languages and even fewer had access to international journals.

Brazil The history of neurology in Brazil centered on developments in Rio de Janeiro and Sa˜o Paulo, and each will be treated in turn. Neurology in Rio de Janeiro has been considered the foundation of Brazilian neurology. In 1878, Joa˜o Vicente de Torres Homem wrote the first Brazilian book exclusively devoted to neurology, Lições Sobre as

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Fig. 49.1. The first journal in South America was the Revista Neurológica de Buenos Aires created by Dimitri in 1936 (Volume 1, issue 3, 1936).

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Fig. 49.2. The Austrege´silo and Esposel sign. It is obtained by stimulating the thigh and, like Babinski’s sign, it is manifested by the upturning of the big toe and also by fanning of the other toes. It is a sign of a pyramidal tract disorder (from Austrege´silo and Esposel, 1912).

Molestias do Sistema Nervoso (Lessons about Nervous System Diseases) (Gomes, 1999a). The University of Rio de Janeiro School of Medicine created the first Brazilian department of neurology in 1912. Its first full professor was Anto˜nio Austrege´silo Rodrı´gues Lima, a politician, a writer, and a skilled physician, now considered Pai da Neurología Brasileira (the father of Brazilian neurology). He was the first to study movement disorders in Brazil, publishing several works on this subject, primarily in Revue Neurologique and L’Encéphale, including an alternate to the Babinski sign (Fig. 49.2), and the first description of a post-traumatic dystonia (Teive et al., 1999). In 1944, Deolindo Augusto de Nunes Couto took over as chairman and consolidated Brazilian neurology. In 1946 he founded the Instituto de Neurologı´a da Universidade Federal do Rio de Janeiro, with extensive research activity in neurology, neurophysiology, and neurosurgery. This institute, later renamed Instituto de Neurologı´a Deolindo Couto da Universidade Federal do Rio de Janeiro, became the international face of Brazilian neurology. His first assistants were Antoˆnio Rodrı´gues de Mello, Ismar Fernandes, and A´lvaro Jose´ de Lima Costa, who published a book on neuroparasitosis in 1967. Neuropathology was further developed by Paulo Elejalde, followed by Alexandre

Alencar, both known for Chagas’ disease research. Bernardo Henrique de Nunes Couto headed the Institute and was followed by Clo´vis Oliveira, He´lcio Alvarenga, and Gianni Temponi (Gomes, 1999a). In 1925, Enjolras Vampre´ was appointed by the School of Medicine of the University of Sa˜o Paulo to take over the Department of Psychiatry and Neurology. Vampre´, through his training at the Salpeˆtrie`re, introduced the fundamentals of French neurology to Sa˜o Paulo and is considered the founder of the Sa˜o Paulo School of Neurology (Reima˜o and Alonso Nieto, 1996; Morato-Leite, 1999). In 1935, the Department was divided into Psychiatry and Neurology. Successive generations of neurologists and neurosurgeons at the Sa˜o Paulo school were associated with Vampre´. They include Adherbal Tolosa, Paulino Watt Longo, Oswaldo Lange, and Carlos Gama (MoratoLeite, 1999). Following a competitive examination, Tolosa was appointed chair of neurology at the University of Sa˜o Paulo. He wrote several semiotic articles (including studies on the cremasteric reflex) that were published in local journals. Longo became the chair of the Paulista School of Medicine, and Lange remained clinical chief of the University of Sa˜o Paulo School of Medicine until 1969. Lange was known outside Brazil for his activity as director of the Arquivos

CLINICAL NEUROLOGY IN LATIN AMERICA 805 Jacinto de Leo´n aspired to be appointed to the Neurology Department of the University of Montevideo, although this never happened (Wilson, 1991, 1992). Jose´ Verocay, another important physician at this time, provided a good neuropathological description of neurofibromatosis or von Reckinghausen’s disease, now also known as Verocay neurinoma (Verocay, 1910). In 1925, the creation of the Department of Neurological Diseases was approved in the School of Medicine of Montevideo, with Ame´rico Ricaldoni as its chairman. Ricaldoni’s acceptance was conditional on financial assistance and the creation of a teaching and research facility. Subsequently, the government created the Instituto de Neurologı´a de Montevideo (in 1927; Fig. 49.3), and Ricaldoni was designated Director of the Institute and Professor of Neurological Disease. This was the first neurological institute in Latin America – preceding the Montreal Neurological Institute by several years. Ricaldoni published articles in journals from Uruguay and Argentina, wrote about Landry’s palsy in Archives Générales de Médicine de Paris, and bilateral cranial nerve VI and VII palsies in the Revue Neurologique. He died in 1928. The creation and abrupt growth of his institute, however, did not mean the birth of neurology as a specialty in Uruguay; the practice of neurology, other than for Jacinto de Leo´n, continued within internal medicine. At the beginning of 1937, Alejandro Schroeder, a neurologist and neurosurgeon, was appointed university professor and institute director. In 1925, he traveled to Germany to work with Jakob and Nonne in Hamburg, and Fo¨rster in Breslau. He then wrote the first book of neurology in Uruguay. Since Schroeder took over, the Institute – renamed Instituto de NeuroUruguay logı´a Prof. Dr. Ame´rico Ricaldoni – has been ranked Neurology in Uruguay started with Francisco Soca, very highly in South America. who graduated in Paris at the end of 1888 with his docThe Institute’s third director, Roma´n Arana In˜iguez, toral thesis Étude clinique sur la maladie de Friedtook over in 1957 and was moved to the second floor of reich (Clinical Study of Friedreich’s Disease) the Hospital de Clı´nicas (Wilson, 1991, 1992). Arana supported by Charcot himself (Soca, 1888). This thesis started his neurosurgical training at the Institute and was important for extending fundamental knowledge then went to the United States. After 1957, different about this disease, and Pierre Marie referred to the role scientific interest sections were created in the Institute. of age in this disorder as “Soca’s law.” After his return Scientific contributions increased in number and quality to Montevideo, Soca gradually left neurology to in the different sections of the Institute. devote himself to internal medicine. From 1945, the Neuropathology Laboratory was Jacinto de Leo´n, who treated patients with neurolodirected by Juan Medoc, who was known for his work gical diseases, is often considered the first neurologist on brain tumors (craniopharingiomas). The Neuropsyin Uruguay. In 1894, he started to teach neurology in chology Laboratory started in 1958 with Carlos internal medicine at the School of Medicine of MonteviMendilaharsu and Selika Acevedo de Mendilaharsu, deo. His works usually consisted of case reports or clinwho had worked in France with He´caen and Ajuriaical reviews, but without new concepts. “Contribution a guerra. These individuals published several papers l’e´tude de la paralyse myastenique,” the most widely and five textbooks (Estudios Neuropsicológicos), and are regarded as “the parents of the Latin known of his reports, was published in the Nouvelle IcoAmerican Neuropsychology.” nographie de la Salpêtrière.

de Neuropsiquiatria journal, and for his research on cerebrospinal fluid and infectious diseases, including syphilis and cysticercosis. Antoˆnio Branco Lefe`vre, Hora´cio Martins Canelas, Antoˆnio Spina Franc¸a Netto, and Gilberto Scaff continued this school (Reima˜o and Alonso Nieto, 1996; Morato-Leite, 1999). Antoˆnio Branco Lefe`vre was recognized as the father of child neurology and neuropsychology for his research and articles (Lefe`vre, 1999). Martins Canelas, who did research on Wilson’s disease, wrote articles in Brazilian journals and in international journals, such as Journal of Neurology, Neurosurgery and Psychiatry and Acta Neurologica Scandinavica. The Academia Brasileira de Neurologia was created in 1962, and Deolindo Couto was its first president. The first neurological journal published in Brazil was Neurobiologia, created in 1938 by Ulysses Pernambucano in northern Brazil (Recife). The first articles included not only theory; they incorporated clinical research in psychology, neurology, and psychiatry (Codeceira, 1999). In 1943, Tolosa, Longo, and Lange created – under Oswaldo Lange’s direction – the Arquivos de Neuropsiquiatria in Sa˜o Paulo. This is the most important journal of neurosciences in Latin America and it is found in Index Medicus, WHO, Bireme, Lilacs, and Latindex (Spina Franc¸a, 1999). In 1949, in Rio de Janeiro, Deolindo Couto created the third neurological journal to come out of Brazil, Jornal Brasileiro de Neurologia, renamed Revista Brasileira de Neurologia in 1983 (Gomes, 1999b).

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Fig. 49.3. Members of the Instituto de Neurologı´a de Montevideo in 1927 (Wilson, 1991, with permission).

Arana retired in 1974, the year he decided to separate neurology from neurosurgery. He´ctor Deffe´minis was appointed professor of neurology. After his retirement, he was succeeded by Marı´a A. Rebollo and, in 1987, by Carlos Chouza (Wilson, 1991, 1992). The Sociedad de Neurologı´a y Neurocirugia de Montevideo was set up in 1939 with Schroeder as its first president. In 1951, the Acta Neurológica Latinamericana was created. The objective was to have a common Latin American neurological journal, preserving the language and making it easier for Spanish-speaking neurologists to publish their work (Wilson, 1991).

Peru Neurology in Peru took its first steps with Carlos Krumdieck, who in 1928 spent a year at the Salpeˆtrie`re. When he returned from Paris, he taught neurology until 1930, but increasingly devoted himself to pediatrics. Juan B. Lastres, who was chief of clinical neurology between 1931 and 1934, later became professor of the history of medicine. The first true neurologist was Oscar Trelles Montes, considered the “father of neurology of Peru.” He worked in Paris from 1930 to 1935, where he acquired neurological training under Jean Lhermitte. He published 35 scientific

papers in collaboration with Lhermitte. He also published a notable book, Précis d’Anatomophysiologie Normale et Pathologique du Système Nerveux, with Franc¸ois Masquin (Cubas, 2002; Escalante Sa´nchez, 2004). In 1935, he returned to Peru and in a few years he joined the elite of doctors in Latin America. In 1940, he was recognized as professor of neuropathology at the Universidad Nacional Mayor de San Marcos School of Medicine (Escalante Sa´nchez, 2004). By this time, he was attending the Refugio de Incurables, a ward under the administration of the Beneficencia Pública of Lima (Escalante Sa´nchez, 2004). The “Refugio” was renamed Hospital Santo Toribio de Mogrovejo thanks to his efforts (Escalante Gavancho, 2004). During the 30-year leadership of Trelles, almost all neurologists in Peru had this hospital as their alma mater. In 1941, Trelles co-authored (with Lazartes) a book titled Cisticercosis Cerebral. Brain cysticercosis is an endemic infection in Latin America caused by the pork tapeworm, Taenia solium (Escalante Gavancho, 2004). Infection occurs when the tapeworm larvae enter the body and form cyst cerci. Neurological symptoms of cysticercosis depend upon where and how many cyst cerci are found in the brain. In 1963, the Hospital Santo Toribio was recognized as Hospital Neurolo´gico and in 1981 it became the

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Instituto de Ciencias Neurolo´gicas (Institute of Neurological Sciences) of Peru, headed by Silvio Escalante Sa´nchez, Ernesto Rı´os Montenegro, and then Luis Trelles Montero (son of Oscar Trelles Montes) (Cubas, 2002). The Sociedad de Neuropsiquiatrı´a y Medicina Legal of Peru was created in 1938 by Honorio Delgado, a prominent psychiatrist, and Oscar Trelles Montes. In 1945, it was renamed the Sociedad Peruana de Psiquiatrı´a, Neurologı´a y Neurocirugı´a. As time went by, the Sociedad Peruana de Neurocirugı´a and the Sociedad Peruana de Psiquiatrı´a were divided, so the Sociedad Peruana de Psiquiatrı´a, Neurologı´a y Neurocirugı´a consisted largely of neurologists. In 1990, it became the Sociedad Peruana de Neurologı´a. In 1937 Honorio Delgado and Oscar Trelles cofounded the Revista de Neuropsiquiatría, which continues to publish quality scientific articles. The Revista Peruana de Neurología was created in 1995 under Jose´ del Carmen’s direction, and it is the official journal of the Sociedad Peruana de Neurología.

Chile Neurology in Chile goes back to 1869, with Jose´ Ramo´n Elguero del Campo, the first professor of mental diseases of the University of Chile. Three years later, however, he devoted himself to medical pathology (Escobar, 2000). The chair remained unoccupied until 1882, when Carlos Sazie´ Heredia took over. Sazie´’s neurological training started when he won a government scholarship to specialize with Magnan, Voisin and Charcot in France (from 1874 to 1879). Fe´lix Vulpian sponsored his doctoral thesis on intellectual problems of aphasics. Sazie´ taught neuropsychiatry at the Hospital San Juan de Dios and then at the Hospital San Vicente de Paul until he was dismissed in 1891, following political problems (Escobar, 2001). In 1892, his disciple Augusto Orrego Luco (Fig. 49.4) took over as professor of nervous diseases at the University of Chile. Orrego Luco graduated in 1873 with a thesis on Alucinaciones mentales (Mental Hallucinations). Trained in France by Charcot, he published in the Iconographie de la Salpêtrière. In 1902 he wrote the book (translated as) Hysterical Hemiplegia and Organic Hemiplegia, in which differences between hysterical and organic symptoms were discussed. He was the most prominent figure in Chilean neurology during the second half of the 19th century, and was nicknamed the “Charcot of America” (Escobar, 2002a). In 1907, Orrego Luco retired and his chair was taken over by his disciple, Joaquı´n Luco Arriagada. The school decided to divide the department, and psychia-

Fig. 49.4. Augusto Orrego Luco, “the Charcot of America” (1902).

try and neurology were coordinated by his assistants, Oscar Fontecilla and Hugo Lea Plaza, respectively. Luco Arriagada was also trained in Europe, in his case by Babinski, showing once again the influence from the French school. In 1925, he created the Hospital del Salvador Neurology Service. He began to serve as clinical chief at the Manicomio Nacional (Neuropsychiatric Hospital) in 1931. When Luco Arriagada retired, Lea Plaza was made chair of neurology at the University of Chile and Jorge Oyarzun became chief of neurology at the Hospital del Salvador (Escobar, 2002b). In 1929, the Hospital San Vicente de Paul’s Neurology Service was created in Santiago, and Oscar Fontecilla took over as chairman. Lea Plaza was succeeded by Guillermo Brinck, Emilio Morales (a neurosurgeon) and then Archibaldo Donoso. At the Hospital del Salvador, he was followed by Jorge Gonza´lez Cruchaga. Later on, the teaching and clinical care sections separated. Alfonso Asenjo Go´mez, trained in the United States by Walter Dandy and in Germany by Toennis, stimulated the creation of the Chilean Service of Neurosurgery. Asenjo worked with He´ctor Valladares, Carlos Villavicencio, Mario Contreras and A. Lepe. In 1953, the Instituto de

808 R.F. ALLEGRI Neurocirugı´a e Investigaciones Cerebrales (Institute of of the new University of Venezuela’s Neurology Neurosurgery and Brain Research) of Chile opened, and Department. The Hospital Clı´nico de la Ciudad it was directed by Asenjo for 34 years. The Institute is Universitaria de Caracas Department of Neurology currently named after Asenjo, is known internationally, and Neurosurgery was also founded that year, with and is sponsored by the University of Chile. Juan Fierro, the collaboration of Enrique Garcia Maldonado Reynaldo Pobrete, Pablo Donoso and Jaime Lavados were (trained at the National Hospital, Queen Square in its directors after Asenjo (Uribe Barreto, 2003). London) and Julio Borges Iturriza (trained at the Neurological teaching at the Catholic University University of Michigan hospitals). School of Medicine started in 1946 at the Instituto de The Cuban neurosurgeon Leo´n Mir, who in 1945 Neurocirugı´a Alfonso Asenjo under Enrique Uiberall, founded the Hospital Vargas Neurosurgery Service, an Austrian neurologist who moved to Chile because was another important figure in Venezuelan neurology. of World War II. The Hospital Clı´nico of the Catholic Hugo Izaba Stevenson (trained in neurology at the University had no staff neurologists until 1961, when National Hospital, Queen Square in London), Pedro Luis Oscar Marin – trained under Derek Denny Brown – Ponce Ducharne (electroencephalography, Hospital joined it. Marin performed teaching and clinical activReina Mercedes, Havana, Cuba), and Frank Risquez ities at the Hospital Clı´nico, and founded the Hospital Cotton (clinical neurology, Salpeˆtrie`re, Paris, France) Barros Luco-Trudeau Neurology Service. In 1964, he were his collaborators. In 1952, Celina Leo´n de Ponce decided to continue his academic activities in the and Jaime Boet joined them (Ponce Ducharne, 2004a). recently created Universidad Austral School of MediGustavo Leal Aldazoro, a pediatrician, traveled to cine in Valdivia. North Carolina in 1950 to attend courses at the Child Between 1964 and 1970, Camilo Arriagada, chairBehavior Clinic in Durham, and then to Boston to man of the Neurology Service at the Hospital Barros broaden his epilepsy and electroencephalography Luco, was in charge of neurology teaching. In 1971, (EEG) training under William Lennox’s guidance. He the Catholic University decided to move the teaching returned to Venezuela in 1953 and settled in the Disactivity to Hospital Dr. Sotero del Rı´o, under Jaime pensario Central de Higiene Mental. He also devoted Court. In 1974, as part of an academic reorganization himself to teaching in the Hospital Universitario de of the School of Medicine, the Department of NeuroloCaracas (HUC) Neurology Service. In 1963, Alberto gical and Neurosurgical Disease was created. It was Abadi (trained in Boston) joined the HUC Department staffed by neurologists from the Hospital Dr. Sotero of Pediatrics (Dı´az Carvajal, 2004) and, in 1959, Izaba del Rı´o and neurosurgeons from the Hospital Clı´nico. and Risquez moved to the Hospital Clı´nico de la In 1971, the Hospital Trudeau Neurology Service Ciudad Universitaria de Caracas. Pedro Luis Ponce became one of the three University of Chile neurology Ducharne continued at the Hospital Vargas, and in units (the others being at the Hospital Clı´nico and at 1959 founded the Neurology Service (Ponce Ducharne, the Hospital del Salvador). Arriagada remained chief 2004a, b). until 1994, training over a hundred specialists. In The study of a Venezuelan family from the Lake 1995, when Jorge Nogales-Gaete became chairman Maracaibo region led to the discovery of a polyand full professor, he wrote the first Chilean textbook morphic DNA marker genetically linked to Huntingof neurology. ton’s disease. This important discovery represented an The Sociedad de Neurologı´a, Psiquiatrı´a y Neurocirinternational collaboration between multiple groups ugı´a de Chile was founded in 1932 and the Revista of clinical and basic scientists (Gusella et al., 1983). Chilena de Neuropsiquiatría has been in circulation In 1942 the Sociedad Venezolana de Psiquiatrı´a was since 1947. created and it grouped all nervous system-related disciplines. It was chaired by Pedro B. Castro and Pedro Luis Ponce Ducharne. A group of neurologists Venezuela met in early 1969 to create another society, the SocieThe history of neurology in Venezuela started with dad Venezolana de Neurologı´a. This organization was Pedro B. Castro’s return from Paris in 1936, where he presided over by, among others, Pedro B. Castro, had trained with Guillain at the Salpeˆtrie`re. In 1938, CasPedro Luis Ponce Ducharne, and Celina de Ponce tro took over as a neurology consultant at the Hospital (Ponce Ducharne, 2004b). Vargas, where he stayed until 1959. In 1940, the Central The Archivos Venezolanos de Otorrinolaringología, University of Venezuela’s Department of Neurology Oftalmología y Neurología was circulated in the 1930s and Psychiatry was created with Castro as chairman. and 1940s. In 1953, the Archivos Venezolanos de PsiIn 1959 neurology and psychiatry became indepenquiatría y Neurología became the official organ of dent, and Castro became the first chairman and founder the two societies. When they separated, the Boletín

CLINICAL NEUROLOGY IN LATIN AMERICA Informativo de la Sociedad Venezolana de Neurología appeared. It was published between 1976 and 1983, and was followed (in 1987) by the Revista Venezolana de Neurología y Neurocirugía, which was published until December 1991 (Ponce Ducharne, 2004b).

Colombia Miguel Jime´nez Lo´pez, who specialized in psychiatry and internal medicine in France, was the first to lead the National University’s Department of Mental and Nervous Diseases (Rosselli and Otero, 2000). By this time, Luis Lo´pez de Mesa, who would become Professor, had trained in neurology, psychopathology and neuropsychology at Harvard (Rosselli, 1985). In the first half of the 20th century, several professors of the National University were showing an interest in neurological diseases, among them Pablo A. Llina´s, Alfonso Uribe Uribe, and Edmundo Rico Tejada (Rosselli and Otero, 2000). The true foundation stage of neurology started with Andre´s Rosselli Quijano (Fig. 49.5), who in 1954 traveled to the Massachusetts General Hospital to study neurology. In 1956, he collaborated in the foundation of a neurology unit annexed to the Neurosurgery Department at Hospital Militar Central de Bogota´ (Rosselli, 1985; Rosselli and Otero, 2000). In 1961, Ignacio Vergara founded the Hospital San Juan de Dios Neurology Service and Jaime Potes founded the Hospital Universitario Del Valle Neurology Service. The first Hospital San Vicente de Paul Department of Neurosurgery and Neurology was created by the neurosurgeon Ernesto Bustamante. Jorge Holguı´n, who trained in France, created the first neuropediatrics service in Medellı´n in 1965 (Rosselli and Otero, 2000). The Sociedad Neurolo´gica de Colombia, which included both neurosurgeons and neurologists, was created in 1963. Neurologists decided to become independent in 1982, creating the Asociacio´n Colombiana de Neurologı´a. In 1985 the journal Acta Colombiana de Neurología was founded (Rosselli and Otero, 2000).

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Bolivia Neurology in Bolivia had largely been the domain of neurosurgeons, and it was not until the second half of the 20th century that neurologists took a more active role. In 1966, the Sociedad de Psiquiatrı´a, Neurologı´a y Neurocirugı´a de Bolivia was at its height, with formal and regular meetings. There were three groups that catalyzed these institution activities, and they were led by Jose´ Marı´a Alvarado, from psychiatry, and Mario Michel Zamora and Hugo Rodrı´guez Serrano, two neurosurgeons who covered neurology and neurosurgery. The only two neurologists then in the city of La Paz had neither independent services nor society affiliations (Trigosso, 2003). In 1975, the Sociedad Boliviana de Neurologı´a was created. The board of directors was constituted by Mario Barraga´n and Adria´n Trigo (Trigosso, 2003). Inactivity led to the creation of a new leadership with Harry Trigosso as president, Luis Fernando Zegada as vice-president, and Humberto Molina as general secretary (Trigosso, 2003). After the Hospital de Clı´nicas and Hospital Obrero neurology and neurophysiology services were created, more neurologists began to be trained in Bolivia (Zegada, 2003). The Sociedad Boliviana de Neurologı´a was itself created in 1975.

Ecuador In 1960 the Sociedad Ecuatoriana de Neurologı´a, Neurocirugı´a y Ciencias Afines was created in Ecuador. Its founding president was Alfonso Martı´nez Arago´n. Until 1967, neurology in Ecuador was practiced within internal medicine and neurosurgery. Rafael Vargas Ortiz, the first neurologist, returned to the country that year, after being trained at the Centro Me´dico Nacional de Me´xico. In 1974 Toma´s Alarco´n, who founded the Hospital Regional de Guayaquil’s Neurology Service, returned from Mexico, and in 1975 Marcelo Cruz, who developed the Hospital Carlos Andrada Marı´n’s Neurology Service, returned from the USA. In 1982 the Sociedad Ecuatoriana de Neurologı´a became a WFN member (Leo´n de Ponce, 1988).

CENTRAL AMERICA Panama

Fig. 49.5. Andre´s Rosselli Quijano, the founder of neurology in Colombia.

The first neurosurgery and neurology service was founded in Panama at the Hospital Santo Tomas de la Ciudad de Panama´ in 1947. Neurosurgeon Antonio Gonza´lez Revilla was first chairman. In 1968, the Sociedad Panamen˜a de Neurocirugı´a y Neurologı´a was created and Gonza´lez Revilla was its first president (Leo´n de Ponce, 1988). From 1990, studies

810 R.F. ALLEGRI revealed that Guaymi Indians residing in Bocas del In 1960, the first Neurology Service was created at Toro (Panama´) had HTLV-II (retrovirus) infections the Hospital de La Raza of the Instituto Mexicano de without typical risk factors, suggesting that it is an Seguro Social (IMSS). It was headed by J. Herna´ndez endemic disease in Panama (Lairmore et al., 1990). Peniche. One year later, clinical neurology groups were established at the Hospital General de la Ciudad de Me´xico by Luis Saez Arroyo, and later, in 1962, at Guatemala the Hospital General del Centro Me´dico Nacional del The history of neurology in Guatemala began with IMSS by Luis Lombardo. Miguel Molina, who did his postgraduate studies at At the beginning of the 1960s, the creation of the the Salpeˆtrie`re with Pierre Marie and returned in 1922 Direction of Neurology, Mental Health and Rehabilitaas chairman of neuroanatomy and neurophysiology. tion was approved by the Secretary of Health, with In 1953, Ricardo Ponce Ramı´rez took over the chair Manuel Velasco Sua´rez (a neurosurgeon) as its direcof neurology at the University of San Carlos. Six years tor. Later, he became chairman of the newly created later, Roberto Rendon, trained in Michigan, founded Service of Neurology and Neurosurgery at the Hospital the Instituto Neurolo´gico de Guatemala; Roberto Jua´rez. The first attending physicians were Francisco Ibarra followed in 1962 and Luis Salguero in 1969. Escobedo, Sergio Go´mez Llata, Enrique Ibarra, and In 1970, the Asociacio´n Guatemalteca de Neurologı´a Jesu´s Sa´nchez Burciaga. was founded. In 1987, the Asociacio´n Guatemalteca de In 1964, the Instituto Nacional de Neurologı´a y NeuCiencias Neurolo´gicas became a WFN member (Leo´n rocirugı´a de Mejico (INNN) was inaugurated (Fig. 49.6), de Ponce, 1988). and Velasco Sua´rez appointed its first director. The INNN was initially conceived as an institution where El Salvador the three main divisions of clinical neurosciences would coexist with equal academic pre-eminence: neurology, In El Salvador, Mario Romero Alvergue was the first neurosurgery, and psychiatry. neurologist, having returned in 1952 after studying in The true neurological consolidation stage started in Vienna. In 1956, he founded the National University 1967, when Francisco Rubio Donadieu, a neurologist of Salvador School of Medicine’s Department of Neutrained at the National Hospital, Queen Square in rology. He died in 1998. The first department of neuLondon, arrived. Velasco Sua´rez would be succeeded rology was founded in 1963 at the Hospital General by Francisco Escobedo (a neurosurgeon). In 1983, Rubio del Seguro Social by the neurosurgeon Julio Bottari. Donadieu was appointed Institute Director and Enrique Otero, Gustavo Vega, Fernando Barinagarrementerı´a, Honduras Carlos Ma´rquez, Sergio Co´rdoba, Vicente Guerrero, Francisco Leo´n Go´mez was the first neurologist in Luis Da´vila, Carlos Cantu´, and Teresa Corona were his Honduras, having done his postgraduate studies in collaborators. the United States. He served as director of the NeuroThe Consejo Mexicano de Neurologı´a was created psychiatric Hospital Mario Mendoza in Tegucigalpa. in 1972, and Rubio Donadieu was its first president. The first service of neurology was founded in 1978 in Rubio Donadieu would be succeeded by Jesus Rodrithe Hospital Escuela from Tegucigalpa. In 1995 the guez Carbajal and Julio Sotelo. In the academic field, Asociacio´n Honduren˜a de Neurologı´a was created the INNN is the largest training center for specialists and it became a WFN member. In 1998, Marcos Tulio in Latin America. In its 40 years, it has graduated Medina developed a neurology training program at almost 1000 specialists in the neurological sciences the Universidad Auto´noma de Honduras. and more than 250 MSc and PhD researchers. The major research contributions from Mexico CARIBBEAN AND LATIN have thus far been those related to regional endemic NORTH AMERICA diseases like cysticercosis. The discovery of the gene for myoclonic epilepsy represented an international Mexico collaboration between Mexico, Japan and the USA In 1880, Miguel Alvarado taught neurology at the School (Elisa Alonso, Adriana Ochoa, Aurelio Jara, Astrid of Medicine of Mexico City. In 1929, when the UniverRasmussen, Jaime Ramos Peek, Sergio Co´rdova, sidad Auto´noma was consolidated, Manuel Guevara Francisco Rubio, Marco Tulio Medina) (Escobedo Oropeza became one of its first professors of neuroland Corona, 2004; Instituto Nacional de Neurologı´a ogy. In the first half of the 20th century, several profesy Neurocirugı´a, 2006). sors showed interest in neurological diseases, but all In 1937, the Sociedad Mexicana de Neurologı´a y were primarily associated with internal medicine. Psiquiatrı´a was founded. In 1976, clinical neurologists

CLINICAL NEUROLOGY IN LATIN AMERICA

811

Fig. 49.6. Photograph of the Instituto Nacional de Neurologı´a y Neurocirugı´a (Mexico, 2006, with permission).

broke away to start a separate organization, the Academia Mexicana de Neurologı´a (http://www.neurologia. com.mx). The first journal published at the INNN was the Revista del Instituto Nacional de Neurología y Neurocirugía, created in 1966, with Gu¨ido Belsasso and Francisco Escobedo as its first editors. In 1980, it was renamed Archivos del Instituto Nacional de Neurología y Neurocirugía and, in 1996, it was further renamed Archivos de Neurociencias (Escobedo and Corona, 2004). The Revista Mexicana de Neurociencias was created in 2000 under Lilia Nun˜ez Orosco’s direction and is the official journal of the Academia Mexicana de Neurologı´a (2006).

Puerto Rico The formal history of neurology started in Puerto Rico in 1958, when Luis Sanchez Longo was hired by the School of Medicine of Puerto Rico to start training in clinical neurology. Rosa Fiol, Iva´n Pe´rez Nazario, and Judith Roman were among his collaborators. In 1968 the Academia Portorriquen˜a de Neurologı´a was founded (Leo´n de Ponce, 1988).

Dominican Republic The Instituto Dominicano de Seguros Sociales Neurology Service was taken over by Mario Tolentino upon

his return from France in 1957. In 1965, the Hospital Moscoso Puello Neurology Service started under Juan Santoni. A year later, the Sociedad Dominicana de Psiquiatrı´a, Neurologı´a y Neurocirugı´a was created. In 1982 Psychiatry became independent, resulting in the Sociedad Dominicana de Neurologı´a y Neurocirugı´a (Leo´n de Ponce, 1988).

Cuba Neurology started in 1925 in Cuba, with the creation of the University of Havana Department of Neurology and Psychiatry and the birth of the Sociedad Cubana de Neurologı´a. But despite advances in neurology and neurosurgery, these disciplines were not officially recognized as specialties for many years. In 1960, when the University of Havana School of Medicine’s Department of Functional Neuroanatomy was created, there were only three neurologists practicing the specialty. With the aim of regrouping existing resources, the Department of Public Health created the Hospital de Neurologı´a, which opened in 1962. This institution provided nationwide neurological care and allowed Cuba to start a postgraduate teaching program. Five years later, it was renamed Instituto de Investigacio´n de Neurologı´a (Severa Ortega and Lo´pez Espinosa, 1997).

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PAN AMERICAN CONGRESSES The idea of organizing a Pan American congress that would meet every 4 years was initially conceived within the framework of the World Federation of Neurology. The first Pan American Congress of Neurology was held in October 1963, in Lima, chaired by J. Oscar Trelles Montes (Fig. 49.7), who was then the Prime Minister of Peru. Official languages were Spanish and English. A.E. Walker, P. Bailey, R. Garcin, and F. Lhermitte were given the decoration Comendador El Sol del Peru by the President of the Republic, Belaonde Terry. The Second Pan American Congress was held in October 1967 in San Juan de Puerto Rico under the direction of Luis P. Sanchez Longo (Culebras, 1998). Subsequent congresses have since been held in Sa˜o Paulo (1971), Mexico City (1975), Caracas (1979), Buenos Aires (1983), San Juan, Puerto Rico (1987), Montevideo (1991), Guatemala City (1995), Cartagena, Colombia (1999), and Santiago, Chile (2003).

CONCLUSION The consistent and long-standing admiration for European training led to the birth of neurology as a discipline in some South American countries, namely Argentina, Chile, Uruguay, Brazil and Peru (Fraiman, 2000). This was followed by greater interest in North American training, which led to further developments in these countries and the start of the specialty in others. Among the most significant landmarks are: ●

The first neurology service in South America, which was created in 1885 at the Hospital San Roque de Buenos Aires and headed by Jose´ Marı´a

Ramos Mejı´a, who took over as professor of neurology at the University of Buenos Aires School of Medicine in 1887. ● The first institute of neurology in Latin America, the Instituto Neurolo´gico de Montevideo, created in 1926 under Ame´rico Ricaldoni’s direction. ● The creation of the most important Latin American journal, the Arquivos de Neuropsiquiatria from San Pablo, started in 1943 and it is still in existence. Unfortunately, the lack of access to scientific, Englishwritten and indexed publications has limited what has come out of Latin America, as have clinical demands and additional responsibilities of neurologists in official positions. Even today, articles written in Spanish are not considered by many international journals, most of which will only accept articles in English (Famulari, 2003). In a recent article published in Scientific American, which is appropriately titled “Lost Science in the Third World,” Gibbs (1995) wrote that investigators who want to become known outside of their own countries are strongly advised to publish in English, despite the fact that Spanish is spoken by more than 400 000 000 individuals worldwide (Famulari, 2003). The major research contributions from Latin America have thus far been those related to regional endemic diseases. From Brazil and Argentina, there have been important studies on Chagas’ disease; neurologists from Peru, Ecuador, Mexico and Colombia have researched cysticercosis; Venezuela stands out for genetic studies of Huntington’s disease; while retrovirus-induced neurological diseases have been studied in Panama. In the last 10 years, “globalization” has been positive for Latin American countries, as cooperative projects among them, as well as with first world countries, are now resulting in a more rapid development of Latin American neurology. This review was aimed at giving an overview of the initial stages of neurology in the Latin American world, highlighting the setting in which it was developed, who its pioneers were, how it was perceived locally and elsewhere, and developments in care, teaching, communications, and research. Given the space constraints, interested readers are encouraged to explore this subject further, possibly beginning with the references that follow.

ACKNOWLEDGMENTS Fig. 49.7. Oscar Trelles Montes, father of neurology in Peru and first Pan American Congress of Neurology chair.

This chapter was supported by a grant from the Research Council of the Secretary of Health of Buenos Aires Government, Argentina.

CLINICAL NEUROLOGY IN LATIN AMERICA The author wishes to specially thank Professors Franc¸ois Boller, Stanley Finger, Roberto E. Sica and Leopoldo Tamaroff for their helpful comments on this chapter and those who provided information on the history of neurology in their respective countries (Argentina: Leopoldo Tamaroff; Brazil: Rubens Reima˜o; Chile: Jorge Nogales Gaete; Colombia: Diego Roselli; Cuba: Calixto Machado; El Salvador: Carlos Diaz Manzano; Guatemala: Luis F. Salguero; Honduras: Marcos Tulio Medina; Mexico: Guillermo Albert; Peru: Carlos Escalante and Oscar Gonzales; Uruguay: Eduardo Wilson and Jorge Lorenzo; Venezuela: Celina Leo´n de Ponce).

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 50

History of tropical neurology ADESOLA OGUNNIYI * Department of Medicine, University College Hospital, Ibadan, Nigeria

INTRODUCTION The tropical region extends between latitudes 23
270 N and 23
270 S on either side of the equator. About 75% of the world’s population live in this region, which includes most parts of Africa (approximately threefifths), South America, Central America, the Caribbean, parts of the Arabian Peninsula, the Indian subcontinent, South East Asia, Indonesia, Papua New Guinea, the Mariana Islands, and the northern parts of Australia. The region enjoys abundant sunshine almost all year round. The topography is varied, ranging from highlands to rain forests, deserts, and coastal areas adorned by beautiful beaches. There are many ethnic groups united principally by common boundaries, political alignments, or other geographical landmarks forming the various countries, and inter-ethnic strife does occur commonly and frequently. Most of the countries have developing economies and constitute the “third world,” where many individuals subsist on less than US $2.00 per day. Allocation to health care in general is miniscule. Due to the pervasive problems of illiteracy, poverty, food deprivation, overcrowding, and socio-political problems, mortality is high and life expectancy is generally short. Communicable diseases of public health importance including malaria, schistosomiasis, leprosy, typhoid fever, filariasis, leishmaniasis, and trypanosomiasis are well documented. In addition, diseases associated with poor nutrition and environmental pollution constitute the bulk of the health problems. Neurology as a specialty developed in Europe in the 17th century, and Thomas Willis (1621–1675) conceived the word “neurology” meaning “the doctrine of the nerves.” The earliest reference to the brain in human history however came from Egypt, and was contained in a papyrus written in the 17th century BC, but Africa

*

remained a dark continent for a long time. Edington and Gilles (1969) noted that “in few centers in the tropics has the study of neurology been pursued intensively; knowledge of diseases affecting the nervous system is therefore fragmentary,” (p. 601). There is some evidence that Yoruba traditional healers resident in southwest Nigeria recognized some neurological disorders, but documentation was rather fragmentary. The transplantation of an elephant’s head on Ganesha, an Indian deity, was found in ancient writings in India. Few neurological disorders bear eponymous names of researchers from the tropics, quite unlike in the western world. Neurology can thus be assumed to have grown with the availability of western trained personnel and out of the necessity to compare the patterns of neurological diseases observed in the tropical region with the rest of the world. As the write-up shows, the initial emphasis was placed on the impact of nutrition and cultural factors in disease pathogenesis. This chapter organizes the history into three time periods: (a) events that occurred before 1900, (b) the period between 1900 and 1946 (i.e., after the end of World War II), and (c) the period after World War II to date.

TROPICAL NEUROLOGY PRE-1900 Documentation of neurological disorders in the tropical region lagged behind Europe by about two centuries. The earliest record showed that neurological surgery took place in Brazil in 1710. Luis Ferreyra, who practiced medicine in the cities of Sabara´ and Vila Rica (present-day Ouro Preto), was reported to have successfully managed a case of compound depressed skull fracture, which resulted from a tree branch falling on a slave’s head, by removing the bone fragments, achieving hemostasis, and covering the bone defect

Correspondence to: Adesola Ogunniyi, Department of Medicine, University College Hospital, PMB 5116, Ibadan, Nigeria. E-mail: [email protected], [email protected], Tel: +234-8038094173, Fax: +234-22413545.

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A. OGUNNIYI

(Ferreyra, 1735; Gusmao and de Souza, 2007). During that time period, diseases caused by the consumption of diets that contained toxins which predominantly affected the spinal cord and peripheral nerves were documented. These conditions, as a group, were later tagged “the tropical myeloneuropathy syndromes.” The affected individuals presented with disabling gait abnormality, which compromised agricultural and economic productivity. Lathyrism is one of such early conditions with interesting historical detail.

Lathyrism The chickling pea, a hardy legume (Lathyrus sativus), provides inexpensive survival food during devastating floods and drought. The legume grows as a weed and is referred to in local Indian dialect as “kesari” or “teori.” Other species consumed include the Spanish vetch (L. clymenum) and flat-podded pea (L. cicera). Its consumption causes a disabling neurological disease referred to as lathyrism. There were early documentations of its consumption from around the 4th century BC (during the Hippocratic era) and from Hindu writings. Lathyrism continues to ravage populations in parts of Asia and East Africa. An epidemic occurred in parts of India in the 19th century when the destruction of wheat and other grains as a result of severe hailstorm, drought, and blight in three consecutive years (1829 through 1831) resulted in severe food shortage. The exuberantly growing legume became a major food source. By 1833 the consequence became evident, when many young individuals of both sexes presented with weakness of their lower limbs, stiffness, unbearable cramps, and difficulty with walking that could not be explained otherwise. The affected persons also manifested features of protein-calorie malnutrition. Those affected ended with total paralysis. The bewildering neurological disorder was initially considered to be a form of paralytic stroke because of the suddenness of its appearance. However, careful study of the cases identified the weed consumed as the etiologic agent. A neurotoxin present was thought to be responsible. Those affected were permanently disabled. Recurrent epidemics continued to be reported from parts of India, Pakistan, and Bangladesh in the 20th century, especially after bad monsoon seasons when the planting fields were flooded. Epidemics occurred in Ethiopia during drought and famine caused by civil wars whenever and wherever the toxic weed was consumed (Roman et al., 1985; Tekle-Haimanot et al., 1990). The last epidemic recorded in Ethiopia was in 1997 when more than 2000 patients were affected (Getahun et al., 1999). The particular neurotoxins responsible for the damage

were later identified as beta-N-oxalylamino-L-alanine (BOAA) and b-oxalyly-L-a-b-diaminopropionic acid (b-ODAP) which act on the glutaminergic pathways resulting in excitotoxic nerve damage (Spencer et al., 1986).

Jamaican neuropathy (Strachan’s syndrome) Jamaican neuropathy was first reported by Henry Strachan, who documented 510 cases of “a form of multiple neuritis prevalent in the West Indies” between 1888 and 1897 (Strachan, 1888, 1897). The illness could be simply described as the “burning feet syndrome.” The affected individuals presented with severe burning pain of the soles of their feet that was worse at night, with associated sleep disturbance, ataxic gait, and muscle wasting. More advanced cases presented with upper extremities involvement, claw hand deformity, depressed deep tendon reflexes, and sensory deficits. The condition was originally named Strachan’s syndrome. Based on the clinical and pathological findings, the etiologic agents considered were: nutritional deficiency, protein-calorie malnutrition, vitamin B deficiency, arsenic poisoning, and malaria fever. Malnutrition was considered because the clinical features resembled the neurological illness observed in prison camps and in prisoners of war who were mostly undernourished. Arsenic poisoning was thought of because of the dark pigmentary changes found during post-mortem examination of various organs including the brain and spinal cord. Lastly, malaria pigments were also found in some internal organs (Strachan, 1888). These were the first set of cases of the “tropical neuropathy syndrome.”

Gnasthosomiasis The first case of gnasthosomiasis was reported from Bangkok, Thailand, in 1889 by Levinsen. He described a girl who presented with fever, malaise, muscle aches, and dry cough. She was reported to have contracted the disease through the consumption of raw seafood. Additional clinical and neurological features that were described later included painless, migratory subcutaneous swelling, ataxia, headache, vertigo, and hemiparesis or paraparesis, which tended to occur during the larval migration, as well as blood eosinophilia on peripheral blood film examination. The causative organism is Gnasthosoma spinigerum, a nematode worm which is usually contracted through the consumption of infected Cyclops along with other seafoods. Cases of this infestation continue to be reported from South East Asia because raw fish is a major food item (Sithinamsuwan and Chairangsaris, 2005).

HISTORY OF TROPICAL NEUROLOGY

TROPICAL NEUROLOGY: 1900^1945 The beginning of neurology in Brazil Formal teaching of neurology as a distinct discipline (separately from psychiatry) started at the Faculty of Medicine of Rio de Janeiro, Brazil, in 1912 and Antoˆnio Rodrigues Lima (1876–1961) was the coordinator (Ribeiro, 1940; Gusmao and de Souza, 2007). Brazil can thus be regarded as being at the forefront in the recognition and teaching of neurology in the tropical region. At that time, general surgeons operated on head-injured cases and also drained cerebral abscesses. Among the pioneer surgeons were Augusto Soares de Souza and Ame´ricano Vale´rio who documented those cases. By the late 1920s, both neurology and general surgery were well established as separate specialties in Rio de Janeiro. Augusto Filho (1881–1957) was the first to perform ventriculography and angiography in 1924 and 1928, respectively (Gusmao and de Souza, 2007).

Epidemic neuropathy In 1918, Henry Scott documented 21 Jamaican patients who were then working on sugar cane plantations that presented with allergic features comprising itchy and swollen eyes, tearing, and mouth ulcers. They developed distal paresthesia and burning sensations in their lower extremities with proximal spread. Later, the cases manifested characteristic gait abnormality of unsteadiness (ataxia) and tendency to fall. The deep tendon reflexes were lost. The cases lacked the dark skin pigmentation described by Strachan, otherwise the neurological features were very similar. Nine of the affected individuals died, and autopsy revealed damage to the posterior columns of the spinal cord with degeneration of the fiber tracts as well as the dorsal root ganglia. Fibers of the optic and auditory nerves were similarly involved. Eight of those that survived were left with dimness of vision and partial deafness. The cases were thought to be the consequence of exposure to toxins present in the sugar cane which they subsisted on, while malnutrition was considered another possibility. That marked the beginning of the tropical ataxic neuropathy saga, as similar cases were reported from a number of countries including Sierra Leone, British Guyana, the Seychelles, Somalia, Sri Lanka, Egypt, Ethiopia, Eritrea, Liberia, Senegal, Nigeria, Uganda, Tanzania, Ghana, Zaire, Zambia, Malawi, Kenya, Rhodesia (now Zimbabwe), Malaysia, India, Trinidad, and the Philippines (Roman et al., 1985). This neuropathic disorder appeared widespread without a clear-cut geographic boundary. It was speculated that the causative agents might not be a single entity.

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The implication of cassava in tropical neurological disorders Cassava (Manihot esculenta), also known as tapioca or manioc, is a popular root tuber that is widely consumed in most countries. The crop is of Portuguese origin, and was first grown in parts of South America in the 15th century. From there, Portuguese traders brought it into Central Africa in 1558 through the Zaire River, and from there, its cultivation and consumption spread to most parts of the tropics, almost in a contiguous fashion from Angola through Congo to Gabon by the end of the 16th century. It was later grown in the coastal cities of Mozambique, Zanzibar, and Mombassa; from where its use eventually spread into Asia and South Pacific territories. It is a cheap source of carbohydrate and virtually all parts of the plant have some uses – the leaves contain protein, calcium, iron, and vitamins (Banea, 1993). The tuber itself undergoes processing and is consumed either as a flour or grain. The details of the preparations and processing have been published in detail elsewhere (Banea, 1993). The dried grain is called “gari” in Yoruba language and is a major staple. It is eaten in various ways including soaking in cold water or added to boiling water to make a thick carbohydrate-rich gruel. The major problem is its high content of cyanogenic glycosides which results from improper processing of the tuber before it is consumed. The high cyanide content is associated with nerve fiber damage.

CASSAVA

AND EPIDEMIC NEUROPATHY

IN SOUTHWEST

NIGERIA

It was observed that the type of gait abnormality and the other neurological manifestations described by Scott was epidemic in the high-cassava consumption area of southwestern Nigeria. Moore (1934) had commented that “the disease occurred among poor laborers living entirely on ‘gari’ supplemented with a little dried fish, oil, salt and peppers, and that in ‘gari’ lies the cause of the disease.” Clark in 1935 postulated that the neuropathy resulted from chronic cyanide intoxication present in the cassava consumed. The following year, he measured the levels of thiocyanate (a detoxification product of cyanide) in the urine and saliva of those affected, and compared these with similar samples obtained from individuals that were not affected. Clark (1936) showed that the thiocyanate levels were higher in those with neuropathy. The era of analytic epidemiology could be presumed to have started then. The subject was investigated in more detail later by Osuntokun.

818

CASSAVA

A. OGUNNIYI LINKED WITH TROPICAL SPASTIC

PARAPARESIS OR

“KONZO”

The first epidemic of acute spastic paraparesis was reported in the Bandudu province, a cassava-growing area, in the former Belgian Congo, now called Democratic Republic of Congo, by Trolli (1938). He used the term “Konzo,” meaning “tied legs,” to describe the cases in his report because of the predominant spastic gait they manifested. Cassava was thus associated with another form of neurological disease quite different from the one Scott, Moore, and Clark had described previously. The term “Konzo” has persisted.

Trypanosoma infections – sleeping sickness and Chagas’ disease SLEEPING

SICKNESS

Trypanosoma infection was largely unknown until the end of the 19th century. In 1900, a sleeping sickness epidemic occurred in Uganda which spread to Kenya in 1901 and thereafter to Tanzania through the Kenyan shores and the islands of Lake Victoria. Initial attempts were made by Patrick Mason and others to investigate any possible Filaria-perstans/trypanosome interaction, and this led the Royal Society to organize a research expedition to Africa in 1902 (Haynes, 2000). The expedition resulted in the eventual identification of the actual causal agent, Trypanosoma gambiense, by Aldo Castellani in 1902 (Wellde et al., 1989; Haynes, 2000). One year later, David Bruce identified the tsetse fly of the Glossina species as the vector (Cattand, 2001). The Gambian strain of Trypanosoma is found mainly in the vegetations lining river banks, streams, and lakes in West Africa, while the Rhodesian species is commonly found south of the Luapula River, in Zambia, Rhodesia (now Zimbabwe), Angola, and Tanzania.

CHAGAS’

DISEASE

Chagas’ disease or American trypanosomiasis caused by the flaggelate protozoan, Trypanosoma cruzi, was first identified in 1909 by Chagas. The first two cases with CNS involvement were described in South America in 1911. The first was a 3-year-old patient who presented with spastic paraplegia and seizures and died within 20 days. The second case presented with behavioral changes, involuntary movements, and spastic diplegia (Chagas, 1911). The organism is known to have both cardiac and neurological manifestations. Cases continue to be seen.

Infantile malnutrition and under-nutrition Nutritional problems are common in tropical countries, mainly because of poverty and cultural taboos about feeding children with protein-rich foods. The common infantile nutritional problems are kwashiorkor, marasmus, and marasmic kwashiorkor. Marasmus occurs when there is severe calorie deficiency and manifests between 6 and 12 months of age when the baby is weaned abruptly either because of a new pregnancy or because the mother has resumed work. The body weight is usually below 60% of expected, and wasting is marked. Kwashiorkor is derived from the Ga language in Ghana meaning “dispossessed child” or “the disease that occurs when a new one is born.” Kwashiorkor was coined by Cecily Williams in 1933 (Williams, 1983). It is due to severe protein deficiency and occurs later than marasmus (between 1 and 3 years), when breast feeding is stopped, and the child is fed on maize gruel with no added protein. The predominant features are fluffy hair, apathy, edema, enlarged liver, and diarrhea, with some degree of body wasting. The body weight is between 60 and 80% of that expected for that age. Marasmic kwashiorkor represents a hybrid condition with features of both conditions. Measles and whooping cough tend to unmask these diseases. Starvation is the adult equivalent of marasmus, while adult kwashiorkor is a distinct entity. Whether poor nutrition in early life has a long-term influence on neurological development and intellect or not has been much debated. Earlier studies were observational, retrospective, and highly confounded by poverty and lack of psychosocial stimulation (Pollitt and Thompson, 1977). Prospective, multi-site studies involving malnourished Black South African, Barbados, and Portuguese children, and controlled for poverty and psychosocial stimulation, suggested that the deleterious effects of malnutrition on brain functions may be permanent (Galler, 1983; da Motta et al., 1990). Grantham et al., (1991), in another study that involved undernourished and stunted Jamaican children aged between 9 and 24 months who had 2 years of nutritional rehabilitation, showed improvement in cognitive functions. Akinyinka et al., (1995) used serial computer tomographic brain scanning to study residual morphological changes in the brains of Nigerian children who suffered protein energy malnutrition and after 2 months of nutritional rehabilitation. The repeat brain scans did not show any residual changes, although the attrition of the study participants was very high. It would therefore seem appropriate to institute effective nutritional rehabilitation for malnourished children for proper cognitive development. The consequence of

HISTORY OF TROPICAL NEUROLOGY severe protein malnutrition affecting many children that are not adequately rehabilitated would be a generation of mentally incapacitated adults in tropical countries. The good news is that kwashiorkor appears to be a dying disease because of the adoption of prolonged breast feeding policies in many countries, and the impact of public enlightenment on proper feeding of infants with protein supplementation. Other neurological complications of protein-energy malnutrition include myelopathy, diffuse slowing on electroencephalography, peripheral neuropathy with delayed nerve conduction, and myopathy (Chopra et al., 1995).

Other diseases documented during the period There were isolated reports of leprosy, tetanus, and rabies in the available literature during this time period (Grey, 1928; Smith, 1928). Shortt et al., (1937) reported cases of endemic fluorosis in the Madras area of India, where the content of fluoride in the drinking water was high. The afflicted individuals developed spinal cord compressive symptoms, mainly in the cervical region, and their bones showed evidence of increased density (osteosclerosis) on X-rays.

1946 TO DATE This was a remarkable time period in the evolution of tropical neurology because there was vast improvement in the availability of diagnostic facilities and it became possible to document more detailed features of many diseases. With the attainment of independence in many countries, relevant specialist training programs were commenced, although referral of cases to western countries did not stop. Local or regional neurological associations of specialists were also established. A chronological sequence of developments in neurology in different regions or countries is presented below.

Neurology in India and South East Asia India, one of the first countries to attain independence, lies at the forefront with regards to the growth and development of neurology in the developing world. Dr. Jacob Chandy of Vellore started neurosurgery in 1949; hitherto, general surgeons performed neurosurgical operations. He was later joined by Dr. B. Ramamurthi who worked in Madras. Dr. S.T. Narasimhan started the first electroencephalography laboratory in Madras in 1950 (Nadkarni et al., 2002). There were three qualified neurosurgeons in the entire country till 1957. The first residency training program in

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neurosurgery was commenced in 1954, and university postgraduate degree programs in the neurosciences started in 1958. Neurology training was initiated in 1966. The establishment of other units took place in rapid sequence to cover most parts of the country. The All-India Institute of Medical Sciences was founded in 1946–1947 and the National Institute of Mental Health and Neurological Sciences (NIMHANS) was later established in Bangalore. These centers have been involved with local training and capacity building. A vibrant neurological association exists in India, with experts in various aspects of the specialty. The Neurological Society of India was inaugurated in Hyderabad in 1951 following meetings between the pioneers – namely Drs. Ramamurthi, Chandy (both neurosurgeons), Singh (the pioneer neurologist), and Narasimhan (electrophysiologist). Today, India has more than 15 centers where skull base surgery, vascular surgery, neuroendoscopy, radiosurgery, interventional neuroradiology, deep brain stimulation, and other high tech, exotic procedures in surgery are carried out (Nadkarni et al., 2002). Traditional practices, allopathic medicine “ayurveda,” continued in parallel with orthodox medicine. With the teeming population, poverty remains a problem in the rural communities and many are vegetarians. These factors had a bearing on the pattern of disease and availability of care.

DISEASE

PATTERNS IN

INDIA

Three types of neurological diseases were documented: (1) those commonly encountered in other tropical regions as well as other parts of the world, (2) diseases peculiar to India, and (3) uncommon diseases. 1. Common diseases: Infectious diseases predominated, and included syphilis, tetanus, neurotuberculosis, cerebrospinal meningitis and leprosy. The other common diseases were: epilepsy, nutritional disorders (vitamin B12 deficiency, dermal pellagra), sensory ataxia with optic atrophy, fluorosis, lathyrism, tropical spastic paraplegia/paraparesis, strokes, and immunological disorders (oculomotor neuritis – Tolosa–Hunt syndrome; and aortic arch syndrome – Takayashu’s disease). The infantile tremor syndromes and congenital malformations of the brain including neurosurgical repair of anterior encephalocoeles were also documented. 2. Unusual local diseases: a. Hot-water epilepsy, a variant of reflex seizures that occurred when hot water was poured on the head during bathing in susceptible individuals, was first described by Mani and others in 1968. Much later, studies were carried out to determine the epidemiology and genetic basis.

820

A. OGUNNIYI

b. Jagannathan (1973) brought the world’s attention to the Madras type of motor neuron disease with onset in the third decade and characterized by slow progression, high incidence of bulbar and facial muscle involvement, bilateral nerve deafness, and negative family history. Similar cases had been described from Guam and New Guinea by Kurland and Mulder (1954), and Gadjusek (1963a), respectively. c. Toxic neuropathy caused by exposure to orthocresyl-phosphate was reported from Bombay by Vora and others in 1962. d. Craniovertebral anomalies with atlanto-axial dislocation, noted to be more common in India than in the rest of the world, were extensively studied by Wadia (1960). He observed that the craniovertebral anomaly resulted from maldevelopment and/or dislocation of the odontoid process (Wadia , 1973). Affected individuals presented in any of these three ways: (1) transient ischemic attacks due to compromise of the vertebral artery supply, (2) cervical pain and stiffness that mimicked cervical spondylosis, and (3) progressive myeloradiculopathy with weakness of extremities and radicular features. None of the cases had cranial nerve involvement, which suggested that the brunt of the compressive features was borne by the upper cervical region. Dysmorphic features like dysplastic faces, short neck, and low hair line were also documented (Wadia, 1973). Noshir Wadia (b. 1925) had his medical education in Bombay and he is regarded as one of the foremost neurologists in India. He currently practices neurology as a private physician after retiring from academic work. The Wadias are renowned for their entrepreneurship in India and rich family heritage. 3. Uncommon/rare diseases: The following neurological conditions were reported to be relatively uncommon: multiple sclerosis, hydatid diseases, temporal arteritis, and neurosarcoidosis. The reasons for their rarity in India were not known precisely.

Toxic neuropathy in Sri Lanka Episodes of toxic polyneuropathy resulting from contamination of cooking oil (gingili oil) with tri-cresyl phosphate during transfers in storage containers occurred in Sri Lanka between 1977 and 1978 (Senanayake and Jeyaratnam, 1981). Adolescent girls were predominantly affected, and they presented with claw hand deformity and wrist drop. The cases were similar to those described by Vora et al., (1962) in India.

West Pacific Region: “lytico” and Kuru AMYOTROPHIC LATERAL GUAM

SCLEROSIS

– PARKINSON’S

DISEASE OF

Unusual clusters of neurodegenerative diseases and ritual practices with attendant high fatality were reported from the West Pacific region. The term “geographic isolates” coined by Len Kurland (1978) appropriately described these cohorts. Amyotrophic lateral sclerosis (ALS), locally referred to as “lytico” (paralytico), was noted to be 50- to 100-times more prevalent among the Chamorros in Guam, other Mariana Islands, and in the Kii Peninsula than elsewhere in the world by Kurland and Mulder (1954). The National Institutes of Health, USA, opened a research station in this region when the observations were made. Apart from the involvement of upper and lower motor neurons in the corticospinal tract, brain stem, and spinal cord, the affected individuals had, in addition, progressive dementia and basal ganglia lesion. The combination was referred to as the amyotrophic lateral sclerosis, parkinsonism-dementia complex (ALS-PD complex). Similar to the story of cassava and tropical neuropathy, the consumption of cycad nuts (Cycas circinalis) which contain cycasin was assumed to be the probable cause of this peculiar disease. Later studies incriminated an excitotoxin, beta-N-methylamino-L-alanine (BMAA), a neurotoxin related to the BOAA extracted from Lathyrus sativus (discussed earlier under Lathyrism), as the cause (Roman et al., 1985; Roman, 1990). BMAA also causes neurodegeneration through its action on the glutaminergic pathway.

KURU In the mid-1950s, up till the early 1960s, and in the same region, Gadjusek and colleagues were involved with the elucidation of the cause of a fatal neurodegenerative disease called Kuru that peculiarly affected the Fore linguistic group in the highlands of New Guinea where ritual cannibalism was practiced (Gadjusek and Zigas, 1957; Gadjusek, 1963b). As part of the traditional mourning rite, the brains of dead relatives were consumed. Those affected were predominantly children of both sexes and adult women who presented with cerebellar ataxia, generalized tremulousness, and motor weakness. Death occurred within 6 to 24 months of presentation. The natives were presumed to contract the disease through the inhalation of an infectious agent during the ritual cannibalism. However, adult males were rarely affected. Due to the long interval between the ritual and the clinical manifestation, an infectious agent with a long incubation period was suspected to be involved, and was most likely

HISTORY OF TROPICAL NEUROLOGY similar to the agent that caused Creutzfeldt-Jakob disease from animal experiments (Gibbs and Gadjusek, 1972). The extensive work carried out by Gadjusek and his colleagues as well as the effective education that followed led to the abolition of cannibalism, with progressive disappearance of the fatal disorder. Gadjusek was awarded the Nobel Prize in 1976 for his outstanding contributions to the origin and dissemination of infectious diseases. Subsequent studies have revealed that people who handled the dead bodies were more likely to contact Kuru than those who only feasted on the brains. The infectious agent most likely got into the central nervous system through rubbing the eyes rather than through eating cooked brains or inhalation. That could explain why older men did not contact the disease despite eating cooked brains. Later studies by Stanley Prusiner, who was awarded the Nobel Prize in 1997, led to the recognition of proteinaceous infectious agents (prion proteins) as the causative agent. Aguzzi (1997) speculated on possible neuroimmune connection in the spread of prions in the body.

Brazil The Brazilian Society of Neurosurgery was founded in Brussels, Belgium, on 26 July, 1957 during the First Congress of the Neurosurgical Society, through the initiative of Jose´ R. Portugal and Jose´ G. Albernaz. The former was elected President and the latter, the Interim Secretary. The first congress of the new Brazilian Society was held in Petro´polis in July 1958, and in 1959 the young society became a member of the World Federation of Neurosurgical Societies.

Africa COMMON

DISEASES

Neurological disorders in parts of Africa are similar to those found in other tropical regions. The common diseases that are well described include epilepsy, infections (predominantly, cerebral malaria, pyogenic and tuberculous meningitis, encephalitis, poliomyelitis, leprosy, tetanus), nutritional neuropathies, strokes, tumors, snake bites, and myelopathies, both obscure and those with defined etiology. Obscurity probably reflected poor facilities available for definitive diagnoses. The savannah region stretching from Burkina Faso, Mali, to parts of Central Africa experienced epidemics of meningococcal meningitis with high-case fatality during the dry season. The relatively low temperatures caused many individuals to crowd together around fires in barracks, camps, and communities as a way of keeping warm, with inadvertent spread of the

821

causative organism through the nasal route. This area is referred to as the “meningitis belt of Africa.” Immunization with the A and C serotype vaccines has limited these epidemics, as has chemoprophylactic treatment of contacts. Apart from meningitis, snake bites were prominent problems in the savannah regions and hilly areas. Neurological complications associated with elapidae snake bites were frequently reported principally among farmers, those who walk around at night without appropriate footwear, and those who search ant-hills for game meat. Among the Bantus, porphyria and scurvy were common conditions (Cosnett, 1973), though these conditions occurred less commonly in other countries. Neurology in Africa was largely practiced by expatriates and a few local physicians who did not necessarily have specialist training in neurology. Language problems existed and Smartt (1959) remarked that “leading questioning in determining pattern of presentation was at times useless because it was characteristic of the rural African to agree with anything suggested by a European,” (p. 91). The dilemma faced by expatriates in fully understanding some of the cases could be imagined.

BURKITT’S

LYMPHOMA

In the late 1950s and early 1960s, many cases of unusual jaw tumors involving the facial and maxillary bones were observed in children in East Africa. Some of them had, in addition, abdominal masses and neurological manifestations such as flaccid paraparesis. The tumors appeared to be fast growing and ended fatally within a few weeks of onset. A British surgeon named Denis Parsons Burkitt (1911–1993) had the rather unique opportunity of diagnosing the cases. Dr. Burkitt had an interesting childhood. He was unfortunate to have lost one of his eyes during a scuffle as a child and was considered unlikely to be a surgeon. He enlisted in the army after specializing and providence brought him to Africa. He rose to the rank of major and worked in Kenya, Somalia, and Uganda from 1943. It was in Uganda that the cases confronted him in 1957 and they aroused his interest. He published the first set of cases in 1958 (Burkitt, 1958). The cases were very similar to those earlier described in 1905 by Albert Cook (1870–1951), a missionary physician working in Uganda. Later, Burkitt and two of his associates, Edward Williams and Cliff Nelson, traveled round many countries in East Africa and Southern Africa, covering some 16 000 kilometers and visiting about 60 hospitals. They mapped the location of the cases to the equatorial rain forest region and highlands (areas up to 1500 meters above sea level). These are regions where malaria was

822

A. OGUNNIYI

endemic, and this observation led them to speculate on a possible insect vector. Cases were also reported from Nigeria, New Guinea, Colombia, and India. It was postulated by Bademosi and Ajayi (1979) that the disease could be related to Guillain-Barre´ syndrome because of the ascending nature of weakness and predominance of lower motor neuron signs in some patients. Burkitt compiled cases of malignant lymphoma in African children. The eponym Burkitt’s lymphoma was given in recognition of this pioneering work. In 1964, subsequent analysis of pathological specimens from the tumor led to the identification of the virus by Michael Epstein, another British scientist who worked in conjunction with an Australian physician, Yvonne Barr. The virus was named the Epstein–Barr virus. Denis Burkitt was later interested in dietary fiber and its possible protective role against the development of colonic cancer based on observations of fecal bulk and frequencies of passage by the natives. He was thus at the forefront of research into the relationship between dietary fiber, obesity, diabetes mellitus, diverticular disease, and lipids.

ROLE

OF PSYCHIATRISTS IN THE DEVELOPMENT

OF NEUROLOGY IN

AFRICA

Psychiatrists dominated the scene early and neurology was largely subsumed under psychiatry as a subspecialty because of common brain involvement, as was the early experience in Brazil. Emphasis was placed on acute and/or sub-acute mental symptoms occurring in the course of diseases of the nervous system which were collectively referred to as acute organic brain syndromes. These included the various encephalopathies, generalized parasitosis, and post-traumatic syndromes, to mention a few. Patients with brain tumors who manifested psychotic features were kept in sanatoria. The undeniable role of traditional healers as being the primary point of contact in the management of cases was also quite evident because social factors, supernatural forces, and stress were believed to be important in the causation of mental disease in most tropical countries (Lambo, 1961). Epilepsy was believed to result from possession by evil spirits, and the sufferer was inhumanly treated. Pepper was rubbed on the eyes, the extremities were thrown into fire, and the hands were shackled down as a way of driving out the offending spirits, a form of traditional exorcism. Up till the 1970s, a cow’s urine concoction was used to treat epileptic patients in most communities in southwestern Nigeria. Unfortunately, its use was associated with many sideeffects and even death because of its contents. It

could be regarded as “unorthodox therapeutic poisoning.” The concoction was made from tobacco leaves (Nicotiana tabacum), garlic leaves (Allium sativum), basil leaves (Ocimum viridae), lemon juice (Citrus medica var. acida), rock salt (Trona), and bulbs of onion (Allium cepa). These items were then soaked in cow’s or human urine and administered to the hapless victim. The smell was very offensive and it was not unusual to find some concoctions in many homes of sufferers. The concoction caused severe hypoglycemia as well as depression of the respiratory, cardiovascular, and central nervous systems in those treated (Oyebola and Elegbe, 1975; Oyebola, 1983). The use added to the morbidity of epilepsy and the very poor prognosis in those so treated. The use of herbal preparation in the management of epilepsy is now mainly of historical interest. Epilepsy is however not the only condition managed the traditional way, and the book by Adelola Adeloye (1977) titled Nigerian Pioneers of Modern Medicine: Selected Writings contains interesting details on this practice with respect to the management of many medical conditions in Nigeria in the past. Such details may also be available in other countries, but suffice it to use the Nigerian example.

PIONEERS OF NEUROSCIENCES AND THE FORMATION OF THE PAN AFRICAN ASSOCIATION OF NEUROLOGICAL SCIENCES Most of the local scholars who proceeded overseas for specialist training in the neurosciences started returning home in the early 1960s. A history of neurology would not be complete without recognizing the contributions of some distinguished neuroscientists. E. Latunde Odeku (1927–1974), the first African neurosurgeon and an accomplished poet, should be remembered for his pioneering role in documenting the patterns of various neurosurgical diseases and for his mentorship. He received his medical and neurosurgical training at Ann Arbor, Michigan, and Howard University, Washington DC, USA. Between 1962 and 1974, Odeku practiced neurosurgery in Ibadan, and contributed extensively to the world literature on many neurosurgical conditions, particularly brain tumors and traumatic injuries. He reported that brain tumors were less commonly diagnosed in Africans when compared with Caucasians, and that meningioma was the most common type, with rarity of glioblastoma multiforme and acoustic neuromas (Odeku and Janota, 1967; Odeku et al., 1972). His studies on the patterns of traumatic lesions of the craniospinal axis as well as missile head injuries with the sequelae were aided by findings from victims of the Nigerian Civil War between 1967

HISTORY OF TROPICAL NEUROLOGY and 1970 (Adeloye and Odeku, 1970). Other injuries resulted from occupation-related falls (i.e., from the palm tree, load carriers) and automobile accidents (Odeku and Richard, 1971). Odeku was the prime mover for the founding of the Nigerian Society of Neurological Sciences (NSNS) in 1966, which brought all the Nigerian neurologists (surgical, medical, and pediatric) together under one umbrella, and later the Pan African Association of Neurological Sciences (PAANS). Among those that participated in the preliminary meetings leading to the inauguration of PAANS were Drs. Critchley, Billinghurst, Odeku, Dada, Girard, Dumas, Osuntokun, Familusi, and Williams (Fig. 50.1). At the inception of PAANS in 1972 in Nairobi, Kenya, brain tumors in the African and those of African descent formed the focus of the discussion. It would be unkind not to recognize the pioneering roles played by O. Sorour of Egypt, the first President of PAANS (1973–1975); Michel Dumas of France, who worked in Senegal, second President (1975–1977); Ben Eddo in Ghana; the late T.O. Dada of Lagos University, Nigeria; R.F. Ruberti of Kenya; M. Abada of Algeria; and Benjamin O. Osuntokun (1935–1995) and Adelola Adeloye, both of Nigeria. Professor Dumas later returned to Limoges, France, and continued to mentor young neuroscientists from Francophone countries. He is still active in reorganizing neurological services in developing countries.

823

Professor Ruberti, an Italian and a fully trained neurosurgeon, started working in Nairobi in 1967. He hosted the first PAANS conference and established one of the very few neurosurgical training units in Africa for manpower development. By all accounts, that would be considered unique at that time. At different time periods, he served PAANS as Honorary Secretary General, Treasurer, and Editor-in-Chief of the African Journal of Neurological Sciences, which was established in 1982. At present, he is one of the two Historians of the Association, the other being Professor Adelola Adeloye. The vigorous leadership of the association and the provision of needed information on the pattern of neurological diseases from these countries attracted world attention. During the formative years of PAANS, tremendous support from both the World Federation of Neurology (WFN) and the World Federation of Neurological Surgery (WFNS) contributed to the successes recorded. The Presidents and Vice Presidents were recognized as honorary fellows. The biennial conferences also attracted eminent scholars from the USA, UK, France, Germany, etc. In 1982, the WFN established a Research Group of Tropical Neurology for the Africa region and Benjamin Osuntokun served as the Secretary. Benjamin Osuntokun made his mark and established himself as a world-renowned neurologist and academic. He trained as a neurologist under Henry Miller and Lord Walton at Newcastle. In conjunction with Odeku and

Fig. 50.1. Picture taken in Ibadan in 1968 at one of the preliminary meetings for the formation of the Pan African Association of Neurological Sciences. Shown in the picture are: E. Lat. Odeku, Dr. Critchley, Michel Dumas, Benjamin Osuntokun, Professor L. Girard, Dr. Billinghurst, J.B. Familusi, and Femi Dada. Courtesy: Professor Michel Dumas.

824

A. OGUNNIYI

Luzzato, he described the first case of congenital insensitivity to pain associated with auditory imperception in a Nigerian, and this was eponymously named after him (Osuntokun et al., 1968). By far, his major contribution was in describing the nosology of the tropical ataxic neuropathy (TAN), which is also referred to in some circles as Osuntokun’s disease (Roman et al., 1985). The syndrome comprised myelopathy, bilateral optic atrophy, bilateral perceptive deafness, and polyneuropathy, which presented as foot drop and dysesthesia. Stigmata of malnutrition and hypovitaminosis were present in some cases as well as dementia, motor neuron disease, cerebellar degeneration, Parkinson’s disease, and psychosis (Osuntokun, 1968, 1971). Alexander Brown, Scotsman, Foundation Professor and Head of Medicine at the University College Hospital, Ibadan, Nigeria, in the 1950s and 1960s, had commented on the peculiar type of peripheral neuropathy in the Epe area of Nigeria and opined that the condition resulted from what the people were eating, not what they lacked in their diet. Osuntokun combined clinical, neurological, epidemiological, biochemical, and pathological findings to convincingly link TAN with linamarin and other cyanogenic glycosides present in cassava. With these, he improved on the earlier clinical and epidemiological observations of Oluwole and Clark (Clark, 1935) and Monekosso, who was formerly called Money (Money, 1958, 1959). Osuntokun’s research findings appeared to have supported Brown’s suspicion. Professor Monekosso later became the Regional Director of the African Regional Office of the World Health Organization (AFRO) in Brazzaville, Congo.

COMMUNITY-BASED (1980–1985)

STUDIES IN NEUROLOGY

The concept of “geographical neurology” was highlighted by Lord Russell Brain at the first Pan African Psychiatric Conference held in Abeokuta, Nigeria, in November 1961 (Lambo, 1961). Lord Brain argued that the assessment of patients in any geographic area should take into account genetic factors, dietary deficiencies and toxins, infections, vectors, social and industrial factors, toxicology, climate, and vegetation to obtain a global picture for regional comparisons. The seeds of neuroepidemiologic research that would dominate tropical neurology in the late 1970s and early 1980s appeared to have been sown at that time. Comparison of disease rates in different parts of the world is always faulted whenever methodology differs, and case ascertainment is questionable. The latter was particularly relevant to developing countries where manpower and diagnostic facilities were limited. To overcome this problem, Benjamin Osuntokun, Bruce

Schoenberg (1944–1986), then of the National Institute of Neurological Communicative Disorders and Stroke, USA (NINCDS; now called NINDS), and Liana Bolis (Head of the Neurosciences Programme of the WHO) initiated the program of community-based studies in neurology and dispersed the seed of neuro-epidemiological studies to many developing countries. They designed a novel screening questionnaire tagged “green forms” for these two-stage studies. The first stage comprised a census to provide the denominator for the calculation of rates and screening interview. In the second stage, those individuals that screened positive were assessed by the neurological specialist. Thereafter, diagnosis was made along defined criteria and crude/adjusted rates determined. It made for efficient use of time and resources, and was considered very appropriate for identifying putative environmental risk factors. “Neurology with few neurologists” appropriately describes the process. The initial studies were carried out successfully in Copiah County of Mississippi, USA (Anderson et al., 1982). The same methodology was adopted for studies in Nigeria, Tunisia, Ecuador, and Chile (Schoenberg, 1982). Those who spearheaded the studies in the listed countries were Benjamin Osuntokun, Mongi Ben-Hamida, Marcelo Cruz, and Patricia Barberis, respectively. A similar design was used to study the epidemiology of cerebrovascular disease in the People’s Republic of China (Li et al., 1985). In a befitting tribute on his death, Osuntokun was aptly described as the “pioneer of neuroepidemiology in Africa” (Ogunniyi, 1996). Similar community-based studies were later organized amongst the Parsi in Bombay, India by Bharucha et al. (1987) and in Thugbah, Saudi Arabia, by Al-Rajeh et al. (1993). The studies have provided some comparable data and showed the predominant neurological disorders in the various communities studied. The manuscripts that emanated from these studies were published in the early issues of the new journal appropriately titled Neuroepidemiology. Interested readers may find these compilations very useful.

WORLD FEDERATION

OF

NEUROLOGY

RECOGNITION

OF TROPICAL NEUROLOGY

Geographical neurology featured as a theme during the 11th World Congress of the World Federation of Neurology (WFN) in Amsterdam in 1977. This followed the acceptance of a proposal by T. Olufemi Dada and Mongi Ben-Hamida, who served as delegates of the African group on the WFN. The quadrennial congress of the WFN was held in a tropical country for the first time in New Delhi, India, in October 1989 (Fig. 50.2), and tropical neurology featured as one of the main themes for the first time. Jagit Chopra, who headed

HISTORY OF TROPICAL NEUROLOGY

Fig. 50.2. Picture of souvenir presented to all delegates at the XIV World Congress of Neurology in New Delhi, October 1989. The background shows the Taj Mahal, one of the Seven Wonders of the World.

the planning committee of the Congress, and his colleagues in India, deserved praise for the excellent planning. To my mind, tropical neurology achieved international status at that meeting. The presentations featured contributions to recent advances in the understanding of various communicable diseases, neurotoxicology, cerebral malaria, neurotoxic snake bites, and tropical myeloneuropathies/spastic paraparesis from the tropical world. Dementia and multiple sclerosis were the rare conditions presented (Chopra et al., 1990). Overall, it was a great beginning, albeit modest, but the impact was substantial and a source of pride for all delegates from tropical countries. It served as impetus for further collaborative research between various countries for the exploration of commonalities and differences which could facilitate the investigation of environmental influences in disease phenotypes. Tropical neurology continues to feature in the WFN programs.

TROPICAL

NEUROLOGY IN THE

1980S

There was reawakened interest in the neurology of tropical spastic paraparesis (TSP) which continued to be diagnosed in many countries. In the early 1980s, the human

825

T-cell leukemia virus types-I and III (HTLV-I and HTLV-III, respectively) were identified. Kelly and De Mol (1982) reported 83 cases of tropical spastic paraparesis on the Seychelles Islands in the Indian Ocean. In 1985, HTLV-I was shown to be a neurotropic virus, and was linked with chronic myelopathy in the equatorial regions (Gessain et al., 1985). Seroepidemiological studies carried out in other regions also linked the virus with the curious myelopathy reported in Japan, the Caribbean, Panama, Colombia, Peru, Brazil, parts of West Africa, and Zaire (Roman, 1989). Thus, HTLV-I-associated myelopathy (HAM) became a subject of intense study. The clinical features were slowly progressive spastic paraparesis with minimal sensory deficit and neurogenic bladder dysfunction. The natural history of the endemic cases on the Seychelles was studied by Roman et al., (1987). The group documented complete paralysis over a varying period of 2–15 years, but no risk factors were identified. Roman and Osame carried out detailed studies on another Japanese cohort and concluded that TSP and HAM were identical conditions because of similarity in clinical, epidemiological, and laboratory profiles (Roman and Osame, 1988; Roman, 1989). The authors, however, admitted that a few cases did not conform to these features, and suggested that genetic factors could be responsible. Researchers in Mozambique and Zaire independently encountered patients with myelopathy and predominantly upper motor neuron signs who fed on cassava. The cases closely resembled those described by Trolli in 1938 (Mozambique Ministry of Health, 1984; Kayembe et al., 1990). There was renewed interest in these cases of cassava-induced myelopathy. Thorkild Tylleskar from Sweden and his collaborators carried out extensive epidemiological studies in rural Zaire and found very high cyanide concentrations in the sera of those affected (Tylleskar et al., 1992). Improperly processed cassava was the etiologic factor incriminated and the name “konzo” acquired prominence again. Konzo is associated with poverty and food shortage which results in improper processing of cassava and premature consumption of the cassava flour before fermentation is completed. Preventive strategies were thus suggested. The disorder continues to generate worldwide interest. It is intriguing that cassava that was initially associated with the tropical ataxic neuropathy with lesion affecting the dorsal columns could in the same region of the world be the putative etiologic agent for the tropical spastic paraparesis syndrome. Osuntokun and Tylleskar met at the 1993 World Federation of Neurology Congress that took place in Vancouver, Canada, and as expected there were arguments, with claims and counter-claims about the veracity of the various

826

A. OGUNNIYI

findings. A conference subsequently followed at the International Institute of Tropical Agriculture, Ibadan, Nigeria, a US-funded research institution, in 1994. Osuntokun died in 1995 and the two conditions (TAN and TSP), both associated with cassava consumption, and involving different neural pathways, continue to be scientifically challenging. They remain subjects of scientific curiosity in the tropical world. One cannot but agree with the description of the tropical myelopathy syndromes as “the hidden endemias” (Roman et al., 1985). It is possible that other agents or genetic predisposition may have parts to play. Fewer cases of TAN are being seen currently in Nigeria, and pursuing that research is limited to a few committed individuals who may be fortunate to trace the earlier cohorts if still living.

CUBAN

NEUROPATHY IN

1991

In the latter half of 1991, Cuba was troubled by an epidemic of visual loss and/or peripheral neuropathy that affected predominantly middle-aged male tobacco growers who were heavy smokers. Over a 2-year period (between January 1992 and 1994) more than 50 000 Cubans were reported to have been affected by the disease (Llanos et al., 1993; Mojon et al., 1997). This occurred at a time of food rationing because of economic difficulties, with consequent increased consumption of cassava products. It was suggested that the epidemic was due to nutritional deficiency possibly combined with exposure to some neurotoxins. No further epidemics have been reported since then.

SEASONAL ATAXIA SYNDROME IN SOUTHWEST NIGERIA Tremulousness as a mode of presentation of neurological disease was not limited to the Fore Island where cannibalism was practiced, as discussed previously. Cases presenting with tremulousness were first reported from southwest Nigeria in 1958 by Wright and Morley. The condition occurred during the rainy season when individuals living in those parts consumed new yams (Discorea sp.). The manifestations included tremulousness, weakness, and ataxia. The condition was rarely fatal, and was initially presumed to be a form of encephalitis (Wright and Morley, 1958). Other possibilities considered included organophosphate poisoning (as contamination during planting or in fertilizers) or as another mode of presentation of the tropical ataxic neuropathy by some workers. In 1993, Adamolekun published his findings from the cohort he studied in the Ile-Ife and Ilesha areas of southwest Nigeria, and convincingly showed that the condition resulted from the consumption of the silkworm (Anaphe venata). The name “seasonal ataxia

syndrome” was ascribed to it. People consumed the silkworm which is locally called “moni-moni” or “koni” as a protein supplement. Subsequent analyses showed that the silkworm contained a thiaminase that degraded thiamin, which resulted in acute thiamin deficiency (Adamolekun et al., 1994; Nishimune et al., 2000). With public enlightenment and improvement in family economy, consumption of food items that lead to interesting tropical diseases will hopefully become a thing of the past and the diseases will die a natural death.

HIV

AND TROPICAL NEUROLOGY

The history of tropical neurology will only be complete with a brief description of the impact of the human immunodeficiency virus infection and the acquired immunodeficiency syndrome (HIV/AIDS). The virus was identified in the US in 1982, but documentation from Africa lagged behind by a couple of years. Since the first case of AIDS in Africa was reported from Kenya in 1984 (Adams, 1990), the sub-Saharan African region has borne a huge toll and it has reached pandemic proportions. More cases are living longer due to the availability of highly active anti-retroviral drugs, hence chronic neurological complications either due to the disease process or drug side effects will become important issues. Many neurological syndromes have been described early and late in the course of the illness. These include distal symmetrical neuropathies manifesting as dysesthesia or burning feet, meningo-encephalitis, acute ascending inflammatory polyneuropathy, cranial nerve palsies, especially facial nerve involvement, opportunistic infections (toxoplasmosis, cryptococcus, tuberculosis, and cytomegalovirus), tumors, demyelinating conditions, myelopathies, and neurocognitive decline. AIDS dementia complex is also seen, and may become more problematic as survivors live longer. Interested readers may consult the review by Howlett (1995) on the patterns of presentations.

EMERGING

DISEASE

–

DEMENTIA

The world’s population is aging, and one of the consequences is predisposition to dementia. The developing countries are not left out of this demographic transition. The prevalence of dementia in western countries in individuals aged 65 years and over varies between 5 and 11%. Prior to 1984, dementia, and, in particular, Alzheimer’s disease (AD), was rarely diagnosed in the indigenous African. This led Henderson (1986) to speculate that AD resulted from exposure to some agents that were absent in the developing countries at that time but present in the industrialized countries. Some researchers were however of the view that the correct facts about

HISTORY OF TROPICAL NEUROLOGY the burden of dementias would emerge when developing countries had enough resources to organize proper epidemiological studies, since concealment within families was a possible confounder. Transnational, cross-cultural studies carried out later confirmed the relatively lower burden of dementia in developing countries (Hendrie et al., 2004). It is speculated that the burden of dementia will increase as the population ages and the western lifestyle is adopted. The observed differences in rates afford unique opportunities for identifying the risk factors for appropriate preventive actions. Many studies are in progress with appropriate cultural adaptations for caring for the elderly (Ogunniyi et al., 2002). These continue to pose interesting scientific challenges.

CONCLUDING REMARKS In the early stages, local specialists were few, and interest in neurology was generally low because it was regarded as a difficult specialty by many physicians. Unorthodox practitioners were consulted by many because some brain diseases were associated with spiritual influences, and native herbs provided a remedy for ailments. It would seem that dietary habits have a strong role to play in the pattern of neurological diseases in the tropics. Contamination by neurotoxins and the presence of various vectors complete the picture in the setting of poverty, malnutrition, poor sanitation, and limited resources. Diseases like Epilepsy, stroke, peripheral neuropathy, myelopathy, and headache syndromes are quite common, and the patterns are not too different from what is reported from western countries. Brain tumors were once thought to be uncommon, as many diseases were, until neurosurgeons came on the scene, aided by diagnostic facilities. Other peculiar diseases in the region have also been described with some historical details. These include lathyrism, TAN, TSP, gnasthosomiasis, ALS-PD, atlanto-axial dislocations, and Madras type of MND. Interested readers may consult the documentations of disease patterns in the classic book Tropical Neurology by John Spillane (1973). In general, the following conditions are still regarded as rare: multiple sclerosis, Me´nie`re’s disease, subacute combined degeneration, dementias, and hereditary ataxias. Genetic disorders also appear to be uncommon either because of low consanguinity rates or high fatality. Interesting regional variations are also noted, such as periodic paralysis and venomous snake bites being more commonly reported from South East Asia than from Africa. The experience from Singapore highlighting changes in disease patterns with more western-type diseases appearing as industrialization

827

advanced would suggest that great variations in disease patterns may occur in the entire region with globalization, improvement in nutrition, affluence, adoption of western lifestyle, and industrialization. Diseases are no longer strictly restricted to geographic areas, as could have happened in the past, and the situation may change with respect to the disorders currently being seen in tropical countries or documented in the past. Thus, neurologists (physicians and surgeons alike) need to be prepared for the ensuing challenges. In life, change is the only thing that is permanent, and certainly, time will tell.

LANDMARK YEARS IN THE DEVELOPMENT OF TROPICAL NEUROLOGY ● ● ● ● ● ● ● ● ● ● ●

● ● ● ● ● ● ● ● ● ●

17th century BC: Reference to the brain found in Egyptian papyrus. 1710: First neurosurgical operation in Brazil by Luis Ferreyra. 1833: Documentation of lathyrism from India. 1888: Strachan described Jamaican neuropathy. 1889: Levinsen first described gnasthosomiasis from Bangkok, Thailand. 1902–1911: Intense research on Trypanosoma in parts of Africa and South America. 1912: Teaching of neurology as a separate discipline started in Brazil. 1918: Henry Scott reported ataxic neuropathy. 1935: Clark identified cassava as the cause of ataxic neuropathy. 1937: Shortt reported endemic fluorosis from India. 1938: Epidemic of acute spastic paraparesis “Konzo” first reported from former Belgian Congo, now DRC. 1949: Neurosurgery started in Vellore, India, by Dr. Chandy. 1951: Neurological Society of India inaugurated in Hyderabad. 1954: Guamanian ALS-PD complex documented. 1957: Carlton Gadjusek reported on Kuru from the Fore Highlands. 1957: Brazilian Society of Neurosurgery founded in Brussels, Belgium. 1960–1967: Atlanto-axial dislocation described from India. 1968: Tropical ataxic neuropathy syndrome described by Osuntokun. 1970: Madras type of MND described from India. 1977: Geographic neurology accepted as topic for WFN meeting in Amsterdam. 1980–1985: Community-based approaches for determining burden of neurological diseases.

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A. OGUNNIYI

1982: 83 cases of TSP reported on the Seychelles Islands. 1984: First AIDS case in Africa diagnosed. 1985: HTLV-I-associated myelopathy recognized as a separate disease entity. 1989: WFN Congress held in New Delhi, India; tropical neurology as main theme. 1991: Epidemic optic and peripheral neuropathy in Cuba. 1993: Anaphe venata entomophagy associated with seasonal ataxia syndrome.

ACKNOWLEDGMENTS The contributions of Professors Michel Dumas, Gilbert Dechambernoit, Olajide Bademosi, Olusegun Akinyinka, and Jagit Chopra are gratefully acknowledged. I thank Drs. R.O. Akinyemi, M.O. Owolabi, and L.F. Owolabi for editorial assistance. Taiwo Olunubi is acknowledged for secretarial assistance.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 51

Recovery of function: redundancy and vicariation theories STANLEY FINGER* Department of Psychology, Washington University, St. Louis, MO, USA

INTRODUCTION Neurologists studying patients and scientists working with laboratory animals have long recognized that recovery of function sometimes appears to occur after brain damage. With more acceptance of the idea that different parts of the cerebral cortex have specialized functions, and with greater survival after brain damage due to improved procedures, 19th-century investigators began to debate the possible underlying mechanisms that might account for what they were observing (Finger, 1978; Finger and Stein, 1982; Finger et al., 1988). Of course, not everyone agreed that there was recovery in every apparent instance. Indeed, one suggested idea was that subjects were often doing no more than showing behaviors that only superficially resembled those that they were capable of displaying prior to brain damage. For example, a patient or a brain-damaged monkey might still be able to make a tactile discrimination or pick up a cup, but not quite in the same way as before. Hence, it was argued, some reported instances of recovery might be nothing more than compensatory behaviors based on uninjured parts of the brain substituting for the damaged areas in ways consistent with their own specialties (Finger and Stein, 1982, pp. 303–317). With more sensitive tests and more careful observations, it was maintained, this would be apparent. A second idea rested on a very different possibility – that the lesion had never really destroyed the critical area. The underlying belief in this case was that some of the critical parts for mediating the behavior were only temporarily rendered non-functional by the trauma. From this premise it could be assumed that, if a specialized area or enough of it survived anatomically, there should be some return of the original function as the shock and *

other distal effects of the trauma dissipated. This idea was central to the thinking of Constantin von Monako(v) (1914), who called his variant of the older shock theory “diaschisis” (Finger and Stein, 1982, pp. 257–270; Finger et al., 2004). A third theory was based on the assumption that some parts of the brain might be redundant for a given function. Consequently, if one of two functionally equal structures were damaged, the other, perhaps but not necessarily on the opposite side of the brain, would still be present to guide behavior. If no deficit appeared after a brain injury, the “sparing of function” could be due to the redundant structure itself. And if there were a deficit followed by recovery, it could be maintained that the redundant part first had to overcome the distal effects of the brain injury before it again became functional. The theories of behavioral compensation, “shock,” and redundancy share a common feature: none requires rewiring the nervous system in a new way or rearranging the functions normally associated with specific parts of the brain. But during the 19th century, reorganizational theories also came into vogue, and of all the recovery models, the so-called vicariation theories were the most questionable and intensely debated. The term “vicariation” has its origins in the Latin word vicis, from which we get the often-used word “vicarious,” meaning substitute. Similarly, the term “vicar” has been used to refer to a priest called upon to fill in for another churchman. In an analogous way, vicariation theorists contended that a brain area not responsible for a specific function could be summoned, reorganized, and possibly even rewired to take over that function after brain damage (Finger and Stein, 1982, pp. 287–302; Slavin et al., 1988; Finger, 1989). Redundancy and vicariation theories were sometimes viewed as distinct opposites. Nevertheless, these

Correspondence to: Dr. Stanley Finger PhD, Department of Psychology, Washington University, St. Louis, MO 63130-4899, USA. E-mail: [email protected], Tel: +1-314-935-6513, Fax: +1-314-935-7588.

834 S. FINGER two recovery theories can also be considered two ends an office manager and an assistant. He maintained of a continuum, with most “examples” falling somethat this relationship normally develops as a result of where between the two extremes. For example, redunexperience and education. In the end, at least for dancy theorists were not always willing to claim healthy people, the two halves of the brain will funcperfect equality, whereas vicariation theorists often tion as a harmonious unit. pointed to substitute structures that might have been Wigan’s thinking about people having two minds had involved with the function earlier in life. In fact, most been based on a neurological observation. He observed a reorganization explanations tended to implicate strucman who had one hemisphere severely damaged. Yet tures thought to play closely related roles in the functhis individual still seemed to possess a sound mind. tion under consideration, veering away from the On examining the skull, one brain was entirely extremist idea of perfect duplication, as well as the destroyed – gone, annihilated – and in its place thought that a surviving cortical area associated with a yawning chasm. All his mental faculties were one functional system could take on a very different apparently quite perfect . . . his mind was clear system’s unique functions. In reality, the theoretical and undisturbed to within a few hours of his propositions were rarely black or white; more often death. He had a perfect idea of his own awful than not, they were in shades of gray. situation. (Wigan, 1844, pp. 32–33)

REDUNDANCY THEORY In the 17th century, Thomas Willis (1664) looked upon the two sides of the brain as equal, writing that the brain is composed of a double hemisphere and a double substance. He believed this duplicate organization allowed the brain to function even after one side sustained an injury. His thought was not new. In De Usu Partium, written in Rome during the 2nd century, Galen had reasoned that the brain is “twinned,” like the eyes or the kidneys, so that when one side is damaged the other might still sustain the function in a useful way (Galen, 1968). During the opening decades of the 19th century, Franz Gall and the phrenologists, who looked upon the cerebral cortex as a collection of specialized organs, continued to rely on the concept of hemispheric redundancy to account for sparing and recovery of function. Like their predecessors, they pondered why unilateral lesions sometimes resulted in profound deficits. If the healthy hemisphere duplicated the injured one, why was there not always a return to normal after unilateral damage? The solution they proposed was that an injury to one side could upset the balance between the two sides. With this logic, they explained the lasting effects of unilateral lesions in some cases, but recovery in others. In 1844, Arthur Ladbroke Wigan came forth with the novel idea that the skull may house two distinct brains and minds: one on the right side and the other on the left. This represented a significant departure from the time-honored concept of a single mind, which had been tied to the belief in an indivisible, single soul. But, reasoned Wigan, there might be internal conflicts and anarchy with two minds, which is why one hemisphere has to assume a leadership role. The need, as he saw it, was for the two hemispheres to function like

Wigan applied his new idea to both madness and amorality. He theorized that disordered states like these arise when the two hemispheres are no longer able to function harmoniously. In fact, not only might a partially damaged hemisphere respond irrationally, it might disrupt higher functions even more than the loss of an entire hemisphere. In summarizing his thoughts, Wigan wrote: I believe that two brains were bestowed – two perfect organs of thought and volition – each, so to speak, a sentinel and a check on the other . . . The two brains have a subordinate object, no doubt – to provide for the continued exercise of the intellectual faculties when one of them shall be injured or destroyed by disease; but when this is the case the mutilated and helpless victim can scarcely be any longer considered a responsible being – he is reduced to mere animal existence . . . he is incapable of sin, or he is mad – consequently, no longer a moral and responsible agent. (Wigan, 1844, pp. 297–298) The views of hemispheric duality accepted by Wigan, the phrenologists, and by most members of the scientific establishment in the first half of the 19th century were in accord with the theories of French histologist Franc¸ois Xavier Bichat. In a book published in 1805, Bichat distinguished between two types of organ. On the one hand, he wrote, there are those that serve “organic life” and the passions (e.g., organs of circulation, generation, and digestion). And on the other, there are those that manage external relationships and understanding (e.g., the cerebral organs and peripheral sensory structures). Bichat maintained that the organs that serve external relations always occur in symmetrical pairs, since duplication allows the organism to deal with the external world equally well with both halves of its body.

RECOVERY OF FUNCTION: REDUNDANCY AND VICARIATION THEORIES 835 Researchers and theorists found no reason to chalcontext that Broca (1865) postulated that the left lenge Bichat’s (1805) theory of perfectly duplicated hemisphere is normally the more important hemisphere cerebral structures prior to the 1860s (see Harrington, for speech, at least in right-handed people, but that the 1985, 1986, 1987). Most simply agreed with him and right hemisphere still has the functional capacity to the great anatomist Charles Bell, who had written: mediate speech. By moving from a subordinate to a “Whatever we observe on one side [of the brain] has a dominant position after damage to the speech region corresponding part on the other; and an exact resemof the left hemisphere, still the speech area on the right blance and symmetry is preserved in all the lateral side could account for the observed recovery. divisions of the brain” (Bell, 1811, p. 118). But serious The case that more than any other led Broca to think questions began to arise in 1865, when the clinical findthat the right hemisphere could become the leading ings of Paul Broca, Marc Dax, and Gustave Dax showed hemisphere for speech was that of a 47-year-old epilepthat the two hemispheres were by no means perfectly tic woman at the huge Salpeˆtrie`re Hospital in Paris. She identical, at least not for speech functions (Broca, had been left-handed and, according to Broca, able to 1865; G. Dax, 1865; M. Dax, 1865; Joynt and Benton, read, keep busy, speak fairly well, and even express 1964; Finger and Roe, 1996, 1999; Roe and Finger, her ideas without difficulty. But her left sylvian artery 1996; see Ch 10). was found to be absent upon autopsy, and there was no Foville’s gyrus, which included the speech area. CEREBRAL DOMINANCE AND “Here,” explained Broca in his 1865 paper, “it was VICARIATION perfectly evident that the third right convolution had compensated for the absence of the left” (1986 trans., In the paper he planned to present in 1836, which was p. 1069). In fact, Broca compared this woman, who based on some 40 patients with left hemisphere lesions had what he surmised was a congenital defect, to a child and 40 others from the literature, Marc Dax (1865) born without a right hand. Such a child, he explained, wrote that left hemispheric damage often affected will inevitably grow into adulthood using his left hand speech, whereas right hemispheric damage rarely did. skillfully. And so, with the third frontal convolution of He also discussed some examples of recovery from her right hemisphere still intact, this woman must have aphasia. Nevertheless, neither he nor his son Gustave, grown up speaking fluently, using what would normally who began to follow up on his findings in the 1850s, have been a subordinate brain area. directly addressed the possibility of the right hemiBroca went on to ask himself the same question that sphere stepping forth to mediate the recovery process the phrenologists before him had asked: why do we not (Finger and Roe, 1996, 1999; Roe and Finger, 1996). always see sparing and recovery following unilateral With Paul Broca, it was different. In 1863, he had lesions, if one hemisphere has the innate capacity to eight cases of aphasia, all with lesions of the left hemicompensate for the other? Indeed, why are there so sphere, and all but one having damage in the third many aphasics in the Salpeˆtrie`re and Biceˆtre, as well frontal convolution of the left hemisphere (Broca, as wandering the streets of Paris? In translation, he sta1863). Statistically, these numbers suggested a rule, ted the problem as follows: yet the notion of hemispheric specialization contradicted Bichat’s law, which Broca and those associated Actually, it seemed that, if the two hemispheres with him had always accepted. Jean Laborde, for examcontribute to the function of language, a lesion ple, openly doubted that the two hemispheres could be in only one hemisphere would not be enough to functionally different. In a discussion of a case precause aphe´mie. Just as one can see with one sented by Parrot in 1863, which involved a lesion of eye, hear with one ear, so one should be able the third frontal convolution on the right side of the to speak with one hemisphere. Even admitting brain without loss of speech, he explained that it was that the left hemisphere plays a preponderant hard for him to accept the idea that two parts of the role in articulate speech (and it is impossible same organ, whose size and detailed anatomy were to deny this evidence), it seems that the right so similar, might have such remarkably different funchemisphere, when healthy, must always assume tions. He added that this “would imply a serious excepthe function of speech instead of the left hemition to the law of organic duality and functional unity” sphere that has become powerless because of a (see Parrot, 1863, p. 386). lesion . . . How is it, then, that the person who Making the situation even more perplexing, Broca has become aphe´mique through a partial or total observed that some of his patients showed sparing or destruction of the third left frontal convolution recovery of function after damage to the frontal cannot learn to speak with the right hemispeech area that now bears his name. It was in this sphere? (Broca, 1865, 1986 trans., p. 1069)

836 S. FINGER To explain those cases where significant recovery of aphasic patient speechless again – possibly without speech fails to take place, Broca postulated three any further recovery. things. One is that relearning speech is more automatic In 1877, a case that seemed to meet some of these and easier for a child than it is for an adult (“There are criteria was described. The salient features of the things you can never learn well beyond a certain age”; new case were: (a) loss of speech after a focal left Broca, 1865, 1986 trans., p. 1069). The second is that hemispheric injury centered in Broca’s area, (b) subsecaregivers and family members do not spend adequate quent recovery, and (c) loss of speech with no recovery time trying to teach adults to speak again (an early call after a second lesion situated in the homologous area for speech therapy). And the third is that cortical of the right frontal lobe. The physician presenting the lesions caused by strokes and injuries typically extend case in the British Medical Journal was Thomas beyond the boundaries of the speech area to affect Barlow, who had an appointment at a London hospital intellect: for sick children. Barlow’s “remarkable” case involved a 10-year-old When a lesion is very circumscribed, it could be boy. He initially exhibited a paralysis on his right side that language is affected and the intellect and loss of speech, which left him only able to say remains intact . . . but such cases are rare. More “haw-haw.” But, as stated in Barlow’s published often, the anatomical change is of an extent conreport, he exhibited fairly good recovery: siderable enough to cause serious impairment to the properly so-called intellect. It follows that In ten days, he was greatly improved. The leg most aphe´miques have weakened minds, and this improved before the arm. The speech had condition prevents them from learning to speak returned on the tenth day; but occasionally he exclusively with the right hemisphere, which up made a mistake, gave the wrong name for a to now had played only an accessory role in boy, and did not seem always quite to understand the function of expression by means of articuwhat was said to him. (Barlow, 1877, p. 103) lated speech. (Broca, 1865, 1986 trans., p. 1069) About a month later, he was again able to run errands. Returning to Bichat, Broca concluded that he was corBut 4 months after his first attack, he suffered another rect when he surmised that the two hemispheres are not episode that affected the voluntary muscles on the left “innately” different. But with development, the correside of his body, now signifying right-hemispheric sponding speech areas in the two hemispheres grow involvement. With regard to his speech, Barlow wrote: apart functionally. The clinical data in brain-damaged The only approach he could make to a voluntary children and adults reflect this change, as does the articulate sound was “Ah.” He could cry vigoremergence of handedness. Thus, on the one hand, Broously; there was no lack of voice. From his ca’s theory of recovery is still tied to the notion of admission, he appeared to understand all that redundancy. But on the other, it is not quite pure was said to him. When asked his age, he counted redundancy theory, since the two hemispheres develop ten on the questioner’s fingers. (Barlow, 1877, differently, with the left speech area normally growing p. 103) into and retaining the leadership position. The boy died less than 2 months after this incident. An autopsy revealed “vegetations” that calcified the heart THE BARLOW CASE valves and blocked some of his arteries, two of which Broca’s 1865 article on speech is one of the most were in the brain and caused focal brain damage. The important papers in the history of neurology. Neverthemost unusual feature of the case was that the hemiless, even his case of the woman with the congenital spheric lesions were symmetrical; one involved the defect of the left frontal speech area falls woefully lower motor cortex and Broca’s area on the left side, short of providing “proof” that the matching region and the other severely damaged the corresponding of the healthy hemisphere was mediating her speech. areas on the right side. Notably, the circular lesion of Could it not be argued that a spared part of the left the left hemisphere looked older than the one on the hemisphere, or perhaps even some other gyrus in the right hemisphere. right hemisphere, was now mediating fluent speech? Barlow did not argue that the right hemisphere Notably missing from all of Broca’s case studies took over the speech functions normally mediated by was a second lesion of the homologous part of the Broca’s region. Instead, he attributed the boy’s speech right hemisphere – a focal lesion that would have no problems to innervation of the midline facial muslasting effect on fluent speech if the left hemisphere cles, which can be controlled by either the left or the were intact, yet one which would render a recovered right motor cortex. He theorized that, because of the

RECOVERY OF FUNCTION: REDUNDANCY AND VICARIATION THEORIES redundancy, the right motor cortex took sole control of the bilateral musculature after the left hemisphere’s mouth region was damaged. The initial speech problems that abated, he contended, could have been due to distal or secondary effects of the first lesion wearing off. After the right cortical facial region was damaged, all circuitry controlling these muscles was lost, and the boy was left “irretrievably deficient.” Many people cited Barlow’s publication, not knowing that it differed in some significant ways from the Great Ormond Street Hospital notes of the case (Hellal and Lorch, 2007). Yet not everyone followed his explanation, which emphasized duplicate or redundant brain parts for controlling the muscles of the mouth, without bringing anything like vicariation into the picture (Finger et al., 2003). For example, in his widely read Manual of Diseases of the Nervous System, William Gowers used language that seemed to suggest some sort of a functional takeover. He wrote that, if the normal speech structures on the left side of the brain are destroyed, the corresponding parts of the right hemisphere may take on the lost functions, and the symptoms of the loss may slowly pass away. The proof of this is that, in several cases of this character, a fresh lesion in the right hemisphere has destroyed the reacquired power, and there has been no recovery . . . If recovery occurs from an organic lesion that destroys the motor speechcentre, the power of speech seldom remains absent for more than a few weeks, compensation by the right hemisphere occurring with great readiness. (Gowers, 1893, pp. 111, 124) James Taylor (1905), author of Paralysis and Other Diseases of the Nervous System in Childhood and Early Life, was another physician who knew about the case. Like many others at the time (e.g., Bastian, 1898), he first divided recovery into two categories. One was restitution or restoration of function in only temporarily affected parts of the brain. This, he contended, often occurs within a week or two, and it can be accounted for by a renewed blood supply, reduced pressure, diminution of shock, and related factors. The other mechanism of recovery, Taylor maintained, involves transference of the function from the damaged area to another part of the brain. He called this “functional compensation,” and argued that it can do a better job accounting for recovery that takes more time to occur. He further stated that the takeover of a function by a neighboring or related area in the same hemisphere, or by the “corresponding locality in the opposite hemisphere,” is most likely to occur in young children. In his words, it is more commonly

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observed “before the various regions of the cortex are indelibly stamped with a special function, provided that there is a sufficient area of normal cortex remaining” (Taylor, 1905, p. 221). In this context, Taylor noted that motor aphasias are almost never permanent with unilateral lesions in children less than 10 years of age. Because the boy described by Barlow had already had his 10th birthday, Taylor presented the case as his first example of transference of function from one part of the cerebral cortex to its corresponding part of the opposite hemisphere. To quote: “As an example of compensation by the opposite hemisphere the well-known case recorded by Sir Thomas Barlow is most illustrative” (1905, p. 218). Since Gowers and Taylor authored the leading English textbooks of neurology and child neurology, respectively, it is easy to understand why their contemporaries would now cite the Barlow case as evidence for vicariation. Indeed, the case would be cited for decades to come as the best proof yet for one area taking over the functions of another (e.g., Henschen, 1920– 1922; Nielsen, 1946). Still, the records show that there were dissenters. The major problem, at least as Henry Charlton Bastian (1898) saw it, was the short time period for recovery after the first lesion. “I very much doubt,” he wrote, “whether complete transference of function could possibly have occurred in the short period of ten days.” Bastian also wondered about the handedness of the boy. For all we know, he continued, “the right hemisphere might have been the leading hemisphere for speech, and the first lesion on the left side may have merely occasioned some functional disability in the right centre, from which in a very short time he recovered” (Bastian, 1898, p. 322). Barlow’s case was interesting, and certainly worthy of attention, but it did not provide the unequivocal proof Bastian was seeking to convince him that this was an instance of functional takeover. (For more on Barlow’s case and what has been discovered with brain scans on recovering aphasic patients, see Finger et al., 2003.)

RESEARCH WITH LABORATORY ANIMALS Many laboratory animal researchers rejected the idea that the damaged nervous system may have an unlimited capacity to reorganize, after the theory of cortical localization of function was accepted. Some ardent localizationists also had considerable difficulty believing that even related areas, such as a homologue on the right side, could acquire precisely the same functions as a damaged area.

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David Ferrier, the leading British experimentalist of Barlow’s day, and the scientist who had encouraged him to write up his case study, was never willing to accept the idea that surviving structures could take on new and unusual functions. As he saw it, the hypothesis is altogether inconsistent with the theory of specific localization of function. If we were to suppose it possible that the functions of the leg centre could be taken up by the neighbouring occipito-angular region, we should have the very remarkable substitution of a motor by a sensory centre. Such a mode of interpretation is no more justifiable than the supposition that the organ of vision may take up the functions of the organ of hearing . . . or perform both functions at once. (Ferrier, 1886, pp. 368–369) Many of Ferrier’s British colleagues, including Barlow, agreed with him. Consider the case for the opposite cortex taking over motor functions. This idea was tested experimentally by subjecting animals to sequential lesions of the motor cortex, first on one side of the brain and then, after a few weeks, on the other side. The paradigm followed that of the Barlow case, although now the lesions were made deliberately and speech was not a dependent variable. The specific question asked was whether the second lesion would be associated only with contralateral motor deficits, indicative of no takeover of function, or whether bilateral motor deficits would appear, suggesting (but not necessarily proving) vicariation. Early on, some individuals, including Eduard Hitzig who had identified the motor cortex with Gustav Fritsch in 1870, reported that the deficits found after the second lesion were strictly contralateral (see Carville and Duret, 1875, for a review of early findings). Nevertheless, it was the highly regarded work of Charles Sherrington that proved most harmful to the theory of vicariation. Sherrington and his colleagues published a series of carefully controlled stimulation and lesion studies on the primate motor cortex early in the 20th century (e.g., Gru¨nbaum and Sherrington, 1901, 1903; Sherrington and Gru¨nbaum, 1901). The most complete paper in the series appeared in 1917, and it summarized findings from 28 great apes (Leyton and Sherrington, 1917). One part of this paper described an ape that had exhibited considerable recovery of motor function after a well-defined lesion of the left cortical arm area. Yet the researchers reported no return of the defect or worsening of the residual deficit after the right cortical arm area was ablated 2 months after the first operation. “The double arm area lesion showed clearly that the regaining of ability to use the limb could not be

attributed to the arm area of one hemisphere taking over the functional powers of the arm area of the other hemisphere after the latter’s ablation” (Leyton and Sherrington, 1917, p. 207). This paper also addressed the possibility that nearby sites on the same side as the damaged area could take over the function. This hypothesis drew even more attention than the opposite hemisphere hypothesis when unilateral lesions were small or when bilateral lesions were followed by some recovery. Friedrich Goltz (1888), who worked in Strasbourg, entertained this hypothesis after he observed the effects of making sequential operations on the same side of the brain in his dogs. Each lesion was followed by the reappearance and eventual remission of symptoms. But others, after conducting stimulation and ablation experiments of their own, questioned this finding (see Dodds, 1877–1878). Sherrington and his coworkers found that electrical stimulation of nearby cortical areas involved with the elbow, the shoulder, and other parts did not produce arm movements before or after behavioral recovery. They also found that additional ablations near the damaged arm region did not reinstate the deficits. They even went on to examine whether the sensory cortex just behind the motor strip might be mediating the recovery. But neither electrical stimulation nor additional lesions provided any evidence for the somatosensory cortex taking on these motor functions. In short, Sherrington and his colleagues found no evidence for vicariation theory. Sherrington’s reports made many theorists pause, because he was regarded as the most talented experimentalist of the era, and because he worked on apes, which were closer than monkeys to human beings. His work on great apes reinforced the fact that conclusions about underlying mechanisms based solely on clinical observations can be dangerous.

LASHLEY, FRANZ, AND VICARIATION THEORY Although Sherrington’s work hurt the idea that one part of the brain could substitute for another, it failed to kill the concept of vicariation. The notion still had its share of vocal supporters, although fewer and fewer people continued to believe that recovery could be mediated by structures having nothing in common with the damaged structure. Karl Lashley, the best-known biological psychologist in the first half of the 20th century, did not deny that there were specialized sensory and motor areas of the cortex. In 1938 he wrote that only focal cortical damage involving the primary visual areas could affect

RECOVERY OF FUNCTION: REDUNDANCY AND VICARIATION THEORIES previously learned, simple visual discriminations. But, he continued, the lost visual habits could be relearned in the same number of trials that it took for original learning. From this repeated observation, Lashley drew two conclusions. First, the visual cortex must play an important role in visual memory under normal conditions. And second, other areas have the potential to mediate visual learning, if the visual cortical areas are damaged. But where might the new learning take place? To find out, Lashley made focal lesions in surviving cortical areas. Yet he was unable to reinstate the visual learning deficits. In fact, it was only after damaging the midbrain tectum that the deficit re-emerged. These findings led Lashley to conclude that, at least for sensory and motor functions, the cerebral cortex does not have an unlimited capacity for vicariation. Instead, any recovery is likely to be mediated by the system “which is more or less directly concerned with the same function under normal conditions” (Lashley, 1938, p. 741). It is interesting to note that, although Lashley worked with Shepherd Ivory Franz when he began to study the effects of brain lesions in 1916, he looked upon Franz as a much freer supporter of unrestricted vicariation than himself. Two decades later, he even wrote that some students of the problem of vicariation, “like S.I. Franz, have believed that almost any part of the brain might take over the functions of other parts and that nervous structure sets almost no recovery limits” (Lashley, 1938, p. 740).

RETURNING TO THE AGE FACTOR In contrast to the conclusions being reached with mature subjects, analogous work with very young animals proved to be another matter (Finger and Stein, 1982; Almli and Finger, 1984; Finger and Almli, 1984, 1985, 1988; Finger, 1991). In 1876, only 6 years after Fritsch and Hitzig discovered the motor cortex, Otto Soltmann published a series of informative stimulation and lesion experiments on the developing motor cortex of the dog (Soltmann, 1876; Finger et al., 2000). In one experiment, Soltmann made a lesion of the left motor region in a 6-day-old puppy. This animal still appeared to walk fairly normally. When it was 3 months of age, he electrically stimulated its right motor cortex and found that he was able to elicit bilateral limb movements. When the same experiments were conducted on dogs with lesions made after the first few weeks of life, or for that matter on adult dogs without brain damage, only the contralateral movements were elicited. Soltmann’s conclusion was that, if the lesions could be made early enough, one hemisphere could retain control over the movements on both sides of the body.

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Some of the paradigms used by Soltmann with his newborn dogs were in themselves “taken over” during the 1930s by Margaret Kennard at Yale University. Kennard shared Soltmann’s interest in motor circuitry, and she showed that monkeys and apes could also exhibit considerable functional sparing and recovery after motor cortex lesions early in life (Kennard, 1936, 1938, 1940, 1942; Kennard and Fulton, 1942; Kennard and McCulloch, 1943; also see Finger and Almli, 1988; Finger and Wolf, 1988; Finger, 1999). Following up on the recovery she witnessed after early unilateral lesions, Kennard reported atypical bilateral effects after the opposite motor cortex was ablated later in life. She also documented motor problems after the somatosensory cortex was damaged, but only in those monkeys that sustained motor cortex damage in infancy. Prior to receiving their additional lesions, electrical stimulation of the somatosensory cortex had also elicited motor responses in these animals. Kennard’s data suggested that some functional takeover might occur in the opposite motor cortex, or in neighboring cortical areas not normally thought of as motor in nature, if the motor cortex is damaged early in life. But in a review of her findings, she made the point that she did not construe her findings to be evidence for vicariation (Kennard and Fulton, 1942). This was because Kennard defined vicariation in the strictest possible sense – as the takeover of a new and unusual function by an unrelated part of the brain. But, she noted, the somatosensory cortex of the ape contains some large pyramidal cells like those found in the motor cortex. Partly for this reason, she maintained that the motor and somatosensory areas really should be considered a single functional unit. From this premise, she concluded that the “reorganization” does not take place in unrelated parts of the brain, but within the same system – in this case, within the partially damaged “frontal-parieto system.” She also postulated that new dendritic growth might contribute to the “within-system” functional reorganization.

THE TANGLE OF SEMANTICS AND CONCLUSIONS One of the difficulties facing people interested in sparing and recovery of function is that different authors have used the same terms in different ways, as well as different terms with the same intent (see Almli and Finger, 1988). Sometimes, the choice of words is dictated by theoretical preconceptions, sometimes by what the data suggest, and sometimes by reasons that are just not easy to understand. The problem is evident in the writings of Margaret Kennard. She argued for “reorganization of function,”

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but preferred not to use the term “vicariation,” because she believed that reorganization of motor function occurred only within the same, broadly defined system. For those unwilling to accept how Kennard defined her cortical motor system, or strict definition of vicariation, her work could be cited as evidence for functional takeover. Indeed, after the motor cortex had been destroyed on one side of the brain, Shepherd Ivory Franz and his associates had used the term vicariation to refer to the use of pyramidal projections from other cortical areas to mediate recovery (e.g., Ogden and Franz, 1917). Even today, there is less than perfect agreement about how a functional system should be defined in the brain. This is because it is not always easy to determine what a structure is doing in the normal brain. In addition, theorists can argue over possible degrees of involvement without ever coming to a consensus. Developmental and experiential histories can make the terms redundancy and vicariation even more problematic (Norrsell, 1988). The prevailing view that both hemispheres might be mediating speech early in life could mean that the right hemisphere is really not “taking over” a new or unusual function after an early left hemispheric injury, at least to some people if not to others. In contrast, with comparable lesions later in life, some individuals might choose to make the case that hemispheric inequality would meet the key demand for some sort of functional takeover, while others would staunchly disagree. The fact that confusions and contradictions have characterized the topics of vicariation and reorganization of function over their checkered histories should not be surprising when issues of semantics, development, and data from only indirect tests of these theories are considered. What would really be surprising would be if there were general agreement, given how much still has to be learned about normal brain functioning at different times in life, coupled with the problems inherent in brain lesion studies, and the strong theoretical biases held by many researchers.

REFERENCES Almli CR, Finger S (1984). Early Brain Damage. Vol. 1. Research Orientations and Clinical Observations. Academic Press, New York. Almli CR, Finger S (1988). Toward a definition of recovery of function. In: S Finger, TE LeVere, CR Almli, et al. (Eds.), Brain Injury and Recovery: Theoretical and Controversial Issues. Plenum, New York, pp. 1–14. Barlow T (1877). On a case of double cerebral hemiplegia, with cerebral symmetrical lesions. Br Med J 2: 103–104. Bastian HC (1898). A Treatise on Aphasia and Other Speech Defects. Lewis, London.

Bell C (1811). Idea of a New Anatomy of the Brain; Submitted for the Observations of his Friends. London, Published by the author; printed by Strahan and Preston. (Reprinted in 1936 in Med Classics, 1: 105–120.) Bichat X (1805). Recherches Physiologiques sue la Vie et la Mort, 3rd edn. Brosson/Gabon, Paris. Broca P (1863). Localisation des fonctions ce´re´brales – sie`ge de la faculte´ du langage articule´. Bull Soc Anthropol 4: 200–208. Broca P (1865). Sur le sie`ge de la faculte´ du langage articule´. Bull Soc Anthropol 6: 337–393. [Trans. in EA Berker, AH Berker, A Smith (1986). Translation of Broca’s 1865 report: localization of speech in the third left frontal convolution. Arch Neurol 43: 1065–1072.] Carville C, Duret H (1875). Sur la fonction des he´misphe`res ce´re´braux. Arch Physiol 7: 352–490. Dax G (1865). Notes sur le meˆme sujet. Gaz Heb Med Chir 2: 260–262. Dax M (1865). Le´sions de la moitie´ gauche de l’ence´phale coincidant avec l’oubli des signes de la pense´e. Gaz Heb Med Chir 2: 259–262. Dodds WJ (1877–1878). On the localization of the functions of the brain. J Anat 12: 340–363, 454–494, 636–660. Ferrier D (1886). The Functions of the Brain. Smith and Elder, London. Finger S (1978). Recovery from Brain Damage. Plenum, New York. Finger S (1989). Reflections on the possible maladaptive consequences of injury-induced reorganization. Neuropsychology 3: 41–47. Finger S (1991). Brain damage, development and behavior: early findings. Dev Neuropsychol 7: 261–274. Finger S (1999). Margaret Kennard on sparing and recovery of function: a tribute on the 100th anniversary of her birth. J Hist Neurosci 8: 269–285. Finger S, Almli CR (1984). Early Brain Damage. Vol. 2. Neurobiology and Behavior. Academic Press, New York. Finger S, Almli CR (1985). Brain damage and neuroplasticity: mechanisms of recovery or development? Brain Res Rev 10: 177–186. Finger S, Almli CR (1988). Margaret Kennard and her “principle” in historical perspective. In: S Finger, TE LeVere, CR Almli, et al. (Eds.), Brain Injury and Recovery: Theoretical and Controversial Issues. Plenum, New York, pp. 117–132. Finger S, Roe D (1996). Gustave Dax and the early history of cerebral dominance. Arch Neurol 53: 806–813. Finger S, Roe D (1999). Does Gustave Dax deserve to be forgotten? The temporal lobe theory and other contributions of an overlooked figure in the history of language and cerebral dominance. Brain Lang 69: 16–30. Finger S, Stein DG (1982). Brain Damage and Recovery: Research and Clinical Perspectives. New York, Academic Press. Finger S, Wolf C (1988). The “Kennard Effect” before Kennard: the early history of age and brain lesions. Arch Neurol 45: 1136–1142.

RECOVERY OF FUNCTION: REDUNDANCY AND VICARIATION THEORIES Finger S, LeVere TE, Almli CR, et al. (Eds.) (1988). Brain Injury and Recovery: Theoretical and Controversial Issues. Plenum, New York. Finger S, Beyer T, Koehler P (2000). Dr. Otto Soltmann (1876) on the development of the motor cortex and recovery after its removal in infancy. Brain Res Bull 53: 133–140. Finger S, Buckner RL, Buckingham H, et al. (2003). Does the right hemisphere take over after damage to Broca’s area? The Barlow case of 1877 and its history. Brain Lang 85: 385–395. Finger S, Koehler PJ, Jagella C, et al. (2004). Monakow’s concept of diaschisis: origins and perspectives. Arch Neurol 61: 283–288. ¨ ber die elektrische Erregbarkeit Fritsch G, Hitzig E (1870). U des Grosshirns. Arch Anat Physiol 37: 300–332. Galen (1968). De Usu Partium. Trans. by MT May as, “On the Usefulness of the Parts of the Body.” Cornell University Press, Ithaca, NY. ¨ ber die Verrichtungen des Grosshirns. Goltz F (1888). U Pflugers Arch 42: 419–467. Gowers WR (1893). A Manual of Diseases of the Nervous System, Vol. 2. P Blakiston, Philadelphia, PA. Gru¨nbaum ASF, Sherrington CS (1901). Observations on the physiology of the cerebral cortex of some of the higher apes. Proc R Soc Lond 69: 206–209. Gru¨nbaum ASF, Sherrington CS (1903). Observations on the physiology of the cerebral cortex of the anthropoid apes. Proc R Soc Lond 72: 152–155. Harrington A (1985). Nineteenth-century ideas on hemisphere differences and “duality of mind.” Behav Brain Sci 8: 617–660. Harrington A (1986). Models of mind and the double brain: some historical and contemporary reflections. Cognit Neuropsychol 3: 411–427. Harrington A (1987). Medicine, Mind, and the Double Brain. Princeton University Press, Princeton, NJ. Hellal P, Lorch MP (2007). The validity of Barlow’s 1877 case of acquired childhood aphasia: case notes versus published reports. J Hist Neurosci 16: 378–394. Henschen SE (1920–1922). Klinische und pathologische Beitra¨ge zur Pathologie des Gehirns. Vols. V–VII. Nordiske Bokhandeln, Stockholm. Joynt RJ, Benton AL (1964). The memoir of Marc Dax on aphasia. Neurology 14: 851–854. Kennard MA (1936). Age and other factors in motor recovery from precentral lesions in monkeys. Am J Physiol 115: 138–146. Kennard MA (1938). Reorganization of motor function in the cerebral cortex of monkeys deprived of motor and premotor areas in infancy. J Neurophysiol 1: 477–496.

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Kennard MA (1940). Relation of age to motor impairment in man and in subhuman primates. Arch Neurol Psychiatry 44: 377–397. Kennard MA (1942). Cortical reorganization of motor functions. Arch Neurol Psychiatry 48: 227–240. Kennard MA, Fulton JF (1942). Age and reorganization of central nervous system. J Mt Sinai Hosp NY 9: 594–606. Kennard MA, McCulloch WS (1943). Motor responses to stimulation of cerebral cortex in absence of Areas 4 and 6 (Macaca mulatta). J Neurophysiol 6: 181–189. Lashley KS (1938). Factors limiting recovery after central nervous lesions. J Nerv Ment Dis 88: 733–755. Leyton ASF, Sherrington CS (1917). Observations on the excitable cortex of the chimpanzee, orangutan and gorilla. Q J Exp Physiol 11: 135–222. Nielsen JM (1946). Agnosia, Apraxia, Aphasia: Their Value in Cerebral Localization. Paul B Hoeber, New York. Norrsell U (1988). Arguments against redundant brain structures. In: S Finger, TE LeVere, CR Almli, et al. (Eds.), Brain Injury and Recovery: Theoretical and Controversial Issues. Plenum, New York, pp. 151–163. Ogden R, Franz SI (1917). On cerebral motor control: the recovery from experimentally produced hemiplegia. Psychobiology 1: 33–49. Parrot JM (1863). Atrophie comple`te du lobule de l’insula et de la troisie`me circonvolution du lobe frontal avec conservation de l’intelligence et de la faculte´ du langage articule´. Bull Soc Anat 8: 372–401. Roe D, Finger S (1996). Gustave Dax and his fight for recognition: an overlooked chapter in the history of cerebral dominance. J Hist Neurosci 5: 228–240. Sherrington CS, Gru¨nbaum ASF (1901). Localisation in the “motor” cerebral cortex. Br Med J 2: 1857–1859. Slavin MD, Laurence S, Stein DG, et al. (1988). Another look at vicariation. In: S Finger, TE LeVere, CR Almli, et al. (Eds.), Brain Injury and Recovery: Theoretical and Controversial Issues. Plenum, New York, pp. 165–179. Soltmann O (1876). Experimentelle Studien u¨ber die Functionen des Grosshirns der Neugeborenen. Jahrb Kinder Erziehung 9: 106–148. Taylor J (1905). Paralysis and Other Diseases of the Nervous System in Childhood and Early Life. JA Churchill, London. Von Monakow C (1914). Die Lokalisation im Grosshirn und der Abbau der Funktion durch Kortikale Herde. JF Bergmann, Wiesbaden. Wigan AL (1844). A New View of Insanity: The Duality of the Mind. Longman, Brown, Green and Longmans, London. Willis T (1664). Cerebri Anatome. Martyn and Allestry, London.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 52

The emergence of the age variable in 19th-century neurology: considerations of recovery patterns in acquired childhood aphasia PAULA HELLAL AND MARJORIE P. LORCH* Department of Neurolinguistics, Birkbeck College, University of London, London, UK

INTRODUCTION In the second half of the 19th century, descriptions of patients with disorders of higher cerebral functions were typically presented in a series heterogeneous with respect to the variables now viewed as crucial to the interpretations of patterns of behavioral impairment and prognosis. A representative example is taken from John Hughlings Jackson’s earliest paper on aphasia (1864). A case series of patients was presented, some taken from the literature, while others were directly observed. The ages of the patients at admission and at relevant points in the history of illness were noted. In the 36 cases detailed, the age ranged from 9 to 69 years, with a fairly even spread across the decades. That is, children, adolescents, and elderly subjects were presented without distinction. In fact, there was no indication in the analysis or interpretation that age was thought to play a role in the signs or symptoms displayed, or that it was even an issue for prognosis. Yet to his credit, in the discussion of case VI (of an 18 year old who had had scarlet fever at the age of 4 and had not spoken for 3 years after his illness), Jackson did make a plea that “more work must be bestowed on the way in which a person learns to articulate who has once lost speech from disease of the brain in childhood” (Jackson, 1864, p. 421). The newly emerging psychological notions of dissolution (Jackson, 1881, 1884) and regression (Ribot, 1881) incorporated “age of acquisition” into patterns of impairment in acquired disorders in adults generally, and of memory loss in aging and dementia more specifically. Ribot hypothesized a memory gradient for word-finding difficulties that preserved the earliest

*

acquired items the longest (see Lorch, 2009, for a more detailed discussion). Although it had been recognized for centuries that advanced aging had implications for cognitive decline, there appeared to be relatively little distinction between patients prior to senescence. Thomas Willis, however, was among those who recognized the significance of puberty in the resolution of childhood “epilepsy,” writing: “It is observed that sometime the epilepsy terminates of its own accord, viz about the time of puberty, so that those who are not cur’d before that period is past, viz their twenty fifth year, scarce ever recover their health” (Willis, 1685, cited in Williams and Sunderland, 2001, p. 508). The role of age in the manifestation of language disorders only became explicit in the late-19th-century literature on acquired childhood aphasia, and in the development of ideas regarding perinatal disorders, developmental difficulties, and the emerging clinical category of “cerebral palsy” (e.g., Bastian, 1875; Osler, 1889; Freud, 1893, 1897; Freud and Rie, 1891). Within the context of these investigations, the notion of “age of onset” became an explanation connected to discussions of severity of symptoms, impact on language and cognitive development, patterns of recovery, and lasting deficits. (For an overview of issues that were explored with regard to age of onset in the late-20th century, see, for example, Obler et al., 1978; Basso et al., 1980; De Renzi et al., 1980; Eslinger and Damasio, 1981; Vargha-Khadem et al., 1985.) This chapter will consider the clinical neurology literature from the 1860s onward to chart the development of ideas about

Correspondence to: Prof. Marjorie P. Lorch, Department of Brain and Language, Birkbeck College, University of London, 43 Gordon Square, London WC1H 0PD, UK. E-mail: [email protected], Tel: +44-207-631-6119, Fax: +44-207-383-3729.

844 P. HELLAL AND M.P. LORCH age, its implied relation to brain maturation, and its symptoms and patterns of recovery in acquired adult significance for recovery of function in neurological clinical cases and the growing awareness of age as a disorders. The focus will be on acquired aphasia in relevant factor in congenital disorders. Broca (1865) children. had noted good language skills in an epileptic woman who he believed had suffered an early lesion or congenital abnormality. At autopsy, Broca found the THE CONCEPT OF FUNCTIONAL patient’s brain displayed a considerable absence of corCOMPARTMENTALIZATION OF THE tex in the seemingly crucial part of the left hemisphere BRAIN for fluent speech. This woman, he reported, had been The second half of the 19th century saw increased hemiplegic but had suffered no serious speech impairinterest in brain organization. Physicians, including ment. Broca suggested that, if lesions are sustained in Gustav Fritsch and Eduard Hitzig (1870) in Germany, early childhood, the resulting impairment might be and David Ferrier (1873, 1878) in Britain, carried out minor, a suggestion that would be supported a few experimental animal studies on cortical localization of years later by a fellow Frenchman. function. Their physiological interests sometimes Jules Cotard (1868) made a detailed study of postincluded the question of recovery of function after mortem findings of seven adults who had exhibited brain injury. For example, Otto Soltmann described (right) hemiplegia since childhood. Although autopsy how very young puppies, unlike older dogs, recovered evidence showed damage to the left frontal lobe or swiftly after their operations and did not exhibit the entire left hemisphere, these people had shown normal equivalent loss of motor function (see Finger et al., linguistic and cognitive development. Cotard con2000). The experiments of these scientists provided cluded that language had developed in the right hemisupport for the importance of the age variable, as well sphere in these patients. He proposed that damage to as the concept of functional compartmentalization of one hemisphere at an early age would lead to the lanthe adult brain. guage functions being taken over by the intact hemiThis notion that different cortical areas serve differsphere. As a result, he claimed, the condition of ent behaviors had been proposed earlier in the 19th cenaphasia could not be said to exist in children. This tury by Franz Joseph Gall and Johann Spurzheim argument was supported by a number of cases in (1810–1819). Nevertheless, their use of craniological which language was observed to be developing normethods to discern the faculties of mind was chalmally despite early, left hemispheric lesions. lenged, and the concept of cortical localization of More attention soon focused on how people who function was discarded along with their “phrenologihad sustained cerebral lesions after childhood recovcal” methods and theories (Cooter, 1984). An alternaered or failed to recover language function. Clinicians tive hypothesis widely supported during this transition hypothesized that language was re-acquired by an period considered the cortical areas of the brain to be undamaged part of the left hemisphere, by the lower functionally equivalent (e.g., Flourens, 1824). brain structures, or by the homologous area of the A new research paradigm in the second half of the right hemisphere (see Ch. 51). Walter Moxon (1866) century sought to link the pathological lesions found suggested that under certain circumstances the right at autopsy with symptoms observed during life. And hemisphere, once educated to carry out its newly as a throwback to earlier arguments about localization acquired role, could function as the dominant hemiof function, the faculty of language became the test sphere for language (for more on Moxon, see Buckingcase for this new clinical approach (e.g., Bouillard, ham, 2003). Samuel Wilks (1883) went further in 1825). During the 1860s, Broca (1861, 1865) began to suggesting that the laterality of function in the hemiamass considerable evidence linking lesions in the third spheres was due to the different education of two sides left frontal convolution with impaired fluent speech. By of the brain, not only referring to each individual’s hislocalizing a specific area in the cerebral cortex with a tory, but “to long usage of one hemisphere through recognizable language impairment, Broca and his sucmany generations,” as demonstrated by size differcessors provided evidence against the earlier hypothesis ences between the two (Wilks, 1883, p. 89). that the cortex of the brain functioned as a whole. Wilks suggested that, in recovered cases of right This interest in specialization of the brain for lanhemiplegia, the right hemisphere was educated to the guage grew in parallel with concerns about language task by a process similar to teaching the left hand to acquisition in children by psychologists on the one write after a paralysis of the right. For language to hand, and about maturation of the brain over the return, “it must come by re-education and what more lifespan by anatomists on the other. There was also a likely than that the part corresponding to the damaged confluence between the behavioral manifestations of one should be the seat of the training – that this should

THE EMERGENCE OF THE AGE VARIABLE IN 19TH-CENTURY NEUROLOGY 845 take up the lost function . . . if speech were originally childhood there is a double center for speech, one on learned in a special way, it must be regained by same each side of the brain . . . But in the course of growth method” (Wilks, 1883, p. 89). the left hemisphere gradually assumes the monopoly Re-education might seem to imply a relatively slow of the speech function” (Cautley, 1889, p. 265). rate of recovery from aphasia. Nevertheless, cases The so-called plasticity of the infant brain was also involving children, in whom language was found to used to account for various cases. For example, Colby recover in a few days or weeks, began to appear in (1892) reported a case of a 10-month-old boy with a the literature. William Gowers (1885) opined that the cerebral hemorrhage in the left hemisphere, who died compensatory use of the right hemisphere occurred 20 days after admission to St. Bartholomew’s Hospital. far more readily in children than in adults, and more Two days before his death, the child briefly regained readily in some adults than in others. He even argued consciousness and “took hold of stethoscope with his that permanent aphasia in childhood was “almost RIGHT hand” (Colby, 1892, p. 152; capitals in text). unknown” (Gowers, 1885, p. 125). In this context, he According to Colby, this demonstrated that “there cited a case published in 1877 by Thomas Barlow on was no paralysis on the right side at a time when the recovery of function after damage to Broca’s area in left hemisphere must have been considerably disorgaa 10-year-old boy. This boy was reported to regain his nised.” At post-mortem, the “whole of left hemisphere ability to speak after an initial lesion in Broca’s area [was] scarcely anything more than mere bag inside on the left side of the brain, only to show a loss of which was some recent clot and a quantity of flaky speech after subsequent damage to the homologous whitish material” (Colby, 1892, p. 152). Hence, Colby region on the right side. Various writers interpreted (1892, p. 153) suggested one possible reason why the this famous case in different ways, and it was used child lived so long without any apparent paralysis as support for a number of different hypotheses about might be “that in so young a child the cortex had not speech and recovery of function throughout the 19th taken on its proper functions.” century and even beyond (Finger et al., 2003). It drew Although the prevailing opinion was that acquired needed attention to the age variable, which Gowers aphasia in childhood is transient, there were also some emphasized was crucial for the boy’s swift recovery examples of young children failing to acquire language following his first cerebrovascular accident. after lesion to the left hemisphere in early life. For We have reviewed the archived case notes for this example, Glissan (1875) wrote about a 4-year-old boy patient (Hellal and Lorch, 2007). Interestingly, the hosseen by the physician for a skin affection, stating: pital records of the child’s impairment, course of illWhen he was 18 months old he received a fall, from ness, and autopsy were found to be at odds with which he had a contusion of the skin and a small Barlow’s published report in crucial details. The tumour in the temporal region (left side). He gradudescription as represented in the case notes calls into ally recovered. Before the accident he was just question the validity of some interpretations of this commencing to prattle a few simple monosyllables, case. Nevertheless, almost everyone viewed the Barlow but since then has not been able to speak, and has case of 1877 as solid evidence that language loss in scarcely ever tried. (Glissan, 1875, p. 319) childhood is likely to be transitory. But just how were the children managing to recover language function A decade later, Cautley (1889) provided another interso quickly and effortlessly, given that most adults esting negative example, although he attempted to remain functionally impaired after large cortical account for it by reasoning that the child had been lesions for years? What could account for the differenunable to educate his undamaged hemisphere: tial recovery of function? At the age of 18 months [he] was suddenly struck by complete right hemiplegia and at the ACQUIRED CHILDHOOD APHASIA age of 4 died without ever having spoken . . . Whereas Gowers had used the Barlow (1877) case as The child suffered from congenital heart disease. evidence for the takeover of language function by the Dr Andrews under whose care he was remarked undamaged hemisphere, Edmund Cautley (1889) prothat he was very intelligent and that there posed that both hemispheres had equal potential for seemed no reason to suppose, had not embolism taking control of language function at birth with lateroccurred on the left side of the brain that he alization of function developing later. Cautley used would not have been able to speak in the usual Barlow’s case as evidence to argue that “some indivicourse of childhood. In this case the centre on duals, with a permanent lesion, recover speech much the right side, the supplemental centre, was little more quickly than others.” He suggested that: “In or not at all developed. (Cautley, 1889, p. 270)

846 P. HELLAL AND M.P. LORCH Other cases were also published in which children preobserved in 37 and right hemiplegia in 33 cases. Gowers, sented with chronic language impairments similar to however, linked right-sided paralyses with aphasia. those seen in aphasia cases acquired after maturity. Archibald Church and Frederick Peterson (1899) noted As noted, in the earlier literature these cases tended aphasia to be well marked only after lesions of the left to be included alongside adult cases without regard to hemisphere in right-handed children older than 6 years the age of the patients. Now, however, they were typiat symptom onset. In infants, however, they found that cally published singly and presented as exceptions. aphasic symptoms might follow brain injury to either Indeed, many physicians seemed to be unaware of hemisphere. the evidence of others showing lasting aphasia in Age at symptom onset gradually became accepted young children. as an important factor in both etiology and prognosis. In his book On Paralysis from Brain Disease in its Common Forms, Henry Charlton Bastian (1875) noted INFANTILE CEREBRAL PARALYSIS that certain types of cerebrovascular disease happened In order for meaningful patterns to become noticeable, at birth, others rarely occurred before the age of 14, more compilations of cases of children with language and vascular degeneration was three times as likely in disorders were required. These came about as a bythe 6th decade as compared to the 3rd. product of the growing interest in the etiology of The clearest investigation of the relevance of age at infantile cerebral paralysis. William John Little (1843, onset to the presentation and prognosis of infantile 1862) first attempted to characterize this group from cerebral paralysis was given by William Osler (1889) an orthopedic point of view. Then, after the growth in his Cerebral Palsies of Children, a book that popuof interest in the special relationship between language larized the use of this new term. The patients were all function and right hemiplegia in the second half of the under the care of the same physician and were all subcentury, neurologists began to investigate this group of jected to comparable assessments and similar treatyoung patients more closely. In addition, there was an ments. Osler followed many of these cases, at a time interest in distinguishing infantile cerebral paralysis when longitudinal descriptions were rarely reported in from paralyses caused by spinal lesions. the literature. This was of theoretical importance given The characterization of cerebral palsy played a that many physicians mistakenly thought that infants major role in the development of neurology and neushowed excellent sparing or recovery from brain roscience in the 19th century, and proved fundamental damage, because they did not follow up on them. to the understanding of cerebral localization (Ashwal Unless the child was observed over the course of many and Rust, 2003). Consideration of the etiology of months, as was the case with many of Osler’s younger cerebral palsy led directly to distinctions among pre-, patients, symptoms that did not present soon after peri- and post-natally acquired nervous system injuries. brain damage but emerged later would not be noted. The large number of reviews of infantile cerebral Osler reported on children ranging from 17 months paralysis carried out in the second half of the 19th to 15 years of age at the time of symptom onset. He century was due to increased neurological expertise noted a clear bias in favor of early onset of symptoms. in specialist children’s hospitals and asylums for the In 81 of his cases (excluding those that seemed to be “feebleminded,” which were founded in this period. congenital), symptom onset had occurred by the time This confluence of clinicians interested in mental functhe child reached 4 years of age (Table 52.1). tion and patients suffering from similar complaints Osler’s (1889) data provided support for his obserprovided a unique opportunity to compare large numvation that, as a rule, the younger the subject the bers of childhood patients. Case series were published greater the liability to serious and permanent disability. that described hundreds of children (e.g., Bastian, His collection of 120 children with cerebral palsy 1875; Osler, 1889; Sachs and Peterson, 1890; Freud, included 13 with aphasic symptoms. These cases pro1893). Given the larger database, new questions regardvided data about the long-term recovery patterns of ing other relevant variables could also be investigated childhood language disorders. Of these 13 cases, only for the first time. Hemiplegia and aphasia were now two made a complete recovery in both language and seen as even more important diagnostic signs, and the motor function, and in the case of the older child, a side of paralysis began to be regularly recorded. second hemiplegic/aphasic attack 2 years after the first In Wharton Sinkler’s (1875) series of 23 cases of left the child impaired in language function. infantile cerebral paralysis, 12 cases were of left and In 1 of these 13 cases, Osler found more motor than 10 of right hemiplegia. Yet in only 3 cases (2 right and language recovery. Osler even described the time 1 left) was any language impairment noted. In the 80 course of recovery for leg, arm, and language funccases reviewed by Gowers (1893), left hemiplegia was tions. In two cases he found recovery of the use of

THE EMERGENCE OF THE AGE VARIABLE IN 19TH-CENTURY NEUROLOGY Table 52.1 Osler’s cases of infantile hemiplegia: age at symptom onset. Modified from Osler, 1889 Age at onset Congenital 1st year 2nd year 3rd year 4th year 5th year 6th year 7th year 8th year 9th year 10th year >10 Age at onset not given

Number of cases 15 45 22 14 1 3 3 3 1 1 1 1 10

the leg muscles to co-occur with recovery in language function. Unlike James Ross, a Scottish physician who published one of the earliest monographs on aphasia in 1887, Osler did not link recovery of motor control with a sensory type of aphasia. In 8 of 13 of Osler’s cases, there was more language than motor function recovery. In three cases showing little recovery, he reported that they had been examined from 21 months to 12 years after symptom onset. This long-term follow-up allowed Osler to write that . . . usually the power of speech begins to return in a short time but recovery may be deferred for a year . . . and in [one case] the child had not spoken 6 months after the lesion. In several instances recovery was incomplete. (Osler, 1889, p. 33) Still, Osler’s 13 cases show that recovery could, in certain cases, take place over a considerable period of time. He summed up “the state of the art” with reference to the aphasic syndrome in children in his textbook, Principles and Practice of Medicine, which was being written at this time. He noted that age at symptom onset was a valuable predictor of outcome, and that a positive prognosis is to be expected with the young: “In young persons the outlook is good, and the power of speech is gradually restored apparently by the education of the centres on the opposite side of the brain” (Osler, 1892, p. 993). Interestingly, he used the term “gradually” at a time when most physicians considered acquired childhood aphasia to be a transient condition. The phrase, “apparently by the education of the centres on the opposite side of the brain,” is germane to

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the ongoing debate about the mechanisms of recovery of function in the child and the adult brain. The term “apparently” might suggest a less than total commitment to the hypothesis. Osler was also cautious with respect to claims that aphasia in childhood is as likely following right as left hemispheric lesion. Although he found a significant number of left hemiplegic cases (68 right hemiplegic, 52 left hemiplegic – 15 of which were congenital cases), it is notable that, in those who also had aphasia, only 1 out of 13 involved left hemiplegia. In his textbook, Osler considered the prognosis of his aphasic patients. And again, he stressed the importance of the age variable: In adults the condition is less hopeful, particularly in the cases of complete motor aphasia with right hemiplegia. The patient may remain speechless, though capable of understanding everything, and attempts at re-education may be futile. Partial recovery may occur, and the patient may be able to talk, but misplaces words. (Osler, 1892, p. 994) He goes on to recommend care and treatment, but again attaching considerable importance to age at symptom onset: The education of an aphasic person requires the greatest care and patience, particularly if, as so often happens, he is emotional and irritable. It is best to begin by the use of detached letters, and advance, not too rapidly, to words of only one syllable. Children often make rapid progress, but in adults failure is only too frequent, even after the most painstaking efforts. (Osler, 1892, p. 994)

LANGUAGE AND COGNITIVE DEVELOPMENT The relation between language and cognitive development was also investigated within the context of infantile cerebral paralysis. For many of these children, language difficulties were seen to co-occur with other mental impairments in development. In fact, most of the case series published in the last decade of the 19th century stressed the link between infantile cerebral paralysis and mental disability. In the case series of Bernard Sachs and Frederick Peterson (1890), various degrees of mental impairment were found, from “weak-mindedness” to “complete idiocy”, with good mental development in only a few cases. They proposed a classification that linked the clinical syndrome to timing of the insult. Thomas Rotch (1896) agreed with Sachs and Peterson that intelligence, in these hemiplegic

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cases, was usually found to be impaired, adding the corollary that “this of course depends on the location and extent of the lesion and the period when it occurred” (Rotch, 1896, p. 651; italics added). In a major review of the etiology, pathophysiology, risk factors, and treatment of infantile cerebral paralysis, Sigmund Freud (1897) suggested that the association of cerebral palsy with sensory disturbances and cognitive impairments provided evidence that the damage occurred during the time of fetal development, rather than during the process of birth. Freud was also significant in drawing a clear distinction between acquired aphasia, as a disturbance of already initiated speaking ability, and developmental language delay, as a symptom of poor cerebral development (Longo and Ashwal, 1993). The separation of aphasic symptoms from “intellectual faculties” helped lead to the perception that sensory aphasia (i.e., Wernicke’s aphasia, 1874), with language comprehension difficulties rather than expressive impairment, does not occur in children. But although childhood aphasic cases presenting with classic Wernicke-type aphasia with fluent paragrammatic speech do not appear in 19th-century English language literature, many physicians did document some receptive language difficulties in their young patients. These problems of comprehension resulted in many child cases labeled as mentally impaired and were typically viewed as not pure aphasic cases. Gowers (1893), arguing for the transience of aphasia in childhood, suggested that the rare cases of long-term speech disorder are due to general cognitive impairment. To quote: “In cases of persistent aphasia in childhood, it will generally be found, on careful investigation, that the defect of speech is part of a general mental defect, and not true, pure aphasia” (Gowers, 1893, p. 124). As might be expected, there were still major limitations in assessment procedures. As Ross (1887, p. 51) pointed out with reference to adult cases of sensory aphasia, they “can hardly be distinguished from the mental confusion which attends the onset of unconsciousness.” Ross was somewhat unusual in holding that sensory-type symptoms can be found in acquired aphasia in children, but only during the initial stages of the disorder. Distinguishing comprehension difficulties from mental impairments was problematic, since assessment of intelligence was usually determined by the patient’s verbal responses to questioning. In younger patients, it was perhaps more likely that Wernicke’s aphasics were mistaken for cases of mental impairment. John Wyllie (1892) suggested that the absence of Wernicke’s aphasia in children was due to the undamaged right hemisphere taking over the function of the damaged left

auditory center faster than it could take over the functions of a damaged motor speech center. He reasoned that, as the auditory center is the first center to receive education in speech (a reference to studies of child language acquisition [e.g., Darwin, 1877] during this period, which showed earlier comprehension of language before first words were uttered), there would be some “overflow” to the other hemisphere. The homologous auditory center in the undamaged hemisphere would therefore require less time than the homologous motor center to be re-educated. The implication was that some children might have presented with Wernicketype symptoms at an early stage in their illness, but that this condition had resolved before admission to the hospital. Just as long-term follow up was vital for the assessment of symptoms that emerged some time after brain injury, so delay in seeking medical treatment might result in symptoms presenting immediately or shortly after injury being missed. It was far from uncommon, during this period, for children to be examined by a physician weeks after the initial trauma when the family accepted that the child was not going to recover without attention.

CONCLUSIONS The age of the patient at symptom onset became an important variable in clinical neurology from the second half of the 19th century. This was most evident in the investigations of acquired childhood aphasia and infantile cerebral paralysis. Aphasic cases, in which age at symptom onset was considered relevant, especially for prognosis and treatment, began to appear in the literature during the 1860s. Generally, although age had been reported in some case histories, it was not considered a factor relevant to the subsequent analysis. The influential Thomas Barlow paper of 1877 generated increased interest in childhood language disorders accompanying paralyses. Although Barlow presented his case as an example of impaired motor function, other commentators used it to support various hypotheses regarding language and the human brain. It became the most widely cited hemiplegic aphasia case to appear in the English language in the 19th century, joining a growing number of child aphasic cases. Through a consideration of such cases, clinical researchers investigated the larger themes of localization of function, hemispheric specialization, and patterns of recovery. The factor of “age at symptom onset” would steadily assume even greater theoretical importance, as explanations of patterns of symptom co-occurrence, etiology, and prognosis were elaborated through the increasing appreciation of a developmental/maturational perspective.

THE EMERGENCE OF THE AGE VARIABLE IN 19TH-CENTURY NEUROLOGY It was in the context of investigating the etiology of infantile cerebral paralysis that larger collections of cases were collected by Bastian (1875), Osler (1889), Sachs and Peterson (1890), and Freud (1897). These studies provided significant databases, permitting the correlation of age at symptom onset with patterns of language acquisition and impairment in children. These cases provided observations that contributed directly to the elaboration of hypotheses regarding laterality and possible right hemisphere involvement in recovery of language function. Although debates about the nature of the deficits and the brain mechanisms underlying the recovery would continue, the work of these 19thcentury pioneers showed that the age at the time of neurological insult can in many instances be crucial to the outcome. Charles West, founding physician of Britain’s first children’s hospital, wrote extensively on the importance of specialist treatment for the young at a time when much of the medical establishment argued against the need for pediatric hospitals (West, 1848, 1871). As the century advanced, more and more of his colleagues came to share his opinion. In effect, children would no longer be considered “miniature adults.”

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Ross J (1887). On Aphasia: Being a Contribution to the Subject of the Dissolution of Speech from Cerebral Disease. Churchill, London. Rotch T (1896). Pediatrics. The Hygienic and Medical Treatment of Children. Vol. 2. Young J Pentland, Edinburgh. Sachs B, Peterson F (1890). A study of cerebral palsies of early life, based upon an analysis of one hundred and forty cases. J Nerv Ment Dis 517: 295–332. Sinkler W (1875). On the palsies of children. Am J Med Sci 69: 348–365. Vargha-Khadem F, O’Gorman AM, Walters GV (1985). Aphasia and handedness in relation to hemispheric side, age at injury and severity of cerebral lesion during childhood. Brain 108: 677–696. Wernicke C (1874). Der Aphasiche Symptomenkomplex. Cohn and Weigert, Breslau. In: GH Eggert, (Ed.) (1977) Wernicke’s works on aphasia: a sourcebook and review. Translated as The Aphasia Symptom Complex: A psychological study on an anatomical basis. Janua linguarum, Series major 28. Mouton, The Hague, 92–117. West C (1848). Lectures on the Diseases of Infancy and Childhood. Longman, Brown, Green and Longmans, London. West C (1871). On Some Disorders of the Nervous System in Childhood. Lumleian Lectures. Longmans, Green and Co., London. Wilks S (1883). Lectures on Diseases of the Nervous System. Churchill, London. Williams AN, Sunderland R (2001). Thomas Willis: the first pediatric neurologist? Arch Dis Child 85: 506–509. Willis T (1685). The London Practice of Physick, or the whole practical part of physick contained in the works of Dr. Willis. Printed for Thomas Basset and William Crooke, London. Wyllie J (1892). The disorders of speech. Edinburgh Med J 1 & 2: 289–314, 401–421, 501–523, 585–604, 681–693, 777–793, 897–907, 977–992.

Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 53

Rehabilitation therapies DAVID E. TUPPER* Neuropsychology Section, Hennepin County Medical Center; Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA

INTRODUCTION The personal and social impact of neurological disorders is immense. There are probably more individuals with neurological disabilities alive today than ever before (Wade, 1997). The cost of disorders of the brain and related neurological illnesses is only beginning to be estimated; recently, direct and indirect economic estimates in the United States topped $400 billion (7.3% of the Gross Domestic Product) in 1991 (National Foundation for Brain Research, 1992), and approached  386 billion in Europe in 2004 (Andlin-Sobocki et al., 2005). According to the World Health Organization’s current classification system (WHO, 1980, 2001), impairments of the nervous system often result in persisting disability and alteration in social roles (handicap). Compared to the history of other concepts or practices in neurology, the history of the rehabilitation of neurological disorders is relatively brief. The word “rehabilitation” is likely derived from the Medieval Latin word rehabilitare, which means to restore or make fit once again. The word rehabilitation can be used in a variety of contexts but, in neurology, rehabilitation therapies are meant to provide interventions that go beyond traditional medical treatment aimed at treating impairments, and to help those with neurological injuries and illness to re-establish themselves as productive and socially integrated citizens (Nagi, 1969; Glanville, 1982). As stated by Swan (1964, p. 938), “Rehabilitation may be described as the restoration of the human being to living in the full sense. It is the treatment of the whole man [person], and not only of his [or her] disability.” Many neurologists in the past believed that neurological deficits were static and resistant to rehabilitation. In fact, even in prominent contemporary neurology *

texts (e.g., Victor and Ropper, 2001) rehabilitation is not mentioned or discussed only in passing. At the root of some of this skepticism is the fact that some degree of spontaneous recovery is always present, and this recovery can range from full to slight improvement. In the past century, however, a more optimistic view of nervous system recovery and response to treatment has emerged (Rothi and Barrett, 2006), due in particular to the influence of several world wars leading to a marked increase in the number of young adult wounded veterans who have required services to become more productive again. Some progress in documenting the effectiveness of rehabilitation therapies has been made, and this will be touched on later in the chapter. Although other rehabilitative specialties are slightly older, it is only in the past 25 years that a defined subspecialty of neurological rehabilitation has been formed (Good and Couch, 1994; Dobkin and Thompson, 2000; Barnes, 2003; Dobkin, 2003; Noseworthy, 2003). Unlike the rest of neurology, neurological rehabilitation has also been described as a process (Delwaide and Young, 1992; Lazar, 1998). Neurological disorders have certain notable characteristics that separate them from other medical conditions. They are large in number, few are totally curable (due to degeneration or limited nervous system plasticity), they are associated with many varied symptoms, and they are a major cause of disability, particularly accounting for a high proportion of severely disabled people under the age of 65 years (Hewer, 1997; Wood and McMillan, 2001). Neurological disorders that are curable or that can lead to more full recovery include some types of infectious disorders that can be treated successfully with medication, and nerve disorders or tumors that can be cured by neurosurgical intervention. Many, if not most, neurological

Correspondence to: David E. Tupper PhD, Director, Neuropsychology Section (G8), Hennepin County Medical Center, 701 Park Ave., Minneapolis, MN 55415, USA. E-mail: [email protected], Tel: +1-612-873-2599, Fax: +1-612-904-4208.

852 D.E. TUPPER disorders cannot be cured completely, and may in fact before the time of death (see Schiller, 1979; Clower be progressive, but they may be responsive to treatand Finger, 2001). ment attempts designed to reduce the suffering and Among primitive peoples or those in earlier civilizadisability caused by their symptoms. tions, children with deformities or adults with lesions This chapter will review the history and evolution of were at times allowed to die or were separated from rehabilitative efforts by physicians and other health prothe social group (Leo´n-Carrio´n, 1997); for numerous fessionals to alleviate the symptoms and disabilities generations, supernatural causes were posited for neuassociated with neurological disorders. Because the rological or functional disorders. As noted, it was not scope of such an endeavor can be quite large, the focus until the ancient Greeks in Hippocratic times, who first of this chapter will necessarily be selective; there will be thought that the brain governed the body and housed greater description of the history and development the soul, that a new way of thinking about brain of rehabilitation for acquired cerebral disorders such damage emerged. Head trauma sustained in sporting as cerebral trauma or cerebrovascular accidents, so contests was particularly noted in Greek and Roman these etiologies will be emphasized, to the exclusion of times, given the beginnings of organized contact sport rehabilitation efforts in developmental or degenerative competitions (McCrory and Berkovic, 2001; Zillmer conditions. In addition, management strategies or rehaet al., 2006); however, development and use of a bilitation therapies for disorders affecting the peripheral helmet for protection did not begin until the Middle nervous system, primary physical, orthopedic, or motor Ages (Blackburn et al., 2000). consequences, or disorders affecting the spinal cord Some ancient peoples used physical means for treat(although often acquired) will generally not be included. ment of injury and illness. Physical agents for healing Although pain is a frequent symptom and co-occurring have included water, heat, cold, massage, light, exerfactor in disability for individuals with a variety of cise, and what would later be found to be electricity neurological illnesses, discussion of pain management (from fish). Many of the physical agents employed in strategies also will not be included here. modern physical therapy were used in ancient times, and joint manipulation and massage was used in China about 3000 BC (Braverman and Schulman, 1999). MasEARLY HISTORY OF REHABILITATION sage and hot poultice (liquefied flax seed bandages) IN NEUROLOGICAL CONDITIONS were primary treatment methods for the effects of It is likely that early in history, as humans recognized stroke in the Assyrian and Babylonian world, and mendefects attributable to nervous system problems, tion of the use of a crutch for lower extremity paralyattempts at remediation were made. As examples, probsis is suggested in a Babylonian diagnostic tablet ably because they represented obvious functional (Reynolds and Wilson, 2004). Early Greek and Roman changes, early descriptions of aphasia can be found writings refer to the beneficial effects of sun and among the oldest medical documents (Benton and Joynt, water, and both exercise and massage were used by 1960), and spinal cord injuries were also frequently the ancient Chinese, Persians, Egyptians, and Greeks noted in ancient Egypt (Eltorai, 2003). Hippocratic phy(Calvert, 2002). The use of massage in ancient Greece sicians and philosophers regarded the brain as important was an integral part of wellness, healing, and sports. for perception and thought based on observations of Written accounts of physical techniques for healing, individuals who sustained head trauma. such as hydrotherapy, can be traced back as far Nevertheless, from the earliest times in human hisas the writings of Hippocrates in 400–460 BC. Hippotory, assistance given to people with physical or brain crates also wrote important papers on the use of lesions has been varied. All cultures have not treated friction after sprains and dislocations, and about these persons in the same manner, and a number of kneading in case of constipation (Knapp, 1990). Pliny, varied “therapies” have been developed from reliAristotle, and Plutarch all knew that electric eels, rays gious, scientific, medical, or spiritual perspectives. and catfish could produce numbness, but knowledge For example, dating as far back as prehistoric times of electricity increased only slowly; it was not until (late Paleolithic and Neolithic periods), skulls have after the Middle Ages when Leyden jars and other genbeen found with openings indicative of trepanation, erators and storage devices were available that the presumably for medical reasons (Gurdjian, 1973; see exploration of other benefits of electricity could occur Ch. 1). Paul Broca, in fact, who subsequently was (Basford, 1990). known for the cerebral localization of expressive lanDuring the Renaissance in Western Europe, society guage but who also had interests in anthropology, was began to take major steps in recognizing its responsibilparticularly fascinated by a Peruvian skull found with ities to its more needy members, including the poor, a man-made hole in it, due to surgery a week or two the sick, and those with injuries. In this period, interest

REHABILITATION THERAPIES 853 in medical conditions increased. It is primarily in the and a large experience base for the development of 18th century, when more clarity in description, etiolmore effective rehabilitative approaches. Not only ogy, and detection of brain dysfunction was being were more individuals able to survive neurological developed, that a greater emphasis was placed on findinsults, as overall medical care advanced, but greater ing new treatments for these disorders. societal acceptance of individuals with persisting disElectrical machines and magnets were used to alleabilities allowed the birth of rehabilitation medicine viate neurological conditions in the 18th and 19th centuand the maturation of various rehabilitation specialties. ries, although not always with success (Harms, 1955; Rehabilitative care for persons with cerebral dysfuncHolcomb, 1967; Gersh, 1992). Benjamin Franklin, for tion was aimed at reducing disability and handicap instance, whose name is not typically associated with resulting from nervous system impairments, and it medical therapies, followed the early work of Nollet promised good returns for the monetary and societal (1746) and used his new understanding of the nature investment. of electricity in the experimental treatment of individuals suffering various palsies, particularly from MEDICAL AND PHYSICAL stroke (Finger, 2006a, b). Although Franklin never forREHABILITATION mally published his case studies and remained skeptical Some of the earliest modern therapists in rehabilitation about the beneficial effects of electricity for palsies of were physical therapists (McKenzie, 1918; Pagliarulo, long standing (Finger, 2006c), he clearly was one of the 2006). The field of physical therapy was established first electrotherapists who tried to treat neurological in Britain in the latter part of the 19th century, and disorders. shortly thereafter American orthopedic surgeons Attitudes toward the injured as different from the trained women in physical treatment methods, such rest of society began to change soon after Franklin. as muscle re-education, to deal with the 1916 epidemic Around 1800, increased knowledge regarding cerebral of poliomyelitis in the United States. Concurrently, the function was gained, as Gall’s phrenological theories American Electrotherapy Association, founded in correlated cerebral geography with mental faculties 1890, was the first American organization to utilize (Miller, 1996) and stimulated subsequent work on physical measures for therapeutic means (Gersh, 1992; brain–behavior relationships and various treatment Opitz et al., 1997). During and after World War I, approaches. And in the opening decades of the 19th additional empirical research indicated that various century, Napoleon, who otherwise did not look favorphysical methods were useful to augment the medical ably on phrenology, required his injured soldiers with care and convalescence of patients. Physicians began a good chance of survival to receive rapid medical practicing physical rehabilitation methods in “reconand appropriate rehabilitative care to assist in the construction hospitals” designed to accommodate the tinuation of their lives (Leo´n-Carrio´n, 1997). injured and disabled soldiers. By the end of the 19th century, based on further World War I transformed rehabilitation medicine by progress concerning the concept of localization of adding a steady flow of maimed and disabled indivifunction by Broca, Jackson, Ferrier, and others, duals to the United States and other countries. Gritzer researchers gave cerebral localization of function a and Arluke (1985) estimate that 123 000 disabled solmore solid scientific foundation (Rosner, 1974). With diers returned to the United States by May 1919. Folthis came the realization that one cortical territory lowing the lead of European nations, the United might not easily substitute for another, except perhaps States was forced to develop medical and rehabilitative in childhood (see Ch. 10). Spontaneous recovery from services for soldiers wounded and disabled in the war. cerebral lesions was therefore thought to be limited. Assisting physicians, World War I-era reconstruction Also, unfortunately, most penetrating brain wounds aides, forerunners of current physical and occupational were, in fact, still fatal. The fatality rate during the therapists, treated primarily patients with orthopedic American Civil War, for example, was about 70% injuries, because few patients with brain injuries sur(Gurdjian, 1973). These factors, among others, likely vived serious war wounds (see Fig. 53.1). increased the skepticism about treating neurological Beginning in the 1920s, medical organizations, such disorders. A more humanitarian approach to dealing as the AMA Congress of Physical Therapy, were with individuals with nervous system disorders paralinitiated. Throughout subsequent years, the organizaleled the advancement of medical approaches and techtions and their names were changed a number of nology in the past two centuries. times to reflect the evolving specialties of physical As will be discussed below, the large numbers of medicine, physical therapy, electrotherapeutics, radisoldiers cared for during the two World Wars in the ology, and rehabilitation. During these early years, early-20th century provided a major societal impetus

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Fig. 53.1. An early occupational therapy unit during World War I. (From Crane, 1927, p. 80.)

physicians pioneering in physical medicine were involved with diagnostic and therapeutic radiology, diathermy, electrocoagulation, hydrotherapy, massage, therapeutic exercise, iontophoresis, and the use of various types of electrical stimulation and infrared heating, as well as the social and vocational reintegration of the disabled into society (Opitz et al., 1997). Radiologists were, in fact, among the first physicians to specialize in a physical method of medical practice (Kottke and Knapp, 1988). The decade of the 1930s brought further organization and purpose to the field of rehabilitation, and an increasing demand and specialization in radiotherapeutics split physical medicine physicians from radiological physicians. At this time, a small group of physicians who practiced physical therapy and rehabilitation worked to identify rehabilitation medicine as a distinct specialty (DeLisa et al., 1998). Frank H. Krusen, MD (Fig. 53.2), working at Temple University in Philadelphia, PA and then the Mayo Clinic in Rochester, MN, promoted physical medicine and rehabilitation as a specialty in the AMA and, in 1938, proposed the term “physiatrist” to identify a physician in physical medicine (Krusen, 1941; Folz et al., 1997). Other prominent

rehabilitation physicians at the time included John Coulter and Walter J. Zeiter (Coulter, 1947; Zeiter, 1954). In spite of this advocacy, it was not until after World War II that societies began to understand the need for more advanced treatment and rehabilitation of the disabled (Krusen, 1946, 1969; Folz et al., 1997). This was based on the more widespread use of physical therapy in the care of patients, not only from the substantial numbers of debilitating war injuries, but also due to the thousands of individuals disabled by another poliomyelitis epidemic. An Australian nurse, Sister Elizabeth Kenny, developed an effective method of treating muscle spasm and deformities from paralytic polio in the 1940s, thus adding significantly to the knowledge of neuromuscular diseases and their physical management, and also demonstrating effective clinical methods for restoration of normal mobility (Knapp, 1969). World War II also broadened the focus of physical medicine, from the more limited goal of restoration of ambulation in the physically disabled to comprehensive activities to restore an optimal level of an individual’s physical, mental, emotional, vocational,

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based on his experiences at Stoke Mandeville Hospital in England (Eltorai, 2003; Silver, 2003). Much like Howard Rusk, Guttmann pioneered active, integrated rehabilitation and demonstrated efficacy for the management of physical consequences of paraplegia, so maximal independence could be achieved (Schu¨ltke, 2001). Importantly, Guttmann also championed re-integration into physical activities for individuals with paraplegia, and he was the organizer of the first sporting event for people with disabilities (the International Stoke Mandeville Games), which has continued as the Paralympics. Thereafter, more rehabilitation centers started, because the value of medical and physical rehabilitative therapies have been demonstrated many times over during the major World Wars, and in other rehabilitative contexts worldwide. The concept and processes of rehabilitation now includes a team of professionals, including physiatrists, occupational and physical therapists, speech-language pathologists, psychologists, and other allied health professionals, working together using interdisciplinary goals for individual patients (see DeLisa, 2004).

Fig. 53.2. Frank Hammond Krusen, MD (1898–1973), considered the “father” of physical medicine and rehabilitation in the United States. By permission of Mayo Foundation for Medical Education and Research. All rights reserved.

and social capabilities (Kessler, 1965; Kottke and Lehmann, 1990). Physician Howard Rusk, another rehabilitation medicine pioneer, initially working in the Army and in private practice, and later establishing the Institute of Rehabilitation Medicine at New York University-Bellevue, introduced the notion of active rehabilitation. He inspired people to develop more comprehensive and dynamic rehabilitation programs that addressed the multiple needs of individuals with various types of functional disabilities. Rusk (1949) advocated an aggressive approach to rehabilitation, which is practiced more widely today. After World War II, physiatry became more solidified in America when the Baruch Committee awarded funds to develop physiatry training programs at selected institutions, the Veterans Administration continued to add rehabilitation medicine departments at many hospitals throughout the United States, and the Office of Vocational Rehabilitation brought about additional expansion of rehabilitative services. On an international level, German-born physician Ludwig Guttmann advocated a comprehensive approach to the rehabilitation of spinal cord injury and paraplegia,

OCCUPATIONAL AND VOCATIONAL REHABILITATION The current clinical belief is that neurological rehabilitation efforts must focus on improving functional and adaptive behaviors. Often, an emphasis on more practical behaviors fosters a patient’s motivation to make further change. As with the early development of physical therapy, the evolution of occupational therapy has occurred primarily in the past 100 years, and primarily due to the influence of the influx of the disabled during World War I and World War II (Cohen and Reed, 1996). Occupational therapists traditionally maintain a focus on improving adaptive behaviors of individuals and foster the goal of independence in self-care during the rehabilitation process (Crepeau et al., 2003). During World War I, occupational therapy’s evolution in the United States was facilitated by the efforts of Army orthopedists, who attempted to establish rehabilitation programs based on the English reconstruction model initiated by a British colonel and orthopedic surgeon, Robert Jones. Jones was in charge of a 400-bed hospital in Liverpool, and soon received national recognition in Britain for his role in the development of rehabilitation centers designed to emphasize restoration of athletic prowess and confidence (Swan, 1964). The reconstruction programs in England were founded to help mitigate the economic strain of disabled soldiers in that country, and to recognize the moral

856 D.E. TUPPER obligation that the nation had to its wounded soldiers see Howard and Hatfield, 1987). The Hippocratic physi(Gutman, 1995). cians (c. 400 BC) similarly implied a dim view of language It was in this context that the United States began recovery, as speech disturbances caused by apoplexy were training female physiotherapists and occupational typically discussed in the context of protracted and fatal therapists as reconstruction aides, thereby fostering the illnesses (Benton and Anderson, 1998). Concepts of aphagrowth of the profession of occupational therapy. sia prior to the 1800s were incompletely developed (Prins Following the war, occupational therapists continued to and Bastiaanse, 2006), and speech loss following work with individuals who had sustained acquired cerecerebral lesions was often ascribed to paralysis of the tonbral and orthopedic trauma, and also began working gue (Howard and Hatfield, 1987; Wollock, 1990). The with children with cerebral palsy and other developmenusual methods for treating palsies, such as stimulants tal anomalies. Initially, the military stopped train(including electricity by the 1750s), were attempted for ing occupational therapists after World War I, but some cases. campaigning and lobbying to sympathetic physicians The remediation of aphasia by language therapy is eventually led to the recognition of appropriate training described in writings in the 16th and 17th centuries arrangements and formal organizational status for the (Eldridge, 1968; LaPointe, 1983; Sarno, 1991). Pierre profession. This occurred during World War II, when Chanet (1649) provides an early account of recovery the medical profession again rediscovered the benefits and re-education of speech and reading, when he of a therapeutic focus on occupational and functional addresses the improvement in reading and speaking of gains through rehabilitation for the war injured. Physical a relative’s aphasia following a head wound sustained medicine physicians in particular were supportive of during the Siege of Hulst in the Low Countries (also cited broadening the role of occupational therapy in rehabiliin Howard and Hatfield, 1987). Benton and Joynt (1960, tation and, although boundary disputes arose, occupap. 209), in an excellent review of the early literature on tional therapists welcomed a close relationship with aphasia, describe the findings of German physician physical medicine (Gritzer and Arluke, 1985). That relaJohann Schmidt, who, in 1673 (Schmidt, 1676), noted that tionship remains strong to the present time. one of his two apoplectic patients with aphasia and alexia Work is the most evident handicap that is affected in responded to retraining more than the other patient, who patients with nervous system dysfunction. The indivishowed no improvement. dual with a disability frequently presents a unique Therapeutic attempts during the 19th century added employment problem. The development of vocational additional refinements, based on a better understandrehabilitation has occurred alongside the increasing sociing of aphasic disorders; in particular, physical interetal recognition that people with disabilities and handiventions were abandoned for methods that involved caps have the same rights to the pursuit of fulfillment attempts at re-education or application of contemporas non-disabled individuals. As stated by Obermann ary teaching methods to patients with aphasic disorders (1965), the history of vocational rehabilitation can best (Schoolfield, 1938; Benton, 1964; Marx, 1966). In 1833, be conceived as a chronicle of the gains made in public for example, Jonathan Osborne in Great Britain attitude and acceptance regarding the vocational rights described an early attempt at re-education of jargon of people with disabilities. Practically speaking, efforts aphasia, and Thomas Hun (1847), a physician at Albany to provide meaningful work situations for individuals Medical College, was also one of the first to recomwith neurological disabilities have a very recent history, mend systematic exercises in spelling, writing, and occurring only in the past 20 or 30 years, unlike reading, when he encouraged a 35-year-old, postvocational rehabilitation efforts for individuals with stroke, aphasic patient to try them to enhance recovery. other disabilities, such as cerebral palsy or blindness Paul Broca (1865/1969; trans. in Berker et al., 1986) (Obermann, 1963). Vocational rehabilitative strategies, is often cited for advocating retraining language skills including supported employment, are often emphasized in his patients. Broca began to teach an aphasic adult in the brain-injured population (Wehman and Moon, to read once again, using a “bottom-up” strategy of 1988; Wehman and Kreutzer, 1990). reading letters and syllables, and subsequently switching to a compensatory strategy of reading the words without breaking them down. Although not formaAPHASIA REHABILITATION lized, he maintained that aphasic individuals could The skepticism regarding recovery of and treatment be taught language in the same way that children attempts for language disturbances began early in learn language skills, but he also believed that chilrecorded history, when the author of the Egyptian Edwin dren had greater potential for recovery. In his 1865 Smith papyrus (c. 2650 BC) wrote that speechlessness is paper, Broca emphasized the compensatory role of an “ailment not to be treated” (Breasted, 1930, p. 286; the right hemisphere in recovery and re-education

REHABILITATION THERAPIES 857 from aphasia of left-hemispheric origin (also Ryalls Unlike the less frequently described treatment of and Lecours, 1996). language disorders associated with stroke, as noted The English neurologist Henry C. Bastian (1898) previously, the two World Wars of the early-20th century presented a developmental perspective on aphasia therprovided a major stimulus for the development of apy at the end of the century, although he is also treatment centers addressing not only the prominent cogknown for his center-based aphasia classification. He nitive sequelae of traumatic head wounds, but partipostulated both functional restitution (spontaneous cularly the acquired language disorders associated with recovery) and functional compensation by the other such wounds. It was at this time that the first large-scale hemisphere following acquired language disorders, reports on aphasia and cognitive rehabilitation were puband proposed language re-education methods based lished, representing the work of Froeschels, Goldstein, on teaching methods for the deaf and dumb or those Luria, and Poppelreuter. with congenital speech defects. He particularly emphaDuring World War I a number of rehabilitation hospisized the need for extensive practice and repetition tals were established for the treatment of the brain (Bastian, 1869). injured, particularly in Germany, to help care for the high Additional commentary on aphasia re-education internumber of people who had suffered such trauma. ventions came from Charles Mills (1880, 1904) and Walther Poppelreuter founded such an institution in William Broadbent (1879). Mills (1904), in particular, pubCologne in 1914, and comparable facilities were devellished a review of training methods utilized to that time, oped in Frankfurt by Goldstein and in Munich by Isserlin and commented not only on the benefits of systematic (Poser et al., 1996). Goldstein, in particular, at his Institute repetition and graded practice exercises during retraining, for Research on the After-effects of Brain Injuries, but also discussed important age differences between worked on both a theoretical foundation and practical normal child language development and relearning of therapies for language disturbances. He downplayed language by an aphasic adult. His report was also notable localizationist perspectives for a holistic approach, and in that he raised concerns about differential influences of maintained that cooperation between brain regions led other non-linguistic aspects of rehabilitation, such as to higher cortical capabilities such as language. His theraemotional factors, education, and premorbid intelligence, peutic approach primarily emphasized compensatory thus presaging several of the additional important recogstrategies. nitions of the rest of the 20th century. The large number of individuals who suffered brain Howard and Hatfield (1987) classify Mills as a practiinjuries during World War II stimulated continued protioner of the German and Austrian school of speech gymliferation of treatment programs in military and civilian nastics, as Mills’ remedial recommendations were very hospitals. In the United States, the Veterans Administrasimilar to those practiced by the German phoniatrist tion Hospital programs came into being, rehabilitation Hermann Gutzmann and the Viennese physician Emil medicine emerged as a medical specialty, and speechFroeschels, in that the gradual introduction and repetition language pathology developed as an allied health profesof speech-sounds, syllables, and words was a core element sion in rehabilitation, having spun off from their educaof his speech therapy. Gutzmann subsequently developed tional roots as teachers of speech in the 1920s and 1930s a treatment center for post-traumatic combat veterans (Moore and Kester, 1953; Simon, 1954). during World War I in Berlin (Sarno, 1998). Clearly, there Additional publications by Kurt Goldstein on the was a major advancement in understanding aphasic disorrehabilitation of language and related disorders appders and their treatment, as well as the development of the eared, based on his follow-up experiences with traumatspecialty of speech-language pathology (Weisenburg and ically injured patients from both World Wars, again McBride, 1935; Moore and Kester, 1953). emphasizing the importance of facilitating compensaRemembered for attempts at nervous and mental tory means of communication (Goldstein, 1939, 1942, re-education (see below), Shepherd Ivory Franz 1948). Butfield and Zangwill (1946) in England docupublished a report in 1905, in which he re-taught a mented the beneficial effects of speech therapy in 57-year-old stroke victim lists of words and related patients with traumatic aphasia, as opposed to aphasia information, and then compared the patient’s scores due to other causes, and Joseph Wepman (1951), from for acquiring new information versus relearning old California, drew attention to the large population of material. He carefully measured the results and untreated individuals with aphasia, both veterans and described the differences as indicating gradual acquisicivilians, who might benefit from direct speech therapy. tion of a new “habit,” while previously learned material Finally, some of the most influential work resulting could be acquired with greater efficiency. A later paper from treatment of aphasic individuals in World War II expanded on his quantitative approach in retraining is that of Aleksandr Luria from the Soviet Union. patients with aphasia (Franz, 1924). Luria (1947, 1970) treated a large series of patients with

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traumatic aphasia and concluded that systematic retraining based on a careful psycholinguistic analysis and aimed at the reorganization (intra-systemic or inter-systemic) of functions provides the foundation for the successful restoration of verbal capabilities (Hatfield, 1981; Christensen, 1986; Kagan and Saling, 1992; Christensen and Caetano, 1996). Since the mid-20th century, the amount of clinical and research activity in aphasia rehabilitation has expanded considerably. There are many theoretical issues still debated with regard to aphasia and its treatment (Shewan, 1986; Byng and Jones, 2003). Currently, although many methods have been proposed (see Sarno, 1998), most approaches to aphasia therapy follow one of two models, either a direct treatment or retraining model, or a substitute skill or compensatory model. Presently, speech-language pathology is an established allied health profession, and aphasia therapy is an important component of the practice of rehabilitation medicine, especially for those individuals with aphasia due to stroke or head trauma (see also Ch. 36 and Ch. 52).

COGNITIVE OR NEUROPSYCHOLOGICAL REHABILITATION Because cognitive or neuropsychological deficits are common sequelae of many neurological conditions, the rehabilitation of cognitive deficits has developed into an expected part of a comprehensive rehabilitation program, if not a specialized field of endeavor in its own right (Boake, 1991; Parent
e and Stapleton, 1997; Boake and Diller, 2005; Prigatano, 2005). Cognitive deficits contribute dually in rehabilitation: these deficits are themselves a primary treatment focus of rehabilitation, and they also are often related to the severity of injury and extent of recovery of the primary neurological deficit. Although various attempts to improve cognitive functioning have been utilized in non-neurologically impaired individuals for many years (see Mann, 1979), neuropsychology and rehabilitation have a relatively short history (Beauvois and Derouesn
e, 1982; Benton, 1988). It is primarily in the past century that direct attempts at intervention for neurologically mediated cognitive deficits have been applied. Many of the early attempts used whatever educational methods were available at the time. Thus, early cognitive rehabilitation efforts consisted of education or “re-education” of impaired cognitive capabilities to optimize the functioning of the individual. Nevertheless, re-education of cognitive functions is not equal to the training of muscles where repetitive practice is beneficial; re-education must rely on principles of learning and development of compensatory strategies to be most beneficial (Kreutzer et al., 1989).

Shepherd Ivory Franz’s work with aphasic patients has been described previously. As a psychologist, Franz is also well known for his experimental work with animals, and especially his use of learned behavior as a baseline for the study of cerebral ablations. Based on techniques developed in animal experiments, including studies of motor recovery and responses to treatment after hemiplegia (Franz et al., 1915; Ogden and Franz, 1917), Franz became a leading advocate for rehabilitation in the early-20th century (Cotola and Bach-yRita, 2002). Franz continued to use his habit-based, functional approach during cognitive rehabilitation efforts (Franz, 1917, 1919) and emphasized quantitative measurements of recovery in his lesion research. In what is perhaps his major treatise, Franz commented on his approach: . . . the principle of re-education is that of habit formation. It is either a replacement of old, inadequate, or harmful methods of reacting with new habits more like those of the other individuals in the environment, or it is the formation of new habits to take the place of those that have been lost. In other words, re-education is to the abnormal what education is to the normal – it is a matter of the acquisition of habits that will enable the individual to take his place in the working, playing, social world. (Franz, 1923, p. 17) As was seen with aphasia rehabilitation, a number of major developments in cognitive rehabilitation took place because of the two World Wars. During World War I, along with Franz’s work in the United States, a number of rehabilitation centers were created in Germany and Austria, including centers that emphasized rehabilitation or restoration of cognitive functions. Kurt Goldstein’s work in Frankfurt with disorders of speech, reading and writing, as well as Walther Poppelreuter’s work in Cologne with visuo-perceptual disturbances, are both notable examples of early neuropsychological rehabilitation efforts (Boake, 1989, 1991). Goldstein developed therapeutic techniques that emphasized the use of preserved skills to substitute for lost skills, and he stressed the need for accurate clinical assessments and direct observation of a patient’s functioning in vocational workshops. Poppelreuter similarly used a pragmatic approach when caring for more than 700 cases of brain wounds in a large neurorehabilitation hospital and in workshops (see Fig. 53.3). He considered treatment of soldiers with cortical damage to be his social responsibility, and he utilized systematic study to differentiate between recovery and treatment effects, especially after occipital cortex lesions (Poppelreuter, 1917/1990). Other notable work was undertaken by

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Fig. 53.3. Visual search testing in a patient with a left occipital gunshot wound. Dr. Walther Poppelreuter, on the right, is carrying out the examination. [Figure 43 (p. 106) from Disturbances of Lower and Higher Visual Capacities Caused by Occipital Damage by W. Poppelreuter (1990, Oxford University Press, translated from the German by J. Zihl); German original, Die Psychischen Scha¨digungen durch Kopfschuss im Kriege 1914/ 16. Band 1: Die Sto¨rungen der Niederen und Ho¨heren Sehleistungen durch Verletzungen des Okzipitalhirns (Leipzig: Leopold Voss, 1917). By permission of Oxford University Press.]

Isserlin in Munich and Hartmann and Froeschels in Austria (Boake, 1996, 2003). The advent of World War II likewise stimulated clinician-researchers in various countries to advance cognitive rehabilitation of injured soldiers. Two units for the rehabilitation of head-injured patients were established in Scotland and emphasized a team approach to rehabilitation, as well as the active participation of the patient in his or her own rehabilitation. An early brain injury unit in Bangour Hospital near Edinburgh, staffed by, among others, psychologist Oliver Zangwill and neurologist W. Ritchie Russell, focused particularly on the assessment of memory and the retraining of impaired cognitive capabilities (Zangwill, 1945; Pentland et al., 1989). Zangwill (1947) should be credited for specifying principles of re-education and direct training, and for considering the roles of compensation and substitution during the rehabilitation process. A second Scottish brain injury unit was set up in Killearn near Glasgow, and served both servicemen and civilian cases.

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Fig. 53.4. Aleksandr R. Luria and Lev S. Zasetsky (on the left), a soldier who suffered a severe left temporo-parietal penetrating wound in World War II. Zasetsky was studied and treated by Luria for many years (described eloquently in Luria, 1972). (From Soviet Life, September 1980, No. 9, p. 28.)

As noted, one of the most prominent neuropsychologists to advance brain injury rehabilitation was Aleksandr R. Luria (more accurately transliterated as Luriia), who was dually trained as a neurologist and psychologist. As director of a neurorehabilitation hospital in the Urals during World War II, Luria was involved in the treatment and rehabilitative care of over 800 patients with penetrating head trauma (see Fig. 53.4). His experiences there formed the basis for his rehabilitative approach that relied on his influential theory of functional systems of the brain (Luria et al., 1969). Luria’s general approach to rehabilitation centered on the idea that diagnosis and treatment of cognitive dysfunction are intrinsically related, and that both patient strengths and weaknesses need to be taken into account in planning intervention strategies (Luria, 1948, 1963). Luria’s theoretical principles for restoration of function included de-inhibition (de-blocking), transfer of function to the opposite hemisphere, and reorganization of functional systems (intra- or

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inter-systemic) (Luria et al., 1969; see also Tzvetkova, 1972, 1985). Following his rehabilitation work, Luria went on to become well known internationally for his theoretical conceptualizations of brain function, his patient-sensitive neuropsychological investigations, and his research into various aspects of language disturbances and frontal lobe functioning. In the post-war era, although many head injury rehabilitation centers started because of the war were now closed, cognitive and neuropsychological rehabilitation continued to evolve. A number of acute head trauma care and rehabilitation centers were added to major hospitals in various countries, such as the Loewenstein Rehabilitation Hospital near Tel Aviv and the Rancho Los Amigos Hospital near Los Angeles (Boake, 1989). Acute neurosurgical care improved due to technological advances in medicine during the 1960s and 1970s, and resulted in increased survival from accidental head trauma, such as that from motor vehicle crashes. Unfortunately, many vehicle-related injuries proved severe (Roberts, 1979), which necessitated the secondary development of more comprehensive brain injury rehabilitation programs. Also historically noteworthy is the Israeli response to the increased number of head-injured soldiers from the 1973 Yom Kippur war. The Ministry of Defense supported development of a day treatment program for head-injured soldiers at Loewenstein Hospital in 1975, jointly run by the Israeli Department of Rehabilitation and New York University (Vakil, 1994). The neuropsychologists Yehuda Ben-Yishay and Leonard Diller initially collaborated on the program, which emphasized a rehabilitative focus on the patient’s cognitive and behavioral disabilities. Later they implemented similar programs in several centers in the United States. Based on these experiences, Ben-Yishay, in particular, became an advocate for a milieu-oriented approach to cognitive rehabilitation of individuals with acquired brain dysfunction (Ben-Yishay, 1996). Similar programs have been established by George Prigatano and his associates in Arizona, using a combined psychotherapeutic and neuropsychological treatment model (Prigatano et al., 1986; Prigatano, 1999). Given the relatively brief history of cognitive rehabilitation, it is perhaps unsurprising that relatively few models of the mechanisms underlying cognitive change in the brain injured have been described (Barat and Mazaux, 1986; Ben-Yishay and Prigatano, 1990; Gianutsos, 1991). In addition, clear practical theories that would underlie the development of specific treatment techniques in cognitive rehabilitation are still lacking, although there have been some recent endeavors in this area. Moehle and colleagues (1987) reviewed the theories or models utilized in the development and application

of cognitive rehabilitation. These authors described five primary models that include: (1) the functional system approach suggested by Luria and his colleagues (Luria and Tzvetkova, 1968; Tzvetkova, 1985); (2) developmental models (e.g., Craine, 1982); (3) learning theory models, or the application of behavioral psychology techniques in cognitive rehabilitation (see Wilson, 1997); (4) process training models (Sohlberg and Mateer, 2001); and (5) pragmatic or functionally applied models, which are not necessarily theory-based. (The reader is referred to the original sources for details.) Several major concepts also underlie the clinical understanding of cognitive dysfunction in brain injury rehabilitation and restitution and substitution of function (see Rothi and Horner, 1983). Oliver Zangwill (1947) considered the practice of re-education to include compensation, substitution, and direct training. More recently, physiologic mechanisms of neurobehavioral recovery have included the notion of restitution of function from any variety of neuronal processes, such as axonal regeneration, collateral sprouting, and denervation supersensitivity, to name just a few (Finger and Stein, 1982). Stimulation or direct retraining methods have been suggested as the main mode of cognitive rehabilitation in such instances. Nevertheless, it is largely assumed that much of the “recovery” witnessed after acute lesions is likely to occur by substitution of function, such as circumvention of deranged links within and across functional systems. Rehabilitation models based on reorganization of function (similar to Luria’s recommendations; see Almli and Finger, 1992) are thought to operate via substitution or compensation of function (see also Wilson, 1997, 2000; Dixon and Ba¨ckman, 1999). Assessment of the efficacy of cognitive rehabilitation efforts is a major contemporary issue in both research and practice. Controlled research is difficult at best (Eslinger and Oliveri, 2002; Johnston et al., 2006). Difficulties in identifying and using appropriate control groups in cognitive rehabilitation are especially notable, and some authors also emphasize that studies in rehabilitation need to yield valid data at reasonable cost (i.e., be tractable) and lead to practical outcomes (Hart and Hayden, 1986). Among efficacious research designs, a controlled study by Ruff et al. (1989) is an example of a randomized parallel design, with a neuropsychological treatment group demonstrating significant improvement over 8 weeks of training, compared to a nonspecific treatment group who receive support and professional attention to an equivalent level. Although utilising different controls, two treatment studies by Prigatano and associates (Prigatano et al., 1984, 1986) also showed beneficial effects of neuropsychological rehabilitation in

REHABILITATION THERAPIES 861 treated groups, compared to groups delayed in receiving and rehabilitation was not the usual treatment method the intervention for extraneous reasons. for the survivors. The evolution of rehabilitation medA new focus on evidence-based medicine has pericine in Britain, the United States, Germany, Israel, vaded cognitive and neuropsychological rehabilitation, and other countries in the mid-20th century occurred leading to supporting evidence that rehabilitation of primarily due to the influx of many war-related TBIs. cognitive dysfunction is not only cost-effective (Diller Many comprehensive rehabilitation programs for TBI and Ben-Yishay, 2003; Wilson and Evans, 2003), but were developed in the United States and other counthat a number of specific cognitive treatment strategies tries during this timeframe. are, in fact, beneficial (Carney et al., 1999; Katz et al., The most common problems in individuals with TBI 2006). For instance, critical reviews by Cicerone and include impairments of attention, speed of information colleagues (2000, 2005) conclude that substantial processing, learning and memory, self-regulation, and evidence exists for the benefit of cognitive-linguistic psychoemotional functioning, including self-awareness. therapies for people with language deficits and apraxia Clearly, a comprehensive approach to the assessment after left hemisphere stroke, as well as for visuospatial and treatment of this array of deficits is necessary to rehabilitation for deficits associated with visual neglect optimize the outcome of the rehabilitation process for after right hemisphere stroke. Strategy training for the individual with TBI. It is beyond the scope of this mild memory impairment and post-acute attentional chapter to consider in detail the main ingredients curdeficits, and interventions for functional communicarently recognized as important in brain injury rehabilitation deficits, have been demonstrated to be effective tion of the individual with TBI, but early intervention in the cognitive rehabilitation of individuals who with a combined medical, neuropsychological, and have suffered traumatic brain injuries (Cicerone social-vocational model is often promoted as optimal et al., 2005). (Prigatano and Ben-Yishay, 1999; Gordon et al., 2006); many of these components of rehabilitation were identified 100 or more years ago. As a consequence, there has COMPREHENSIVE BRAIN INJURY been a trend toward the development of communityREHABILITATION based models of rehabilitation for individuals with head Traumatic brain injury (TBI) and stroke have been, and trauma (Katz et al., 2006). remain, by far the most prominent neurological etioloCerebrovascular disease leading to stroke is one of gies treated in comprehensive brain injury programs the leading causes of death and chronic disability that (Licht, 1975; Giles, 1994). Both etiologies represent has been described throughout history (Fields and acquired insults to the brain, usually in adult life, and Lemak, 1989; Benton, 1991). Rehabilitation of stroketypically show spontaneous recovery, although the related impairments should recognize the fact that extent and pattern of recovery differs dramatically greater specificity in symptoms is more often seen in between them. Individuals who have suffered a closed a stroke survivor than in TBI or other neurological head injury, particularly from accidental, non-wartime impairments. Frequent neurobehavioral sequelae of causes, often demonstrate a diffuse or non-focal patstroke include speech and language disturbances (aphatern of neurological and cognitive dysfunction and sia, alexia, etc.), visuoperceptual difficulties such as recovery. In contrast, individuals who have suffered unilateral neglect, memory and learning deficits, emoan open, penetrating, missile wound to the brain (often tional disorders, and resultant adaptive functioning during war), or a localized stroke, often demonstrate a deficits in daily life. A truly comprehensive intervenmore focal pattern of neurological deficit, especially tion approach to the management of stroke-related difweeks after the initial event, leading to a combination ficulties deals with the neurologic, behavioral, and of specific deficits. Thus, the histories of rehabilitation social aspects to varying degrees, depending on the efforts for TBI and stroke have differed. cerebral lesion location and the individual’s particular The incidence of TBI has varied throughout the life circumstances (Kaplan and Cerullo, 1986; Tupper, ages (Gurdjian, 1973; Torner and Schootman, 1996), 1991). and the history of TBI rehabilitation has been strongly The efficacy of stroke rehabilitation has only relatied to war-related trauma (Walker and Jablon, 1961; tively recently been investigated in terms of outcome Walker and Erculei, 1969). Bakay (1971) documents or the quality of the intervention process as a whole. the early history of head injury treatment during the Wade (2003) provides comprehensive evidence, which Thirty Years’ War (1618–1648), which occurred just as shows overwhelmingly that treatment by a specialized the modern age was dawning. Although central nerstroke service results in reduced mortality, lower incivous system function was suspected to be associated dence of stroke recurrence, faster recovery, shorter with brain trauma, surgical intervention was primary hospital stay, and lower levels of emotional distress

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in patient and caregiver than unspecialized, uncoordinated services. Similarly, Wade notes that involvement of the patient and family in the rehabilitation process is important. Studies of therapeutic approaches have so far shown mixed results, suggesting that severity of impairment may affect response to therapy. Early implementation of comprehensive stroke rehabilitation programs results in better outcomes, especially with moderately disabled survivors (Johnston and Keith, 1983). Along with some of the therapeutic interventions discussed above, the development of new methods, such as constraint-induced movement therapy (Taub et al., 1999; Uswatte and Taub, 1999; Taub and Uswatte, 2000, 2006; Taub et al., 2002; Wolf et al., 2006) or constraint-induced language therapy (Maher et al., 2006), indicates that individuals who have suffered a stroke can benefit from direct rehabilitative efforts, even after the expected period of spontaneous recovery has ended (Sunderland and Tuke, 2005).

GENERAL COMMENTS Unlike neurology’s early history, which emphasized understanding of nervous system disorders leading to a diagnosis, an increasing number of neurologists have joined professionals from other specialties to promote the rehabilitation of already-identified disorders of the nervous system (Selzer, 1992). The early skepticism of neurologists regarding cerebral recovery and response to treatment has subsided, and a somewhat more optimistic perspective on the benefits of the rehabilitation process for the individual with a neurological disability has arrived (Moore, 1980). Nevertheless, there is a great deal to be learned in order to understand better the effectiveness of neurological rehabilitation, and to help develop effective, empirically based rehabilitative strategies and therapies for individuals with neurological disability. For instance, from a neurological perspective, the basis of nervous system plasticity is yet to be fully understood (Selzer, 1994; Boller and Grafman, 2003; Boller, 2004), and use of a disability-based perspective (e.g., WHO, 2001) may challenge neurologists to consider both the medical and the social sides of rehabilitation practice. Development and application of a cognitive neuroscience perspective will likely dominate brain injury rehabilitation in the future (Feinberg and Farah, 2006). In today’s society, cost-effectiveness of rehabilitative care is an issue (Rosenthal, 1989), and evidence-based medicine approaches will help refine and determine the therapies and/or technology most utilized to treat various disorders. Principles and standards of care in neurological rehabilitation will soon be determined (Moore, 1973; European Federation of Neurological

Societies Task Force, 1997), but during this future evolution, it is hoped that both the art and the science of neurological rehabilitation can be maintained (Siegert et al., 2005; Tate, 2006). In present-day society, it is taken for granted that there is a treatment for every disability. Historically, however, that has not always been the case, and it is only in the recent past that rehabilitation has helped address the real-life consequences of neurological disorders. The personal and societal benefits of rehabilitation are probably incalculable, but rehabilitation of various neurological disorders has been a positive evolving art and science for the past century or longer. As stated almost philosophically by German-American neurologist, Walther Riese, almost 50 years ago: With the victorious rise of the reshaped human figure, medical assistance was extended from the cure of the sick to the care for the infirm. Here ends the history of neurology to merge into the history of human charity and medical ethics. (Riese, 1959, p. 180)

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 54

The discovery of neurotransmitters, and applications to neurology THEODORE L. SOURKES * Departments of Psychiatry, Biochemistry, and Pharmacology and Therapeutics, McGill University, Montreal, Canada

INTRODUCTION Communication within the nervous system is generally recognized today as dependent upon chemicals released by neurons at their endings. These chemicals act upon specific receptor molecules embedded in the membrane of successor neurons, initiating transmission in them. In the case of target organs, the released substances evoke glandular secretion or muscular contraction. The modern phase of this subject began at the end of the 19th century with the study of the action of adrenal extracts on blood pressure. This was followed by numerous investigations in which the actions of pressor and depressor substances were explored. By the 1950s neuroscience research had revealed many new substances meeting the criteria of neurotransmitters and functioning in modalities other than regulation of the circulatory system. The theory of chemical transmission has proved to be a powerful tool in the analysis of many aspects of neurological function, and its implications loom large on the horizon of neurology and psychiatry. Drugs are evaluated for their ability to stimulate or to block specific receptors, and in that way modify activity to achieve some desirable therapeutic effect. This chapter is concerned with the historical development of our knowledge of some of the principal neurotransmitters, and the evidence that ensured their recognition.

THE BEGINNINGS What triggers the contraction of a muscle? In the 17th century Rene´ Descartes (1596–1650) wrote that “animal spirits” were at work, and that the nerves serve as conduits for them. Giovanni Alfonso Borelli *

(1608–1679) of Pisa thought that there was a nervous juice generated in the brain from blood, and that this juice was distributed by the nerves. In the next century Luigi Galvani (1737–1798) of Bologna dispensed with the theory of liquid flow. Having discovered the electrical properties of isolated tissues, he now attributed the action of nerves on muscle to electrical phenomena. The work of Carlo Matteucci (1811–1868), professor of physics at the University of Pisa, provided firm evidence of such phenomena. Emil du Bois-Reymond (1818–1896) took up Matteucci’s work, finding new electrical phenomena in muscle and nerve, such as the production of measurable electrical currents in these tissues during their activity (Brazier, 1957). But he also envisioned the possibility of some other process at work in the contraction of muscle besides electrical action, namely chemical stimulation of the tissue. The electrical theory of nervous transmission dominated for many years, but found competition from the concept of chemical mediators beginning in the early 20th century, especially through the work of Otto Loewi and Henry Dale. In the mid-1950s the leading proponent of electrical theory, the Australian neurophysiologist John Carew Eccles (1903–1997), conceded that mediation occurs chemically, with limited exceptions, and this mechanism was recognized as the mode of nervous action upon muscles, glands, and other nerves. Thus ended the battle of the “soups” and the “sparks” (Valenstein, 2005).

THE ADRENAL SUBSTANCE Edme´ Fe´lix Alfred Vulpian (1826–1887) came from a family of very modest means, but chance encounters

Correspondence to: Theodore L. Sourkes OC, PhD, Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, Canada H3A 1A1. E-mail: [email protected], Tel: +1-514-398-7316.

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brought him to the attention of Pierre Flourens (1794– 1867), who encouraged him to study medicine. Vulpian’s successes in the academic field eventually brought him appointment to the chair of pathological anatomy in the Faculty of Medicine in Paris in 1867 (Fardeau, 1988). In 1866 Vulpian, recognized as the founder of pathological histology in France, wrote about an intermediate area between nerve and muscle. His concept received its justification in the studies of Ramon y Cajal (1852–1934), whose examination of the histological structure of the nervous system gave substance to Vulpian’s insight: neuronal connections were discontinuous, separated by a space, later termed “synapse” by Charles Scott Sherrington (1858–1952). How did a neuron transmit information across the synapse to a targeted structure? Vulpian had conceived a substance that would bring together the impulse carried in the nerve and the ultimate endorgan in which the response was observed. The initial evidence for this idea came from studies of adrenal extracts, whose potent action in raising the blood pressure of experimental animals was demonstrated in the 1890s by British and Polish investigators. George Oliver (1841–1915) and Edward Albert Scha¨fer (1850–1935), who worked at the Physiological Laboratory, University College, London, found that the active pressor principle is restricted to the medulla and that it acts directly upon the smooth muscle of the blood vessels (Oliver and Scha¨fer, 1896). They recalled Vulpian’s observation (1856–1857) of a reducing substance in extracts of the adrenal gland, detected by the emerald-green color that develops upon addition of ferric chloride, and concluded that it is the pressor principle of the medulla. About the same time, two Polish investigators at the Jagellonian University in Cracow, Napoleon Cybulski (1854–1919) and Wladyslaw Szymonowicz (1869–1939), published similar results (Cybulski, 1895; Szymonowicz, 1895). Their work also showed that adrenal extracts contain a powerful pressor substance. They thought that the action occurred at the vasomotor center, whereas their British counterparts placed it at the periphery, at the blood vessels. The distinct contribution to the problem by the Polish scientists was the demonstration of blood collected from the suprarenal vein during stimulation of the gland containing the pressor agent (Bilski and Kaulbersz, 1987). Soon, more widespread actions of that “pressor principle” were recognized. Max Lewandowsky (1876–1918), working at the University of Berlin, was recording the effects of adrenal extracts on organs of the cat and rabbit. In the former he noted the dilatation of the

pupil, retraction of the nictitating membrane, and protrusion of the eyeball. He was able to elicit the same effects even after the postganglionic neurons had degenerated following excision of the superior cervical ganglion. Hence, it was evident that the extract was acting directly on the muscle (Lewandowsky, 1899). This work was carried forward on an even broader scale by John Newport Langley (1852–1925), who showed that electrical stimulation of sympathetic nerves had the same effects as injection of adrenal extract (Langley, 1901). Thomas Renton Elliott (1877–1961) then postulated that the sympathetic nerves, on stimulation, released at their endings a pressor principle, which was given the name “adrenalin.” This was the first time that chemical transmission in the autonomic nervous system was proposed. Elliott related the action of “adrenalin” to the excitation of the sympathetic visceral nerves (Elliott, 1905), with the action occurring at the junction of muscle and nerve.

THE CHEMICAL NATURE OF ADRENALIN The report of Oliver and Scha¨fer excited considerable interest in the pharmacological and chemical communities as to the nature of the pressor substance secreted by the adrenal medulla. A definitive solution came only after five decades. John Jacob Abel (1857–1938) (Fig. 54.1) was one of the first to attempt the chemical identification of “adrenalin.” Following medical studies at various European centers from 1884 to 1891 (MD degree from the University of Strassburg in 1888), Abel was appointed professor of pharmacology at the University of Michigan, the first such professorship in the United States. Two years later (1893) he moved to Johns Hopkins University, where he worked with sheep adrenal glands (supplied by P.D. Armour and Company of Chicago), subjecting the medullary portion to extensive extractive procedures, by means of which he obtained the pressor principle, now renamed “epinephrine,” as its monobenzoyl derivative. This compound was physiologically active, but not in the same way as adrenal extracts (Abel, 1899). At the same time, Otto von Fu¨rth (1867–1938; Fig. 54.2) at the University of Strassburg developed an interest in what was now recognized as the hormone of the adrenal gland. He questioned Abel’s work on this substance, and carried out his own purification of the active substance, naming it “suprarenin” (Lieben, 1948), and commercializing it. In 1901 Jokichi Takamine (1854–1922; Fig. 54.3) set himself the task of obtaining a pure and stable preparation of the hormone. Takamine had begun his scientific

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Fig. 54.3. Jokichi Takamine (1854–1922). Fig. 54.1. John Jacob Abel (1857–1938).

Fig. 54.2. Otto von Fu¨rth (1867–1938). Photograph reprinted from Lieben (1948); courtesy of Springer Publishers, Vienna and New York.

career in a government post in Japan, but decided to make his future in the United States as a consulting chemist. His first success was in enzymology with the development of Taka-diastase, an enzyme extract used industrially in the malting process in alcohol manufacture. The product was also presented to the public by Parke, Davis & Company as a digestive. His next effort was directed to obtaining a purified and stable extract of the adrenal medulla (obtained from sheep and oxen), which he patented in 1901. This product (Takamine, 1901) was then marketed by Parke, Davis under the name “Adrenalin” (Kawakami, 1928; Bowden et al., 2003). In order to avoid confusion with the commercial product, the official name selected for the hormone in the United States was that coined by Abel: epinephrine. In England the name remained “adrenaline” (Aronson, 2000). These names are used interchangeably in this chapter. Thomas Bell Aldrich, Abel’s assistant at Johns Hopkins University, left in 1898 to join the Parke, Davis research laboratories. There he also obtained a crystalline product of the adrenal medulla in 1900, but before he could complete the research, Takamine announced his achievement. Aldrich then worked on Takamine’s extract, obtaining a crystalline product from it. Adrenaline was finally synthesized independently by Friedrich Stolz (1860–1936) working at the German drug firm

872 T. L. SOURKES Hoechst (Stolz, 1904), and by Henry Drysdale Dakin about his future, Dale opted for an industrial position (1880–1952), working at the Jenner Institute in London at the Wellcome Research Laboratories in London, hav(Dakin, 1905). ing been assured that he would be free to choose his The analysis of Aldrich’s crystals agreed with own area of research. the theoretical formula for epinephrine, which is In his new post Dale investigated the pressor activity of C9H13NO3. But Takamine’s formula was incorrect, a host of amines in association with the chemist George for he had assigned an extra CH2 group to the Barger (1878–1939). Barger, with his assistant A.J. Ewins, molecule. Almost 50 years later the source of his error synthesized dozens of compounds. These were then tested was made evident by application of the then new techby Dale on smooth muscle and gland preparations. Their nique of paper chromatography. This technique enables paper (Barger and Dale, 1910) describes the relation the separation of closely related substances, and its between amine structure and pharmacological action. application to various commercial lots of epinephrine, The authors state that they were dealing with including the United States Pharmacopoeia reference a range of compounds which simulate the effects standard, revealed the presence not only of adrenaline, of sympathetic nerves not only with varying intenbut also its non-methylated analog noradrenaline sity but with varying precision . . . A term at once (norepinephrine), or arterenol (Goldenberg et al., wider and more descriptive than “adrenine-like” 1949; Tullar, 1949). Development of methods for measeems needed to indicate the type of action suring adrenaline and noradrenaline separately in tiscommon to these bases. We propose to call it sues showed that Takamine must have purified an “sympathomimetic,” a term which indicates the admixture of the two amines from the adrenals of beef relation of the action to innervation by the sympaand sheep. As it turned out, the former contain 15–25% thetic system, without involving any theoretical noradrenaline; the latter, 20–45% of the catecholamine preconception as to the meaning of that relation content. or the precise mechanism of the action. (Barger For many years adrenaline was considered the neuand Dale, 1910, p. 21) rotransmitter at sympathetic nerve endings. This was true of the vago-sympathetic nerve to the heart of Dale then undertook an examination of the action the frog, but the function of adrenaline as a transmitof choline-containing compounds, and their relation ter in mammals remained unsettled for many years. to the pharmacology of muscarine, a compound Adrenaline’s action on the smooth muscle of blood extracted from certain mushrooms. He described vessels was well recognized, but then it was found “two distinct types of action. . .– a ‘muscarinic’ action, that smooth muscle of the bronchioles, gastrointestparalysed by atropine, and a ‘nicotine’ action, paralinal tract and uterus is relaxed by it. Walter Bradford ysed by excess of nicotine” (Dale, 1914). Cannon (1871–1945) attempted to resolve the matter Among the many compounds that Barger and Dale by postulating the presence of two tissue substances synthesized was 3-hydroxytyramine (later named dopathat, together with the material released at sympamine), an achievement matched at the same time by thetic nerve endings, resulted in either an excitatory C. Mannich and W. Jacobsohn in Germany (1910). This or inhibitory effect (Sympathin E and Sympathin I). compound, along with noradrenaline and adrenaline, This hypothesis fell away as later research demonwas then tested for pressor activity. The latter two synstrated that the sympathetic neuro-effector is northetic substances were obtained as racemic mixtures, adrenaline, and that differential effects on tissues i.e., as dl-compounds, in which the biological activity is depend upon receptors at the surface of the cellular carried by the l-form. The authors found that “the membrane, with which the transmitter temporarily approximate average activity-values by the blood-prescombines. sure method” for these three compounds were 1:50:35. Because of its minimal activity in the pressor test, dopamine was regarded as biologically unimportant. NorDEFINING THE ROLE OF adrenaline, significantly more effective than adrenaline NORADRENALINE in the pressor test, had its advocates as the sympathetic After graduation in medicine Henry Hallett Dale (1875– transmitter. Two investigators in particular were gather1968) expressed more interest in research than clinical ing evidence for the natural occurrence of noradrenaline work. He seized the opportunity to undertake research and its role in physiological activity: these were Peter at University College, London, under Professor Ernest Holtz in Germany and Ulf von Euler in Sweden. Starling. During this period he spent some time in Peter Holtz (1902–1970) (Fig. 54.4) studied medicine, Frankfurt at the Institute headed by Paul Ehrlich. On beginning in 1920, but spent much time on chemistry, returning to London in 1904, and faced with a decision following the advice of one of his teachers, Albrecht

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methods were available. “Urosympathin” was found to consist of the three catecholamines, but principally of noradrenaline (Holtz et al., 1944/1947). His group then followed with studies of renal and essential hypertension; the relation of discharges of the carotid sinus to the adrenals; and the sympathomimetic activity of brain extracts. By 1948 Holtz had sufficient evidence to declare noradrenaline a new adrenal hormone (Holtz and Schu¨mann, 1948). But the essential experimental evidence for its neurotransmitter function eluded him. Holtz was the recipient of many prizes, including one that he shared with von Euler (Herken, 1972; Schu¨mann, 1972). Ulf Svante von Euler (1905–1983) was born into a scientific family. His father, Hans von Euler-Chelpin, shared the Nobel Prize in Chemistry in 1929, and his mother had a doctorate in botany. He began his studies in 1922 at the Medical Faculty of the Caroline Institute in Stockholm. A few years later he obtained a Rockefeller fellowship which allowed him to travel abroad. In Dale’s laboratory he collaborated with J.H. Gaddum (1900–1965) on the discovery of Substance P, an intestinal peptide with biological activity. In 1946, during his professorship in Stockholm, von Euler succeeded in demonstrating that noradrenaline, not adrenaline, is the sympathomimetic neurotransmitter (von Euler, 1956, 1970; Stja¨rne, 1999). Fig. 54.4. Peter Holtz (1902–1970). Reprinted from Schu¨mann (1972). With kind permission of Springer Science and Business Media.

Kossel (1853–1927), a Nobel laureate. On a scholarship from the Rockefeller Foundation he was able to spend 2 years (1928–1930) in England, some of it with Dale in London. It was this experience that convinced him to carry on his research on endogenous regulatory substances. On returning to Germany, Holtz began his studies of amino acid and amine metabolism. Taking his cue from Bloch and Pino¨sch (1936), who had shown that after giving large amounts of histidine to guinea pigs they could detect excessive amounts of histamine in the lungs, Holtz realized that only one step – the loss of carbon dioxide – is required to convert the amino acid to histamine. He then sought similar reactions affecting other amino acids. The most exciting one was the very rapid conversion of dihydroxyphenylalanine (Dioxyphenylalanin in German; hence the acronym Dopa) to hydroxytyramine (Holtz et al., 1939). The enzyme catalyzing this reaction was given the name “dopa decarboxylase,” later termed “aromatic amino acid decarboxylase.” Holtz began extensive studies aimed at elucidating the nature of pressor substances in the urine. He made use of pharmacological methods, as at the time no chemical

PARKINSON’S DISEASE, SCHIZOPHRENIA, AND THE MULTIPLE FUNCTIONS OF DOPAMINE The very weak showing by dopamine in Barger and Dale’s experiments had consigned that compound to laboratory curiosity, until 1939 when Holtz reported his discovery of it as the product of the activity of dopa decarboxylase (Holtz et al., 1942). Holtz drew the conclusion, as did Hermann Blaschko (1900–1993) in England, that this reaction was a step in the biosynthesis of adrenaline (Blaschko, 1939; Holtz, 1939) and that dopamine was a precursor of the adrenal medullary hormone. But questions were raised about further functions of this amine by the finding of dopamine in urine (Holtz et al., 1944/1947), various viscera (Schu¨mann, 1958), nervous tissue (Schu¨mann, 1956) and, especially, in the brain (Carlsson et al., 1958; Bertler and Rosengren, 1959; Sano et al., 1959). As a matter of historical record, the first noteworthy biological activity of L-dopa/dopamine was detected around 1920, when Markus Guggenheim, director of pharmacological research at HoffmanLaRoche Company in Basel, ingested L-dopa that he had extracted from home-grown legumes, and soon vomited (Guggenheim, 1962). He attributed this to non-specific irritation of the gastric mucosa, and thus

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missed the fact, established later, that dopamine formed from the amino acid stimulates the trigger zone of the emetic center in the medulla oblongata, an action mimicked by apomorphine. Many years later a second pharmacological action of L-dopa was discovered in the attempt to overcome the tranquilizing effect of reserpine. In this case, it was demonstrated in experimental animals that L-dopa, but not 5-hydroxytryptophan, the precursor of serotonin, was effective in reversing the sedation (Carlsson et al., 1957). L-dopa is similarly effective in humans receiving reserpine (Degkwitz et al., 1960). The establishment of dopamine as a neurotransmitter came through several approaches (Foley, 2003): pharmacology (Carlsson, 1998); chemical pathology (Sano et al., 1959; Ehringer and Hornykiewicz, 1960); and pathological chemistry and experimental neurology (Sourkes, 2000). The definitive findings were established by creation of an experimental model of Parkinson’s disease through multifaceted work in monkeys with lesions in the ventromedial tegmental area of the brain. Such lesions resulted in coordinate loss of cells in the pars compacta of the substantia nigra and loss of dopamine from the ipsilateral caudate nucleus and putamen; along with display of sustained postural tremor and hypokinesia of the limbs on the side contralateral to the lesion (Poirier and Sourkes, 1964, 1965; Poirier et al., 1966). Lesions differently located in the tegmentum of the pons and mid-brain did not produce these changes. These findings revealed the existence of a nigrostriatal tract, and were supported by further experiments in lesioned cats (Duncan et al., 1972), as well as by histofluorescence techniques in the rat (Ande´n et al., 1964, 1965). The discovery of the nigrostriatal tract brought about a rapid reorientation of research in Parkinson’s disease and the search for additional dopaminergic tracts in the brain. That search was motivated in the first place by the recognition that major tranquilizers in the treatment of schizophrenia and other mental disorders sometimes lead to the appearance of symptoms of parkinsonism. In fact, drugs such as the phenothiazine neuroleptics and haloperidol are now known to act at other sites in the brain where dopamine serves as a neurotransmitter.

MYASTHENIA GRAVIS AND THE CHOLINERGIC NEUROTRANSMITTER In myasthenia gravis (MG), an autoimmune disease, antibodies react with the acetylcholine (nicotinic) receptors at the postsynaptic neuromuscular junction, making the muscles relatively unresponsive to the physiologically released neurotransmitter.

Fig. 54.5. Mary Broadfoot Walker (1888–1974). Photograph reprinted from Keesey (1998). Courtesy of Karger Publishers.

In 1934 Mary Broadfoot Walker (1888–1974) (Fig. 54.5), acting upon the resemblance of the “abnormal fatiguability in myasthenia gravis” to curare poisoning, gave a patient physostigmine salicylate, a curare antagonist. The parenteral injection had “a striking, though temporary, effect” (Walker, 1934). The next year she tested prostigmine in a second patient, again with success (Walker, 1935). Her accomplishments (Keesey, 1998; Johnston, 2005) represent the culmination of a long history of attempts to find an effective treatment of myasthenia gravis (Keynes, 1961). When a standardized commercial preparation of curare became available it was used in the treatment of spastic conditions. Curare preparations also found a use in psychiatry, to counteract the convulsions engendered in electroshock therapy. The use of curare was then extended to ensure muscular relaxation during general anesthesia (Griffith and Johnson, 1942). In the same period, Daniel Bovet (1907–1992) reinvestigated succinylcholine (Bovet and Bovet-Nitti, 1952), a choline derivative originally synthesized by R. Hunt in 1911. This substance proved to have curare-like activity, and was then introduced into the anesthesiologist’s armamentarium. The action of succinylcholine is brief-lasting, for it is readily hydrolyzed by plasma cholinesterase. Nevertheless, subjects

THE DISCOVERY OF NEUROTRANSMITTERS receiving it must be protected with oxygen and artificial ventilation, until the drug is fully metabolized (Kalow, 2004). Certain snake venoms have an action resembling curare poisoning. In snakes of the genus Bungarus found in Taiwan, C.C. Chang (1928–) and C.Y. Lee (1915–2001) were able to separate a venom fraction which they named a-bungarotoxin (Chang and Lee, 1963). The substance binds postsynaptically and irreversibly to the acetylcholine receptor, a property that has been used to isolate that receptor (Chu, 2005). The Lambert–Eaton myasthenic syndrome is a rare autoimmune disorder affecting the cholinergic system, in this case the presynaptic nerve terminations. Plasma contains an IgG autoantibody that affects voltagegated calcium channels in the axon terminals, resulting in decreased release of ACh (Flink and Atchison, 2003; Takamori, 2004).

DISCOVERING THE NEUROTRANSMITTER ROLE OF ACETYLCHOLINE When Dale joined the Wellcome Research Laboratories he was asked to investigate ergot, extracts of which were known to have potent pharmacological actions. Unexpectedly, that work proved to be most fruitful, for in the following years many discoveries in pharmacology stemmed from this work. One of the most significant was Dale’s discovery of acetylcholine in an extract of ergot. This was the first recognition of the substance as a natural product. Its actions were then studied, and it was found to exert both muscarinic and nicotinic activity. In his extensive study of choline derivatives, Dale pointed out the resemblance of the pharmacodynamic effects of these compounds to the results of stimulating parasympathetic nerves (Dale, 1914). In the same period, Otto Loewi (1873–1961) was working in Graz, Austria, on the mechanism of slowing of the frog heart when the vagus nerve is stimulated. He showed that the perfusate from such a heart, passed through a denervated heart, provided exactly the same result as in the first heart. He named the active agent “Vagusstoff.” By 1926 he was quite sure that Vagusstoff was identical to acetylcholine, based on the following evidence: the catalysis was specifically inhibited by physostigmine; heart extracts catalyzed the hydrolysis of Vagusstoff in exactly the same way as they acted upon acetylcholine (Engelhart and Loewi, 1930); and acetylation of the inactivated Vagusstoff preparation restored the original activity of the heart (Loewi and Navratil, 1926a).

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In the decade after Loewi’s work, investigators reported the widespread occurrence of acetylcholine in the animal body. An outstanding aid in this work was the extremely sensitive detection of acetylcholine by its action in causing contraction of eserinized leech muscle (Fu¨hner, 1918). This biological assay facilitated the discovery of many new facts about acetylcholine. Wilhelm Feldberg and Gaddum (1934) found that stimulation of the cervical sympathetic nerve of the cat causes the release of acetylcholine from the superior cervical ganglion. Shortly afterwards Dale et al., (1936) observed the release of acetylcholine when motor nerves to skeletal muscle are stimulated (Dale, 1938). Hitherto the discoveries about acetylcholine had been made by pharmacologists and physiologists. Now, a biochemical dimension was introduced by Juda Hirsch Quastel (1899–1987) and his colleagues in Cardiff. Quastel had his early education in Sheffield, the city of his birth. His university training was at Imperial College, London, and then Trinity College, Cambridge, where he worked in the laboratory of Frederick Gowland Hopkins (1861–1947), the professor of biochemistry. After some years in Cambridge, Quastel accepted the post of director of research at a mental hospital in Cardiff (MacIntosh and Sourkes, 1990). Quastel had followed the research on acetylcholine, and speculated that this substance might be important in the brain as well as at peripheral synapses. And so, from 1936 to 1941, he turned to the study of the biosynthesis of acetylcholine in the brain. Making use of the leech bioassay the team now demonstrated that acetylcholine was actually synthesized in the brain, and that the process requires energy, supplied by the concurrent oxidation of glucose (Quastel et al., 1936; Mann et al., 1938). Quastel’s group also described a “bound” form of acetylcholine in the brain (Mann et al., 1939), thus providing early evidence that the neurotransmitter is sequestered in presynaptic vesicles. In ensuing years MacIntosh and Oborin completed the demonstration of acetylcholine’s cerebral function by showing that it is released from the intact cerebral cortex during normal brain activity (MacIntosh and Oborin, 1953).

PHYSOSTIGMINE AND OTHER CHOLINESTERASE INHIBITORS In 1876 E. Harnack, working in O. Schmiedeberg’s department at the University of Strassburg, showed that physostigmine potentiates the effect of electrical stimulation on mammalian striated muscle (Harnack and Witkowski, 1876). Fu¨hner’s work with leech muscle

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produced similar results, and laid the basis for the valuable bioassay of acetylcholine already mentioned. Loewi showed that physostigmine prolongs the response of the heart to stimulation of the vagal nerve, as well as to the action of Vagusstoff. This corresponds precisely to the biochemical action of the drug: inhibition of the hydrolysis of both Vagusstoff and acetylcholine by the esterase of heart extract (Loewi and Navratil, 1926b). He also found that physostigmine is a specific and potent inhibitor of the acetylcholinesterase of plasma and erythrocytes (Engelhart and Loewi, 1930). Physostigmine is extracted from the Calabar bean, indigenous to western Africa around the Gulf of Guinea. It is also called the “ordeal bean,” because persons suspected of criminal actions or witchcraft who survived the ordeal of consuming the beans were judged innocent. The bean belongs to the genus Physostigma. The native name for the seeds of the plant was eséré, thus providing a second name – eserine – for the extracted drug. An early account of the bean and its pharmacological and therapeutic properties has been provided by Harley (1863). Physostigmine is a methylcarbamate ester, and acts on cholinesterase by carbamylation of a serine site on the protein. The reaction is reversible, in contrast to that of organophosphorus inhibitors, which act irreversibly. Physostigmine is the first of a series of derivatives with similar action (Aeschlimann and Reinert, 1931), among them the drug now known as prostigmine (neostigmine). Physostigmine is a potent antagonist of atropine, and has served in the treatment of poisoning by that alkaloid since the discovery of the phenomenon by Kleinwachter, a German ophthalmologist, in 1864 (Nickalls and Nickalls, 1988).

1991). Assessment of the actions of drugs such as donepezil, rivastigmine, and galantamine show that they produce modest improvement in cognition and behavior over a period of 1–2 years.

THE MULTIPLE ROUTES TO DISCOVERY OF SEROTONIN AS A NEUROTRANSMITTER In the course of utilizing silver impregnation to detect melanin, the eminent pathologist Pierre Masson (1880– 1959) discovered the argentaffin reaction of certain intestinal cells, i.e., their direct reduction of silver nitrate. These were the enterochromaffin cells, which he described in a paper read at the Paris Academy of Sciences in 1914. He also noted that these cells are prominent in carcinoid tumors. Masson described how the silver-staining cells form “a diffuse endocrine gland of endodermic nature, homologous to the Langerhans islands of the pancreas” (Masson, 1914; Michalany, 1983). The nature of the reducing substance was recognized only some 40 years later. At the Cleveland Clinic, studies of essential hypertension by Irvine H. Page (1901–1991) (Fig. 54.6) focused on identifying substances that might be responsible for the heightened peripheral resistance in

SENILE DEMENTIA OF THE ALZHEIMER TYPE (SDAT) The richest concentrations of cholinergic neurons in the brain have been located in the nucleus basalis of Meynert, the midbrain reticular formation, and the basal ganglia. The first of these provides the major contribution of cholinergic fibers to the cerebral cortex, many of which are lost in senile dementia of the Alzheimer type (Whitehouse et al., 1981; Rossor et al., 1982; McGeer et al., 1984). In contrast, the gamma-aminobutyric acid system is not significantly affected. The prominent loss of cholinergic fibers in the brain has prompted trials of anticholinesterases in Alzheimer’s disease, with the aim of protecting whatever reduced amounts of acetylcholine may be released by residual cholinergic neurons (Becker and Giacobini,

Fig. 54.6. Irvine H. Page (1901–1991). Photo courtesy of the National Hypertension Association, New York.

THE DISCOVERY OF NEUROTRANSMITTERS that condition, particularly renin and angiotensin. As previous investigators had noted, samples of shed blood contain a vasoconstrictor substance, and its presence frustrated Page’s attempts to identify other vasoactive compounds. The serum vasoconstrictor, named “serotonin” by Page, came from plasmolysis of the platelets which, in turn, obtain the substance from the intestinal argentaffin cells. This became a prime area of research by M.M. Rapport in New York. Examining the amines in a concentrate of partially purified bovine serum, Rapport excluded the presence of adrenaline, tyramine, histamine and tryptamine. Further investigation revealed that the substance was 5-hydroxytryptamine, crystallizing as its creatinine sulphate complex (Rapport et al., 1948; Rapport, 1949). For many years Vittorio Erspamer (1909–1999) (Fig. 54.7) had been working in Italy in the field of comparative pharmacology, with special emphasis on biogenic amines, among other categories of bioactive compounds (Renda, 2000). In the 1930s he took up the matter of the argentaffin tissue of the gastrointestinal tract that Masson had described two decades earlier. To the reactive substance, the nature of which was unknown, he assigned the name “enteramine.” Enteramine, he found, had an excitatory action on the molluscan heart. In 1952, following Rapport’s work, he identified enteramine as 5-hydroxytryptamine (Erspamer and Asero, 1952). This was, in fact, the reducing compound that Masson had described many decades earlier.

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In the Biological Laboratories of Harvard University, John Henry Welsh (b. 1901) was concerned with neurotransmission in invertebrates. Having established acetylcholine as the inhibitory transmitter in the heart of the quahog clam, Mercenaria mercenaria (Welsh, 1939), he now sought an excitatory transmitter. His student Betty Mack Twarog was working with the clam Mytilus, smooth muscle of which could be made to undergo prolonged contraction under the influence of acetylcholine. When serotonin became available, Twarog and Welsh tested it by bioassay on Mercenaria heart and Mytilus muscle. The new amine proved to be excitatory for the heart (Welsh, 1953, 1957), but inhibitory for the smooth muscle. This was the first evidence of serotonin acting as a neurotransmitter. The amine was, in fact, identified in ganglia of both species of invertebrate (Twarog, 1988). Moving to the Cleveland Clinic, Twarog showed that serotonin is present in the mammalian brain (Twarog and Page, 1953). A decade later Dahlstro¨m and Fuxe (1965) showed by means of the histofluorescence technique that there are serotonin-containing nerve tracts in the brain of mammals, emanating from the raphe nuclei. These nuclei have differentiated functions, as has been demonstrated in the response of the adrenal glands to stress (Quik and Sourkes, 1977; Quik et al., 1977).

AMINO ACIDS ACTING AS NEUROTRANSMITTERS As we have seen, the neurotransmitter function of noradrenaline was established by classical physiological means (predominantly by measuring vasopressor activity) over a period of more than 50 years, beginning at the end of the 19th century and culminating in the 1940s. Recognition of the function of dopamine required the combination of techniques of several disciplines during the period 1960–1965 (Sourkes, 2000), in order to bring to fruition the discovery of dopa decarboxylase in 1938 and the formation of its product dopamine, under physiological conditions (Holtz et al., 1942). Clearly, the methods of detecting neurotransmitters have changed over time, especially with the introduction of new technologies. This has been the case with the three amino acid neurotransmitters: g-aminobutyric acid (gamma-aminobutyric acid; GABA), glutamic acid and glycine. In their cases recognition as neurotransmitters has depended upon electrophysiological as well as biochemical techniques in the period 1953–1967.

GABA Fig. 54.7. Vittorio Erspamer (1909–1999). Reprinted from Renda (2000). With kind permission from Elsevier Publishers.

The role of GABA began with the discovery by Ernst Florey (1927–1997) (Fig. 54.8) of an inhibitory factor in brain. Florey was born in Austria, and had his education

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Fig. 54.8. Ernst Florey (1927–1997). Courtesy of the Montreal Neurological Institute.

there. A fellowship brought him the opportunity to work with C.A.G. Wiersma (1905–1979) at the California Institute of Technology on a research project involving investigation of the stretch receptor in crayfish. When this receptor is stimulated either by stretch or acetylcholine, it generates impulses in the efferent fibers. An extract from horse brain contained a substance exerting inhibitory action on the stretch receptor neuron. Florey then labeled the unknown substance (or substances) in brain Factor I, for inhibition (Florey, 1954). Its activity was blocked by picrotoxin, but not by strychnine. At the same time T. Hayashi was studying the action of various amino acids on convulsive activity in animals, and reported in his monograph that GABA displays inhibitory activity (Hayashi, 1956). It took another few years before this finding was verified and developed further. In 1954 K.A.C. Elliott (1903–1986) (Fig. 54.9) invited Florey to take up a post at the Montreal Neurological Institute, where a concerted effort was initiated to identify the chemical nature of Factor I with the help of Alva Bazemore, a chemist at Merck & Co. Inc. in Rahway, NJ. At some stage of the work, Elliott recalled that GABA had been found in brain a few years earlier by Awapara and Roberts (Awapara et al., 1950; Roberts and Frankel, 1950; Udenfriend, 1950). Formation of GABA from glutamic acid by decarboxylation was demonstrated in Awapara’s laboratory (Wingo and Awapara, 1950). Interest in the compound grew when it was realized that its formation depends on the

Fig. 54.9. K.A.C. Elliott (1903–1986). Courtesy of the Montreal Neurological Institute.

presence of the vitamin B6 coenzyme, pyridoxal phosphate, and, further, that a deficiency of the vitamin results in convulsive activity. In short order, Bazemore’s purified material, isolated by the aid of ion-exchange chromatography, was shown to be identical with GABA (Bazemore et al., 1957). Moreover, the compound was normally present in cells in a bound form (Elliott and Florey, 1956), and released upon cerebral stimulation (Jasper and Koyama, 1969). The story of the identification of Factor I has been recounted by both Florey and Jasper (Florey, 1984; Jasper, 1984). Substances with excitatory action on the brain had long been known, but an inhibitory agent, naturally occurring in that organ, was of prime interest. On the basis of microiontophoretic studies of cortical neurons conducted in another McGill University laboratory, Krnjevic and Phillis (1963) suggested that the newly identified GABA might be a physiological neurotransmitter. The iontophoretic method was devised by J. del Castillo and Bernard Katz in the 1950s, and entailed the release of agents from micropipettes, guided under the microscope to neurons of interest. Although the evidence for a central inhibitory role of GABA had accumulated impressively, its synaptic action still required demonstration. This was achieved in Krnjevic’s laboratory by the application of GABA

THE DISCOVERY OF NEUROTRANSMITTERS 879 directly to single cortical neurons: this resulted in spinal neurons. In this case it was necessary to take changes in membrane potential and conductance, just into account the fact that interneurons in the gray matas occurs in synaptic inhibition (Krnjevic and Schwartz, ter of the spinal cord are responsible for inhibition 1966, 1967; Galindo et al., 1967). (Aprison and Werman, 1965). Chemical analysis of Parallel studies by E. Kravitz and his colleagues in carefully dissected areas of the spinal cord revealed the 1960s established the physiological action of GABA the differential distribution of glycine, the highest released by crustacean inhibitory neurons (reviewed by values occurring in the ventral gray matter, and lower Harris-Warrick, 2005). GABA was now assured its values in the dorsal gray and in the white matter. These place among the neurotransmitters. authors conducted an interesting check upon this The function of GABA in the nervous system has glycine–interneuron relationship by ligating the thorencouraged the search for synthetic compounds that acic aorta; this resulted in selective loss of interneurons mimic its actions and can serve therapeutically. Gabaand a decrease in the concentration of glycine in the pentin is one such drug, exhibiting antiseizure activity ventral gray matter (Aprison, 1990). in experimental animals. Its structure resembles that of There is an uptake mechanism for glycine in nervous GABA, but its mode of action has not been clarified. tissue, ensuring that the amino acid will once again be available for physiological action. When this mechanism Glutamic acid is studied in vitro with the radiolabeled amino acid in association with slices of spinal cord, microscopic analyThe identification of GABA, an amino acid, as an inhibisis reveals that uptake of the glycine is mainly at nerve tory neurotransmitter functioning in the brain, encouraged terminals (Ho¨kfelt and Ljungdahl, 1971). the search for other amino acids exhibiting excitatory The microiontophoretic application of glycine action. Glutamic acid has long been recognized to play a brings about hyperpolarization of nerve cells, and central role in cerebral metabolism, but it was not until reduces the membrane resistance, just as in the case the early 1960s that there was any thought of its possible of physiological release. The inhibitory action of this function in neurotransmission. D.R. Curtis, at the National amino acid can be detected in the medulla as well as University in Canberra, Australia, investigated the action the spinal cord (Galindo et al., 1967), but not in the of many compounds on neurons by using the microiontocerebral cortex (Kelly and Krnjevic, 1969). phoretic technique. His work (e.g., Curtis and Johnston, There are other transmitters such as purines and 1974) has revealed the pharmacological actions of various peptides involved in communication within the nervous amino acids and analogs of specific neurons. The earliest system, as well as some substances – histamine comes evidence of an excitatory action of glutamate came from to mind – with relevant biological activity. Those that his laboratory (Curtis and Watkins, 1960) in their study have been described above suffice to illustrate how of spinal neurons. Krnjevic and Phillis (1963), focusing the discovery of physiological function and clinical on cortical neurons, proposed that glutamic acid could pertinence are interwoven. Over fifty years ago, in function as an excitatory neurotransmitter. his Nobel Prize address Daniel Bovet stated: One of the criteria for neurotransmitter function of a compound is the presence of a system to terminate Putting to good use the vast possibilities which its action after its release into the synaptic cleft and organic synthesis offers, a number of workers its excitation of the postsynaptic neuron. Neurochemhave directed their efforts towards applying it ical studies reveal that there is such a mechanism to therapeutics, and have sought to establish for glutamate (Logan and Snyder, 1971; Balcar and the bases of a science of pharmaceutical chemisJohnston, 1972, 1973), whereby it is taken up into vesitry, or more exactly perhaps, the bases of a cles (Storm-Mathisen et al., 1983), the storage form of science of chemical pharmacology worthy of this the neurotransmitter presynaptically. name. (Bovet, 1964, p. 552) Glutamate-sensitive neurons are found in many Those efforts have borne fruit. Today, neurotransmitregions of the brain (summarized by Fonnum, 1984). ter molecules serve as models for the synthesis of new agents in Bovet’s sense. And where useful Glycine therapeutic agents have been found by other means, The work of Curtis and his colleagues had provided research is quickly directed to determining in what evidence also for the inhibitory action of glycine. At way neurotransmitter functions are affected. The the same time, R. Werman and M. Aprison at the Indiresult is that we have drugs that modify specific ana University School of Medicine employed a combineurological functions, contributing to treatment. This nation of neurophysiological and neurochemical is an ongoing process, and the historical record is an methods to explore the action of this amino acid on open file.

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ACKNOWLEDGMENTS I thank Stanley Finger for his valuable editorial comments, and Myra Sourkes for casting a critical neurologist’s eye over earlier drafts of this chapter.

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Handbook of Clinical Neurology, Vol. 95 (3rd series) History of Neurology S. Finger, F. Boller, K.L. Tyler, Editors # 2010 Elsevier B.V. All rights reserved

Chapter 55

Neural transplantation STEPHEN B. DUNNETT * School of Biosciences, Cardiff University, Cardiff, UK

INTRODUCTION The idea of neural transplantation in the adult mammalian brain has been around for 400 years, the first experimental attempts were made 130 years ago, and the first successful engraftment into the neonatal brain achieved nearly 100 years ago. In spite of a number of effective transplantation studies in adult animals through the first half of the 20th century, these results did not enter the mainstream of neurology because of the enduring prejudice that plasticity is absent in the brain once development is ended. Once the possibility of neuronal plasticity was at last recognized in the late 1960s – even though neither sprouting nor neurogenesis are prolific – experimental studies of cell transplantation were more widely accepted. The first experiments of the modern era, from the 1970s onward, focused on identifying suitable cells, and characterizing the conditions for cell survival and integration in the host brain. Rapid progress was in part dependent upon the powerful new tools that were emerging at that time to study anatomical and developmental principles of axon growth and connectivity in the nervous system with a level of specificity that was hitherto not possible. A second wave of interest, from the 1980s onward, was stimulated by the first demonstrations of functional recovery in grafted animals. If grafted cells can survive, then they have the potential to impact on host function, leading to many studies of cell transplantation as a replacement therapy for brain damage and disease, in a wide range of experimental model systems: motor systems of the basal ganglia and cerebellum; cognitive and memory processes in the hippocampus and cortex; and neuroendocrine and regulatory processes of the hypothalamus and pituitary axis. From these experimental studies emerged the first clinical applications, first in Parkinson’s disease (PD) and subsequently in Huntington’s disease, Alzheimer’s

*

disease, stroke, motor neuron disease (amyotrophic lateral sclerosis, ALS) and spinal cord injury. Continuing work at the experimental level has highlighted the diverse potential mechanisms of action of grafted cells on host function, recognizing that not all disorders will be equally amenable to treatment and reinforcing the need to design and select specific cells for specific targets. Clinical success for cell transplantation therapies has been demonstrated as a “proof of principle” but is still rarely achieved, not least because of the present dependence on using human fetal donor tissues, which impose significant constraints on ethical, logistic, practical and quality control domains. The 21st century opens a new era with rapid development of alternative sources of cells (stem cells, genetic engineering, xenografts) that are expected to allow more precise specification and quality control. Neural transplantation is at last coming of age with the prospect of off-the-shelf cell-based therapies eventually becoming available on demand.

AN EARLY FANTASY Finger (1990) has brought to our attention the first known speculation by a surgeon of the prospects for treating a neurodegenerative condition by neural transplantation. In his Ten Books of Surgery (1564), Ambroise Pare´, surgeon to the King of France, wrote: A gentleman, otherwise well, had the idea his brain was rotten. He went to the King, begging him to command Monsieur Grand, physician, Monsieur Pigray, the King’s surgeon-in-ordinary, and myself to open his head, remove his diseased brain and replace it with another. We did many things to him but it was impossible for us to restore his brain. (Pare´, 1564; see Linker and Womack, 1969, for translation and Finger, 1990 p. 367, for this specific quotation with commentary)

Correspondence to: Dr Stephen B. Dunnett, School of Biosciences, Cardiff University, Museum Avenue, Box 911, Cardiff, Wales, CF10 3US, UK. E-mail: [email protected], Tel: +44-2920-875188, Fax: +44-2920-876749.

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Unfortunately, Pare´ does not tell us what they did try, although, as Finger concludes, it was unlikely to have included explicit brain tissue replacement. Nevertheless, it is not just in popular imagination and gothic fiction, but also in the medical literature, that the prospect of altering the personality and repair of neurological damage and disease by tissue transplantation in the brain has been considered for a long time.

EARLY YEARS: FIRST TRIALS W. Gilman Thompson The first experimental attempt at cell transplantation in the adult mammalian brain is widely considered to have been undertaken by W. Gilman Thompson (1890). He reports on four experiments in which pieces of cortical tissue, excised from the occipital lobe of the dog, were transplanted into a homotopic occipital placement in the brains of another adult dog or cat. Based on macroscopic inspection, graft tissue was declared to still be present after 3 days’ survival in three cases, and in each case the donor tissue was seen to be adherent to the host brain by a layer of fibrin. In the fourth case the host cat was sacrificed after 7 weeks and the brain removed for fixation, celloidin embedding, sectioning and staining. The published report shows a histological photomicrograph of the host–graft junction separated by a reactive layer of connective tissue, and apparent survival of the donor tissue containing a mixture of healthy and degenerating cells (Thompson, 1890). With the methods of the day, it is not possible to determine that the putative transplant tissue is indeed derived from the donor, nor whether the cells it contains constitute surviving neurons, although from the perspective of present knowledge it is more likely that the grafts were undergoing rejection and contain predominantly inflammatory host-derived macrophages and astrocytes. We cannot conclude, therefore, from this evidence that the grafts were surviving and healthy. Nevertheless, Thompson did introduce a number of important and surprisingly modern concepts into experimental neurology for the first time. These include using experimental transplantation to address issues of neural tissue vitality and growth. He considered the role of blood vessels in the graft providing the nutrition necessary for its vitality, and he speculated on the trophic influences of the environment on graft survival. He sought unsuccessfully for axonal connectivity between graft and host, as well as recognizing reactive degenerative changes in the host brain, in particular in projections from the contralateral hemisphere. At the same time, two features of his methods violated principles we now know to be critical for good survival:

(i) brain tissue from adult donors does not survive well in any environment, even in tissue culture, and (ii) xenotransplants, i.e., transplantation between species, will eventually be rejected, even if not as rapidly as typically takes place for organ transplantation outside the privileged environment of the brain. Thompson concluded that: I think the main fact of this experiment – namely that brain tissue has sufficient vitality to survive for seven weeks the operation of transplantation without wholly losing its identity as brain substance – suggests an interesting field for further research, and I have no doubt that other experimenters will be rewarded by investigating it. (Thompson, 1890, p. 702) Perhaps the most remarkable feature of this early report is how little further experimentation it did in fact stimulate for several decades following, some of the reasons for which shall be addressed below.

The brain and anterior eye chamber as privileged sites The studies of the first three decades of the 20th century can be considered under two main themes. One theme directly sought to transplant neural tissues in the brain, with the main attempts summarized in Table 55.1. The second theme explored the unique features of the brain and anterior eye chamber as privileged transplantation sites in the context of emerging concepts of immune rejection based on systemic reactions to foreign tissues. Interpreting the early failures and subsequent successes in the first enterprise – transplantation of neural cells and tissues – depends in significant part upon the emerging understanding of vitality and rejection in the brain as a transplantation environment. By the early 1920s it was well understood that a wide range of adult tissues could be transplanted into diverse sites in the body of the same animal (autografts) whereas transplants undertaken between genetically unrelated individuals of the same species (allografts) fail to thrive. The allografted tissues induce a distinct cellular reaction, involving invasion by host cells of a lymphoid type, degeneration of the graft cells within 7–9 days, following which the grafts are completely resorbed. A significant number of these studies were undertaken using tumors as donor tissue, since the growth is both more vigorous and more reliable. Since even such plastic tissues generally fail to thrive in allografts and reliably fail when undertaken between donor and host of different species (xenografts), it was widely held that xenotransplantation is impossible among

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Table 55.1 Early history of neural grafting in the mammalian central nervous system (CNS). Reproduced from Bjo¨rklund and Stenevi (1985) Year

Name

Location

History

1890

W.G. Thompson

New York, USA

1898

J. Forssman

Lund, Sweden

1907

G. del Comte

Naples, Italy

1909

W. Ranson

Chicago, IL, USA

1911

F. Tello

Madrid, Spain

1917

E. Dunn

Chicago, IL, USA

1921

Y. Shirai

Tokyo, Japan

1924

G. Faldino

Pisa, Italy

1940

W.E. Le Gros Clark

Oxford, UK

1957

B. Flerko´ and J. Szenta´gothai

Pecs, Hungary

First attempt to graft adult CNS to brain First report of neurotrophic effects of grafted CNS tissues to brain First attempt to graft embryonic tissues to brain First successful grafting of spinal ganglia to brain First successful grafting of peripheral nerve to brain First successful grafting of neonatal CNS tissue to neonatal brain First demonstration of brain as an immunologically privileged site First successful grafting of fetal CNS tissue to anterior eye chamber First successful grafting of fetal CNS tissue to neonatal brain First successful intraventricular grafting of endocrine tissue First reports of reliable grafting to brain and anterior eye chamber

1970–1972

mammals (Murphy and Sturm, 1923). Conversely, if the host animals were X-irradiated, eliminating the lymphoid cells of the spleen, the grafts were not rejected so rapidly, and in many cases survived long term (Murphy, 1914). Most of these studies were undertaken with the tumors grafted into subcutaneous tissue or muscle, but in 1921 Shirai reported that heteroplastic tumors grafted into the brain could survive in the absence of X-irradiation of the host, the first evidence of the brain being an immunologically privileged site. Murphy and Sturm (1923) therefore undertook a more systematic evaluation of the brain as a privileged site, finding relative protection of mouse sarcoma and carcinoma tissues when implanted into the anterior cerebrum of the rat brain. Eighty to ninety percent of xenograft tumors inoculated into the brain thrived and grew rapidly in size. The tumors were heavily vascularized, rich in mitotic figures and exhibited none of the necrotic core typical of tumor xenografts placed in

peripheral sites, nor importantly did they exhibit invasion by the lymphoid-like cells that characterized rejecting tumors. Indeed, the few cases that failed to thrive in the brain all showed placement that exposed the grafts to the ventricle and choroid plexus, and in these cases were accompanied by invasion by lymphoid cells. In a further series of studies, Murphy and Sturm (1923) extended their experiments to explore a similar privilege of the brain environment for survival of allografts, in particular demonstrating that mouse adenocarcinoma cells readily survive transplantation into the mouse brain, even when the host mouse is immunized by a peripheral injection of defibrinated mouse blood, which precipitates rapid rejection of identical grafts placed subcutaneously in the groin. Murphy and Sturm were therefore able to replicate the privileged status of the brain for hosting both alloand xenotransplants, and they clearly associated the absence of lymphoid cell invasion as an important

888 S.B. DUNNETT component in that protection. Although they were able signalled to the lymph glands, and an efferent arm to speculate that “lymphoid cells find the brain tissue whereby an immune reaction is mounted, via bloodan uncongenial environment” (Murphy and Sturm, borne mechanisms, to attack the foreign molecules and 1923, p. 195) they were unable to define the mechanism cells in the brain. for this effect, in spite of a series of further experiments evaluating the effects of co-grafting autologous Grafting neural tissues to the brain spleen cells into the brain which did precipitate rejecThe difficulty for many readers is that many of these tion of tumors, whether involving xenografts in rats early reports were published in Italian (Altobelli, 1914; or allografts in mice. Faldino, 1924), Spanish (Tello, 1911a, b), German (ForThese and subsequent studies showed that foreign ssman, 1900; Saltykow, 1905; Del Conte, 1907) and tissues grafted to the brain can survive; either they do French (Marinesco, 1907; Nageotte, 1907; May, 1930). not provoke an immune reaction, or they do not With the exception of the many collected works of respond to it. This applies not only to tumor tissues Cajal (1928), very little of this early literature has been but a wide variety of other tissue types, in particular translated into English. Nevertheless, there are several when taken from young or embryonic donors (Willis, excellent reviews of the first attempts and first suc1935). Medawar (1948) finally pulled together the cesses in neural transplantation during the early years diverse strands of evidence to show that transplantaof the 20th century (Gash, 1984; Bjo¨rklund and Stenevi, tion rejection is the outcome of a systemic not a local 1985), and key events are summarized in Table 55.1. reaction with both afferent and efferent arms. In these Whereas Elizabeth Dunn (1917) is generally credited experiments, rabbits were first immunized by a skin with providing the first clear evidence of successful graft from another rabbit, followed 20 days later by transplantation and survival of central nervous system further skin grafts into either the brain, the anterior (CNS) tissues into the brains of adult mammals, her eye chamber or the sub-integumentary connective work was preceded by a series of intermediate steps tissue in the chest. As expected, the majority of subwith successful implantation of peripheral nervous tisintegumentary skin grafts were rapidly rejected in 6– sues or implantation of various tissues into peripheral 10 days showing that the immune state induced by sites that set the scene for eventual neural transplantathe initial skin graft is systemic, not just local. The section in the brain itself. One early strand is provided by ond condition, involving allografts in the anterior eye Forssman (1898, 1900), who used transplantation methchamber, was interesting, since the vitreous fluids of ods to study regeneration in peripheral nerves. Pieces the eye can provide sufficient nourishment for a graft of brain and other organs were inserted into straw tubes in the absence of vascularization. In this site some and sutured onto the proximal stumps of transacted grafts do become vascularized and are rapidly rejected, nerves in rabbits. From these studies the concept of neuwhereas those grafts that remain avascular were seen rotropism as a form of chemoattraction was introduced to survive long term. This suggests that vascularization as a stimulant of peripheral nerve regeneration: is necessary for rejection to occur, and so must be mediated by some circulating factor. The skin grafts The force which drives the nerve fibres into in the brain were all vascularized by the host and the tubes filled with brain substance I have rapidly rejected when the host had been pre-immunamed neurotropism . . . which chemical subnized. However, based on the evidence that they enjoy stances or combination of substances possess prolonged or indefinite survival when grafted to the this attracting property in the disintegrating brains of non-immunized animals (Shirai, 1921; Murtissue I had then, and I have also now, no opiphy, 1926; Tansley, 1946), Medawar (1948) concluded nion about. (Forssman, 1898, translated in that allografts in the brain “submit to but cannot illicit Bjo¨rklund and Stenevi, 1985, p. 6) an immune state.” In particular it was proposed that Nevertheless, while using transplantation of degenerat“a lymphatic drainage system is necessary for immuing nerves to study release of some unidentified chenity to be called into being and that penetration by moattractant factor or factors, there is no expectation blood vessels must occur before it can come into in these studies of neural graft survival. Similarly, Salteffect” (Medawar, 1948, p. 68). ykow (1905) used an autograft method to study proWe have here then the foundations of transplantation cesses of scar formation in the brain, in which immunology. Our understanding has advanced significonical-shaped pieces of cortex were excised and recantly in subsequent years in its cellular and molecular implanted in young rabbits. The grafts themselves detail, but stands in terms of the fundamental principles: clearly degenerated and were resorbed over 1–3 weeks. a systemic graft rejection process involves an afferent Further studies in subsequent decades seeking to arm whereby the presence of foreign antigens are

NEURAL TRANSPLANTATION transplant adult brain tissues were equally unsuccessful (D’Abundo, 1913; Altobelli, 1914; Wenzel and Ba¨rlehner, 1969; Frotscher et al., 1970; Olson et al., 1983). Both D’Abundo and Altobelli considered that some of their grafts derived from adult donors had exhibited surviving neurons. However, in the absence at that time of any specific methodology for distinguishing graft from host tissues, either the observations were derived from relatively short-surviving grafts (12–21 days) before ongoing degeneration was completed or, at longer survival times, the cells considered to be graft-derived were almost certainly of host origin (Gash, 1984). Notwithstanding the recent interest in identifying resting populations of stem cells in the adult brain that might still give rise to neuronal precursors that can be expanded for grafting (Reynolds and Weiss, 1992), these early studies highlight the general principle that differentiated mature mammalian CNS neurons are not suitable cells for transplantation and do not survive transplantation, however nurtured or nourished. Other early studies, by contrast, did find good survival of peripheral neural and non-neuronal tissues in the brain. Thus, following initial studies of successful transplantation of spinal ganglia under the skin (Marinesco and Minea, 1907; Nageotte, 1907), Ranson (1909, 1914) and subsequently Tidd (1932) showed good survival of ganglia transplanted into the brain. Similarly, Tello (1911a), and subsequently others (Sugar and Gerard, 1940; Le Gros Clark, 1942; Horvat, 1966), successfully implanted pieces of peripheral nerve into the adult rabbit cortex to stimulate nerve regeneration in the brain. Thirdly, as for example in the studies of immunological factors (op. cit.), the brain environment can readily support transplantation of tumor tissues provided the issues of immunocompatibility or protection are addressed (Shirai, 1921; Greene and Arnold, 1945). Indeed, one of these latter studies is the first to employ behavioral assessment of transplanted animals to evaluate graft function: The existence of human brain in lower animals also excites speculation from a purely philosophical standpoint. On the assumption that the human brain is the seat of the intellect, some alteration might be expected in the behaviour of guinea pigs bearing such transplants. However, observation has shown no change suggestive of higher faculties. In fact, the only variation differentiating a guinea pig bearing a human brain from a normal pig is a marked increase in libido. (Greene and Arnold, 1945, p. 328) The key insight was provided by Dunn (1917), namely that whereas adult neuronal tissues did not survive transplantation, immature tissues can survive better.

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Previous studies had not been particularly propitious. Del Conte (1907) had first attempted using pieces of embryonic tissue for implantation into the brains of adult dogs. Although he achieved partial survival of cartilage, connective and pituitary tissues, embryonic brain tissues survived poorly and he concluded that the adult brain is itself an unfavorable site for transplantation. By contrast, Dunn transplanted small slabs of neonatal rat cortex into cortical cavities of the same shape in littermate hosts. Clear graft survival is reported in 4 of the 44 cases attempted (Fig. 55.1), and the description and illustrations suggest that the cavities for the surviving grafts had exposed one lateral ventricle, allowing the grafts to make contact with ventricular surfaces and/or the choroid plexus. Dunn concluded: The two points of chief importance in successful cerebral transplantation are first the retention in place of the material transferred, and second the furnishing to it of an adequate blood supply . . . In my own successful operations the transplanted portions have remained adherent to the denuded portions of the cortex but have taken some position near the choroid plexus of the lateral ventricle and have apparently received their blood supply from that source. (Dunn, 1917, p. 572) The importance of this study lies in bringing together the key features required for successful transplantation of nervous tissues in the brain – the use of immature neural donor tissues; the immunological matching of donor and host (which for brain generally requires allo- but not necessarily auto-transplantation); and the selection of an appropriate donor site that can provide adequate nourishment of the transplanted tissue. This necessary combination of factors was achieved in practice in several studies in the following decades, as described in the following section, but was not clearly and explicitly formulated until nearly 60 years later (Stenevi et al., 1976).

THE MIDDLE ERA (1940^1970) Raoul May: intraocular grafts The half century between 1917 and 1970 exhibited sporadic investigations of progressive refinement, but even modestly successful outcomes had surprisingly little impact on the neuroscience thinking of the day. Following Elizabeth Dunn’s report in 1917, the even better survival of fetal neural tissues was confirmed by May (1930), using the anterior eye chamber as the transplantation site. Faldino (1924) had earlier identified the rabbit anterior chamber as a favorable transplantation site for caudal embryonic tissues, although

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Fig. 55.1. A surviving graft of neonatal cortical tissue implanted in 1904 by Elizabeth Dunn (1917). The parietal cortex tissue was positioned homotopically into the cortex of another neonatal albino rat of the same litter. (A) Low magnification drawing of graft (A) positioned in the dorsal parietal cortex and exposed to the lateral ventricle. (B) Higher magnification view of surviving neurons in inverted cortical layers in the graft tissue, adjacent to but clearly separate from the host hippocampus (H) and in direct apposition to the host choroid plexus (A) from which the graft draws vascular nourishment.

he had achieved rather poor success with neural tissue grafts. May used a fine glass aspiration pipette to transfer small pieces of rat fetal cortex into the anterior eye chamber of adult host albino rats, under aseptic conditions, using a transplantation technique that is remarkably similar to contemporary methods (Olson et al., 1983). With these improved methods, May (1930) was able to achieve a high rate of survival of embryonic neocortex in the host eye, and direct visualization in the living animal allowed confirmation of graft survival up to 6 months in several of the cases. Histological analysis showed attachment of all surviving grafts to the iris, from which a rich fine vascularization of the grafts was sustained, a factor highlighted by May as critical for the good survival of the grafts. The grafts contained both neurons and glia-like cells encapsulated in a fine meningeal cell layer. Using a Cajal silver impregnation method to visualize cell morphology, the grafts were seen to contain morphologically mature pyramidal cells, with neuronal cell bodies and proximal fibers that were essentially normal and embedded in a rich network of fiber plexus within the grafts, although a strong laminar organization was not noted. May (1930) concluded that he could extend Dunn’s demonstration of relatively short-term survival of neuronal grafts from immature mammalian donors into an immature host, to lifelong survival of implants with appropriate neuronal differentiation in adult hosts. In particular, in a suitable environment, embryonic tissues can survive a period of anoxia (“asphyxie”)

until the grafts become incorporated into the host vasculature, necessary for long-term nutrition. The intraocular transplantation site provided a model system that May and colleagues employed over 25 years to study the principles of neuronal differentiation and development within neural grafts with the anatomical techniques that were then available to them. Indeed many of the key principles that guide neuronal transplantation today were addressed in this model system first by May, and then three decades later with refined methodologies by Olson and Seiger (see The anterior eye chamber model below). Thus, May investigated systematically the effects of embryonic donor age on continuing mitosis of cells within the grafts, and on cortical graft maturation and differentiation (Chatagnon, 1952; May, 1966); the determination of neuronal fate provided by tissue dissection, in particular with the development of specific Purkinje cell phenotypes from grafts derived from mouse cerebellar anlage (May, 1954, 1966); and the effects of using cograft strategies to explore interactions between different graft tissues (May, 1966). In particular nerve fibers from cortical grafts appear to have the capacity to innervate peripheral nerve (May, 1945), muscle (May, 1949) or thymus (May, 1952) co-grafts, whereas no afferent or efferent growth could be observed between the grafted neurons and the host eye (May, 1930, 1966). This latter conclusion of graft isolation contrasts with more recent observations of extensive reciprocal graft interconnectivity with the host iris (q.v.), and is most

NEURAL TRANSPLANTATION likely to be attributable to the more sensitive and specific nerve tracing methods that are now available, rather than to a fundamental difference in transplant technique.

Le Gros Clark and Paul Glees A further decade passed before a remarkable study by Le Gros Clark (1940), in which he provided very clear evidence of excellent survival of embryonic cortical neurons implanted into the rat cortex. In his analysis of preceding work he concluded that “in none of these experiments has any attempt been made to determine how far individual neurones in different parts of the brain can proceed in their differentiation toward the attainment of the cytological characters of the corresponding mature nerve cells” (Le Gros Clark, 1940, p. 264). He therefore sought to address this specifically developmental issue by exploring “the capacity for self-differentiation of mammalian cerebral cortex . . . by a consideration of its relative structural independence of connections with other parts of the brain” (Le Gros Clark, 1940, p. 264) using transplantation methods. This is a remarkably modern question in the current era of exploring stem and precursor cell capacity to respond to positional cues in directing differentiation into mature phenotypes (Whittemore and Snyder, 1996). In his study, Le Gros Clark (1940) transplanted isolated fragments of embryonic rabbit neocortex into the neocortex of immature rabbits at approximately 6 weeks of age, by inoculation using an aseptic technique. Most notably, after approximately 1-month survival, grafts were seen to have undergone maturation as a distinct tissue mass, with grouping of cells in distinct “whorls or in somewhat indistinct laminar formation,” and differentiation of the cell types into typical small, medium-sized and pyramidal populations of neurons, with morphologies and clustering comparable to the normal cortex at a similar developmental age. Although based on Nissl rather than primary fiber staining, the apical and basal dendrites could be distinguished on the pyramidal cells, oriented appropriately “with the type of lamination characteristic of the normal cortex.” In the case described in most detail, in rabbit “number 62” (see Fig. 55.2), it was also noted that the transplant had established itself in the hippocampus, with a dorsal surface eminence bulging into the lateral ventricle, recalling the emphasis Dunn had placed on the necessity of contact with the choroid plexus to provide a source of nutrient vascularization. Moreover the key insights raised by the Le Gros Clark study relate to the intrinsic plasticity and growth capacity of “neuroblastic” cells in the developing embryonic

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brain, to continue their differentiation into mature neuronal phenotypes following transplantation. In a direct follow up to this study, Paul Glees (1940) implanted the whole head of a young (E12) rabbit embryo into a subpial placement on the brain surface of an adult rabbit. After 24 days’ survival, continuing differentiation was seen of rudimentary cerebral hemispheres containing cortical laminae and subcortical nuclei, as well as bone, skin, cartilage, tooth, and optic tissues within discrete compartments within the grafts. In particular: At a higher magnification the surface layer of nervous tissue shows all the structural characteristics of a cerebral cortex. The nerve cells are arranged in definite layers, and it is possible to distinguish small and large pyramidal cells, as well as cells of the granular type . . . the pyramidal cells are seen to have a normal arrangement of Nissl granules, and . . . the presence of neurofibrillary structure. The apical dendrites of the small and large pyramidal cells are in general orientated in a common direction. (Glees, 1940, pp. 242–243) Perhaps more remarkable still, however, is the fact that neither Le Gros Clark nor Glees followed up on these observations. In their subsequent anatomical studies on cell transplantation both authors (Le Gros Clark, 1942, 1943; Glees et al., 1949; Erikson and Glees, 1953; Glees, 1955) directed all their attention to studies of peripheral nerves, ganglia, and peripheral tissues as substrates for axon regeneration, rather than on the use of embryonic neuronal tissues for cell replacement transplantation. In his autobiography, Le Gros Clark (1968) did not even refer to the 1940 study for which he is today most remembered by the transplant community (Bjo¨rklund and Stenevi, 1985).

Spinal cord regeneration The essential problem to be addressed in spinal cord injury is that whereas cut peripheral nerves can regenerate, no similar regeneration is seen following transection of CNS axons. Very detailed anatomical experiments at the turn of the century by Santiago Ramo´n y Cajal in the developing and regenerating spinal cord and peripheral nerves of young cats and dogs defined the field. Cajal (1906a, b, 1910a, b, 1928) used silver staining methods to identify the acute formation of growth cone-like structures at the cut axon terminal, which undergo a period of “abortive” sprouting, followed by diminishing numbers of regenerated axons and a process of successive atrophy and resorption. As reviewed by Clemente (1964):

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Fig. 55.2. Embryonic cortical tissue grafted through the neocortex of a 6-week-old host rabbit (“no. 62”), and established in the hippocampus, visualized by silver staining at 4 weeks’ graft survival at low (A) and high (B) magnification. (Reproduced from Le Gros Clark, 1940.)

The experiments of Stroebe, Fickler and Cajal, and the astute observations of Bielschowsky, thus, were especially responsible for the thesis that the regenerative efforts in the central nervous system of adult mammals resulted in abortive growth. In their opinions central nerve fibers commenced to regenerate, but for some reason, the newly formed sprouts would not continue across the transection site and make functional connections in the opposite stump. (Clemente, 1964, p. 283) As recounted by Clemente (1964), Cajal’s belief that peripheral nerves secreted some regeneration-promoting “neurohumor” that is not present in the CNS led to his direct recommendation to Tello that a peripheral nerve implant may stimulate regeneration in the damaged spinal cord, leading to the important studies cited above (Tello, 1911a, b). Although Tello’s experiments were

unsuccessful, with failure of initial extensive growth as the implants were themselves resorbed, a number of subsequent studies have sought to use cell transplants to bridge or promote regeneration across the glial scar in the damaged spinal cord. Sugar and Gerard (1940) first used muscle and nerve transplants oriented longitudinally to bridge the proximal and distal stumps of a transacted spinal cord in young rats, and reported structural and functional regeneration across the injury site. Although Barnard and Carpenter (1950) were unable to replicate this observation, these studies were a clear forerunner of the complex reconstructive surgical techniques now being used to achieve similar bridge reconstruction (Bregman, 1987; Cheng et al., 1996). Most other studies of the period sought to resolve this issue, not in spinal cord transection per se, but in the potentially less traumatic transplantation sites in the brain. Thus, as noted above, Le Gros Clark (1942, 1943) implanted pre-degenerated

NEURAL TRANSPLANTATION 893 nerve stumps into the brains of adult rabbits. The grafts and connections; (ii) new methods for labeling dividwere observed to become filled with fine fibers which Le ing cells, and hence for labeling to-be-transplanted Gros Clark concluded to have originated from peripheral cells and timing neuronal birthdates; and (iii) new (meningeal and perivascular), rather than central, nerves. anatomical methods for identifying specific cell pheSimilarly in Clemente’s own studies, peripheral axons notypes by neurochemical, neurotransmitter and other running in nerves inserted into the brain can penetrate features, combined with selective methods for tract the brain provided the glial barrier at the interface is tracing. reduced by bacterial polysaccharide or deoxycorticosterDetailed descriptions of axon sprouting in response one treatment (Windle et al., 1952; Clemente, 1958). to axotomy had been provided by Cajal (1928), in central nerve paths as well as peripheral ones. However, in the context of subsequent retraction and atrophy, The legacy of Cajal there was no clear evidence that such growth was truly A remarkable feature of this period of neural transplanregenerative or functional. Unequivocal evidence that tation’s history is how the first half of the 20th century collateral axon sprouts can establish synaptic connecis laced with numerous provocative reports of successtions with new targets was first provided by Raisman ful regeneration and transplantation, while being largely (1969; Raisman and Field, 1973), in a serendipitous serignored by the neurology and neuroscience communities ies of observations arising from experiments addresof the day. To some extent, this was attributable to a sing a quite different question. The original purpose naı¨ve interpretation of the conclusions of Cajal: was to characterize the afferent anatomical connections of the septum at the ultrastructural level, using Once development was ended the founts of growth the new techniques of electron microscopy. Raisman and regeneration of the axons and dendrites dried cut either the brainstem or fornix afferents in order up irrevocably. In the adult centres, the nerve paths to be able to identify the different inputs from the are something fixed and immutable; everything degeneration and subsequent loss of terminals in the may die, nothing may be regenerated. (Cajal, septum 2–7 days after axotomy. However, at longer 1928, p. 750) survival times, contrary to expectation, once one pathIt is but a short step from the general principle that way had degenerated, axon terminals of the other type regeneration does not (normally) take place in the adult were seen to reoccupy the vacated synaptic spaces. mammalian CNS, to conclude that it cannot take place Alongside the restoration of a normal number of as an absolute dictum. We now know many of the synaptic contacts, abnormal structures were seen with factors that do indeed normally restrict axon regenerathe appearance of double or split axon boutons, providtion in the adult brain, including the presence of inhibiing a direct manifestation of collateral sprouting of tory factors, the absence of tropic and trophic factors synaptic connections, explicitly in response to deafferto promote and direct growth, the absence of suitable entation. Thus spared terminals were seen to repopuglial substrates for promoting axon growth, and the late the synaptic spaces previously occupied by the limited plasticity of adult neurons (Fawcett et al., lost connections. 2001). However, none of these principles are absolute, What started as a routine (albeit technically sophistiand do not preclude the possibility of nerve growth cated) anatomical study was quickly accepted as the following transplantation of suitable cells or approprifirst clear evidence of the regenerative sprouting of ate manipulation of their environment. axon terminals in the adult mammalian CNS. The stanHowever, the strong form of Cajal’s hypothesis dard theory – that the CNS cannot regenerate – could (that almost certainly would not have been maintained not be absolute. Similar evidence for the capacity of by Cajal himself, as demonstrated not least by his interthe adult CNS environment to support significant ests in peripheral nerve transplantation in the CNS) long-distance axon growth under appropriate condiremained widely and strongly held. In the absence of tions was soon provided by elaboration of light and methods that allowed the selective labeling and tracing electron microscopic observations of reinnervation in of graft-derived cells and their fibers, it was easy to other systems also. For example, the hippocampus maintain that any positive result that challenged the deafferented following fimbria-fornix lesions is Zeitgeist was either non-specific or artifactual. rapidly reinnervated by “sympathetic sprouting” from As so often happens in the history of science, peripheral adrenergic nerve terminals that normally successful challenge of the received position required innervate the capillary microvasculature of the brain the development of new methods. Three main techni(Loy and Moore, 1977), reminiscent of Le Gros Clark’s cal developments may be identified: (i) new electron attribution a generation earlier of innervation of permicroscopic methods for studying axon arborization ipheral grafts in the brain from a similar source.

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The second major challenge to the belief in the nonregenerative capacity of the brain came with the observation of neurogenesis in the adult mammalian CNS. As part of a systematic program of autoradiographic studies using [3H]thymidine labeling to mark the (typically neonatal and embryonic) birthdates of different neuronal populations in the rat brain, Altman (1962) noted that they could occasionally observe labeled neurons even after thymidine injection into adult animals. The number of labeled cells was small, and restricted to particular loci in the hippocampus, but nevertheless suggested continuing neurogenesis throughout adult life, at least in this one structure. Although hotly contested at the time, upon such issues as whether the labeled cells were truly neurons as opposed to glia, and whether the phenomenon was restricted to rodents (Rakic, 1985), the issue is now resolved with better labeling techniques, such as BrDU, more specific markers of neuronal phenotypes, such as NeuN, and in particular with the demonstration of in vitro expansion of neuronal precursors from adult brain with the capacity to mature into neurons as well as glia (Alvarez-Buylla et al., 1988; Reynolds and Weiss, 1992). Thus, although the absolute principle that the adult brain has no capacity for regeneration has been challenged, there remains very little evidence that either neurogenesis or sprouting has any significant impact on functional recovery after brain damage (Finger and Almli, 1985). Once neurons are lost there is not any significant intrinsic functional replacement. Rather, a changing world view is increasingly allowing for the prospect of functional repair by extrinsic replacement, i.e., via cell transplantation. The modern era is therefore characterized by a greater willingness to accept cell transplantation as a feasible and effective strategy for functional cell replacement and repair. Nevertheless the change in perspective did not occur overnight, and the 1970s was characterized by the introduction of new and progressively sensitive methods for visualizing identified populations of neurons in the developing and transplanted brain, such as provided by catecholamine fluorescence to identify individual populations of noradrenaline, dopamine and serotonin neurons in the brain (Falck et al., 1962) or acetylcholinesterase staining to mark central cholinergic neurons (Lewis and Shute, 1959) specifically.

1999). Das and Altman combined the transplantation methods that had been elucidated by their forerunners over the previous half century (an altogether less receptive climate), with the new anatomical and labeling methods that this laboratory had pioneered. In their first study Das and Altman (1971, 1972) injected 7-dayold rat pups with [3H]thymidine in order to label large numbers of still-proliferating cells in the internal and external granular layers of the cerebellar cortex. An hour later slabs of cerebellar cortex were dissected and implanted into the cerebella of unlabeled host rats of the same ages. Within 3 h, the grafts were seen to attach to the host cerebellar cortex, with many labeled cells in the grafts but not in the host brain. After 2–4 days, the grafted tissue was still surviving and contained streams of elongated cells that migrated through the grafts and into the host brain. By 10–16 days, there was little evidence of explicit surviving graft mass, but many labeled cells had taken up residence in the host cerebellum. Dilution of label suggested that some graft cells had further divided following implantation. This then suggested that cells, grafted as precursors, can divide following transplantation, and indeed were seen to differentiate to express granule, basket and stellate cell morphologies within the host brain. In describing the rationale for their studies, Das and Altman highlight the specificity afforded by the use of the [3H]thymidine labeling method, as a strategy to address the skepticism that was still rife:

Grafts to cerebellum

All these studies [Ranson, Saltykow, Altobelli, Dunn and Le Gros Clark, among others, are all cited] have used standard histological stains, including silver stains, and possibly because of this the findings of these studies have been treated with some degree of scepticism. Furthermore, with these staining techniques the investigators could not detect active migrations of the transplanted neuronal elements, even when they might have been present, and their incorporation as normal cells into the brains of host animals. In our studies . . . we have employed young animals as the recipients in whose brains various structures like cerebellum, hippocampus and olfactory bulbs show extensive postnatal neurogenesis. In order to distinguish the host cerebellar cells from the donor cells, we labelled the precursors of neuronal elements in the donor animals before transplantation and studied their fate in the brains of the host animals autoradiographically. (Das and Altman, 1972, pp. 233–234)

Gopal Das, working in the laboratory of Joseph Altman, has been credited for launching the modern era of neural cell transplantation in the brain (Bjo¨rklund,

In considering the transplantability of neural tissues, Das has affirmed that “it is the survival, growth, differentiation and integration of the neural tissue

THE MODERN ERA (1970s): GRAFT SURVIVAL AND DEVELOPMENTAL ANATOMY

NEURAL TRANSPLANTATION itself that indicate whether it is transplantable or not” (Das, 1983, p. 9). In his first studies (Das and Altman, 1971, 1972; Das et al., 1973), the grafts did not themselves survive as a discrete tissue mass; rather the migration and integration of labeled grafted cells into the host brain lay at the basis of their survival. In subsequent studies, the techniques of transplantation were refined and modified, in particular involving transplantation of tissue from younger embryonic donors (Das, 1983), for which parenchymal attachment and integration of the implanted tissue was seen as critical for long-term survival, recalling the nutritive and vascular requirements identified in earlier studies.

The anterior eye chamber model A second defining theme of the new era was provided by the studies of Lars Olson and colleagues at the Karolinska Institute in Stockholm. The Karolinska group combined the intraocular model system pioneered by May with the new anatomical techniques for visualizing specific neuronal populations in graft and host brain, in particular the catecholamine fluorescence method of Falck and Hillarp (Falck et al., 1962). In the first study using this method, Lars Olson and colleagues (Olson, 1970; Olson and Malmfors, 1970) demonstrated survival following intraocular transplantation of iris, sympathetic ganglia, smooth muscle and other peripheral tissues, including the adrenalin-secreting chromaffin cells of the adrenal medulla (see Fig. 55.3), with the earliest studies focusing on factors stimulating the growth and regeneration of axon fibers between the graft tissues and host brain (Olson and Malmfors, 1970). The studies based on peripheral tissues were soon extended to CNS tissues, in particular embryonic central neurons. Thus, in parallel with their use of catecholamine fluorescence to characterize and map the early

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and late development of brainstem dopamine, serotonin and noradrenaline neurons and their forebrain projections in the developing embryos (Olson and Seiger, 1972a; Seiger and Olson, 1972), Olson and Seiger (1972b) demonstrated survival, differentiation and growth of central noradrenergic, serotonergic and dopaminergic neurons in grafts derived from selective dissections of embryonic dorsal midbrain (containing primordial locus ceruleus), ventral midbrain (containing primordial raphe´ nucleus) and ventral mesencephalon (containing primordial substantia nigra), respectively. The fluorescence methods allowed characterization not only of the survival and development of individual populations of cells defined by their transmitter phenotypes, but also of the extent and elaboration of fiber outgrowth from those cells. Not only did the grafts give rise to extensive fiber ramification within the grafts, but also to establishment of axon connections between the grafts and host brain. Thus, locus ceruleus grafts give rise to an extensive noradrenergic innervation of the host iris, following sympathectomy to remove its intrinsic noradrenergic innervation (Olson and Seiger, 1972b; Olson et al., 1978). Conversely, the sympathetic and parasympathetic innervation of the host iris can give rise to an extensive collateral innervation of suitable graft targets, such as neocortex, with the host origin of the fibers observed in the grafts confirmed by their elimination following ciliary or submaxillary ganglionectomy (Seiger and Olson, 1975). Putting the two components together, co-transplantation of different source and target tissues allows the timing and conditions of the development of interconnections to be studied systematically (Olson et al., 1979). With its ease of transplantation and direct monitoring of graft survival, intraocular grafts have provided an important model system within which to evaluate

Fig. 55.3. (A) Adrenal chromaffin cells within a graft of adrenal medulla tissue implanted in the anterior eye chamber, and (B) fiber outgrowth onto the host iris, visualized by catecholamine fluorescence. (Reproduced from Olson, 1970, with permission.)

896 S.B. DUNNETT critical parameters of the cell transplantation method. engraftment of different tissues, including neonatal Thus, Olson and colleagues (Seiger and Olson, 1977; and adult superior cervical ganglia and embryonic, Olson et al., 1983) have collated the most systematic neonatal and adult CNS tissues (Stenevi et al., information on the optimal developmental ages of dif1976). Embryonic tissues were dissected to include ferent neural tissues for survival and growth after dopamine, noradrenaline and serotonin neurons, transplantation in oculo. Each nervous tissue has an following the dissection schema of Olson and Seiger optimal window for transplantation that corresponds (1972a), and transplanted to the choroidal fissure adjato the period of neurogenesis and birthdates of the cent to the hippocampus or over the dorsal striatum. cells to be implanted, and within 1–2 days later survival Critically, grafts only survived well when placed in declines dramatically. This information is equally relecontact with vessel-rich tissue, such as the choroidal vant to transplantation into other sites in the brain or fissure, or when an artificial vascular bed was created elsewhere, and indeed for cell culture in vitro, and by previous transplantation of iris, but not when placed the in oculo data is widely used as the reference standirectly into brain parenchyma. In addition, both gangdard for all other transplant applications (Dunnett lionic and immature central grafts contained many and Bjo¨rklund, 1992). catecholaminergic neurons of the appropriate type, In their own studies, the Karolinska team have conwhich gave rise to extensive fiber growth into the host tinued to develop the in oculo transplantation model to brain. By contrast catecholamine neurons were not develop our understanding of the principles of surviseen to survive in the CNS grafts derived from postnaval, growth and function of embryonic neural tissues. tal or adult donors. The Stenevi et al., (1976) study Thus, for example, it has provided a powerful system was important for providing the first detailed descripin which to study the electrophysiological properties tion of techniques and conditions for achieving reliable of grafted neurons, since the living grafts can be visuaengraftment of embryonic neuronal tissues implanted lized directly in vivo for ease of electrode placement into the adult brain, and became the basis for a (Hoffer et al., 1974). It has also been an important sysseries of studies exploring the mechanisms underlytem within which to study factors that promote the ing reformation of axonal connections in the adult extent or selectivity of fiber growth, such as in aged mammalian CNS. hosts (Granholm et al., 1987), and the effects of pharEarly studies using the new central transplantation macological manipulation, such as delivery of trophic technique focused on the factors governing fiber factors to the grafts (Olson and Malmfors, 1970; outgrowth into the hippocampus, not least because its Bjo¨rklund et al., 1983; Eriksdotter-Nilsson et al., 1989). distinctive laminar organization offered a simple and sensitive visualization of the appropriateness of organization of regenerating graft axons. Using two Central grafting of catecholaminergic different placements of graft tissues on the choroidal and cholinergic systems fissure, in apposition to the anterior or posterior surA second Swedish team, led by Anders Bjo¨rklund at face of the hippocampus, and with different lesions the University of Lund, has similarly utilized the to remove different subsets of intrinsic hippocampal power of new anatomical techniques to develop cell afferents, several clear principles for reinnervation transplantation methods, in their case focusing on were elucidated: (a) the pattern of terminal arbointracerebral transplantation of embryonic donor tisrization of fibers from grafted noradrenergic, serotosues. The first studies were stimulated by the apparent nergic, dopaminergic and cholinergic neurons is sprouting response of endogenous central catechoappropriate for the normal innervation of each cell lamine nerve terminals that was observed in catecholaphenotype; (b) the grafted cells can reinnervate the mine fluorescence images following axotomy of the appropriate target field via abnormal routes, e.g., from axons (Katzman et al., 1971; Moore et al., 1971). In a caudal placement, suggesting trophic rather than order to investigate whether the central axons would purely mechanical guidance; (c) in-growth is far more have a greater growth capacity when confronted by a extensive if the target area is deafferented by a lesion more supportive target for regeneration, muscle, iris of the major subcortical afferents than if they remain and other tissues were transplanted into sites of lesion intact; and (d) the denervation does not need to be spein the forebrain (Bjo¨rklund and Stenevi, 1971; Stenevi cific to the transmitter type, e.g., cholinergic deafferand Bjo¨rklund, 1973). Having achieved successful entation can stimulate in-growth of noradrenergic engraftment of peripheral tissues in the lesioned fibers, suggesting the action of separate trophic and adult brain, these first studies of host innervation of tropic influences (Bjo¨rklund et al., 1976; Bjo¨rklund the graft targets were followed by a systematic study and Stenevi, 1977a, b; Bjo¨rklund et al., 1979a). It was of the conditions required to achieve successful within this model system, in fact involving grafted

NEURAL TRANSPLANTATION locus ceruleus, that the first demonstrations of electrophysiological activity in grafted neurons in the brain were achieved (Bjo¨rklund et al., 1979b). In contrast to hippocampal placement of the grafts, early studies seeking to place dopamine neurons adjacent to their target in the dorsal striatum yielded rather poor survival due to limited vascularization of the grafts in this site (Stenevi et al., 1976). This was first addressed by creating artificial vascular beds by prior transplantation of vascularized peripheral tissues, such as iris (Stenevi et al., 1976). Subsequently, a less cumbersome protocol was developed using a delayed transplantation method, in which the new pial lining that would reform over the floor and walls of a preformed cavity was used as the transplant bed (Bjo¨rklund and Stenevi, 1979; Stenevi et al., 1985). Finally, in a third iteration of the protocols, it was found that graft tissues could be implanted stereotaxically as a dissociated cell suspension, which for the first time allowed good survival after direct intraparenchymal injection (Bjo¨rklund et al., 1980a; Schmidt et al., 1981). A fourth alternative was intraventricular placement of the grafts (Perlow et al., 1979) following the earlier demonstration by Rosenstein and Brightman (1978) (and of course Elizabeth Dunn in 1917 before that) that intraventricular sites could provide a good transplantation site for embryonic tissues. The cell suspension method in particular has been widely adopted subsequently for application in many different model systems due to its flexibility, reliable survival throughout the neuraxis, the absence of a requirement to make additional neural damage in forming the transplant site, and ease of combining multiple implant sites of either the same or different graft tissues (Bjo¨rklund et al., 1980a; Schmidt et al., 1981).

Reconnecting the visual system A fourth tradition originating in the 1970s commenced with the studies by Ray Lund and colleagues on restoration of connections in visual pathways. Lund and Hauschka (1976) first introduced the model system involving transplantation of fragments of superior colliculus overlying the tectum in neonatal rat pups. Degeneration staining following eye removal was utilized to show that the grafts attracted inputs from the contralateral retina. In subsequent studies, retina was transplanted overlying the host tectum and the grafted retinal ganglion cells grew into the host brain to establish appropriate patterns of connections in the tectum (McLoon et al., 1981). Most remarkably, the grafted retina appears competent to transduce and relay visual information to the host, as demonstrated both physiologically by restitution of responses in host neurons

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to a light flash illuminating the grafts (Simons and Lund, 1985), and by recovery of the pupillary eye reflex in the host eye to illumination of the grafts (Klassen and Lund, 1987). Nevertheless, these results do not resolve whether the restitution of a physiological reflex constitutes a recovery of the animal’s ability to “see,” a topic that has been much discussed in the context of the animals needing to be trained to use the transplants, which may reflect a process of relearning the meaning of visual information initially acquired in early postnatal life (Coffey et al., 1989; Do¨bro¨ssy and Dunnett, 2001).

THE MODERN ERA (1980s): FUNCTIONAL CELL REPLACEMENT A turning point in the field of cell transplantation, which was dominated by anatomical and developmental studies of the determinants of survival and regeneration in the 1970s, was the realization that the grafted cells might have an impact on the functional capacities of the host animal. As such, the new technology not only provided an interesting neurobiological phenomenon; furthermore it captured widespread popular attention for the new possibilities that appeared to be on offer for repair of brain damage and disease. The first clear evidence for functional recovery after cell transplantation in the brain was provided in the Parkinson model in rats, but the following 5 years showed rapid investigation of similar strategies in a wide range of different disease models and applications (see Table 55.2).

Nigral grafts Following the development of the techniques to achieve survival of brainstem catecholamine neurons grafted into the anterior eye chamber and the brain (op. cit.), teams led by the two Swedish groups independently showed that nigral grafts can alleviate the motor deficits induced by dopamine depletion in an experimental model of PD. Unilateral lesions of the forebrain nigrostriatal dopamine pathway (made by stereotaxic injection of the toxin 6-hydroxydopamine) induce a strong motor asymmetry; following pharmacological activation with direct or indirect agonists, such as apomorphine or amphetamine, the animals rotate in tight circles for the duration of drug action (Ungerstedt and Arbuthnott, 1970). The nigral grafts (containing the developing dopamine cells of the brainstem) were implanted adjacent to the denervated striatum, either into the lateral ventricle (Perlow et al., 1979) or into a cortical cavity (Bjo¨rklund and Stenevi, 1979), and were seen in each case to reduce the rotation asymmetry in comparison to

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Table 55.2 First studies of different functional model systems in the modern era Lesion model

Graft tissue

Deficits alleviated

Reference

Dopamine depletion

VM (DA) Adrenal medulla Hypothalamus Hypothalamus Hypothalamus Septum (ACh) Brainstem (NA/5-HT) Septum (ACh) VM (DA) Septum (ACh) WGE, LGE WGE, LGE Brainstem (NA) Spinal cord

Motor rotation Motor rotation Sexual immaturity Diabetes mellitus Circadian rhythm Maze learning Physiological inhibition Hyperactivity Maze learning Motor deficits Maze learning Motor and maze deficits Motor and maze deficits Hindlimb flexion Hindlimb coordination

(Bjo¨rklund and Stenevi, 1979; Perlow et al., 1979) (Freed et al., 1981) (Krieger et al., 1982) (Gash et al., 1980) (Ralph et al., 1990) (Dunnett et al., 1982a) (Bjo¨rklund et al., 1979b) (Dunnett et al., 1982b) (Fine et al., 1985) (Gage et al., 1983) (Gage et al., 1984) (Isacson et al., 1986) (Johansson and Grabowski, 1994) (Buchanan and Nornes, 1986) (Kunkel-Bagden and Bregman, 1990)

GnRH mutation VP mutation SCN lesion FF lesion

NBM lesion Aged rats Striatal lesion MCA occlusion Spinal cord lesions

5-HT, serotonin; ACh, acetylcholine; DA, dopamine; FF, fimbria-fornix; GnRH, gonadotrophin-releasing hormone; LGE, lateral ganglionic eminence; MCA, middle cerebral artery; NA, noradrenaline; NBM, nucleus basalis magnocellularis; SCN, suprachiasmatic nucleus; VM, ventral mesencephalon; VP, vasopressin; WGE, whole ganglionic eminence.

non-transplanted lesion rats. In each case the Swedish teams collaborated with US and UK colleagues in developing the functional models for assessing graft function, demonstrating long-term survival, extensive fiber growth and connectivity of the grafts and associated restoration of catecholamines in the host striatum (Bjo¨rklund et al., 1980b; Freed et al., 1980; Schmidt et al., 1982), normal electrophysiological firing patterns by grafted nigral neurons (Wuerthele et al., 1981), reformation of synaptic connectivity (Freund et al., 1985) and alleviation of a range of spontaneous as well as druginduced sensory and motor impairments (Bjo¨rklund et al., 1980b, 1981; Dunnett et al., 1981a, b, 1983a, b). From the very first report, Perlow et al., (1979) speculated on whether cell transplantation might come to offer a therapeutic strategy for human Parkinson’s Disease (PD). One key issue was what source of cells to use. Freed and colleagues (1981, 1983) introduced the possibility of using adrenal medulla tissue as an alternative cellular source of secreted catecholamines (avoiding the requirement to use fetal tissues). However, although adrenal grafts could alleviate apomorphine-induced rotation, the extent of functional recovery is typically limited in comparison to nigral grafts (Freed, 1983; Brown and Dunnett, 1989), and the mechanisms of action more restricted (Brown and Dunnett, 1989; Barker and Dunnett, 1994). A second issue related to scaling up rat studies to show that a similar alleviation of motor impairments could be achieved in primate models of Parkinson’s Disease

(PD) (Morihisa et al., 1984; Bakay et al., 1985; Redmond et al., 1986). In the subsequent two decades, many experimental studies have addressed “preclinical” issues related to development of clinical cell transplantation protocols. These include studies to refine methods of cell preparation and graft delivery; to understand the extent and limitations of immunological privilege across different levels of histocompatibility difference; to develop methods of cell storage, cryopreservation and hibernation; and to seek biomarkers, such as in vivo imaging, that can yield more direct independent measures of graft survival and function (Freeman and Widner, 1998). The second main contemporary theme is that the nigrostriatal lesion model remains the most widely used paradigm to evaluate alternative strategies for genetic and cell-based therapies, such as encapsulation of cells, in vivo and ex vivo gene therapy, and of course non-cellular surgical alternatives, such as deep brain stimulation (Fawcett et al., 2001). The third contemporary theme is that the nigral lesion and graft model has been the most widely analyzed in terms of understanding the mechanisms of graft function (Bjo¨rklund et al., 1987), and contemporary studies providing refined analyses of the extent and limits of recovery in precisely controlled operant tasks are still yielding surprises in terms of the capacity of the grafted cells to participate in complex processes, such as dopamine mediation of reward signaling and habit learning in the striatum (Fray et al., 1983; Dowd and Dunnett, 2004).

NEURAL TRANSPLANTATION

Grafts in the hippocampus Following observations of functional recovery in nigral grafted rats, it was natural to explore whether grafts of other brainstem regulatory aminergic or cholinergic neurons might exhibit a similar capacity for functional plasticity. The hippocampus was the obvious target in view not only of its role in the development of techniques for transplantation in the brain (op. cit.), but also of the extensive lesion and pharmacological investigations that had revealed its key role as a neural substrate of spatial learning and memory (Seifert, 1983). Fimbria-fornix lesions disconnect the hippocampus from its primary regulatory brainstem innervation, associated with disturbance of critical electrophysiological theta rhythms, signaling reinforcement pathways, and spatial learning functions, and it was into this site that the methods for transplantation of noradrenergic, serotonergic and cholinergic grafts had been established (Bjo¨rklund et al., 1976, 1979a). Such grafts were already known to give rise to a selective denervation-dependent hippocampal reinnervation, and to be functional at the physiological level (Bjo¨rklund et al., 1979b). The demonstration that cholinergic grafts can alleviate deficits in both delayed alternation in a T-maze and working memory in a radial maze task (Dunnett et al., 1982b; Low et al., 1982) provided the first evidence for recovery of a more complex “cognitive” function in any transplant model, as well as the first evidence of behavioral recovery in this system. The conditions for graft integration of cholinergic-rich septal grafts and recovery in a variety of spatial navigation tasks, such as the Morris water maze, has subsequently been analyzed in considerable detail (Nilsson et al., 1987, 1990; Clarke et al., 1990; Nilsson and Bjo¨rklund, 1992). By contrast, whereas both serotoninrich raphe´ and noradrenaline-rich locus grafts can modulate hippocampal physiological activity (Bjo¨rklund et al., 1979b; Segal and Azmitia, 1986; Buzsaki et al., 1988), there is only rather limited evidence that either can exert a significant behavioral effect on their own within overt lesion models (Dunnett et al., 1982a; Richter-Levin and Segal, 1989).

Aging animals Interest in cholinergic grafts acquired increased attention with the concurrent emergence of the cholinergic hypothesis of age-related cognitive impairment (Bartus et al., 1982) and in particular of the dementia of Alzheimer’s disease (Coyle et al., 1983). In fact the first reported functional effect of grafts in aged rats lay in the alleviation of motor coordination impairments following striatal implantation of nigral cell suspensions (Gage et al., 1983), but this was closely followed by demonstration of alleviation of impairments in

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spatial memory following implantation of cholinergic grafts into the hippocampus of aged rats (Gage et al., 1984). The age-related decline almost certainly extends across multiple regulatory systems, even in the cognitive domain, since both noradrenergic and cholinergic grafts in the cortex can alleviate different aspects of the memory problems of aged rats (Collier et al., 1988; Dunnett et al., 1988). Although the experimental studies that followed have indicated the important role of brainstem regulatory systems in age-related memory impairments, preclinical studies have increasingly focused on neuronal protection rather than cell replacement strategies, for example by the development of methods for ex vivo engineering of cells to deliver nerve growth factor, which can be equally effective in aged animals (Martinez-Serrano et al., 1995) and after explicit lesions (Rosenberg et al., 1988). Conversely, interest in transplantation approaches for Alzheimer’s disease has waned with the progressive recognition that the cholinergic impairments are almost certainly secondary to the plaque and tangle pathology that underlies the primary progression of the disease.

Neuroendocrine grafts in hypothalamus Transplantations within aminergic and cholinergic pathways all involve regulatory systems in which each population of brainstem neurons – comprising the socalled isodendritic core (Ramon-Moliner and Nauta, 2006) – exerts a highly branched and relatively diffuse regulation of their respective target nuclei. Functional repair might be predicted to be more readily achieved in such systems than in neuronal pathways dependent upon precise point-to-point reorganization (Sotelo and Alvarado-Mallart, 1986). Another group of neurons that may be similarly effective for functional repair is the neuroendocrine neurons of the hypothalamus, which also exert relatively diffuse actions via local interneurons and secretory pathways of the hypothalamo-pituitary axis. Mutations or lesions in several discrete populations of hypothalamic neurons can give rise to quite specific regulatory impairments, with distinct functional consequences that are easy to measure, as well as often being of fundamental consequence to the health of the animal. The first studies of functional recovery in neuroendocrine systems were undertaken, prior to the modern era, by transplantation of non-neuronal tissues into the hypothalamus. Thus, in order to investigate the local effects of estrogen on different nuclei in the hypothalamus, Flerko´ and Szenta´gothai (1957) grafted pieces of ovary into discrete hypothalamic and hypophysial sites in order to probe the role of estrogen on gonadotrophic activity. They were able to show that uterine responses to the estrous cycle in female rats are mediated exclusively

900 S.B. DUNNETT through a CNS mechanism in the region of the paraventrilesions; however, after transplantation of normal hypothacular nuclei. Similarly, Knigge (1962) utilized neonatal lamic grafts, the lesioned mutant hamsters show a restorapituitary tissue implants to influence testicular develoption of normal circadian periodicity; conversely, after ment in hypophysectomized male rats. transplantation of hypothalamic grafts derived from Moving into the modern era, Dorothy Krieger, Gibson mutant donors, the lesioned normal hamsters also show and colleagues (1982) picked up the neuroendocrine a restoration of their circadian rhythm but with a foreshortheme, restoring gonadotrophin-releasing hormone tened periodicity (Ralph et al., 1990). (GnRH) activity in GnRH-deficient hypogonal mice by implantation of embryonic hypothalamic preoptic area Spinal cord bridges and repair tissue rich in GnRH-secreting neurons into the third venThe problem to be resolved in spinal cord repair is sometricle of the mutant mice. In male hosts, not only did the what different. Although focal damage can disrupt specigrafts increase concentrations of hypothalamic GnRH fic neural circuits at the specific spinal level, the most and pituitary and plasma gonadotrophin, but normal tesdebilitating consequences of spinal cord trauma result tis development was reinstated, with evidence of full sperfrom disconnection of ascending and descending sensory matogenesis and interstitial cell development (Krieger and motor pathways from higher levels of control. The et al., 1982). Female hypogonadal mice are sterile, an goal is thus to seek to reconnect the transected pathways effect which can also be reversed by similar grafts, as over and above the replacement of lost neurons. The demonstrated by restitution of mating, pregnancy and major challenge is therefore to overcome the limited capadelivery of healthy litters in grafted female mice (Gibson city of central axons to regenerate in the CNS to reinneret al., 1984). Not only has this model system proved vate distal targets. Taking advantage of the observation powerful for the subsequent analysis of the mechanisms that the peripheral nervous system is more supportive of of neuroendocrine signaling in gonadotrophin regulation axon regeneration, David and Aguayo (1981) implanted within the hypothalamus (Silverman et al., 1990), it has segments of peripheral nerve to bridge the gap in the also allowed the identification and development of other transected rat spinal cord. The grafted peripheral nerves strategies of neuroendocrine repair, such as involving were seen to support long distance re-growth of both gene transfer of GnRH genes (Silverman et al., 1992) ascending and descending axons through the graft, and and other mechanisms of targeting (Livne et al., 1992). to cross back into the host brain at the distal end. The A different model system but involving similar capacity for central axons to grow long distances through mechanisms of signaling and repair was suggested by peripheral nerves has been replicated for other populaGash, Sladek and colleagues with the demonstration of tions of central neurons, also as retinal or striatal neurons recovery from the diabetic syndrome associated with vaso(Aguayo et al., 1984, 1987), and to exhibit appropriate phypressin (anti-diuretic hormone) deficiency in the mutant siological conduction properties (Munz et al., 1985). HowBrattleboro rat strain (Gash et al., 1980). Although recovery ever, the greatest problem with all such methods is that in either model system could theoretically be attributable once they cross the distal graft border the penetration of simply to the grafted cells secreting the deficient neurohorthe regenerating axons back into the CNS typically mone into the local or peripheral circulation, not only the remains extremely limited (David and Aguayo, 1981). location of the grafts but also the reformation of neuronal The major focus in the spinal cord has been on developconnections seems to be an important factor in grafting more effective strategies for bridging long-distance derived recovery (Boer et al., 1985; Silverman et al., 1985, regeneration of axons within the CNS environment. There 1986). Thus, in each of these neurohormonal systems, the is now a large literature exploring multiple combinations repair remains essentially a matter of reconstruction of criof peripheral nerves, peripheral glia (Schwann cells), olfactical regulatory neuronal projections, not simply a diffuse tory ensheathing cells, treatments with growth-promoting release of the missing neurohormone. and anti-inhibitory factors, and stabilizing matrices, which The nature of the signaling from hypothalamic neurons have led in some cases to significant alleviation of hindcan be quite specific. This is illustrated by the restitution of limb paralysis in spinal lesioned rats (Buchanan and circadican rhythms, lost after suprachiasmatic nucleus Nornes, 1986; Bregman et al., 1993; Cheng et al., 1996). (SCN) lesions in rats, following transplantation of anterior Both neuronal replacement and neuroprotection strahypothalamic grafts (containing the developing SCN) into tegies may be more appropriate in diseases involving the third ventricle (Drucker-Colı´n et al., 1984). Most selective motor neuron degeneration, most notably remarkably, using mutant hamster strains with abnormally Amyotrophic Lateral Sclerosis. Thus several groups have foreshortened rhythms, Ralph et al., (1990) demonstrated shown that embryonic motor neurons can survive transthat the neurons that constitute the SCN pacemaker retain plantation into the ventral horn of the spinal cord after the rhythm of the donor tissue. Thus, rhythmicity is abolvarious lesions depleting motor neurons (Sieradzan and ished in mutant and normal hamsters alike after SCN

NEURAL TRANSPLANTATION 901 of cell transplantation to patients in the modern era Vrbova´, 1989; Demierre et al., 1990; Garbuzova-Davis were undertaken in PD. Although fetal nigral tissues et al., 2001), and other studies have used trophic grafts certainly provided the best results experimentally, ethito slow motor neuron degeneration in both lesion and cal concerns about using human fetal tissues led first genetic models of ALS (Tan et al., 1996; Garbuzova-Davis to the exploration of the adrenal medulla as a potential et al., 2001; Klein et al., 2005). alternative source of catecholamine-secreting cells. Mechanisms of graft function Rapidly following on from Bill Freed’s preliminary observations in rats (Freed et al., 1981), Backlund and From the observation of functional recovery after transcolleagues in Sweden transplanted the first two patients plantation in different models it has become apparent in 1982 and 1983 by stereotaxic implantation of fragthat grafted cells and tissues can influence host function ments of adrenal medulla autografts (i.e., taken from via a variety of more or less specific mechanisms the patients themselves) unilaterally into the striatum (Table 55.3). Analysis of the alternative mechanisms of (Backlund et al., 1985). Although the operation was recovery is not only of theoretical interest to understand without complication and both patients showed minor the basic biology of nervous system plasticity, but of and transient alleviation of motor symptoms, there practical importance in developing potential cell therawas no evidence from scanning or electrophysiology pies for clinical application based on rational as well as of long-term graft survival, and no sustained functional empirical principles (Freed et al., 1985; Bjo¨rklund et al., benefit (Lindvall et al., 1987). In spite of this apparent 1987; Dunnett and Bjo¨rklund, 1994). failure, in 1987, Madrazo and colleagues in Mexico City reported a dramatically better outcome in two patients THE MODERN ERA (1990s): CLINICAL following a different open ventricular surgical approach TRIALS for implanting larger pieces of adrenal medulla tissue Parkinson’s disease directly into the medial wall of the caudate nucleus: Notwithstanding the earlier treatment by Ambroise Pare´ (Finger, 1990) (op. cit.) of the 16th-century man who considered his brain was rotten, the first applications

Clinical improvement was noted in both patients at 15 and 6 days (respectively) after implantation and has continued in both. Rigidity and

Table 55.3 Hypothetical methods of graft function, with exemplars Mechanism

Description

Example

Reference

Non-specific

Grafts cause non-specific damage that compensates Grafts secrete deficient neurochemical Grafts secrete trophic factors inducing plasticity in host circuits Grafts provide new targets to support axon survival Grafts provide a substrate for long-distance axon growth in CNS Grafted neurons reinnervate target to provide local synaptic regulatory control Grafts provide reciprocal connections to integrate into host neuronal circuits Full reconstruction of damaged circuitry of host brain

Striatal lesions for PD

(Meyers, 1958)

Dopamine replacement by nigral or adrenal grafts Adrenal graft neuroprotection in AD, HD or ALS

(Hargraves and Freed, 1987)

Pharmacological Trophic

Target support Bridge grafts

Tonic reinnervation

Circuit reconstruction

Full repair

(Bohn et al., 1987)

Grafts rescue axotomized rubrospinal projections Septo-hippocampal or spinal cord bridges

(Bregman and Reier, 1986) (David and Aguayo, 1981; Segal et al., 1981)

Nigral grafts in PD models

(Bjo¨rklund et al., 1987)

Striatal grafts in HD models

(Dunnett, 1995)

Not (yet) achieved

AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; HD, Huntington’s disease; PD, Parkinson’s disease.

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akinesia had virtually disappeared in the first patient at 10 months after surgery, and his tremor was greatly reduced. A similar degree of improvement was present in the second patient at three months. (Madrazo et al., 1987, p. 831) The apparent benefit from this revised operative procedure led to the rapid widespread adoption of adrenal autograft operations based on the open microsurgical approach in many centres worldwide, including more than a dozen centers in the United States. Critically, whereas the Mexico City studies were based on individual case reports of outcome, American Associations of Neurologists and of Surgeons set up separate registries for systematic collection of details of the surgical procedures, side effects and outcomes employed in different centers, and introduced of systematic objective assessment protocols (Bakay et al., 1990; Goetz et al., 1990). The outcome of these systematic multicenter comparisons was that the dramatic effects initially claimed for the open microsurgical approach could not be replicated. Although a modest improvement could be seen in some patients, it was typically transient and associated with a serious level of mortality and morbidity (Quinn, 1990; Goetz et al., 1991). Adrenal transplantation has therefore largely been discontinued. After the poor initial outcome with adrenal grafts, the Swedish teams reconsidered the use of fetal nigral grafts. The ethical issues were addressed in a national debate under the auspices of the Swedish Society of Medicine in 1986 to define provisional principles and conditions for ethical use of fetal tissues for neural transplantation. A consensus position was reached that collection of fetal tissues from elective abortions for research and clinical application is ethical, providing there is appropriate consent, separation of the initial decision for the abortion from any subsequent use of the tissue, non-commercialization, and proper ethical committee approval. This provided the basis for the first internationally adopted voluntary ethical guidelines for fetal tissue transplantation (Boer, 1994), and similar sets of principles have been adopted into national guidelines in a number of countries within Europe (de Wert et al., 2002). Nevertheless, in other countries, in particular those in which elective abortion is itself illegal, the use of human embryonic tissues for transplantation remains precluded. The first two patients to receive embryonic tissue grafts received minced pieces of substantia nigra tissue dissected from four 8–10 week fetuses implanted into the caudate nucleus and putamen on one side. However, the grafts provided only modest benefit and were not accompanied by graft survival sufficient to induce

a detectable increase in striatal fluorodopa binding in positron emission tomography (PET) (Lindvall et al., 1989). Several reasons may have accounted for the limited survival of the grafted tissues, and protocols were modified for subsequent studies: the age of donors was reduced, more tissue was implanted, and a narrow injection cannula was used to reduce trauma in the host brain. This was successful, and the third and fourth patients, operated on in 1988, exhibited significant clinical benefit, as evidenced by improved motor function, assessed in “defined Off,” improved duration of response to L-dopa, and a greater proportion of the day spent in “On” state (Fig. 55.4) (Lindvall et al., 1990, 1992). The functional benefit was associated with a significant recovery in PET fluorodopa binding in the grafted putamen (Fig. 55.4). Both the functional alleviation and recovery of PET into normal range have continued for more than 10 years post operation (Piccini et al., 1999), and this is replicated in the majority of the 17 patients that have received transplants in this series at the time of writing (Lindvall and Hagell, 2000). Similar profiles of recovery have also been reported in open label studies from other centers (Kordower et al., 1998; Mendez et al., 2002; Cochen et al., 2003). Therefore in the mid-1990s, the National Institutes of Health (NIH) initiated two double-blind placebo controlled trials of neural transplantation in Parkinson’s Disease, neither of which have found evidence for long-term graft survival nor of significant functional benefit (Freed et al., 2001; Olanow et al., 2003). Although the poor outcome may be related to the particular selection of tissue preparation and surgical parameters, such that the limited functional benefit relates to the relatively poor survival achieved in these studies (as evidenced by limited recovery in PET, in comparison to the reports of greater success in several open label trials), a more significant concern was raised in the observation of “runaway” graft-induced dyskinesias in several patients (Freed et al., 2001). Although most studies have not observed side effects of similar magnitude, retrospective analysis of the Swedish open label series certainly identifies similar concerns (Hagell et al., 2002). Consequently, the clinical trials in Parkinson’s Disease are currently suspended worldwide, pending understanding and resolution of the origin (and conditions for elimination) of the dyskinetic side effects observed in some patients. The positive outcome of the NIH trials has therefore been to highlight a potential problem that has become the focus of an international effort to understand and resolve (Winkler et al., 2005). Notwithstanding the issues surrounding dyskinesia in some patients, there is sufficient evidence for “proof of principle” that neural tissue transplantation

NEURAL TRANSPLANTATION

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Fig. 55.4. Fetal nigral grafts implanted into a Parkinson’s disease patient. PET scans were undertaken to visualize a selective return of [18F]fluorodopa binding sites in the grafted (left) putamen following transplantation (B) in comparison to preoperative binding (A). The patient also exhibited a marked reduction in the number and duration of “off” periods following transplantation (C) and an improvement of neurological scores, as illustrated by a reduction of the time required to complete 20 pronation-supination movements (D). Neurological recovery was greater on the right side (solid bars, under the control of the grafted striatum) in comparison to the smaller changes on the left (untreated) side. (Reproduced from Lindvall et al., 1990, with permission.)

can, under appropriate conditions, yield significant lasting clinical benefit to at least some patients in at least one neurodegenerative condition, Parkinson’s Disease. This has stimulated consideration of whether similar benefits might be achieved in other diseases (see Table 55.4).

Other CNS diseases Based on the capacity of embryonic striatal grafts to alleviate both motor and cognitive deficits in rats and monkeys with striatal lesions (Dunnett, 1995), the second disease to be addressed was Huntington’s disease (HD). The first case studies of cell transplantation in HD were undertaken in 1990 and reported in 1992 (Sramka et al., 1992), but it was not until the mid1990s that the first proper clinical trials commenced. These were based on the adoption and validation of a

core assessment battery to monitor progression of the disease, and which would allow the longitudinal progress of individual or small groups of patients to be monitored after transplantation, and allow outcomes to be compared between centers (Quinn et al., 1996). Feasibility and safety have been reported from several centers (Kopyov et al., 1998; Bachoud-Le´vi et al., 2000a; Rosser et al., 2002), although one center has reported three subdural hemorrhages when operating on more advanced patients (Hauser et al., 2002). At the time of writing, only one centre has reported significant functional benefit in three of five Huntington’s disease patients tested on a range of motor and cognitive objective tests. Recovery correlated with graft survival and physiological indices of restored cortical sensory evoked potentials (Bachoud-Le´vi et al., 2000b), and was stabilized over 6 years following operation (BachoudLe´vi et al., 2006).

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Table 55.4 Key reports of clinical trials of tissue transplantation in neurological diseases Application

Tissue

First report

Functional benefit?

Parkinson’s disease

Adrenal medulla Embryonic nigra Embryonic neural tissues Embryonic striatum Adrenal medulla CNTF-secreting cell line Embryonic spinal cord hNT stem cells Oligodendrocyte precursors NGF-secreting fibroblasts

(Backlund et al., 1985) (Lindvall et al., 1989) (Kolarik et al., 1988) (Sramka et al., 1992) (Winnie et al., 1993) (Buchser et al., 1996) (Falci et al., 1997) (Kondziolka et al., 2000) (Stangel and Hartung, 2002) (Tuszynski et al., 2005)

(Madrazo et al., 1987) (Lindvall et al., 1990)

Schizophrenia Huntington’s disease Pain ALS Spinal cord injury Stroke Multiple sclerosis Alzheimer’s disease

(Bachoud-Le´vi et al., 2000b)

ALS, amyotrophic lateral sclerosis; CNTF, ciliary neurotrophic factor; hNT, human neuroteratoma cell line; NGF, nerve growth factor.

The first human trial of neurotransplantation in stroke also for the first time used a human neuronal precursor cell line rather than primary fetal tissue for implantation (Kondziolka et al., 2000). The human neuroteratoma cell line of hNT cells (“LBS-neurons” provided by Layton Bioscience) were used, with 2–6 million cells implanted into the site of infarction in each of 12 stroke patients 6 months to 6 years after basal ganglia infarct. As a group, the patients exhibited significant reduction in European Stroke Scores, improved cognitive function, and improved fluorodeoxyglucose uptake in PET imaging (Kondziolka et al., 2000; Stilley et al., 2004). However, since this is a non-progressive condition, which can show partial recovery, the absence of independent control groups is particularly critical. In parallel developments, based on experimental studies in animals, which suggest that adult stem cells can migrate via the circulation to target sites of ischemic damage (Eglitis et al., 1999), stroke is the first neurodegenerative condition for which human mesenchymal stem cells have been injected peripherally with the goal of targeting CNS repair (Bang et al., 2005). Applications in Alzheimer’s disease, spinal cord injury, multiple sclerosis and other disorders are at an even earlier stage of clinical application (Table 55.4). Studies in the experimental literature over the last two decades suggest that a protocol that might work well in one disorder will not automatically be transferable to other conditions. Rather, therapeutic efficacy will almost certainly depend on matching transplantation strategies to the appropriate mechanism of functional activity required for each particular condition, depending on the specific nature and pattern of neurodegeneration and symptoms of particular concern (Dunnett, 2007).

Other strategies to CNS repair In the present “history” I have concentrated on what is already accomplished experimentally, leading up to the (at present) still extremely limited applications in neurology. As a consequence the primary focus has been on understanding the principles for neuronal replacement and repair of neuronal cell loss, whether resulting from injury or disease. The technical complications and practical limitations of neuronal replacement therapies are at least as great as the possibilities, so that the balance between optimism and pessimism (realism?) waxes and wanes. However, within an historical perspective, we can also detect emerging trends that are likely to take neural transplantation and repair down new and different paths. First and foremost is the search for alternative sources of cells that can replace our present dependence on primary fetal tissues. This imperative is in part driven by the ethical sensitivities surrounding use of fetal tissues, but is equally attributable to practical limitations of supply, and the impossibility of achieving the level of standardization, sterility and quality control necessary for routine therapeutic application. Stem cells, tumor-derived, immortalized and engineered cell lines, and xenografts all offer potential alternatives (Fawcett et al., 2001). Equally, each has its own technical and ethical problems, and none of the alternatives are yet resolved to the level that they can provide a practical replacement to fetal tissues at this time. The search for alternative cell sources goes hand in hand with probing alternative methods for functional effect. In particular, there is a growing interest in developing trophic strategies where the grafts are employed as a tool for stable cellular delivery of large

NEURAL TRANSPLANTATION molecules, such as growth factors, at physiological concentrations, into precisely defined loci within the brain, while circumventing the blood–brain barrier. It will be much easier to engineer or encapsulate a secretory cell than to achieve good survival and precise integration of a developing neuron that must establish precise patterns of connection in order to exert its functional impact. A further issue that requires emphasis is the need for critical consideration of the relationship between animal models and human disease. Side effects, such as the graft-induced dyskinesias that can follow nigral cell transplantation, only emerged from the clinical trials; they were not even considered, let alone identified, in the preceding preclinical studies. This is in part because the standard clinical situation of combining ldopa with grafts had not been considered important experimentally prior to the emergence of the specific problem in the human trials. More general, however, is the problem that most animal models represent a considerable simplification of the full richness and complexity of the human condition. Experimental lesions can (and do) reliably reproduce specific aspects of human neuropathology, such as selective loss of dopamine or cholinergic neurons. However, the specificity that makes for experimental power through analytic purity, by selection and selective manipulation of specific components of the disorder, inevitably fails to represent the full complexity of the human disease, whether in terms of variability of causation, progression, symptomatic expression, or the interactions with clinical treatment. As a consequence, when it comes to the clinic, experimental studies may over-represent the ease with which clinical syndromes may be reversed by selective cell replacements, since the target human conditions are not similarly “clean.” A related feature that is typically not well represented in preclinical studies is that most target diseases are slowly progressive, whereas most experimental studies have been conducted in acute lesion models that artificially induce advanced stages of the disease in a single step. There are good experimental reasons for this, including for example welfare concerns, and the need to avoid or circumvent spontaneous compensatory processes that can confound studies conducted with partial lesions. Also, for most conditions it is difficult to reproduce the pathogenic development of the human disease accurately in animals. Even when a simple genetic causation can be identified, the development of both pathological and symptomatic phenotypes can differ markedly between man and mouse. Not only are developmental and compensatory processes in disease progression therefore ignored, but so also are critical issues related to how the

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transplant intervention interacts with disease progression. Ultimately, therefore, the preclinical scientist is responsible for developing the fundamental neurobiology and identifying potential therapeutic targets, but there will always remain significant translational issues that can only be addressed in well-designed, well-controlled clinical studies. The history of neural transplantation to date indicates that this is not a unidirectional process from laboratory to clinic. Rather, effective progress is achieved only through a dynamic reciprocal interaction between basic and clinical scientists working together to design, modify and refine transplantation methodology and its applications, based on rigorous rational as well as empirical principles. In summary, at the time of writing, neural transplantation is in transition. Primary fetal cells survive transplantation well in a variety of animal models of human neurodegenerative disease, and have offered “proof of principle” of therapeutic benefit in case reports and small open-label trials in several disease conditions. However, significant constraints have arisen on safety, reliability, and the practicalities of sourcing suitable donor cells and tissues, that are inhibiting the rate of translation from the laboratory into the clinic. Considerable technical advances are still required before cell transplantation can offer a routine therapy for human brain trauma and neurodegenerative disease.

ACKNOWLEDGMENT The early history of neural transplantation has been the topic of several previous reviews (Gash, 1984; Bjo¨rklund and Stenevi, 1985; Freed, 2000), and I acknowledge my heavy reliance in particular on the review of Bjo¨rklund and Stenevi (1985).

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Subject Index Page numbers in italic e.g. 96 refer to figures; page numbers in bold e.g. 96 refer to tables

A

¯ lı˘ibn, 65 al-‘Abba¯s al-Maju¯sı¯’, A brain structure/function, 66–7 Abbie, Andrew Arthur, 783 abducens nerve (cranial nerve VI), 219 Abel, John Jacob, 870, 871 Abercrombie, John apoplexy, 406–7 bacterial meningitis, 420 absence seizures EEG classification, 396 original definitions, 393 abstraction, frontal lobes, 562 Abulcasis, 67 Academia Brasileira de Neurologia, 805 accessory nerve (cranial nerve XI), 221–2 acetylcholine, 874–5 identification as neurotransmitter, 179 acetylcholinesterase (AChE), 363 acoustic-vestibular nerve (cranial nerve VIII), 220–1 acquired childhood aphasia, 845–6 recovery, 843–50 acromegaly, The Bible, 39–40 action potentials Moruzzi, Giuseppe, 172 theories of, 362 action tremors, 503–4 Adamkiewicz, Albert, 749 Adams, Raymond, 529 metabolic tremor, 528 multisystem atrophy (olivo-pontocerebellar degeneration), 514 addiction therapy, United States, 611 Addison, Thomas, 461–2 Adie, William John, 783 primitive (atavistic) reflexes, 226 adrenal grafts, Parkinson’s disease, 901–2 adrenalin (epinephrine), 869–72 Abel, John Jacob, 870 Aldrich, Thomas Bell, 871 Cannon, Walter Bradford, 872 Cybulski, Napoleon, 870 Elliott, Thomas Renton, 870 extraction, Japan, 773 identification as neurotransmitter, 179 Langley, John Newport, 870 Lewandowsky, Max, 870 Olivier, George, 870 Scha¨fer, Edward Albert, 870

adrenalin (epinephrine) (Continued) Stolz, Friedrich, 871–2 structure, 872 Szymonowicz, Wladyslaw, 870 Takamine, Jokichi, 870–1 von Fu¨rth, Otto, 870 Vulpian, Fe´lix Alfred, 869–70 b2-adrenergic receptors, 365 adrenocorticotropic hormone (ACTH), 341 Adrian, Edgar Douglas, 171–3, 172 EEG, 171–2, 181 electromyography, 171–2, 183 neurophysiology, 177 single-neuron studies, 172 adult T-cell leukemia (ATL), Japan, 776 Aesculapius, headache, 376 Africa, 821–5 brain tumors, 822 Burkitt’s lymphoma, 821–2 common diseases, 821 see also specific diseases community-based studies, 824 epilepsy, 822 meningococcal meningitis, 821 Pan African Association of Neurological Sciences (PAANS), 822–4, 823 psychiatrists’ role, 822 snake bites, 821 aging animals, neural transplantation, 899 agraphia, 583–601 Bastian, Henry Charlton, 587, 588, 589–90, 590 Bateman, Frederick, 585 Benedikt, Moritz, 586 Charcot, Jean-Martin, 590 Exner, Sigmund, 589 Gerstmann, Josef, 597 Hughlings Jackson, John, 586–7 isolated, 591 Lordat, Jacques, 584 Marce´, Louis Victor, 584–5 Mills, Charles K, 216 neurological examinations, 216 Ogle, John William, 216, 586 Pitres, Albert, 650 publications, 584 Rush, Benjamin, 606

agraphia (Continued) Trousseau, Armand, 585–6 Wernicke, Carl, 587, 589 see also aphasia Aguayo, A J, 900 AIDS frontal lobe involvement, 564 tropical neurology, 826 Ainslie, James, 788 akathisia, 512 Akhenaten, Pharaoh, 34 Alajouanine, The´ophile, 642–3, 643 Alalie, 635 Albucasis, 378 Album de Photographies Pathologiques (Duchenne de Boulogne), 291 Alcmaeon of Crotona, 50–1 cranial nerve I, 216 senses, 491 Aldazoro, Gustavo Leal, 808 Alderotti, Taddeo animal studies, 131 brain vs. heart controversy, 83–4 Aldini, Giovanni, 137 Aldrich, Thomas Bell, 871 Alexander, G E, 564 Alexandria, 53–4, 62 animal studies, 130 alexia, 583–601 19th Century, 583–5 with agraphia, focal injury identification, 236 Bastian, Henry Charlton, 587 Bateman, Frederick, 585 Ferrier, David, 589 Goldstein, Kurt, 597 Hinshelwood, James, 593–4, 596 Hughlings Jackson, John, 586–7 Kussmaul, Adolf, 589 pronunciation, 598 publications, 584 Skwortzoff, Nadine, 589 Trousseau, Armand, 585–6 Wernicke, Carl, 587, 589, 589 see also agraphia; aphasia Algeri, Giovanni, anterograde tract tracing, 164 Alhazen see al-Haytham, Ibn Allen, Ivan MacDonald, 792–3, 793 All-India Institute of Medical Sciences, 819

914 allografts, 886 All-Union Congress of Neuropathologists and Psychiatrists (Russia), 749 All-Union Society of Neuropathologists and Psychiatrists (Russia), 752 alpha-synuclein gene, Parkinson’s disease, 510 Altman, J, 894–5 Altobelli, R, 889 Alurralde, Mariano, 802 Alvergue, Mario Romero, 810 Alzheimer, Alois, 680 Alzheimer’s disease aging animals, 899 anticholinesterases, 876 Bonfiglio, Francesco, 724 dementia testing, 251 Italy, 724 memory assessment tests, 244 molecular biology, 369 neural transplantation, 904 pharmacological therapy, 180 tropical neurology, 826–7 America, Latin see Latin America American Board of Psychiatry and Neurology, 610 American Civil War see United States of America (USA) Amici, Gustave Battista, 157 Amidon, R W, 193 amino acids, as neurotransmitters, 877 amyotrophic lateral sclerosis (ALS) Charcot, Jean-Martin, 207–9, 210, 637 spinal cord changes, 208–9 tropical neurology, 820 analepsy, 391 Anatome Medullae Spinalis Nervorum (Blasius), 154 Anatomical Exercises on the Generation of Animals (Harvey), 132 anatomical reprojection, vision, 73 Anatomie et Physiologie du Système Nerveux en Général et du Cerveau en Particulier (Gall), 119 anatomo-clinical method Charcot, Jean-Martin, 203, 205–7 Laennec, R T H, 205 anatomy, 149–68 17th Century, 94, 95–6, 152–5 18th Century, 155–6 Alexandrian medicine, 53 Ancient Egypt, 31 Arabic/Islamic period, 68 art, 149–52 Australia, 783 brain vs. heart controversy, 149 cerebral cortex lamination/ architecture, 165–6 comparative see comparative anatomy contribution of, 163–4 epilepsy pathology, 393 European Middle Ages, 81, 82 frontal lobes, 564 German-speaking countries, 677

INDEX anatomy (Continued) Greco-Roman World, 50 gross anatomy, 156–63 Japan, 773 localization theory, 125 Mesopotamia, 18, 20 microscopic organization, 156–63 “cell theory”, 157 fixation, 157 microscope development, 157 microtome, 157 stains, 157, 158 neural pathways, 164–5 neuron doctrine, 159, 162–3 Renaissance, 151–2 reticular theories, 158, 160–2 Scandinavia, 661 sleep medicine, 547–8 traditional Chinese medicine (TCM), 760–2 workers in Amici, Gustave Battista, 157 Aranzio, Giulio Cesare, 152 Baglivi, Giorgio, 155 Berengario, Jacopo, 151 Bonnet, Charles, 156 Casserio, Giulio, 152 Colombo, Realdo, 152 Cotugno, Domenico, 155, 721 Cuvier, Georges, 156 d’Acquapendente, Gerolamo Fabrici, 152 da Vinci, Leonardo, 149–51, 150 d’Azir, Fe´lix Vicq, 156 Descartes, Rene´, 152–3 Estienne, Charles, 152 Eustachio, Bartolomeo, 152 Falloppia, Gabriele, 152 Fontana, Felice, 156 France, 633 Freud, Sigmund, 681–2 Gall, Franz Joseph, 156 Gennari, Francesco, 155 Herophilius, 53–4 Huber, Johann Jacob, 155 Hunter, John, 156 Leuret, Franc¸ois, 156 Lister, Joseph Jackson, 157 Lower, Richard, 153 Magendie, Franc¸ois, 156 Malacarne, Vincenzo, 155 Malpighi, Marcello, 154 Massa, Nicolo´, 151 Mistichelli, Domenico, 155 Newton, Isaac, 155 Pacchioni, Antonio, 155 Panizza, Bartolomeo, 722 Piccolomini, Arcangelo, 152 Pourfour du Petit, Franc¸ois, 155 Reil, Johann Christian, 156 Retzius, Gustav Magnus, 157 Rolando, Luigi, 156 Santorini, Giovanni, 155 Scarpa, Antonio, 155

anatomy (Continued) Soemmering, Samuel Thomas, 155 Spurzheim, Johann Caspar, 156 Swedenborg, Emmanuel, 155–6 Sylvius, Franciscus de la Boe¨, 152 van Leeuwenhoek, Antony, 154, 154 Varolio, Costanzo, 152 Vesalius, Andreas, 151–2 Vieussens, Raymond, 154–5 von Haller, Albrecht, 156 von Luschka, Hubert, 157 Wren, Christopher, 153 The Anatomy of the Brain (Ridley), 105, 615 The Anatomy of the Brain, Explained in a Series of Engravings (Bell), 271, 283 Anaxagoras, senses, 491 Anaximander, 50 Anaximenes, 50 Ancient Egypt see Egypt, Ancient Ancient trepanation see trepanation, Ancient Andral, Gabriel, 407 Andre´-Thomas, A, 324 anemia, pernicious see pernicious anemia anesthetics general see general anesthesia traditional Chinese medicine (TCM), 764–5 Angelman syndrome (AS), 366 Angier, R B, 458 angiography, early stroke studies, 412 “animal electricity”, Galvani, Luigi, 721, 722 animal experimentation, 129–48 19th Century see nineteenth Century 20th Century, 143–4 Alexandria, 130 ancient world, 129–31 animal breeding and species, 140–2 cancer research, 142 genetic homogeneity, 143 higher apes, 141 metropolitan zoos, 142 monkeys, 141 anti-vivisectionist movements see antivivisectionist movements Arabic/Islamic period, 131 ballism, 523 basal ganglia, 502 brain function localization, 844 the Enlightenment, 135–8 epilepsy, 397 Greco-Roman World, 129–31 Huntington’s disease, 520 Renaissance, 131–5 vicariation, 837–8 workers in Alderotti, Taddeo, 131 Aldini, Giovanni, 137 Bacon, Francis, 132 Bell, Charles, 138 Berger, Hans, 140

INDEX animal experimentation (Continued) Bichat, Marie Franc¸ois Xavier, 140 Borelli, Giovanni Alfonso, 134 Bouillaud, Jean-Baptiste, 140 Broca, Paul, 140 Brown, James Crichton, 141 Brown-Se´quard, Charles-E´douard, 139–40, 621 Charcot, Jean-Martin, 140 Descartes, Rene´, 134 Donaldson, H H, 143 Du Bois-Reymond, Emil, 138 Duchenne de Boulogne, Guillaume Benjamin, 140 Flourens, Marie-Jean-Pierre, 138 Foster, Michael, 140 Fritsch, Gustav, 141 Gall, Franz Joseph, 138 Galvani, Luigi, 136–7 Glisson, Francis, 135 Golgi, Camillo, 143 Gowers, William Richard, 140 Greenman, Milton J, 143 Harvey, William, 132 Hitzig, Eduard, 141 King, Helen Dean, 143 Lashley, Karl, 142 Loeb, Jacques, 142 Ludwig, Carl, 140 Magendie, Franc¸ois, 138–9 Malpighi, Marcello, 132 Matteucci, Carlo, 138 Mesmer, Franz Anton, 137–8 Morgagni, Giovanni Battista, 132 Mu¨ller, Johannes, 139 Nansen, Fridtjof, 142 Owen, Richard, 139 Paget, James, 139 Paley, William, 136 Pavlov, Ivan Petrovitsch, 140 Pourfour du Petit, Franc¸ois, 133 Sharpey-Schaefer, Edward Albert, 141–2 Spurzheim, Johann Caspar, 138 Swammerdam, Jan, 134–5 Tyzzer, Ernest Edward, 142 Vesalius, Andreas, 131–2 Volta, Alessandro, 137 von Haller, Albrecht, 135–6 von Helmholtz, Hermann, 140 Whytt, Robert, 136 Wilks, Samuel, 139 Willis, Thomas, 132–3 animal hybrids, experimentation, 143 Animal Locomotion (Muybridge), 294, 294 ‘animal magnetism’, 110–11 German-speaking countries, 670, 672 ‘animal soul’, Willis, Thomas, 99–101 ‘animal spirits’ 17th Century, 92–3 Willis, Thomas, 96 animists, German-speaking countries, 669–70 Annali Frenopatici Italiani, 730

anterior eye chamber model, neural transplantation, 886–8, 895–6 anterograde tract tracing, 164–5 anticholinesterases, Alzheimer’s disease, 876 anticonvulsants, 319–20 epilepsy therapy, use in, 396 Merritt, Houston, 609 Putnam, Tracy, 609 United States, 609 antidiuretic hormone (ADH) see vasopressin antilocalizationist tendencies language, 578–9 Lashley, Karl, 173–4 anti-phrenology views, Flourens, Marie-Pierre, 583–4 antiseptic techniques, 191–3 carbolic acid, 192–3 Horsley, Victor, 197 von Bergmann, Ernst, 312 anti-vivisectionist movements, 141 20th Century, 144 Bennett–Godlee case, 196 Antoni, Nils, 659, 659 aphasia, 571–82 16th Century, 572 19th Century see nineteenth Century acquired childhood see acquired childhood aphasia Alalia 635 Ancient Egypt, 571 Aphemia 635 assessment, 235–41 20th Century, 236–7 word fluency tests, 240 see also specific tests case descriptions, 572–3 causes of, 573 clinical approach, 579 cognitive assessment Broca, Auguste, 235–6 Dejerine, Joseph Jules, 237 De Renzi, Ennio, 241 Goodglass, Harold, 239–40 Kaplan, Edith, 239–40 McBride, Katherine, 239, 240 Marie, Pierre, 236–7, 642 Moutier, Franc¸ois, 237 Thurstone, Louis, 240 Trousseau, Armand, 236 Vignolo, Luigi, 241 Weisenburg, Theodore, 239, 240 Wilson, Samuel A Kinnier, 239 Edwin Smith Surgical Papyrus, 572 neurological examinations, 215–16 rehabilitation see aphasia rehabilitation Renaissance, 572 workers in Alajouanine, The´ophile, 643 Aristotle, 571 Bouillaud, Jean-Baptiste, 584 Broca, Auguste, 560 Broca, Paul, 190–1, 215, 583, 585

915 aphasia (Continued) Charcot, Jean-Martin, 590 Crichton, Alexander, 573 Dejerine, Joseph Jules, 583 Descartes, Rene´, 571 De Vigo, Giovanni, 572 Galen, 571 Gesner, Johann, 573 Head, Henry, 596–7 Hughlings Jackson, John, 571, 623, 843 Jakobson, Roman, 573 Kozhevnikov, Alexei Yakolevich, 739 Lichtheim, Ludwig, 215–16 Lordat, Jacques, 584, 635 Alalie, 635 McBride, Katherine, 579 Magendie, Franc¸ois, 215 Morgagni, Giovanni Battista, 572–3 Pick, Arnold, 571 Rommel, Peter, 572 Schmidt, Johann, 572 Schuell, Hildred, 579 Steinthal, Chaim, 571 Trousseau, Armand, 635 Weisenburg, Theodore, 579 Wepfer, Johann Jakob, 572 Wepman, Joseph, 579 Wernicke, Carl, 215, 583, 587 see also agraphia; alexia; neurolinguistics Aphasia: A Clinical and Psychological Study (Weisenburg & McBride), 579 Aphasia and kindred disorders of speech (Head), 238, 578, 625 aphasia rehabilitation, 856–8 16th Century, 856 17th Century, 856 19th Century, 856 Bastian, Henry Charlton, 857 Broadbent, William, 857 Broca, Paul, 856–7 Edwin Smith Surgical Papyrus, 856 Franz, Shepherd Ivory, 857 Froeschels, Emil, 857 Goldstein, Kurt, 857 Gutzmann, Hermann, 857 Hippocrates, 856 Hun, Thomas, 856 Luria, Aleksandr, 857–8 Mills, Charles K, 857 Osborne, Jonathan, 856 Poppelreuter, Walther, 857 Wepman, Joseph, 857 World War I, 857 World War II, 857 aphemia see aphasia apomorphine, Parkinson’s disease therapy, 509 apoplexy 17th Century, 102 definition, 401 diminution of, 412 early concepts, 402–3

916 apoplexy (Continued) Hippocratic writings, 52, 402 mechanisms, 408 pathology, 405–9 embolism, 408 thrombosis, 408 re-classifications, 408 vascular origins, 403–5 workers in Abercrombie, John, 406–7 Andral, Gabriel, 407 Aretaeus, 56 Baillie, Matthew, 406 Bayle, Franc¸ois, 405 Bonet, The´ophile, 405 Cooke, John, 406 Cullen, William, 406 Fernel, Jean, 403 Galen, 402–3 Hall, Marshall, 619 Harvey, William, 403 Kirkes, William, 408 Kirkland, Thomas, 402 Lower, Richard, 404 Magendie, Franc¸ois, 407 Mistichelli, Domenico, 405 Morgagni, Giovanni Battista, 405 Nymann, Gregor, 404 Portal, Antoine, 406 Rokitansky, Carl, 407 Rostan, Le´on, 407 van Swieten, Gerard, 408 Vesalius, Andreas, 403 Wepfer, Johann Jakob, 403, 404–5 Willis, Thomas, 403–4 see also stroke apraxia, Liepmann, Hugo, 597 Aprison, M, 879 Aquinas, Thomas, 87 Arabic/Islamic period, 64–70 anatomy, 68 animal studies, 131 brain, ideas of, 65, 66 cataracts, 70 clinical applications, 69–70 dissection, 65 eye, structure of, 66 fevers, 69 France, influences on, 629 Galenism, criticism of, 70 headache, 378 hospitals, 305 hydrostatic models, 68–9 light/vision developments, 70–3 nerves, 66 sensory nerves, 69 pineal gland, 66–7 sources, 67 translations, 64–6 venesection (bloodletting), 69 ventricular localization, 67–8 vermis, 66–7 see also Galenism; specific people Arago, Franc¸ois, 289

INDEX Aranzio, Giulio Cesare, 152 Archivio Italiano per le Malattie Nervose e più particolarmente per le Alienazioni Mentali, 730 Archivio per l’Antropologia e la Etnologia, 730 Aretaeus the Cappadocian, 55–6 headache, 377 Argentina, 801–2 Argyll-Robertson, Douglas, 218 Aristotle animal studies, 129 aphasia, 571 brain vs. heart controversy, 55, 272–3 De somniis, 491–2 developmental disorders, 496 motion aftereffect, 491–2 senses, 489–90 disorders, 491–2 sleep, 547 strabismus, 498 Arling, Phillip, 429 Army Alpha and Beta tests, 239, 240 Arnaud, Marcel, 653 Arnold, Friedrich, 677 Arnold, H, 889 Arnold of Villanova, 391 Arquivos de Neuropsiquiatria, 804 Arriagada, Joaquin Luco, 807 art, anatomical studies, 149–52 arteriosclerosis, Bayle, Franc¸ois, 405 ascending functions, Willis, Thomas, 97 āipu, Mesopotamia, 18–19 Asklepios, 49–50 Greco-Roman World, 304–5 Asperger, H, 321, 328 Assyrian-Babylonian culture, epilepsy, 388 asterixis, 528–9 astronomical observations, Gassendi, Pierre, 93–4 Astvatsaturov, Mikhail Ivanovich, 746 asû, Mesopotamia, 18–19 asylums, Italy, 723 atavistic (primitive) reflexes, 226 Athenae Oxonienses (Wood), 281 atherosclerosis, Cerletti, Ugo, 729 athetosis, 520–2 Carpenter, Malcolm, 522 Charcot, Jean-Martin, 521 Gowers, William Richard, 521, 522 Hammond, William A, 501, 520, 521, 522 lesions, 520 Mitchell, Silas Weir, 520–1 Atlas des Peripherischen Nervensystems des Menschlichen Körperes (Ru¨dinger), 290 Atlas of Truth, 760 attention deficit hyperactivity disorder (ADHD), 324–5 Aubertin, Simon Alexandre Ernest, 121 Aulus Cornelius Celsus, 376–7 aura, migraine, 379

Australasian Medical Gazette, 783 Australia, 781–92 anatomy, 783 Australasian Medical Gazette, 783 Australian Association of Neurologists (AAN), 791–2, 794, 795, 797 Australian Medical Association (ASA), 782 Australian Medical Journal, 783 Australian Neurological Foundation, 797–8 clinical neurology, 793–5 communication difficulties, 781–2 encephalitis lethargica, 784–5 historical background, 781 Intercolonial Medical Journal of Australasia, 783 medical schools, 782 multiple sclerosis, 783 neuropathology, 785 neurosurgery, 788–9 poliomyelitis, 784 pre Second World War, 782–5 Royal Australian College of Physicians (RACP), 782, 789, 794 Royal Perth Hospital, 788 universities, 796–8 Flinders University (Adelaide), 797 Melbourne University, 796 Sydney University, 796 Australian Association of Neurologists (AAN), 791–2, 794, 795, 797 Australian Medical Association (ASA), 782 Australian Medical Journal, 783 Australian Neurological Foundation, 797–8 Austrege´silo and Eposel sign, 804, 804 Austria see German-speaking countries autistic-like behaviors, child neurology, 321, 328 autografts, 886 “automatic activities”, 17th Century, 97–8 autonomous nervous system, 335 17th Century, 98 autopsy studies Charcot, Jean-Martin, 206 Galen, 56 tuberculous meningitis, 423 Wernicke’s encephalopathy, 449–50 autoradiography, neural transplantation, 894 autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), 366 autosomal recessive juvenile parkinsonism (AR-JP), 775 Avicenna, 67–8 animal studies, 131 headache, 378 ventricular localization, 67–8 writings, 67 Avis au Peuple sur la Santé (Tissot), 379 axon sprouting, neural transplantation, 893

INDEX

B Babinski, Joseph Felix, 224, 639–40 cerebellar examination, 228 Babinski extensor toe reflex, 224–5, 640 Babinski–Fro¨hlich syndrome, 347 Babylonia, epilepsy, 389 Backlund, E O, 901 Bacon, Francis, 132 bacterial meningitis, 417–33 17th Century, 417–18 therapy, 428–9 18th Century, 420 therapy, 428–9 19th Century, 418–19, 420 therapy, 429 20th Century, 428 therapy, 429–30 Ancient Egypt, 417 bacterial etiologies, 426–7 cerebrospinal fluid examination, 423–6 clinical signs, 427 clinical subtypes, 421–3 France, 421 Greco-Roman World, 417 Haemophilus influenzae, 427 Kernig’s sign, 427, 427 Listeria, 427 meningococcal, Africa, 821 Mycobacterium tuberculosis, 427 Neisseria meningitidis, 426 Neolithic skeletons, 417 Streptococcus pneumoniae, 426 therapy, 428–30 17th Century, 428–9 18th Century, 428–9 19th Century, 429 20th Century, 429–30 Cooke, John, 428 Domagk, Gerhard, 429 Finland, Maxwell, 429 Flexner, Simon, 429 immunotherapy, 428 Jochmann, Georg, 429 Keefer, Chester, 429 narcotics, 428 North, Elisha, 428 penicillin, 429–30 Rosenberg, David, 429 Schwentker, Franc¸ois, 429 stimulants, 428–9 sulfachrysoidine, 429 sulfanilamide, 430 vaccines, 430 Whytt, Robert, 428 Willis, Thomas, 428 workers in Abercrombie, John, 420 Arling, Phillip, 429 Brudzinski, Josef Polikarp, 427 Cheyne, John, 419–20 Coindet, Jean-Franc¸ois, 420 Cullen, William, 419 Fothergill, John, 419

bacterial meningitis (Continued) Fraenkel, Albert, 426 Guersent, Louis, 421 Herpin, Franc¸ois, 420 Kernig, Vladimir, 427 Koch, Robert, 427 McBride, David, 419 Merritt, Houston, 428 Neufeld, Friedrich, 426 Nyfeldt, A, 427 Odier, Louis, 420 Pasteur, Louis, 426 Pfeiffer, Richard, 427 Rolleston, Humphrey, 428 Sternberg, George, 426 therapy see above Villemin, Jean-Antoine, 427 Weichselbaum, Anton, 426 Whytt, Robert, 418–19 Willis, Thomas, 417–18 Baelz, Erwin, 771–2 Baelz, Erwin Otto Eduard von, 771–2, 772 Baer, Karl Ernst von, 163, 677 Baginsky, Adolf, 576, 576 Baglivi, Giorgio, 155 Baillarger, Jules Gabriel Franc¸ois, 633 cerebral cortex studies, 165 language comprehension localization, 575 Baillie, Matthew, 406 Balinsky, Ivan Mikhailovich, 742 Ballance, Charles A, 199 ballism, 522–4 animal studies, 523 therapies, 523 Bangladesh, lathyrism, 816 Banting, F, 348 Ba´ra´ny, Robert cranial nerve VIII (acoustic-vestibular nerve), 220 nystagmus, 495 Ba´ra´ny chair, 495 Barbeau, Andre´ movement disorders, 502 progressive supranuclear palsy, 515 Barger, George, 872 Bargmann, Wolfgang, 339 Barlow, Thomas brain function localization, 845 language and cognitive development, 848 vicariation, 836–7 Barraquer-Roviralta, Lluis, 524 Barre´, Jean-Alexander, 642 University of Strasbourg, 650–1 Barrough, Philip, 614 Barthez, Paul-Joseph, 648 Bartholin, Caspar, 658 Bartholin, Thomas the elder, 658 Bartisch, G, 498 Bartolomaeus Anglicus, 614

917 basal arteries, Willis, Thomas, 281 basal ganglia, 501–3 animal studies, 502 balance of firing rates, 502 disorders, Mesopotamia, 24 Ferrier, David, 501 Fritsch, Gustav, 501 function models, 502–3 Hitzig, Eduard, 501 pharmacology, 502 Piccolomini, Francesco, 501 positive feedback models, 502–3 surgery, 502 Vesalius, Andreas, 501 Willis, Thomas, 501 Basics of Cerebral Functions Doctrine (Bekhterev), 745 Bastian, Henry Charlton agraphia, 587, 588, 589–90, 590 alexia, 587 aphasia rehabilitation, 857 cerebral dominance, 837 language comprehension localization, 576 On Paralysis from Brain Disease in its Common Forms, 846 Bateman, Frederick, 585 Batten, Frederick Eustace, 625 Batten–Spielmayer–Vogt’s disease, 664 Bayle, Antoine, 645 Bayle, Franc¸ois, 405 Bazemore, Alva, 878 Beard, George, 609 jumping, 529–30 writer’s cramp, 526 Beccari, Giacomo Bartolomeo, 721 Becker, Peter, 484 Becker’s muscular dystrophy, 322, 484 Beeson, Kenneth, 789 behavioral neurology Damasio, Antonio, 562–3 frontal lobes, 562–3 Geschwind, Norman, 562 Bekhterev, Vladimir Mikhailovich, 744–5, 745 Basics of Cerebral Functions Doctrine, 745 Conductive Ways of Spinal Cord and Brain, 744–5 hallucinations, 744 higher function localization, 745 Belgian Neurological Institute, 700 Belgian Neurological Society, 693, 695, 696 Belgium, 694–5 Belgian Neurological Institute, 700 Belgian Neurological Society, 693, 695, 696 Bunge Institute (Antwerp), 699–700 Flemish Society of Neuropsychiatrists, 696–7

918 Belgium (Continued) Oto-Neuro-Ophthalmological Group, 699 universities, 705–9 Universite´ Catholique de Louvain La Neuve, 706 University of Antwerp, 709 University of Brussels, 708–9 University of Ghent, 706–7 University of Lie`ge, 707–8 University of Louvain, 705–6 Bell, Charles, 618–19 The Anatomy of the Brain, explained in a series of engravings, 271, 283 animal studies, 138 cranial nerve VII (facial nerve), 219–20 Engravings of the Arteries and the Nerves of the Brain, 618 Essays on the Anatomy of Expression in Painting, 283, 618 An Idea of a New Anatomy of the Brain, 283, 619 illustrations, 283 phantom limbs, 494 redundancy theory, 835 senses, 492 A System of Dissection Explaining the Anatomy of the Human Body, 283, 618 writer’s cramp, 525 Bell, J R, 463 Bell’s palsy, Ancient Egypt, 33–4 Belmondo, Ernesto, 724 Benabid, Alim Louis, 508 Bender, Lauretta, 245 Bender Gestalt Test, 245 Benedikt, Moritz, 586 Bennett–Godlee case, 196–7 Ben-Yishay, Yehuda, 860 Benzi, Ugo, 83 benzodiazepines, epilepsy therapy, 397 Berengario, Jacopo, 151 Bergamini, Lodovico, 730 Bergen, C A von, 437 Berger, Hans, 685 animal studies, 140 EEG, 181, 395 frontal lobes, 561 pediatric epilepsy, 320 sleep, 547 Bergin, John Daniel, 793 Bergmann, Ernst von, 199, 312 beriberi 19th Century, 445 Brontius, Jacobus, 445 Chao Yen-feng, 763 Eijkman, Christiaan, 445–6 Takaki, Kanehiro, 446 traditional Chinese medicine (TCM), 763–4 Vorderman, Adolphe, 447 Berlin Medical Papyrus, 30, 33–4 Berlucchi, Carlo, 728

INDEX Bernard, Claude, 346 animal studies, 138 experimental medicine, 633–4 Besta, Carlo, 727, 727 b2-adrenergic receptors, 365 Beta examination, 242 Bianchi, Leonardo frontal lobes, 561, 725 localization theory, 124 neuropathology, 725 Bianchini, Marco Levi, 729 The Bible, 37–41 acromegaly, 39–40 epilepsy, 40 hand dominance, 40 head injuries, 38–40 penetrating head injuries, 39 history of, 37–8 languages, 37–8 macroadenoma, 39 peripheral nerve injury, 38 physicians, 38 right hand paralysis and speech, 40 sciatic nerve neurapraxia, 38 see also The Talmud Bichat, Marie Franc¸ois Xavier, 632 animal studies, 140 peripheral nervous system (PNS), 346 redundancy theory, 834 Biemond, A, 715, 715 Brain Diseases, 715 Diseases of the Spinal Cord and the Peripheral Nervous System, 715 Municipal University of Amsterdam, 703 Biffi, Serafino, 723 bilingualism, the Low Countries, 692–3 Binet, Alfred intelligence tests, 241 memory assessment tests, 244, 244 mental status examinations, 215 binocular vision, 497 biochemical fermentation doctrine, 17th Century, 92 biomembranes, 362–3 proteins see membrane proteins Birkmayer, W, 508–9 Bitot, Pierre, 437 Bjo¨rklund, Anders, 896 Black Death, hospitals, 306 black reaction, Golgi, Camillo, 161 blacktongue, 455 Blaschko, Hermann, 873 Blasius, Gerard, 154 Blessed, Garry, 250–1 Bleuler, Eugene, 681 childhood autistic-like behaviors, 321 blindsight, 178 Bloch, Carl E, 437–8 Block, Felix, 264 Block-design test, 247 Blocq, P, 507 blood–brain barrier (BBB), 17th Century, 98–9

blood oxygen level dependent (BOLD) contrast, magnetic resonance imaging (MRI), 264–5, 266 Blood Vessels of Human Spinal Cord (Die Blutgefasse desmenschlichen Ruckenmarke) (Adamkiewicz), 749 Blumenau, Leonid Vasil’evich, 746–7 Blumenbach, J F, 676–7 body–soul problem, German-speaking countries, 669 Boerhaave, Hermann, 107 University of Leiden, 700 University of Nijmegen, 704 Bogaert, Ludo van, 514, 713, 713–14 Bogen, Joseph, 597–8 Bolis, Liana, 824 Bolivia, 809 Neolithic trepanation, 5, 8 Boll, Franz, 438 Bolsi, Bernardino, 725 Bonet, The´ophile, 405 Bonfiglio, Francesco, 724 Bonhoeffer, Karl, 577 Bonnet, Charles, 156 Bontius, Jacobus, 437 Book of Optics (al-Haytham, Ibn), 272 Booth, C C, 466 Bordeaux (France), 649–50 Borelli, Giovanni Alfonso animal studies, 134 De Motu Animalium, 134 neurotransmitters, 869 Borsieri, Giovanni Battista, 721 Bosch, Hieronymous, 285 Boston Diagnostic Aphasia Examination, 240 botulinum toxin, writer’s cramp, 526 Bouillaud, Jean-Baptiste, 120, 574, 634 animal studies, 140 aphasia, 584 speech localization, 560, 573–4 Bouman, Leendert, 701 Bourneville, De´sire´-Magloire, 291–3 Bovet, Daniel acetylcholine, 874–5 glycine, 879 Bowditch, Henry Pickering, 224 Boyle, Robert, 281 brachial plexus, Leonardo da Vinci, 151 brain 17th Century, 97–8 abscesses, Mesopotamia, 23 Arabic/Islamic period, 65, 66 blood circulation, 258 damage see brain damage functional imaging see functional brain imaging Galenic function theories, 57, 57 Galenism, 62–3 heart controversy vs. Alderotti, Taddeo, 83–4 anatomical studies, 149 European Middle Ages, 83–4 Greco-Roman World, 54–5

INDEX brain (Continued) Mesopotamia, 20 The Talmud, 43 tumors see brain tumors ventricles 17th Century, 97 Arabic/Islamic period, 67–8 da Vinci, Leonardo, 274 Galenism, 63–4 Willis, Thomas, 97 Brain, Russell, 824 brain damage children see child neurology cognitive rehabilitation, 860 Gall, Franz Joseph, 118–19 Brain Diseases (Biemond), 715 brainstem reticular formation, 175 brain tumors Africa, 822 Cox, Leonard Bell, 790 EEG, 183 frontal lobes, 563 Macewen, William, 195 Mesopotamia, 23 Bramwell, B, 513 Brazil, 802, 804–5, 817, 821 Brazilian Society of Neurosurgery, 821 Breasted, James, 30 Breinl, Anton, 785 Bremer, Fre´de´ric, 174 lesion-EEG studies, 174 University of Brussels, 708–9 Breuer, Joseph, 495 Breughel, Peter, 285 brewer’s yeast, pellagra treatment, 455 Bright, Richard, 619 Brissaud, E, 507 Bristol Royal Infirmary, pediatric epilepsy, 319, 320 British anti-lewisite (BAL), Wilson’s disease therapy, 513 Broadbent, William H, 623–4 aphasia rehabilitation, 857 striatal dysfunction, 501 Sydenham’s chorea, 517 Broca, Auguste aphasia, 235–6, 560 brain function localization, 844 surgical neurology, 199 Broca, Paul, 574, 634–5 ancient trepanation, 3–4, 9–10 animal studies, 140 aphasia, 190–1, 215, 583 rehabilitation, 856–7 aphemia, 585 cerebral dominance, 835–6 childhood brain damage, 322 cortical localization, 121–2 language, 121 Société d’Anthropologie de Paris, 4 speech, 4 localization, 574–5 loss studies see above, aphasia surgical neurology, 189

Broca, Paul, (Continued) cadaver studies, 190 Broca’s aphasia, focal injury identification, 236 Brodal, Alf, 661 Brodmann, Korbinian, 684–5 cerebral cortex studies, 165 functional brain imaging, 257 bromocriptine, Parkinson’s disease therapy, 510 Brontius, Jacobus, 445 Brouillet A, 637 Painting of Charcot’s lecture, 638 Brouwer, Bernardus, 714, 714–15 Central Institute for Brain Research (Amsterdam), 698 Municipal University of Amsterdam, 703 Netherlands Study Club for Neurosurgery, 699 neurosurgery, 696, 714 Brown, Alexander Crum, vertigo, 495 Brown, Christy, 328 Brown, James Crichton, 141 Brownell, Gordon, 260 Brown-Se´quard, Charles-E´douard, 622, 640 analysis of movement, 293 animal studies, 139–40, 621 cranial nerve VIII (acoustic-vestibular nerve), 220 epilepsy, 622 Queen Square Hospital, 310, 621 sensory defects, 622 Bru¨cke, Ernst Wilhelm von, 673–4 Brudzinski, Josef Polikarp bacterial meningitis, 427 meningismus, 229 Brugnoli, Giovanni, 722 Bruyn, George W, 700–1 Buchthal, Fritz, 663 electromyography, 183 Buck, Pearl, 328 Buckland, A W, 11 Budd, George, 437 bulbospinal muscle atrophy, 774 Bulow, K, 550 a-bungarotoxin, 875 Bunge Institute (Antwerp), 699–700 Burckhardt, Gottlieb, 683 Burdach, Karl Friedrich, 677 Burke, William, 793 Burkitt, Denis Parsons, 821–2 Burkitt’s lymphoma, 821–2 Burns, Richard John, 797 Burns, R S, 512 Busch, Herman, 704 Butzke, Victor, 160

C

C14-deoxyglucose autoradiography, functional brain imaging, 258–9 Cabanis, Pierre-Jean, 631–2 CACNA1A gene mutations, 366 CACNL1A3 gene mutation, 366 Caemaert, J, 707

919 Caffe´, J, 552 CAG trinucleotide repeat, Huntington’s disease, 519 Cairns, William Bell, 788 Cajal, Santiago Ramo´n y, 893–4 illustrations, 284 neural transplantation, 888 neuron doctrine, 162–3 neuron visualization, 159 spinal cord regeneration, 891–2 Textura del Sistema Nervioso del Hombre y los Vertebrados, 163 Calcar, Jan von, 477, 478 Caldani, Leopoldo, 111 Calear, Jan Stefan van, 275 Callot, Jacques, 285 Cambyses II of Egypt, 33 Campbell, Alfred Walter, 625–6, 785, 786, 786–7 Canadian Neurological Society, 610 Canani, G B muscular dystrophy, 477, 478 Musculorum Humani Corporis Picturata Dissecto, 477, 478 cancer therapy, folate antagonists, 459 Canfield, Ralph, 523 Cannon, Walter Bradford, 609 adrenalin, 872 Capello, Giovanbattista, 380–1 Caramazza, Alfonso, 579 CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy), 775 carbamazepine, epilepsy therapy, 397 carbolic acid, antiseptic techniques, 192–3 carbon monoxide poisoning, 762 Cardano, Gerolamo, 719–20 Caribbean, 810–11 Carlsson, Arvid, 663 L-DOPA, 508 neural plasticity, 180 carotid artery studies Chiari, Hans, 410 Fisher, Charles Miller, 410 Moniz, Egas, 410 Ramsay-Hunt, J, 410 stroke, 410 carotid endarterectomy (CEA), 411 carotid surgery, 411 Carpenter, Malcolm, 522 Carrel, Alexis, 651 Carver, George Washington, 456 Casa`l, Gaspar, 452 cassava, tropical neurology, 817–18 Casserio, Giulio anatomical studies, 152 illustrations, 282 Castle, William B, 465 Castro, Pedro B, 808 Casualty Clearing Stations (CCSs), World War I, 312 catalepsy, 391 cataracts, Arabic/Islamic period, 70

920 catecholaminergic system central grafting, 896–7 catechol-O-methyltransferase (COMT) inhibitors, Parkinson’s disease therapy, 509 Catholic University School of Medicine (Chile), 808 Caton, Richard EEG, 181 narcolepsy, 549 Cautley, Edmund, 845–6 cell identification, neural transplantation, 893 cell sources, neural transplantation, 904 “cell theory”, 157 Celsus, 55 Ceni, Carlo, 727 Central America, 809–10 Central Institute for Brain Research (Amsterdam), 698 “centrecephalic” seizures, epilepsy, 396 Centre National de la Recherche Scientifique (CNRS), 647 cerebellum 17th Century, 97–8 examination, 228–9 grafts, 894–5 cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), 775 cerebral cortex Baillarger, Jules Gabriel Franc¸ois, 165 Brodmann, Korbinian, 165 convolution studies, Willis, Thomas, 153 cytoarchitectural subdivisions, 174 Gall, Franz Joseph, 583 lamination/architecture, 165–6 Lashley, Karl, 142 localization studies Broca, Paul, 121–2 Exner, Sigmund, 589 Gall, Franz Joseph, 118 Mesulam, M-M, 564 Meynert, Carlo, 165 myeloarchitectural subdivisions, 174 organization, 172 spreading depression, 367 subcortical nuclei vs., 501–2 Swedenborg, Emmanuel, 117–18 Vogt, Oskar, 165 von Economo, Constantin, 165 white matter vs., 501–2 cerebral dominance, 122–3, 835–6 Bastian, Henry Charlton, 837 Broca, Paul, 835–6 Dax, Gustave, 835 Dax, Marc, 835 Gowers, William Richard, 837 Hughlings Jackson, John, 122–3 right hemisphere, 122–3 Taylor, James, 837

INDEX cerebral malaria Cerletti, Ugo, 729 child neurology, 326–7 Mesopotamia, 25 Cerebral Palsies of Children (Osler), 846–7 cerebral palsy (Little’s disease), 321–2 Mesopotamia, 24 cerebral paralysis, infantile, 846–7 “cerebral sleep substance”, Japan, 773 cerebral vs. cardiac controversy see brain, heart controversy vs. Cerebri Anatome (The Anatomy of the Brain) (Willis) see Willis, Thomas cerebrospinal fluid (CSF) bacterial meningitis, 423–6 Corning, James Leonard, 423 Morton, Charles, 423 Quincke, Heinrich, 423–4 Wynter, Walter, 423 cerebrovascular accident (CVA), 401 cerebrovascular disease (CVD), 401–15 carotid surgery, 411 Cooke, John, 401 Foix, Charles, 409–10 Galen, 401 Greco-Roman World, 402 International Classification of Disease (ICD), 401 Japan, 775 Scandinavia, 663 vascular anatomy, 409–10 see also apoplexy; stroke Cerletti, Ugo, 728–9 cervical spinal cord injuries, Ancient Egypt, 32 Cestan, Raymond, 649 Chagas’ disease Argentina, 802 Brazil, 804 tropical neurology, 818 Chandy, Jacob, 819 Chang, C C, 875 Chang Ching-yua, 762 Chao Yen-feng, 763 Charcot, Jean-Martin, 203–12, 204, 635–40, 638 agraphia, 590 amyotrophic lateral sclerosis identification, 207–9, 210, 637 anatomo-clinical method, 203, 205–7 animal studies, 140 aphasia, 590 athetosis, 521 autopsy studies, 206 clinical documentation, 205–6, 206, 207, 637 disorder identification, 203 see also specific diseases/disorders epilepsy studies, 211 hysteria studies, 211 illustrations, 283–4 international relations, 638 lesion studies, 210 localization theory, 209–10

Charcot, Jean-Martin (Continued) language localization, 576, 634 locomotor ataxia studies, 210 microscopy, 206–7 neurological examinations, 213 neurological lesion vs. clinical presentation, 209 Paralysie pseudo-hypertrophique, 140 Parkinson’s disease, 210–11, 503, 503, 506, 637 multiple sclerosis vs., 207, 210 photography, 291–3 Salpeˆtrie`re Hospital see Salpeˆtrie`re Hospital stroke studies, 209 teaching, 636 word blindness, 590 Charcot-Marie-Tooth disease type 2 (CMT2), 367 Charcot’s disease see amyotrophic lateral sclerosis (ALS) Chase, Walter Greenough, 297 Chauliac, Guy de, 648 Chaussier, Franc¸ois, 559 The Chemical Constitution of the Brain (Thudichum), 361 chemical neuroanatomy, 175 Chen Yeng, 763 Cheyne, John, 419–20 Chiari, Hans, 410 child neurology, 317–34 antenatal screening, 325 aphasia, Gowers, William Richard, 848 attention deficit hyperactivity disorder (ADHD), 324–5 autistic-like behaviors, 321, 328 brain damage, 322–9 Andre´-Thomas, A, 324 Broca, Paul, 322 Dax, Marc, 322 Griffiths, Ruth, 324 Kennard, Margaret, 324 Sachs, Bernard, 324 Saint-Anne Dargassies, S, 324 Soltmann, Otto, 322–4 Willis, Thomas, 324 breathing disorders, sleep medicine, 551 cerebral malaria, 326–7 cerebral palsy (Little’s disease), 321–2 changes in attitudes, 327–9 epidemiological changes, 325–7 epilepsy, 319–21 hospitals, 329–30 infantile cerebral paralysis, 846–7 infantile hemiplegia, 846–7, 847 interventions, 325–7 gastrostomies, 326 malnutrition, 818–19 mental retardation, 317–19 Mesopotamia, 24 muscle disorders, 322 neurological societies, 329 neuromuscular conditions, 321–2 see also specific diseases/disorders

INDEX child neurology (Continued) prevention, 325–7 seizures ancient trepanation, 9–10 Mesopotamia, 21 sulfonamides, 325–6 textbooks/publications, 329–30 workers in Asperger, H, 321, 328 Buck, Pearl, 328 Down, John Langdon, 327–8 Dubowitz, Victor, 322 Duchenne de Boulogne, Guillaume Benjamin, 322 Gowers, William Richard, 322 Johnson, Samuel, 327 Kanner, L, 321 Kolvin, Israel, 321 Locke, John, 327 Meryon, Edward, 322 Se´guin, Edouard, 327 Thelwall, John, 327 Willis, Thomas see Willis, Thomas Wing, Lorna, 321 Chile, 807–8 China, 756–67 Chinese Journal of Neurology and Psychiatry, 766 Chinese Society of Neurology, 766 Christian missionaries, 761–2 dynasties, 756 rehabilitation therapies, 852 see also traditional Chinese medicine (TCM) Chinese Journal of Neurology and Psychiatry, 766 Chinese Society of Neurology, 766 Chipault, Antony, 199 Chizh, Vladimir Fedorovich, 748 chloroform, general anesthesia, 191 cholinergic system central grafting, 896–7 cholinesterase inhibitors, 875–6 Chomsky, Noam, 579–80 choreoathetosis, 516–24 see also specific diseases/disorders Christian missionaries, China, 761–2 chronic frontal sinusitis, The Talmud, 46 Church, Archibald cranial nerve I, 216 neurological examinations, 214 Chu Tan-chi, 763 CICN-1 gene, 366 Ciechanover, Aaron, 511 cinematography, 295–9 Chase, Walter Greenough, 297 France, 296 Marey, E´tienne-Jules, 296 Marinesco, Georges, 297, 298 Matuszewski, Boleslav, 296 movement/gait disorders, 297 Negro, Camillo, 297–8 pioneers in, 297–8 Popesco, Constantin, 297

cinematography (Continued) surgical, 296–7 van Gehuchten, Arthur, 299 Weisenburg, Theodore H, 297 see also illustrations circle of Willis, nomenclature, 341 Cisticercosis Cerebral (Montes), 806 Clark, A, 817 Clarke, R, 352 Cleland, John Burton, 785 Clemente, C D, 892 clinical documentation, Charcot, JeanMartin, 205, 206, 207, 637 The Clinical Examination of the Nervous System (Monrad-Krohn), 660 Clinical Lectures on Paralysis, Disease of the Brain and Other Affections of the Nervous System (Todd), 620 clinical neuroanatomy, German-speaking countries, 677 clinical neurology Australia, 793–5 Denmark, 660 Finland, 659–60 German-speaking countries, 685–6 Iceland, 661 Italy, 723 Norway, 660–1 Scandinavia, 658–61 Scarpa, Antonio, 721 Sweden, 658–9 Clinical Neurology in Relation to Neuroanatomy (Brodal), 661 clinical neurophysiology, Scandinavia, 662–3 clinical trials, neural transplantation, 904 Coates, Albert, 788 cognitive assessment, 235–56 19th Century, 235 aphasia see aphasia, assessment dementia, 250–2 executive functions, 248–50 Gall, Franz Joseph, 235 Geschwind, Norman, 252 intelligence tests see intelligence tests Luria, Aleksandr, 235 memory, 243–4 Nielsen, J M, 252, 252 Piercy, Malcolm, 252 visuoconstructive skill tests, 244–7 visuospatial skill tests, 244–7 cognitive development, language, 847–8 cognitive manifestations, pellagra, 457–8 cognitive rehabilitation, 858–61 Ben-Yishay, Yehuda, 860 brain injury, 860 Diller, Leonard, 860 efficacy assessment, 860 Franz, Shepherd Ivory, 858 Goldstein, Kurt, 858 Luria, Aleksandr, 859–60 models, 860 Poppelreuter, Walther, 858–9 Russell, W Ritchie, 859

921 cognitive rehabilitation (Continued) World War I, 858–9 World War II, 859 Yom Kippur War, 860 Zangwill, Oliver, 859 Coindet, Jean-Franc¸ois, 420 Collier, James Stansfield Babinski extensor toe reflex, 224 Queen Square Hospital, 621 Collin, R, 338 Colombia, 809 Colombo, Realdo anatomical studies, 152 cranial nerve IV (trochlear nerve), 218 color blindness, Quaglino, Antonio, 722 Color Cubes test, 247 Color Form Sorting Test, 248, 248–9 color vision Gowers, William Richard, 217 Newton, Isaac, 492 testing of, 217 Young, Thomas, 492 coma, Mesopotamia, 21 community-based studies, Africa, 824 comparative anatomy 17th Century, 99–100 Gall, Franz Joseph, 118 Vicq-d’Azyr, Fe´lix, 631 Willis, Thomas, 99–100 Comparetti, Andrea, 720 compensated hydrocephalus, Ancient Egypt, 34 compensatory behaviors, recovery of function, 833 comportment, 566 orbitofrontal circuits, 565 compressive myelopathy secondary to calcified ligaments in the spinal canal, Japan, 776 computed tomography (CT), 259 epilepsy studies, 398 frontal lobes, 563 Parkinson’s disease, 508 stroke, 412 concentration camp syndrome, 665 conduction aphasia, Wernicke, Carl, 215 conductive hearing loss, Rinne, Heinrich, 220–1 Conductive Ways of Spinal Cord and Brain (Bekhterev), 744–5 connexins, 367 conscious activities, 17th Century, 97–8 Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), 251–2 Conte, Gaetano, 477, 479 continuous positive airway pressure (CPAP), obstructive sleep apnea syndrome (OSAS) treatment, 550–1

922 contralateral hemiballismus, Martin J P, 523 contre-coup injuries, Ancient Egypt, 32 Controlled Oral Word Association Test, 240 Cooke, John, 618 apoplexy, 406 bacterial meningitis therapy, 428 cerebrovascular disease, 401 A Treatise on Diseases of the Nervous System, 401, 618 copper deposition, Wilson’s disease, 513 Cormack, Alan computed tomography (CT), 259 positron emission tomography (PET), 260 corneal ulceration, Magendie, Franc¸ois, 437 Corning, James Leonard, 423 corpus callosum, Sperry, Roger Wolcott, 176–7 Corti, Alfonso, 722 cortical epilepsy surgery, Horsley, Victor, 197 cortico-basal ganglionic degeneration, 516 corticotropin-releasing hormone (CRH), 336 early work, 341 Coryell, Charles, 264 Cotard, Jules, 844 Cotugno, Domenico, 721 anatomical studies, 155, 721 cranial nerve VIII (acoustic-vestibular nerve), 220 Cotzias, G C, 509 Cox, Jerome, 260 Cox, Leonard Bell, 790, 790 Australian Association of Neurologists (AAN), 792 cranial defects, ancient trepanation vs., 6 cranial nerve(s) 17th Century, 98 Galen, identification by, 56 Herophilius, 53 Leonardo da Vinci, 150, 151 Willis, Thomas, 153, 281 see also specific cranial nerves cranial nerve I (olfactory nerve), 216 cranial nerve II (optic nerve) Alcmaeon of Crotona, 50–1 examination, 216–17 see also specific tests Leonardo da Vinci, 150 cranial nerve III (oculomotor nerve), 217–18 cranial nerve IV (trochlear nerve), 218–19 cranial nerve V (trigeminal nerve), 219 cranial nerve VI (abducens nerve), 219 cranial nerve VII (facial nerve), 219, 219–20 cranial nerve VIII (acoustic-vestibular nerve), 220–1

INDEX cranial nerve IX (glossopharyngeal nerve), 221 cranial nerve X (vagus nerve), 221 cranial nerve XI (accessory nerve), 221–2 cranial nerve XII (hypoglossal nerve), 222, 222 craniotomies, Horsley, Victor, 197 craniovertebral anomalies, India, 820 Creutzfeldt–Jakob disease (CJD), 368 Crevel, H van, 703, 704 Crichton, Alexander aphasia, 573 attention deficit hyperactivity disorder (ADHD), 325 An Enquiry into the Nature and Origin of Mental Derangement, 325 Critchley, McDonald essential tremor, 505 language antilocalizationist theories, 578–9 primitive (atavistic) reflexes, 226 Crocq, Jean J, 694–5 Croone, William, 616 Crothers, Bronson, 329 Cruelty to Animals Act (1876), 139, 141 Cuba, 811 neuropathy (1991), 826 Cube Test, 248 Cullen, William, 109–10, 112, 617 apoplexy, 406 bacterial meningitis, 419 epilepsy, 392 First Lines of the Practice of Physic, 392, 617 Synopsis Nosologicae Methodica, 406 Cummings, J L, 565–6 Curtis, D R, 879 Cushing, Harvey neurohypophysis, 338–9 neuropeptides, 341–2 pituitary gland, 347 surgical neurology, 189, 199–200, 609 cutaneous reflexes, 224–6 abdominal, 226 Babinski extensor toe reflex, 224–5 glabellar reflex, 225 palmomental reflex, 225–6 Cuvier, Georges, 156 cyanocobalamin deficiency, 461–7 see also pernicious anemia Cybulski, Napoleon, 870 cyclotrons, positron emission tomography (PET), 260 Cyclopaedia of Anatomy and Physiology (Todd), 620 cystatin B gene, 528 cysticercosis, Mexico, 810 cytoarchitectural subdivisions, cerebral cortex, 174

D d’Abano, Pietro, 84 D’Abundo, G, 889

d’Acquapendente, Girolamo Fabrici, 152 da Foligno, Gentile, 82–3 daguerreotypes, 289 Dale, Henry Hallet acetylcholine, 875 neurohypophysis, 339 noradrenalin, 872 synapses, 179 d’Almeida, Luis, 769 Dalton, John, 217 Dalton, John Call Jr cerebellar examination, 228 cranial nerve III (oculomotor nerve), 217 cranial nerve X (vagus nerve), 221 cranial nerve XI (accessory nerve), 221 Damasio, Antonio, 562–3 Dana, Charles Loomis, 609 essential tremor, 504–5 spinal cord subacute combined degeneration, 462 d’Angers, Charles Ollivier, 633 da Panicale, Masolino, 284 Darkshevich, Livery Osipovich, 742, 744 Darkshevich’s nucleus, 742 Darwin, Erasmus, 112 vertigo, 495 Das, Gopal, 894–5 David, Marcel, 646 David, S, 900 Davidenkov, Sergei Nikolaevich, 750 da Vinci, Leonardo anatomical studies, 149–51, 150 epilepsy, 391 frontal lobes, 558 illustrations, 273–4 ventricles, 274 Davis, C H Jr, 505 Davis, Hallowell, 183, 395 Davis, Marguerites, 439 Dax, Gustave, 122 cerebral dominance, 835 language localization, 634–5 speech production localization, 575 Dax, Marc, 122 cerebral dominance, 835 childhood brain damage, 322 language localization, 634–5 speech localization, 560 d’Azir, Fe´lix Vicq, 156 Dean, John, 290 De Anima Brutorum (Willis) see Willis, Thomas Debaisieux, George, 695 de Baveriis, Baverius, 83 De Busscher, Jacques, 707 De Catarrhis (Schneider), 153 decerebrate rigidity, Sherrington, Charles Scott, 170 De Cerebri Cortice (Malpighi), 154 De Cerebro (Malpighi), 154 de Chauliac, Guy, 648 De Dissectione Partium Corporis Humani Libri Tre (Estienne), 278

INDEX deep brain electrical stimulation, 508 De Externo Tactus Organo (Malpighi), 154 De Generatione (Harvey), 616 degenerative CNS diseases, Japan, 773–5 De Giovanni, Achille, 725–6 De Humani Corporis Fabrica see Vesalius, Andreas dei Lucci, Mondino 131 Deiters, Karl, 158, 160 deities see religion Dejerine, Joseph Jules, 640–1, 641 aphasia, 583 cognitive assessment, 237 collaborations, 641 language, antilocalizationist theories, 578 multisystem atrophy (olivo-pontocerebellar degeneration), 514 muscular dystrophy, 477 neuropsychology, 641 pure alexia, 593 pure word blindness, 592–3, 594–5 Sémiologie des Affections du Système Nerveux, 237, 641 Traité d’Anatomie des Centres Nerveux, 641 word blindness with agraphia, 591–2 de La Mettrie, Julien Offray, 630 Delay, Jean, 645–6 del Castillo, J, 878 Del Conte, G, 889 De l’Electrisation Localisée et son Application ¼ la Pathologie et ¼ la Thérapeutique (Duchenne de Boulogne), 140 De l’Homme (Descartes), 134 De Lingua (Malpighi), 154 delirium, 17th Century, 103 De Lisi, Lionello, 729 Delprat, C C, 703 Delwaide, Paul J, 708 Dement, William, 652 dementia(s) Ancient Egypt, 32, 33 assessment, 250–1 frontotemporal, 563 with motor neuron disease, 773–4 Scandinavia, 665 tropical neurology, 826–7 Demeny¨, Georges, 295 Democratic Republic of Congo, konzo, 818 Democritus, senses, 491 demons ancient trepanation, 9 epilepsy in the The Talmud, 44 Mesopotamia, 17 De Morbum Artificum (Ramazzini), 720 De Motu Animalium (Borelli), 134 De Motu Locali Animalium (Harvey), 616 Den Hartog, W A, 703 Denmark, 660 Denny-Brown, Derek, 787, 787–8 electromyography, 183 Reflex Action of the Spinal Cord, 787–8

de Nunes Couto, Deolindo Augusto, 804 De Osse Cribiformi (Schneider), 153 Depage, Antoine, 709 de Pomis, David, 720 depressed skull fractures, ancient trepanation, 8, 9 De Proprietatibus Rerum (Bartolomaeus Anglicus), 614 Dercum, Francis Xavier analysis of movement, 293–4 Text-book of Nervous Diseases by American Authors, 294 De Renzi, Ennio, 241 Dereymaeker, Albert, 706 de Saint-Armand, Jean, 83, 87 De Sanctis, Sante, 726 de Savages, Boissier, 495 Descartes, Rene´, 630 anatomical studies, 152–3 animal studies, 134 aphasia, 571 De l’Homme, 134 illustrations, 281–2 nerves, ideas of, 337 neurotransmitters, 869 phantom limbs, 493 pituitary gland, 336–7 three parts of the soul, 93 descending functions, Willis, Thomas, 97 De Sedibus et Causis Morborum per Anatomen Indagatis (Morgagni), 405 de Sgobbis, Antonio, 380 Des Maladies Mentales (Esquirol), 632 De Stella, Hector, 706–7 de Torres Homem, Joa˜o Vicente, 802, 804 developmental disorders, 496–8 17th Century, 496–7 Aristotle, 496 Ptolemy, 496 De Vigo, Giovanni aphasia, 572 Practica copiosa in arte chirurgia, 572 De Viribus Electricitatis in Motu Musculari (Galvani), 137, 722 de Watteville, A, 223 De Wied, D, 342 Diagnosis of Diseases of the Brain, Spinal Cord and Nerves (Reynolds), 620 Diamond, Hugh Welch, 290 Die agrammatischen Sprachstörungen (Pick), 578 Die Blutgefasse des menschlichen Ruckenmarke (Blood Vessels of Human Spinal Cord) (Adamkiewicz), 749 Die Lehre von den Tonempfindungen (von Helmholtz), 675 diencephalon, 346–7 Hess, Walter, 174 dietary deficiency diseases, 435–6 see also specific diseases/disorders dietary restriction, 436

923 diffuse Lewy body disease, Japan, 775 Diller, Leonard, 860 Dimitri, Vicente, 802 Diogenes of Apollonia, 51 diphenylhydantoin see phenytoin diplopia, 496–7 Dirk, Enno, 702 disability, European Middle Ages, 87–8 disconnection syndromes, 176–8 Sperry, Roger Wolcott, 176 disease, theories of 18th Century, 107 Ancient Egypt, 31 European Middle Ages, 82, 87–8 Diseases of the Spinal Cord and the Peripheral Nervous System (Biemond), 715 dissections 17th Century, 96–7, 337 Arabic/Islamic period, 65 illustrations, 273 traditional Chinese medicine (TCM), 757–60 Willis, Thomas, 96–7, 338 Divry, Paul, 708 Djadkowsky, Justinus, 737 Doctrine of Five Elements, 756 doctrine of the four elements, Hippocrates, 52, 52 Domagk, Gerhard, 429 Dominican Republic, 811 Donadieu, Francisco Rubio, 810 Donaggio, Arturo, 727 Donaldson, H H, 143 Donders, Franciscus Cornelius, 694 positron emission tomography (PET), 263 University of Utrecht, 701 Donne´, Alfred, daguerreotypes, 289 L-DOPA, 508–9 Guggenheim, Markus, 873–4 dopa decarboxylase, 873 dopamine, 873–4 frontal lobes, 567 synthesis, 872 dopamine agonists, Parkinson’s disease therapy, 509–10 dopamine receptors, 510 Dorscherholmen, A, 466 dorsolateral prefrontal circuits, 564, 565 executive functions, 565, 566 Down, John Langdon, 327–8 Down’s syndrome, 327 Doyen, Euge`ne-Louis, 296–7 Drachman, D B, 550 Drager, G A, 514 Dr Deijman’s Anatomy Lecture (Rembrandt), 337, 337 drug-induced parkinsonism, 512 DTY1 gene, 525 du Bois-Reymond, Emil, 674 animal studies, 138 nerve conduction, 493

924 du Bois-Reymond, Emil (Continued) neurotransmitters, 869 vasogenic vs. neurogenic “nerve storm” headache theory, 384 Dubowitz, Victor childhood muscle disorders, 322 Gowers’ sign, 323 Duchenne de Boulogne, Guillaume Benjamin, 639 Album de Photographies Pathologiques, 291 animal studies, 140 childhood muscle disorders, 322 De l’Electrisation Localisée et son Application ¼ la Pathologie et ¼ la Thérapeutique, 140 “histological harpoon”, 481, 482 Mécanisme de la Physionomie Humaine, 291, 291 photography, 290–1 Duchenne muscular dystrophy, 322, 477, 481, 481–2, 483 gene isolation, 322 Gowers, William Richard, 482–3, 482–4, 484 illustration, 481, 483 therapies, 611 Dudley, Benjamin Winslow, 606 Dunn, Elizabeth, 888, 889, 890 Duplessi-Bertaux, Jean, 285 Durante, Francesco, 199 Duret, Henri, 409 Dutch medicine, Japan, 769–71 Dutrochet, Rene´ Joachim-Henri, 157 Du Vigneaud, Vincent, 340 dystonias, 524–6 therapy, 524 see also specific types

E Eadie, Mervyn John, 797 Ebbinghaus, Hermann, 243 Ebers Papyrus, 30, 32–3 strabismus, 498 Eccles, John Carew, 796 neurotransmitters, 869 postsynaptic potentials, 362 synapses, 179 Ecuador, 809 Edinger, Ludwig, 677 hospital development, 311 neuroembryology, 163 Edinger–Westphal nucleus, 163 The Education and Training of the Feeble in Mind (Down), 327–8 Edwin Smith Surgical Papyrus, 30, 32, 39 aphasia, 572 rehabilitation, 856 frontal lobes, 557 hospitals, 304 Effective Prescriptions from Physicians of a Distinguished Medical Lineage (Wei Y-lin), 765 Egypt, Ancient, 29–36

INDEX Egypt, Ancient, (Continued) anatomy, 31 aphasia, 571 bacterial meningitis, 417 Bell’s palsy, 33–4 brain, function of, 31 cervical spinal cord injuries, 32 closed head injury, 33 compensated hydrocephalus, 34 contre-coup injuries, 32 dementia, 32, 33 disease, theories of, 31 empirical diagnosis, 31 epilepsy, 33 facial hemiatrophy, 35 headaches, 33, 376 health and healing theories, 29 Herodotus, 30 hospitals, 304 illustrations, 271 injuries, 30 macrocephaly, 34 medical practice, 30–1 meningioma, 34 meningitis, 33 migraine, 33 mummification, 31–2 neuroanatomy, 31 neurological symptoms, 31–3 night blindness, 437 open head injury, 33 papyri, 29, 30 see also specific types paralysis, 32 Parkinson’s disease, 34 physicians, 30 poliomyelitis, 33, 34, 271 rehabilitation therapies, 852 skull fractures, 31 sources, 30 see also specific papyri spinal injuries, 31 stroke, 30, 32, 33 surgeons, 30 symptoms, 29 traumatic cervical myelopathy, 33 unconsciousness, 32 vascular dementia, 33 Ehrenberg, Christian Gottfried, 677 microscopy studies, 157 Ehringer, H, 508 Ehrlich, Paul, 462 eighteenth Century, 107–14 anatomical studies, 155–6 bacterial meningitis, 420 therapy, 428–9 disease pathology, 107 electricity, 111–12 frontal lobes, 558–9 German-speaking countries see German-speaking countries Great Britain, 617–18 headache, 379–80 hollow nerves, 108–9

eighteenth Century (Continued) hospitals, 306–8 ‘injury currents’, 112 invisible, subtle fluids, 110–11 irritable nervous system, 109–10 life forces, 110 medical practices, 110 microscopy, 108, 108–9 phantom limbs, 493–4 sensitive nervous system, 109–10 strabismus, 498 vertigo, 495 vibrations, 110–11 Eijkman, Christiaan, 445–6 Eisenlohr, Carl, 311 Ekbom, Karl-Axel, 551 Ekman–Lobstein syndrome, 650 electrical brain activity, Todd, Robert Bentley, 620 electrical stimulation experiments Ferrier, David, 124 hypothalamus, 344, 345 Karplus, J, 344, 345 Kreidl, A, 344, 345 electricity, 18th Century, 111–12 electroconvulsive shock therapy (ECT), Cerletti, Ugo, 729 electroencephalography (EEG), 181–4 absence seizure classification, 396 Adrian, Edgar Douglas, 171–2, 181 Berger, Hans, 181, 395 Caton, Richard, 181 clinical investigation, 181–2 Davis, Hallowell, 183, 395 with electromyography, 183, 550 epilepsy, 387, 395–6 focal seizure classification, 396 Gibbs, Erna, 183 Gibbs, Fred, 183 Lennox, William, 183 myoclonic seizure classification, 396 partial seizure classification, 396 pediatric epilepsy, 320 sleep, 547, 651–2 tonic–clonic seizure classification, 396 Walter, Grey, 183 electromyography (EMG), 181–4 Adrian, Edgar Douglas, 171–2, 183 Buchthal, Fritz, 183 Denny-Brown, Derek, 183, 788 with EEG, 183, 550 Kugelberg, Eric, 183 uses of, 182–3 electron microscopy, neural transplantation, 893 electrophysiology du Bois-Reymond, Emil, 674 metabolic tremor, 528 electrotherapy, Mo¨bius, Paul Julius, 680 Elliott, K A C, 878 GABA, 878 Elliott, Thomas Renton, 870 El Salvador, 810 Elvehjem, Conrad Arnold, 456

INDEX embolism, apoplexy, 408 embryonic tissues, neural transplantation, 896 emotions, diencephalon, 346–7 Empedocles of Agrigentum, 50 empirical diagnosis, Ancient Egypt, 31 encephalitis, Muratov, Vladimir Aleksandrovich, 741 encephalitis lethargica, 511–12 Australia, 784–5 post-encephalitic parkinsonism, 511–12 von Economo, Constantin, 511 Encephalography (Robertson), 791 England see Great Britain Engravings of the Arteries and the Nerves of the Brain (Bell), 618 An Enquiry into the Nature and Origin of Mental Derangement (Crichton), 325 ephedrine, traditional Chinese medicine (TCM), 765 epidemic meningitis, 421–2 epidemic neuropathy, 817 epilepsy, 387–400 17th Century, 98–9 Africa, 822 anatomical pathology, 393 Ancient Egypt, 33 ancient trepanation, 10–11 animal models, 397 Babylonian culture, 388, 389 The Bible, 40 children, 319–21 adults vs., 319 classification, 396 computed tomography (CT), 398 definitions, 388 EEG, 182–3, 387, 395–6 European Middle Ages, 82 functional brain imaging, 398 functional magnetic resonance imaging (fMRI), 398 genetic techniques, 398 Greco-Roman World, 388 hospitals, 387 Indian culture, 389 interictal EEG, 395 magnetic resonance imaging (MRI), 398 magnetoencephalography (MEG), 398 malformations of cortical development (MCDs), 398 Mesopotamia, 21–2 modern period, 393–4 neuroimaging, 398 nomenclature, 393 pediatric, 319–20 positron emission tomography (PET), 398 recent developments, 397–8 Renaissance, 387, 391–3 hospitals, 392–3 lexicon, 393 monographs, 393

epilepsy, (Continued) Scandinavia, 665 sleep studies, 398 Su wen, 763 The Talmud, 44–5 traditional Chinese medicine (TCM), 762–3 treatment, 396–7 workers in Aretaeus, 56 Arnold of Villanova, 391 Brown-Se´quard, Charles-E´douard, 622 Charcot, Jean-Martin, 211 Cullen, William, 392 da Vinci, Leonardo, 391 Esquirol, Jean-E´tienne Dominique, 393 Ferrier, David, 394 Galen see Galen Gloor, Pierre, 396 Godlee, Rickman, 394 Hippocrates, 388, 389 Horsley, Victor, 394 Hughlings Jackson, John see Hughlings Jackson, John Kozhevnikov, Alexei Yakovlevich, 739 Locke, John, 391–2 Macewen, William, 394 Muratov, Vladimir Aleksandrovich, 741 Penfield, Wilder see Penfield, Wilder Rulandus, Martinus, 391 Shen Jin-ao, 763 Soranus, 389–90 Tissot, Samuel, 392 Vesalius, Andreas, 391 Willis, Thomas, 391, 392 see also seizures Epilepsy: Its Symptoms, Treatment and Relation to Other Chronic Convulsive Diseases (Reynolds), 393 epinephrine see adrenalin (epinephrine) episodic ataxia (EA1), 366 episodic ataxia type 2 (EA2), 366 Erasistratus, 54 Erb, Wilhelm Heinrich, 686 internistiche neurology, 311 limb-girdle dystrophies, 484–6 muscle tendon reflexes, 222 muscular dystrophy, 477 Parkinson’s disease therapy, 507 reflex testing, 222 Erb–Duchenne muscular dystrophy, 686 Erb’s sign, 486 ergotamine, isolation, 384 ergotism, France, 629, 630 Erlanger, Joseph, nerve conduction, 183–4, 609 Errors of Medicine Corrected (Wang Ching-Jen), 757

925 Erspamer, Vittorio, 877, 877 Eschner, Augustus, 504, 504 Esquirol, Jean-E´tienne Dominique, 632, 632 epilepsy nomenclature, 393 Essay on Febrile Diseases, 756 An Essay on the Shaking Palsy (Parkinson), 505–6, 618 An Essay on the Vital and Other Involuntary Motion of Animals (Whytt), 617 Essays on the Anatomy of Expression in Painting (Bell), 283, 618 essential myoclonus, 526, 528 essential tremor, 504–5 Este´vez, Jose´ A, 802 Estienne, Charles anatomical studies, 152 De Dissectione Partium Corporis Humani Libri Tre, 278 illustrations, 278, 279 ether, general anesthesia, 191 ethosuximide, epilepsy therapy, 397 Euler, Ulf Svante von, 873 Europe Japan, influence on, 769 Middle Ages, 79–90 brain vs. heart controversy, 83–4 diagnosis vs. prognosis, 84 disability, 87–8 disease concepts, 82, 87–8 early (Dark Ages), 79–80 epilepsy, 82 herbal remedies, 84–5 High Middle Ages, 80 ‘humors’, 82 Late Middle Ages, 80 leprosy, 86, 87–8 magic, 85, 86–7 nerve anatomy, 82 neurological conditions, 81–5, 85–8 see also specific diseases/ disorders plague, 86 religious pathology, 85 tuberculosis, 86 Neolithic trepanation, 6, 9 see also specific countries Eustachio, Bartolomeo anatomical studies, 152 cranial nerve VIII (acoustic-vestibular nerve), 220 illustrations, 278, 280 euthanasia practices, Nazi Germany, 313 event-related potentials, neurophysiology, 182 evoked potentials, neurophysiology, 182 Ewarten, Sigmund Exner von, 683 Ewins, A J, 872 examinations see neurological examinations excessive waking, 17th Century, 102

926 executive functions, 566 dorsolateral prefrontal circuits, 565, 566 testing of, 248–50 Goldstein, Kurt, 248, 248 Halstead, Ward, 249 Scheerer, M, 248 Stroop, Ridley, 249–50 Exercitationes de Structura Viscerum (Malpighi), 132 Exner, Sigmund, 589 external supernatural “hands”, Mesopotamia, 17–18 Ey, Henri, 645–6 eye, structure of, Arabic/Islamic period, 66

F facial hemiatrophy, Ancient Egypt, 35 facial nerve (cranial nerve VII), 219, 219–20 facio-scapulo humeral dystrophy (FSHD), 487 Falloppia, Gabriele anatomical studies, 152 cranial nerve III (oculomotor nerve), 217 cranial nerve VI (abducens nerve), 219 illustrations, 281–2 Observationes Anatomicae, 152 familial hemiplegic migraine (FHM), 366 FAS test, 240 fatal familial insomnia, 368 Fay, Temple, 221 Fazio, Eugenio, 728 febrile convulsions, children, 319 Fechner, Gustav Thomas, 686 Fernel, Jean, 403 Ferreya, Luis, 816 Ferrier, David, 123–5 alexia, 589 animal studies, vicariation, 838 basal ganglia, 501 electrical stimulation experiments, 124 epilepsy, 394 The Functions of the Brain, 125 Localization of Cerebral Disease, 125 motor areas, 123–4 motor strength examination, 226 somatotrophic organization, 124 surgical neurology, 193, 195, 197 visual field testing, 216 fetal alcohol syndrome, 324 fetal familial insomnia, 551–2 fetal nigral grafts, Parkinson’s disease, 903 Feuchtwanger, Ernst, 561 fevers, Arabic/Islamic period, 69 Fiamberti, Adamo Mario, 725 Finkelnberg, Ferdinand, 576–7 Finland, 659–60 Finnish Disease Heritage (FDH), 664 Finland, Maxwell, 429 Finnish Disease Heritage (FDH), 664 First Lines of the Practice of Physic see Cullen, William

INDEX Fisher, Charles Miller carotid artery studies, 410 transient ischemic attacks (TIAs), 410–11 Fist-Edge-Palm test, 248, 248 fixation, 157 Flashman, James Froude, 785 Flatau, E, 524 Flechsig, Paul Emil, 683 Fleischer, Bruno, 513 Flemish Society of Neuropsychiatrists, 696–7 FLENI, Argentina, 802 Flerko´, B, 899–900 Flexner, Simon, 429 Flinders University (Adelaide), 797 floppy baby syndrome, Mesopotamia, 24 Florey, Ernst, 878 GABA, 877–8 Flourens, Marie-Jean-Pierre, 120 animal studies, 138 anti-phrenology work, 583–4, 633 cerebellar examination, 228 cranial nerve VIII (acoustic-vestibular nerve), 220 nystagmus, 496 reticular theories, 161–2 fluid-mosaic model, biomembranes, 363 18 F-2fluoro-2-deoxy-D-glucose (FDG), 261 focal seizures EEG classification, 396 identification, 391 Foerster, Otfried, 683–4 hospital development, 311 Fog, Mogens, 663 Fog, Torben, 665 Foix, Charles, 409 cerebrovascular disease, 409–10 praxis assessment tests, 247 vascular anatomy, 409–10 folate Angier, R B, 458 antagonists, cancer therapy, 459 deficiency, 458–61 homocysteine metabolism genetic polymorphisms, 461 symptoms, 459 see also neural tube defects isolation, 458 metabolism, 458–9 Mitchell, H K, 458 neural tube defect prevention, 459–61 pernicious anemia, administration risks, 458 synthesis, 458 Wintrobe, M M, 458 Foley, Joseph, 528 Folkers, Karl, 466 Folkerts, J F, 703 Flling, Asbjrn, 664 phenylketonuria, 326, 664 Folstein, Marshal, 251 Folstein, Susan, 251

Fontana, Felice anatomical studies, 156 Traité sur le Venin de la Vipère, 110 forced sterilization practices, Nazi Germany, 313 Forel, Auguste, 680, 682 neuron doctrine, 162 neuron theory, 680 subthalamic nucleus, 523 Forssman, J, 888 Fortuyn, J Droogleever, 702 Foster, Michael, 140 Fothergill, John, 618 bacterial meningitis, 419 Foucault, Le´on daguerreotypes, 289 pediatric hospitals, 329 four basic humors, Galen, 390 Fowler, Richard, 112 fractionization, 597–9 Fraenkel, Albert, 426 fragile X syndrome (FRaX), 368 France, 629–56 19th Century, 633–40 hospitals, 308 Arabic/Islamic influences, 629 bacterial meningitis, 421 Bordeaux, 649–50 cinematography, 296 ergotism, 629, 630 experimental medicine, 633–4 French Revolution, 631–2 Greco-Roman World, 629 Lyon, 651–2 Marseille, 652–3 Middle Ages, 629 Montpellier, 648–9 Neolithic trepanation, 4–5, 5 neuroanatomists, 633 phrenology, 632–3 research institutes, 647–8 Sainte Anne Hospital (Centre Hospitalier Sainte Anne), 645–7, 646 Strasbourg, 650–1 Toulouse, 649 Franco-Prussian War, the Low Countries, 695 Francotte, Xavier, 708 Frank, Johann Peter, 721 Franklin, Benjamin, 111, 605 rehabilitation therapies, 853 Franz, Shepherd Ivory aphasia rehabilitation, 857 cognitive rehabilitation, 858 vicariation, 839 Frapolli, Francesco, 452 Freed, Bill, 901 Freeman, Walter, 611 frontal lobes, 562 Free University of Amsterdam, 702–3 Fremont-Smith, Frank, 425–6 French Revolution, 631–2 frenzy, 17th Century, 103

INDEX Freud, Sigmund antilocalizationist language theories, 578 cerebral palsy (Little’s disease), 322 language and cognitive development, 848 neuroanatomy, 681–2 pediatric hospitals, 329 Salpeˆtrie`re Hospital, 637–8 Frey, Max von, 227 Friedreich, Nikolaus, 677 essential myoclonus, 526, 528 limb-girdle dystrophies, 484–5 neurological examinations, 214 spinocerebellar ataxia, 485 Friedreich’s ataxia, 368 Fritsch, Gustav, 123 animal studies, 141 basal ganglia, 501 frontal lobes, 559–60 FRM1 gene, 368 Froeschels, Emil, 857 frontal lobe(s), 557–70 17th Century, 558–9 18th Century, 558–9 19th Century, 559–61 20th Century, 561–4 abstraction, 562 AIDS, 564 antiquity, 557–8 behavioral neurology, 562–3 current knowledge, 564–7 dopamine, 567 Edwin Smith Surgical Papyrus, 557 evolutionary importance, 567 frontal-subcortical circuits see specific circuits functional magnetic resonance imaging, 563, 563 future prospects, 567–8 Greco-Roman World, 557 imaging, 563 injury, 559–60, 560 lesions, localization theory, 124–5 localization of function, 559–60 neuroanatomy, 564 neurochemistry, 567 neurodegeneration, 563 neuropsychology, 563 neurotransmitters, 567 structure–function relationship, 568 tumors, 563 violence, 568 workers in Berger, Hans, 561 Bianchi, Leonardo, 561, 725 Chaussier, Franc¸ois, 559 da Vinci, Leonardo, 558 Feuchtwanger, Ernst, 561 Freeman, Walter, 562 Fritsch, Gustav, 559–60 Gage, Phineas, 559–60, 560 Galen, 558 Gall, Franz Joseph, 559 Goldstein, Kurt, 561–2 Hippocrates, 557

frontal lobe(s) (Continued) Hitzig, Eduard, 559–60 Lhermitte, Franc¸ois, 643 Luria, Aleksandr Romanovich, 562 Owen, Richard, 559 Pick, Arnold, 561 Poppelreuter, Walther, 561 Spurzheim, Johann Caspar, 559 Starr, Moses Allen, 561 Swedenborg, Emanuel, 558–9 Vesalius, Andreas, 558 Watts, James, 562 Willis, Thomas, 558 frontal-subcortical circuits Alexander, G E, 564 Cummings, J L, 565–6 frontotemporal dementia, 563 Fry, Henry Kenneth, 794 function, recovery of, 834–41 compensatory behaviors, 833 neural transplantation, 885, 894, 904–5 semantics, 839–40 see also redundancy theory; vicariation functional brain imaging, 257–68 blood flow, 257–9 Brodmann, Korbinian, 257 C14-deoxyglucose autoradiography, 258–9 epilepsy studies, 398 future work, 265–6 imaging averaging, 265–6 Ingvar, David, 259 131 I-labeled trifluoroiodomethane, 258 Lassen, Neils, 259 metabolism, 259 physiology, 257–9 see also specific methods functional localization, 174–5 20th Century, 173–5 history of theory development, see localization theory lesion studies, 174 see also functional brain imaging functional magnetic resonance imaging (fMRI), 265 epilepsy studies, 398 frontal lobes, 563, 563 The Functions of the Brain (Ferrier), 125 fundoscopy, invention of, 217 Funk, Casimir, 436 Fu¨rth, Otto von, 870, 871 Further Studies in Encephalography (Robertson), 791 Fuse, Gennosuke, 773

G GABA, 877–9 Bazemore, Alva, 878 del Castillo, J, 878 Elliott, K A C, 878 Florey, Ernst, 877–8 Hayashi, T, 878 Katz, Bernard, 878 Kravitz, E, 879 Wiersma, C A G, 878

927 GABAA receptors, 364 mutations, 366 Gaddum, J H, 873 Gage, Phineas, 559–60, 560 “gain-of-function” hypothesis, Huntington’s disease, 520 gait neurological examinations, 229 Parkinson, James, 229 see also under movement Gajdusek, Carleton, 665, 820–1 Galen, 55–7 anatomical studies, 149 animal studies, 56, 130 aphasia, 571 apoplexy, 402–3 autopsy, 56 brain function theories, 57, 57 brain vs. heart controversy, 273 cerebrovascular disease, 401 cranial nerves, 56 cranial nerve II, 216 cranial nerve IX (glossopharyngeal nerve), 221 cranial nerve X (vagus nerve), 221 De usu partium, 130 epilepsy, 388, 390–1 four basic humors, 390 frontal lobes, 558 headache, 377 Jewish physicians, criticism of, 41 laryngeal nerve, 56 migraine, 377 “nerves of voice”, 130 night blindness, 437 non-human primate dissection, 56 senses, 491 spinal cord transections, 56 strabismus, 498 tinnitus, 46 tremors, 503 vertigo, 494 voice production, 56 Galenism, 61–4 Arabic criticism of, 70 Arabic definition of, 64–6 brain, priority of, 62–3 brain function localization, 63–4 emergence of, 62–4 European Late Middle Ages, 81 headache, 378–9 modifications, 62 ventricles, recognition of, 63–4 Galilei, Galileo, 504 Gall, Franz Joseph, 118–20 anatomical studies, 156 anatomie et Physiologie du Système Nerveux en général et du Cerveau en particulier, 119 animal studies, 138 brain damage studies, 118–19 cerebrum, 583 cognitive assessment, 235

928 Gall, Franz Joseph (Continued) comparative anatomy, 118 cortical localization, 118 frontal lobes, 559 heretic views, 118 lesion studies, 120 phrenology, 632–3, 670, 672 redundancy theory, 834 rehabilitation therapies, 853 speech production localization, 573 Galvani, Luigi, 111–12, 631 animal electricity, 721, 722 animal studies, 136–7 De Viribus Electricitatis in Motu Musculari, 137, 722 muscular dystrophy, 477 nerve conduction, 492 neurotransmitters, 869 Gama, Carlos, 804–5 gamma-aminobutyric acid see GABA gap-junction pathologies, molecular biology, 367 Garcin, Raymond, 643 Gash, D M, 900 Gaskell, Walter Holbrook, 625 Gassendi, Pierre, 92–4, 93 astronomical observations, 93–4 reception in Oxford, 94 Gasser, Herbert Spencer, 183–4, 609 Gastaut, Henri, 652, 652–3 epilepsy therapy, 397 sleep medicine, 549 gastrostomies, child neurology, 326 Gazzaniga, Michael, 597–8 Gehuchten, Arthur van see Van Gehuchten, Arthur Gehuchten, Paul van, 706, 713 Ge´lineau, Jean-Baptiste, 552 Gellhorn, E, 352 gene identification, Huntington’s disease, 519 general anesthesia, 191 Bennett–Godlee case, 197 charts for, 200 Hwa To, 764–5 Long, Crawford W, 191 Morton, William, 191 traditional Chinese medicine (TCM), 764–5 Wells, Horace, 191 generalized primary tortion dystonia, 524–5 genetic polymorphisms, 461 genetics epilepsy, 398 linkage analysis, Huntington’s disease, 518 Scandinavia, 664 Gennari, Francesco, 155 genome sequencing, 365–6 genomics, 369–70 Genus–Species test, 240 Gerard, R W, 892 Gerardy, Werner, 550

INDEX Gerebtzoff, Michel, 708 Gerhard, William, 423 Gerlach, Joseph von, 161 German medicine, Japan, 771–2 German-speaking countries, 667–89 16th Century, 667 17th Century, 669 18th Century, 669, 677 19th Century, 672–6, 677 animal magnetism, 670, 672 animists, 669–70 body–soul problem, 669 clinical neurologists, 685–6 neuroanatomy, 676–85 clinical, 677 pathological, 677 neurophysiology, 686–7 neuropsychiatry, 677–85 phrenology, 670, 672 surgery, 687 vitalists, 669–70 see also Germany Germany hospitals 18th and 19th Century, 308 19th to 20th Century, 310–12 Kriegssanitätsordnung, 312–13 Nervenheilanstalten, 310–11 post World War II, 314 Siechenhäuser, 311–12 World War I, 312–13 Nazi period see Nazi Germany see also German-speaking countries Gerstmann, Josef, 597 Gerstmann–Stra¨ussler–Scheinker syndrome (GSS), 368 Geschwind, Norman behavioral neurology, 562 cognitive assessment, 252 language models, 598 neurolinguistics, 579 Gesner, Johann, 573 Giannuzzi, Giuseppe, 724 Gibbs, Erna EEG, 183, 395 epilepsy, 395 Gibbs, Fred EEG, 183, 395 epilepsy, 395 Gibson, M J, 900 Gilbertus Anglicus, 613–14 Gilles de la Tourette, Georges, 639 tics, 530, 531–2 Gioja, L, 479 glabellar reflex, 225 Glees, Paul, 891 glial cytoplasmic inclusions (GCIs) Japan, 774 multisystem atrophy (olivo-pontocerebellar degeneration), 515 Glissan, B J, 845 Glisson, Francis, 615 animal studies, 135 Tractatus de Ventriculo et Intestinis, 135

Gloor, Pierre, 396 Glorieux, Ze´non, 694 University of Brussels, 708 glossopharyngeal nerve (cranial nerve IX), 221 glutamic acid, 879 glycine, 879 glycine receptors (GlyRs), 364 glycogen storage disease, Japan, 777 gnasthosomiasis, 816 Godlee, Rickman, 196, 196–7 epilepsy, 394 gods see religion Goering, D, 348, 350 Goldberger, Joseph, 454–5 Goldstein, Kurt alexia, 597 aphasia rehabilitation, 857 cognitive rehabilitation, 858 executive function testing, 248, 248 frontal lobes, 561–2 language, antilocalizationist theories, 579 Golgi, Camillo, 724 animal studies, 143 black reaction, 161 On the Fine Anatomy of the Central Organs of the Nervous System, 161 illustrations, 284 microscopy studies, 160 neuron visualization, 159 reticular theories, 161–2 Goliath, 39–40 Goltz, Friedrich Leopold, 674 nystagmus, 495 University of Strasbourg, 650 Go´mez, Alfonso Asenjo, 807–8 Go´mez, Francisco Leo´n, 810 Gomori techniques, 342 Goodenough, F L, 245 Goodenough Draw-a-Man Test, 245, 246 Goodenough Intelligence Test, 245, 246 Goodglass, Harold, 579 aphasia cognitive assessment, 239–40 neurolinguistics, 579 neuropsychology, 563 good luck charms, ancient trepanation, 5 Gowers, William Richard animal studies, 140 athetosis, 521, 522 brain function localization, 845 cerebellar examination, 228 childhood aphasia, 848 childhood muscle disorders, 322 color vision testing, 217 cranial nerve V (trigeminal nerve), 219 cranial nerve XII (hypoglossal nerve), 222 Duchenne muscular dystrophy, 482–3, 482–4, 484 hearing, 221 A Manual of Diseases of the Nervous System, 381 cerebral dominance, 837

INDEX Gowers, William Richard (Continued) mental status examinations, 214 motor strength examination, 226 movement disorders, 501–2 see also specific diseases/disorders muscle tendon reflexes, 222, 223, 223 muscular dystrophy, 479 neurological examinations, 213–14 Parkinson’s disease studies, 506, 506–7 Pseudo-hypertrophic Muscular Paralysis, 479 pupillary reaction testing, 218 Queen Square Hospital, 310 temperature sensation testing, 227 vasogenic vs. neurogenic “nerve storm” headache theory, 384, 386 writer’s cramp, 526 Gowers’ sign, 323, 482–4, 485 Broadbent, William, 624 Dubowitz, Victor, 323 G-protein-coupled receptors, 364–5 Graham, J G, 514–15 grammatic disorders, 576–8 Bonhoeffer, Karl, 577 Finkelnberg, Ferdinand, 576–7 Heilbronner, Karl, 577 Hughlings Jackson, John, 577 Isserlin, Max, 578 Kleist, Karl, 578 Pick, Arnold, 577–8 Steinthal, Chajim, 577 grand mal epilepsy, 393 Granit, Ragnar, 662–3 grasping reflexes, 226 Grasset, Joseph, 649 Gratiolet, Pierre, 121, 633 Great Britain, 613–28 17th Century, 614–17 18th Century, 617–18 hospitals, 306–8 19th Century, 618–20, 622–5 hospitals, 306–8 palsy, 618 paraplegia, 618 20th Century, 625–6 hospitals 18th Century, 306–8 19th Century, 306–8 post World War II, 313–14 professional specialization, 308–10 Queen Square Hospital see Queen Square Hospital Victorian era, 303 World War I, 312 Neurological Society of London, 613 physical rehabilitation, 853 specialization, 613 Victorian era, hospitals, 303 see also specific people Great Depression, United States, 610 Great Patriotic War (World War II), Russia, 750–1

Greco-Roman World, 49–59 Alexandria, 53–4, 62 animal studies, 129–31 Arabic translations, 61–2 bacterial meningitis, 417 brain vs. heart controversy, 54–5 cerebrovascular disease, 402 definition of, 49 epilepsy, 388 France, effects on, 629 frontal lobes, 557 headache, 376–8 Hippocratic neurology, 51–3 apoplexy, 52 disease, concept of, 53 doctrine of the four elements, 52, 52 headache, 52 speech disorders, 52 stroke, 52 therapies, 52 see also Hippocrates hospitals, 304–5 night blindness, 437 pre-Hippocrates, 49–50 anatomy, 50 Asklepios, 49–50, 304–5 head injury, 50 healing deities, 49–50 individuals, 50–1 rehabilitation therapies, 852 see also specific people Greene, H S N, 889 Greenman, Milton J, 143 Greisinger, Wilhelm, 678, 678, 694 The Grey Substance of the Medulla Oblongata and Trapezium (Dean), 290 Griffiths, Ruth, 324 Grijns, Gerrit, 448 Grinshtein, Alexander Mikhailovich, 750 gross anatomy, 156–63 gross lesions, epilepsy, 394 Gru¨newald, Matthias, 285 Guatemala, 810 Gudden, Bernhard von, 678, 678–9 Gudmundsson, Gudmund, 661, 663 Gudmundsson, Kjartan Ragnar, 661 Guersent, Louis, 420 Guggenheim, Markus, 873–4 Guillain, George, 642 Guillain–Alajouanine–Garcin syndrome, 642 Guillain-Barre´ syndrome, 650 Guilleminault, C, 549 Guislain, Jozef, 706 Guldenarm, J A, 695 Gumnit, R J, 550 Gunn, Marcus, 218 Gusella, J F, 518 Guttmann, Ludwig, 855 Gutzmann, Hermann, 857 Guy’s Hospital, 307 Guze, Sam, 262

929

H Haartman, Johan, 659 Haeckel, Ernst, 674–5 Haemophilus influenzae, bacterial meningitis, 427 Hagen, P S, 466 Hall, Marshall, 619 Hallager, Frederik Kristoffer, 665 Hallaran, William nystagmus, 496 ‘spin chairs’, 496, 497 Haller, Albrecht von, 109, 615, 669 anatomical studies, 156 animal studies, 135–6 irritability, 721–2 Mémoires sur la Nature Sensible et Irritable des Parties du Corps Animal, 135 hallucinations, Bekhterev, Vladimir Mikhailovich, 744 Halstead, Ward, 249 Halstead Category Test, 249 Halstead–Reitan Battery, 249 Halstead Tactual-Performance Test, 249 Hamelinck, Maurice, 707 Hammond, William Alexander, 606 athetosis, 501, 520, 521, 522 cerebellar examination, 228 Civil War, 607 miryachit, 530 A Treatise on Diseases of the Nervous System, 608 Hand, Eye and Ear tests, 238, 239 Handbook of Neurology: The Structure of the Nervous System (Winkler), 711 Handbuch der Physiologie (Mu¨ller), 673 handedness The Bible, 40 The Talmud, 45 Hannover, Adolph microscopy studies, 158 tissue fixation, 157 Hansen, Gerhard Armauer, 661 Harpestreng, Henrik, 658 Harnak, E, 875–6 Harris, Alfred W, 610 Hartley, David, 110 vertigo, 494 Harvey, William, 616 Anatomical Exercises on the Generation of Animals, 132 animal studies, 132 apoplexy, 403 De Generatione, 616 De Motu Locali Animalium, 616 German-speaking countries, 669 illustrations, 281–2 Prelectiones, 616 Hashimoto, Tsunatume, 771 Hayashi, T, 878 al-Haytham, Ibn Book of Optics, 272 vision, 62, 70–3 anatomical reprojection, 73

930 al-Haytham, Ibn (Continued) image formation, 72, 72–3 point-to-point correspondence, 71–2, 72 ‘visual image’ theory, 71 HCRT-2 gene, 344 HD gene, 368 Head, Henry, 625 aphasia, 596–7 Aphasia and kindred disorders of speech, 238, 578, 625 language localizationist theories, 578 sensations, 625 sensory examination, 227–8 Serial Tests (aphasia cognitive assessment), 237–9, 238 Hand, Ear and Eye Test, 238, 239 Naming and Recognition of Common Objects, 238 visuospatial/visuoconstructive skill tests, 245 headaches, 375–86 17th Century, 101–2 18th Century, 379–80 19th Century, 379, 381–4 pharmacology, 381–2 20th Century, 384–5 Ancient Egypt, 33, 376 ancient trepanation, 375–6 Arabic/Islamic period, 378 Galenism, 378–9 Greco-Roman civilization see GrecoRoman World Hippocratic neurology, 52 imaging, 385 magic and mythology, 375–6 Medieval medicine, 378, 378 Mesopotamia, 20 publications, 385 Renaissance, 378–9 Salernitan Medical School, 378 serotonin, 384 The Talmud, 43–4 therapy pharmacology, 380–1 potassium bromide, 381, 384 sodium salicylate, 381 Trautmann, 384 wild poppy, 378 vasogenic vs. neurogenic “nerve storm” theory, 382, 384 du Bois-Reymond, Emil, 384 Gowers, William Richard, 384, 386 Liveing, Edward, 384, 385 workers in Aesculapius, 376 Albucasis, 378 Aretaeus the Cappadocian, 55–6, 377 Aulus Cornelius Celsus, 376–7 Avicenna, 378 du Bois-Reymond, Emil, 384 Galen, 377 Gowers, William Richard, 384, 386

INDEX headaches (Continued) Hildegard von Bingen, 378 Hippocrates, 376 Le Pois, Charles, 378–9 Liveing, Edward, 384, 385 Plinius, 376 Quintus Serenus Sammonicus, 377 Ramazzini, Bernardino, 379 Tissot, Samuel, 379 Trallianus, Alexander, 377–8 Wepfer, Johann Jakob, 379 Willis, Thomas, 379 see also migraine head injuries Ancient Egypt, 33 The Bible, 38–40 closed, 33 open, 33 pre-Hippocratic Greco-Roman World, 50 rehabilitation, 861–2 ancient, 852 surgical neurology, 192 The Talmud, 43 see also penetrating head injuries; traumatic brain injury (TBI) hearing, 489–90 17th Century, 101 Gowers, William Richard, 221 Mills, Charles K, 221 tests for, 220–1 Heath, Robert, 611–12 Heberden, William, 617 night blindness, 437 Hebrew Bible see The Bible Hebrew neurology see The Bible; The Talmud He´caen, Henry, 177, 643, 644, 644–5 heel-to-knee-to-shin-to-knee test, 229 Heilbronner, Karl, 577 Heimans, J J, 703 Heine, Jacob von, 687 Helmholtz, Hermann von, 675 analysis of movement, 293 animal studies, 140 invention of fundoscopy, 217 hemichorea-hemiballismus, 523 hemiplegia, infantile, 846–7, 847 hemispheric specialization, Sperry, Roger Wolcott, 177 hemoglobin structure, Ingram, Vernon, 361–2 Henle, Friedrich Gustav Jakob, 675 Henschen, Solomon Eberhard, 661 language center localization, 596 Heraclitus of Ephesus, 50 herbal remedies, European Middle Ages, 84–5 hereditary dentatorubral-pallidoluysian atrophy (H-DRPLA), 774 hereditary disorders, Davidenkov, Sergei Nikolaevich, 750 hereditary hyperkalemic periodic paralysis (HyperKPP), 366

Hering, Ewald, 687 Herodotus, 30 Herophilus, 53, 53–4 anatomical studies, 53–4 cranial nerves, 53 motor vs. sensory nerves, 54 retiform plexus, 53 Herpin, Franc¸ois, 420 Herring, P T, 338 Hershko, Avram, 511 Herz, M, 494–5 Hess, Walter Rudolph, 682 diencephalon studies, 174 sleep, 547 Hibbard, Brian, 459 Higher Cortical Functions in Man (Luria), 562 higher function localization, Bekhterev, Vladimir Mikhailovich, 745 Hildegard von Bingen, 378 Hill, Leonard, 258 Hinshelwood, James alexia, 593–4, 596 Letter-, Word- and Mind-Blindness, 593–4, 596 hippocampus grafts, 899 neuronal map, 173 Hippocrates, 51–3 aphasia rehabilitation, 856 apoplexy, 402 brain function, 51–2 doctrine of the four elements, 52, 52 frontal lobes, 557 headache, 376 On the Sacred Disease, 52 brain vs. heart controversy, 54 epilepsy, 388, 389 sleep, 547 tinnitus, 46 transient ischemic attack (TIA), 410 writings, 51 Hirano, A, 773 Hirayama disease (juvenile muscular atrophy of distal upper extremity), 776 His, Wilhelm, 677 hypothalamus, 335 microtome, 157 neuron doctrine, 162 Histoire naturelle de l’½me (de La Mettrie), 630 “histological harpoon”, Duchenne de Boulogne, Guillaume Benjamin, 481, 482 The History of Paediatrics (Still), 317 Hitzig, Eduard, 123, 679 animal studies, 141 vicariation, 838 basal ganglia, 501 frontal lobes, 559–60 localization theory, 124 Querulantenwahnsinn, 679 HIV infection, tropical neurology, 826

INDEX HLA markers, narcolepsy, 552 Hobson, Benjamin, 761–2 Outline of Anatomy and Physiology, 762 Hodgkin, A L, 178–9 Hodgkin, Dorothy Crowfoot, 466 Hoffman, Johann facio-scapulo humeral dystrophy (FSHD), 487 limb-girdle dystrophies, 484–5 Hoffmann, Edward positron emission tomography (PET), 260 Hoffmann, H, muscular dystrophy, 477 Hoffmann, P, 183 Hoffmann, Theodore, 771 Hogarth, William, 285 Holmes, Gordon Morgan, 626 cerebellar examination, 228–9 hospital development, 312 neurophysiology, 169 sensory examination, 227–8 Holt, Emmett, 320 Holtz, Peter, 873 dopa decarboxylase, 873 noradrenalin, 872–3 Home´n, Ernst Aleksander, 659 homocysteine metabolism, 461 Honduras, 810 Hooke, Robert, 281 Hooper, Robert The Morbid Anatomy of the Human Brain, 423, 424 tuberculous meningitis, 423, 424 Hopf, H C, 223–4 Hopkins, Frederick, 436 Hopkins, Gowland, 439 Hornykiewicz, O, 508 Horsley, Victor, 197, 197–8 ancient trepanation, 10 antiseptics, 197 cortical epilepsy surgery, 197 craniotomies, 197 epilepsy, 394 imaging, 352 Queen Square Hospital, 310 spinal cord tumor removal, 197 tuberculoma removal, 198 Hospice Central at Ettelbruck (Luxemburg), 710 hospital(s), 303–16 18th Century, 306–8 19th Century, 306–8 20th Century, 312–13 Ancient Egypt, 304 Arabic/Islamic period, 305 child neurology, 329–30 Edinger, Ludwig, 311 Eisenlohr, Carl, 311 epilepsy, 387, 392–3 Foerster, Otfried, 311 Greco-Roman world, 304–5 Holmes, Gordon, 312 institutional specialization, 303 leprosy, 306

hospital(s) (Continued) Middle Ages, 305–6 Nonne, Max, 311 Oppenheim, Hermann, 311 plurality of, 303 post World War II, 313–14 professional specialization, 303, 308–12 Remak, Robert, 311 Renaissance, 305–6, 307 Victorian Britain, 303 Wallenberg, Adolf, 311 see also specific countries Hospital Clı´nico de la Ciudad Universitaria de Caracas, 808 Hospital de La Raza (Mexico), 810 Hospital Santo Toribio (Peru), 806–7 Hospital San Vicente de Paul (Chile), 807 Hospital Trudeau (Chile), 808 hot-water epilepsy, India, 819 Hounsfield, Godfrey computed tomography (CT), 259 positron emission tomography (PET), 260 Ho¨weler, Chris, 704 HTLV (human T-cell leukemia viruses), tropical neurology, 825 HTLV-1-associated myelopathy (HAM) Japan, 776–7 tropical neurology, 825 Huang Di Nei Ching, 756 Hubbenet, V von, 437 Hubel, David, 176 inborn neural connections/ organization, 176 visual cortical neurons, 172, 176 Huber, Johann Jacob, 155 Hughlings Jackson, John, 622, 622–3 agraphia, 586–7 alexia, 586–7 ancient trepanation, 10 aphasia, 571, 623, 843 cerebral dominance, 122–3 epilepsy, 387, 392, 393–4, 623 gross lesions, 394 seizure focus identification, 394 grammatic disorders, 577 motor pathways, 623 praxis assessment tests, 247 Queen Square Hospital, 621 striatal dysfunction, 501 A Study on Convulsions, 393, 623 Sydenham’s chorea, 517 ‘humors’ European Middle Ages, 82 Galen, 390 Italy, 719 Hun, Henry, 609 Hun, Thomas, 856 hunger, Mu¨ller, L R, 351, 351 Hunter, John Irvine, 783 anatomical studies, 156 mental status examinations, 214 pernicious anemia, 463 senses, 492

931 Hunter, William, 107 huntingtin protein, 519 Huntington, George, 517–18 neurological examinations, 214 Huntington’s disease, 368, 517–20 animal models, 520 CAG trinucleotide repeat, 519 “gain-of-function” hypothesis, 520 gene identification, 519 genetic linkage analysis, 518 Gusella, J F, 518 neural transplantation, 903 neurodegeneration, 520 Osler, William, 518 pathology, 518 restriction fragment length polymorphisms, 518 therapies, 611 Venezuela, 808 Hurst, A F, 463 Huss, Magnus, 658 Huxley, A F, 178–9 Hwa To, 764–5 hydrocephalus, compensated, Ancient Egypt, 34 hydrostatic models, Arabic/Islamic period, 68–9 hyperekplexia, 530 hyperglycemia studies, Bernard, Claude, 348 hyperhomocysteinemia, genetic polymorphisms, 461 hypochondria, 17th Century, 98–9 hypocretin, 552 cataplexy, 344 hypoglossal nerve (cranial nerve XII), 222, 222 hypokalemic periodic paralysis (HPP), 366 hypothalamo-neuro-hypophysial system (HNS), 336 hypothalamus, 335 autonomic function control, 344–55 blood supply, 340–1 electrical stimulation, 351–2 functions, 347–8 neuroendocrine grafts, 899–900 tracing techniques, 352 workers in Flerko´, B, 899–900 Gash, D M, 900 Gellhorn, E, 352 Gibson, M J, 900 His, Wilhelm, 335 Ingram, W, 352 Isenschmid, R, 347 Krieger, Dorothy, 900 Magoun, Horace, 174 neural transplantation, 899–900 Ranson, S, 352 Sladek, J R, 900 Szenta´gothai, J, 899–900

932 hysteria 17th Century, 98–9 Aretaeus, 56 Charcot, Jean-Martin, 211

I

al-iba¯dı¯, “ Hunayn ibn Isha¯q, 64 131 I-labeled trifluoroiodomethane, functional brain imaging, 258 Iceland, 661 An Idea of a New Anatomy of the Brain (Bell), 283, 619 ideomotor apraxia, tests for, 247 illustrations, 271–87 17th Century, 278–83 Ancient Egypt, 271 in Art, 284–6 Bell, Charles, 283 Bosch, Hieronymous, 285 Boyle, Robert, 281 Breughel, Peter, 285 Cajal, Santiago Ramo´n y, 284 Callot, Jacques, 285 Casserio, Giulio, 282 Charcot, Jean-Martin, 283–4 da Panicale, Masolino, 284 da Vinci, Leonardo, 273–4 Descartes, Rene´, 281–2 dissections, 273 Duplessi-Bertaux, Jean, 285 Estienne, Charles, 278, 279 Eustachio, Bartolomeo, 278, 280 Falloppia, Gabriele, 281–2 Golgi, Camillo, 284 Gru¨newald, Matthias, 285 Harvey, William, 281–2 Hogarth, William, 285 Hooke, Robert, 281 Livingstone, Margaret S, 285–6 Lower, Richard, 281 Oporinus, Johannes, 274–5 prehistory, 271–2 pre-Renaissance, 272–3 printing, 273 Purkinje, Jan Evangelista, 284 Renaissance, 273–8 Ribera, Jose´, 285 Rubens, Peter Paul, 286 Ruysch, Frederick, 283 van Calear, Jan Stefan, 275 Wood, Anthony, 281 Wren, Christopher, 281, 282 see also cinematography; photography image analysis, positron emission tomography (PET), 263 image averaging functional brain imaging, 265–6 positron emission tomography (PET), 262 image formation, al-Haytham, Ibn, 72, 72–3 imaging Clarke, R, 352 epilepsy, 398

INDEX imaging (Continued) functional see functional brain imaging headache, 385 Horsley, Victor, 352 neurophysiology, 178 United States, 611 see also specific methods immunocytochemistry, neuropeptide central pathway, 342–3 immunohistochemistry, subthalamic nucleus, 523–4 immunotherapy, bacterial meningitis therapy, 428 inborn neural connections/organization, 176 Inca, ancient trepanation, 5, 8, 9 India, 819–20 epilepsy, 389 lathyrism, 816 infants see child neurology infections Mesopotamia, 25 pellagra, 453–4 pernicious anemia, 463–4 Russia, 750 Scandinavia, 665 see also specific infections Information–Memory–Concentration Test, 250–1 infundibular (arcuate) nucleus, 336 Ingram, Vernon, 361–2 Ingram, W, 352 Ingvar, David Henschen, 663 functional brain imaging, 259 polysomnogram recordings, 550 In˜iguez, Roma´n Arana, 805 injuries, Ancient Egypt, 30 ‘injury currents’, 18th Century, 112 insanity, 17th Century, 103 Institute of General Pathology (Pavia), 728 Institut National de la Sante´ et de la Recherche Me´dicale (INSERM), 648 Instituto Nacional de Neurologia y Neurocirugı´a de Mejico (INNN), 810, 811 insulin, 348 The Integrative Action of the Nervous System (Sherrington), 170, 625 intelligence tests, 241–3 19th Century, 241 20th Century, 241–2 Binet, Alfred, 241 Knox, Howard, 241–2 Se´guin, Edouard, 242 Simon, Theodore, 241 Terman, Lewis, 242 USA immigration, 241–2 Wechsler, David, 242–3 Intercolonial Medical Journal of Australasia, 783 interictal EEG, epilepsy, 395

International Classification of Disease (ICD), cerebrovascular disease, 401 International League Against Epilepsy (ILAE), 388 internistische neurology, 311 intraocular grafts, neural transplantation, 889–94 see also anterior eye chamber model invisible, subtle fluids, 18th Century, 110–11 ion channels, 178–81 ionotropic glutamate receptors (iGluRs), 364 ion receptors, 178–81 ions, 178–81 irritability 18th Century, 109–10 von Haller, Albrecht, 721–2 Isenschmid, R, 347 Isha¯q, Hunayn Ibn, 65–6 Ishimori, Kuniomi, 773 isolated agraphia, 591 isoniazid, 430 Isserlin, Max, 578 Italian Journal of Neurological Sciences, 731 Italy, 719–35 19th Century, 724–6 Alzheimer’s disease, 724 asylums, 723 clinical neurology, 723 humoral theories, 719 Institute of General Pathology (Pavia), 728 journals, 730–1 Middle Ages, 720 neuropathology, 720 neuropsychiatric hospitals, 723 origins, 719–22 phrenology, 722 psychiatry, 726–30 Renaissance, 720 San Lazzaro Asylum, 727 San Salvi Clinic (Florence), 727–8 scientific societies, 730–1 Universities, 723 see also specific people Itard, Jean Marc Gaspard, 631 tics, 530 Itoˆ, Gemboku, 770

J Jacksonian epilepsy, 123 Jaeger, Eduard, 216 Jagannathan, K, 820 Jakob, Christofredo, 802 Jakobson, Roman aphasia, 571 neurolinguistics, 579 Jamaican neuropathy (Strachan’s syndrome), 816

INDEX James, William brain blood circulation, 258 memory assessment tests, 243 neural plasticity, 180 Principles of Psychology, 258 Jamieson, James, 783 Jansen, Jan Birger, 661 Japan, 769–79 20th Century, 773–7 adrenalin extraction, 773 adult T-cell leukemia (ATL), 776 autosomal recessive juvenile parkinsonism (AR-JP), 775 bulbospinal muscle atrophy, 774 cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), 775 “cerebral sleep substance”, 773 cerebrovascular disease, 775 Chinese medicine, 769 compressive myelopathy secondary to calcified ligaments in the spinal canal, 776 degenerative CNS diseases, 773–5 see also specific disease dementia with motor neuron disease, 773–4 diffuse Lewy body disease, 775 Dutch medicine, 769–71 European culture, 769 German medicine, 771–2 glial cytoplasmic inclusions (GCIs), 774 glycogen storage disease, 777 hereditary dentatorubral-pallidoluysian atrophy (H-DRPLA), 774 HTLV-1-associated myelopathy and tropical spastic paraparesis (HAM/TSP), 776–7 juvenile muscular atrophy of distal upper extremity (Hirayama disease), 776 Lewy body disease, 774–5 Moyamoya disease, 775 multiple system atrophy (MSA), 774 muscular dystrophy, 777 myelopathy, 775–6 myopathies, 777 neuroanatomy, 773 neuropathology, 773 neurophysiology, 773 olivopontocerebellar atrophy (OPCA), 774 Parkinson’s disease, 774–5 Segawa disease, 775 Shy–Drager syndrome (SDS), 774 spinocerebellar ataxia type 1 (SCA1), 774 striatonigral degeneration (SND), 774 subacute myelo-optic-neuropathy (SMON), 776 thiamin extraction, 773 see also specific people

Jasper, Herbert epilepsy EEG, 395 neurophysiology, 169 Jaspers, Karl, 680 jaw jerk, 223–4 al-Jazza¯r, Ibn, 69 Jelgersma, Gerbrandus, 711, 711–12 The Physiological Function of the Cerebellum, 712 Jelliffe, Smith Ely cerebellar examination, 229 mental status examinations, 215 Jendrassik, Erno¨ analysis of movement, 295 muscle tendon reflexes, 224 Jennekens, Frans G I, 701–2 Jensen, Viggo, 665 Jochmann, Georg, 429 Johannitius, 64 John of Ardenne, 614 John of Gaddesden, 614 Johnson, Samuel, 327 Jolliffe, N, 451 Jones, Robert, 855–6 journals see publications/journals Jouvet, Michel, 651 rapid eye movement (REM) sleep, 548 jumping, 529–30 Tourette’s syndrome vs., 531–2 Jung, Carl Gustav, 681–2 Jung, Richard, 685 polysomnogram recordings, 550 Jurin, James, 216 juvenile muscular atrophy of distal upper extremity (Hirayama disease), 776

K Kandel, Eric, 180 Kanner, L, 321 Kaplan, Edith aphasia cognitive assessment, 239–40 neuropsychology, 563 Kappers, J Arie¨ns, 698 Karplus, J, 344, 345 Karrer, Paul, 440 Katz, Bernard GABA, 878 synapses, 178–9 Katzman, Robert, 251 Kawahara, Hiroshi, 772, 772 bulbospinal muscle atrophy, 774 Kayser, Bernard, 513 Keefer, Chester, 429 Keen, William W, 609 surgical neurology, 199 Kemp, A, 701 Kennard, Margaret childhood brain damage, 324 vicariation, 839–40 Kennedy, Robert Foster, 621–2 Kenny, Elizabeth, 784 physical rehabilitation, 854 keratomalacia, 437–8 see also night blindness

933 Kerner, Justinius, 670 Kernig, Vladimir, 748 bacterial meningitis, 427 meningismus, 229 Kernig’s sign, 427, 427 Kety, Seymour, 258 Kimura Jun, 225 King, Helen Dean, 143 Kirkes, William, 408 Kirkland, Thomas, 402 Kleist, Karl, 578 Kleitman, Nathaniel rapid eye movement (REM) sleep, 548 sleep, 651 Klien, H, 348 Klumpke, Augusta, 640–1, 641 knee jerk, 222 Sherrington, Charles Scott, 170 Knox, Howard, 241–2 Knox’s Cube Imitation Test, 242, 242 Koch, Robert, 427 Kocher, Emil Theodor, 687 Koelliker, Rudolf Albert von, 161, 675 Ko¨hler, August, 339 Ko Hung, 763 Ko¨lliker, A, 161 Ko¨lliker–Fuse nucleus, 773 Kolvin, Israel, 321 Konovalov, Nikolai Vasil’evich, 750 “konzo”, 818 Democratic Republic of Congo, 818 tropical neurology, 825 Kopp, J H, 525 Korsakoff, Sergei, 449, 740, 740 memory assessment tests, 244 Korsakoff’s syndrome, 449, 740 Wernicke’s encephalopathy vs., 449–50 Kozhevnikov, Alexei Yakolevich, 738, 738–42 aphasia, 739 epilepsy, 739 Nervous Diseases and Psychiatry, 738–9 Kraepelin, Emil, 679 Krafft-Ebing, Richard von, 682 Kramer, Vasily Vasil’evich, 743, 750 Krause, Fedor, 199 Kravitz, E, 879 Kriedl, A, 344, 345 Krieger, Dorothy, 900 Kriegssanitätsordnung, 312–13 Krol’, Mikhail Borisovich, 743, 750 Krusen, Frank H, 855 physical rehabilitation, 854 Kuffler, S W, 172 Kugelberg, Eric, 663, 664 electromyography, 183 glabellar reflex, 225 Kuhlo, W, 550 Kuhn, Roland, 685 Ku¨hne, Willy, 438–9 Kulmus, Johann Adam, 770 Kunkle, E C, 505 Kuno, Yas, 773

934 Kurland, Len, 820 kuru, 368, 820–1 Kussmaul, Adolf alexia, 589 language comprehension localization, 576 speech blindness, 589 text blindness, 589 University of Strasbourg, 650 word blindness, 589 Kuypers, Henricus G J M, 165 kwashiorkor, 818

L Laennec, R T H, 205 Lakke, J P W F, 702 La Mettrie, Julien Offray de, 630 Lance, James Waldo, 529, 796 Lance–Adams syndrome (posthypoxic action myoclonus), 529 Lange, Carl Georg, 665 Lange, Oswaldo, 804–5 Langley, John Newport, 625 adrenalin, 870 Langston, J W, 512 language antilocalizationist theories, 578–9 Broca, Paul, 121 cognitive development, 847–8 Ribot, T, 843 disorders age effects, 843–4 see also specific diseases/disorders localization, 575–6 Baginsky, Adolf, 576, 576 Charcot, Jean-Martin, 576, 634 Dax, Gustave, 634–5 Dax, Marc, 634–5 diagrams, 576, 576 Henschen, Solomon, 596 Lashley, Karl, 596 Lichtheim, Ludwig, 576, 577 Marie, Pierre, 596 Nielsen, J M, 596 Nielsen, Johannes M, 596 von Monakow, Constantin, 596 Wernicke, Carl, 575–6, 596 models, Geschwind, Norman, 598 see also neurolinguistics La Psichiatria la Neurologia e le Scienze Affini, 730 Laruelle, Le´on, 708 laryngeal nerve, Galen, 56 Lashley, Karl animal studies, 142 antilocalizationist tendencies, 173–4 cerebral cortex, 142 inborn neural connections/ organization, 176 language center localization, 596 vicariation, 838–9 Lasker, Mary, 611 Lassen, Neils A, 663 functional brain imaging, 259

INDEX Latham, Oliver, 785 lathyrism, 816 Latin America, 801–14 Caribbean, 810–11 Central America, 809–10 Latin North America, 810–11 Pan American Congress, 811 South America, 801–9 see also specific countries Latin North America, 810–11 Lauterbur, Paul, 264 Lavater, Johann Christian, 573 Leavitt, S, 528 Lectures on Diseases of the Nervous System (Wilks), 622 Lee, C Y, 875 Leegaard, Christopher Blom, 660 Leeuwenhoek, Antony van, 154, 154 Le Gros Clark, W E, 891 spinal cord regeneration, 892–3 Leksell, Lars, 663 Lennmalm, Frithiof, 658–9 Lennox, William EEG, 183, 395 epilepsy, 395 pediatric epilepsy, 320 de Leo´n, Jacinto, 805 Le´pine, Jean, 651 Le Pois, Charles, 378–9 leprosy Chen Yeng, 763 Chu Tan-chi, 763 European Middle Ages, 86, 87–8 Hansen, Gerhard Armauer, 661 hospitals, 306 Ko Hung, 763 Middle Ages, 306 Sun Si-miao, 764 traditional Chinese medicine (TCM), 763, 764 tropical neurology, 819 Leriche, Rene´, 651 lesions athetosis, 520 Broca, Paul, 574–5 Charcot, Jean-Martin, 210 EEG, Bremer, Fre´de´ric, 174 functional localization, 174 Gall, Franz Joseph, 120 Macewen, William, 195, 195 von Gudden, Bernhard, 679 Letter-, Word- and Mind-Blindness (Hinshelwood), 593–4, 596 Leuret, Franc¸ois, 156, 633 Levinsen, G M R, 816 Levy-Valensi, Joseph, 645 Lewandowsky, Max, 870 Lewis, Morris, 223 Lewy bodies Parkinson’s disease, 507, 510 Tre´tiakoff, C, 507 Lewy body disease, Japan, 774–5 lexicon, epilepsy, 393 Leydig, Franz, 160

Lhermitte, Franc¸ois, 643, 644, 644 Lhermitte, Jean, 644 Lichtheim, Ludwig aphasia studies, 215–16 language comprehension localization, 576, 577 Liepmann, Hugo apraxia, 597 praxis recognition, 247 life forces, 18th Century, 110 ligand-gated ion channels, 179–80, 364 mutations, 366 see also specific ion channels Likhterman, Boleslav Vladimirovich, 748 Lima, Almeida, 562 Lima, Anto˜nio Austrege´silo Rodrigues, 804 limb-girdle dystrophies, 484–7 Erb, Wilhelm Heinrich, 484–6 Friedreich, Nikolaus, 484–5 Hoffman, Johann, 484–5 Natrass, F J, 486–7 Walton, J N, 486–7 Lindemulder, F G, 528 Line bisection tasks, 245, 247 lipodystrophy, 348, 351 Goering, D, 348, 350 Lister, Joseph Jackson, 192 anatomical studies, 157 surgical neurology, 191–3 Listeria, bacterial meningitis, 427 Little, William John, 321–2 infantile cerebral paralysis, 846 Liveing, Edward, 622 vasogenic vs. neurogenic “nerve storm” headache theory, 384, 385 Livingstone, David, 437 Livingstone, Margaret S, 285–6 Lobstein, Jean Frederic, 650 Localization of Cerebral Disease (Ferrier), 125 localization theory, 117–28, 844–5 anatomical evidence, 125 Bianchi, Leonardo, 124 cerebral dominance, 122–3 Charcot, Jean-Martin, 209–10 frontal cortex lesions, 124–5 frontal lobes, 559–60 Galenism, 63–4 Gowers, William Richard, 845 Hitzig, Eduard, 124 language see language motor cortex, 123 surgical evidence, 125 see also functional localization Locke, John child neurology, 327 epilepsy, 391–2 Locock, Charles pediatric epilepsy, 319–20 potassium bromide, use of, 393 locomotor ataxia, Charcot, Jean-Martin, 210 Loeb, Jacques, 142 Loewi, Otto, 875

INDEX Lombroso, Cesare, 723 pellagra, 453 London Infirmary for Epilepsy and Paralysis, 310 Long, Crawford W, 191 Longo, Paulino Watt, 804–5 long-term depression (LTD), 180–1 long-term-potentiation (LTP), 180 Loomis, Lee, 547 Lo´pez, Miguel Jime´nez, 809 Lordat, Jacques agraphia, 584 alalia, 635 aphasia, 584, 635 language comprehension localization, 575 Montpellier Medical School, 649 Louis, Pierre, 423 the Low Countries, 691–717 bilingualism, 692–3 Franco-Prussian War, 695 geopolitical background, 691–2, 692 institutes, 696–700 journals, 696–700 Luxemburg, 709–10 neurosurgery, 695–6 societies, 696–700 World War I, 695 see also Belgium; The Netherlands Lower, Richard, 96 anatomical studies, 153 apoplexy, 404 illustrations, 281 Lucas-Championnie`re, 191 Luciani, Luigi, 725–6 Luco, Augusto Orrego, 807, 807 Lucretius, vertigo, 494 Ludwig, Carl, 675 animal studies, 140 Lugaro, Ernesto, 724 Lund, Johan Christian, 664 Lund, Otto, 295 Lund, Ray, 897 Lundborg, H, 528 Lunin, Nicolai I, 436 Luria, Aleksandr Romanovich, 859 aphasia rehabilitation, 857–8 cognitive assessment, 235 cognitive rehabilitation, 859–60 frontal lobes, 562 Higher Cortical Functions in Man, 562 praxis assessment tests, 247–8 Restoration of Brain Functions after War Trauma, 751 Traumatic Aphasia, 751 Luschka, Hubert von, 157 luteinizing releasing factor (LRF), 341 Luxemburg, 709–10 Luys, Jules, 522–3 Lyon, 651–2 lypophilic dyes, anterograde tract tracing, 165 Lysholm, Erik, 659

M MacKenzie, Donald, 788 McBride, David, 419 McBride, Katherine aphasia, 579 cognitive assessment, 239, 240 McCarthy, Daniel J, 225 McCollum, Elmer Verner, 439 McHugh, Paul, 251 McIntyre, Archibald Keverall, 796 McLeod, James Graham, 796 macaques, single-neuron studies, 172 Macewen, William, 194, 194–6 epilepsy, 394 lesion studies, 195, 195 post-mortem studies, 194–5 right hemispheric damage, 195 tumor studies, 195 Mach, Ernst, 687 vertigo, 495 macroadenoma, The Bible, 39 macrocephaly, Ancient Egypt, 34 madness, 17th Century, 103–4 Madrazo, I, 901–2 Maeno, Ryoˆtaku, 770 Magendie, Franc¸ois anatomical studies, 156 animal studies, 138–9 aphasia studies, 215 apoplexy, 407 corneal ulceration, 437 cranial nerve I, 216 experimental medicine, 633 keratomalacia, 437 Recherches sur le Liquide CéphaloRachidien, 139 reflex testing, 222 magic, European Middle Ages, 85, 86–7 Magini, Giuseppe, 163–4 magnetic resonance imaging (MRI), 184, 263–5 Block, Felix, 264 blood oxygen level dependent (BOLD) contrast, 264–5, 266 Coryell, Charles, 264 epilepsy studies, 398 frontal lobes, 563 instrumentation, 263–4 Lauterbur, Paul, 264 Ogawa, Sieji, 264 Pauling, Linus, 264 Purcell, Edward, 264 magnetoencephalography (MEG), 184 epilepsy studies, 398 Magoun, Horace, 174 brainstem reticular formation, 175 hypothalamus studies, 174 sleep, 547–8 Malacarne, Vincenzo, 721 anatomical studies, 155 Les Maladies Nerveuses (van Gehuchten), 299

935 malformations of cortical development (MCDs), 398 malnutrition, infantile, 818–19 Malpighi, Marcello anatomical studies, 154 animal studies, 132 De Cerebri Cortice, 154 De Cerebro, 154 De Externo Tactus Organo, 154 De Lingua, 154 Exercitationes de Structura Viscerum, 132 microscopy, 720 Mantegazza, Paolo, 723 Manual of Diseases of the Nervous System (Gowers) see Gowers, William Richard marasmus, 818 Marat, Jean-Paul, 630 Marcantonio della Torre, 274 Marce´, Louis Victor, 584–5 Marchi, Vittorio, 726 anterograde tract tracing, 164 Marchiafava, Ettore, 725–6 Marchiafava–Bignami disease, 726 Marey, E´tienne-Jules analysis of movement, 293, 294–5 cinematography, 296 Marie, Pierre, 578, 641–2 aphasiacognitiveassessment,236–7,642 language center localization, 578, 596 Marinesco, Georges analysis of movement, 295 cinematography, 297, 298 palmomental reflex, 225 Parkinson’s disease pathology, 507 maristans, 305 Marseille, 652–3 Martin, Paul, 695 Martin J P, 523 Marxow, Ernst Fleischl von, 682 Ma¯sawayh, Yuhanna¯ ibn, 64–5 ˙ ´ , ˙151 Massa, Nicolo Masson, Pierre, 876 Maastricht, State University, 704–5 Matsumoto, Ryoˆjun, 771 Matteucci, Carlo action of nerves on muscles, 493 animal studies, 138 neurotransmitters, 869 Matthey, Andre´, 422 Matuszewski, Boleslav, 296 May, Raoul, 889–91 Mayo, Charles H, 609 MécanismedelaPhysionomieHumaine (DuchennedeBoulogne),291,291 Medawar, Peter, 888 medial frontal/anterior cingulate circuit, 564, 565 Medical Inquiries and Observations upon Diseases of the Mind (Rush), 605 medical rehabilitation, 853–5 Medieval medicine, headache, 378, 378

936 Medin, Oscar, 665 Medoc, Juan, 805 Meerdervoort, J L C Pompe van, 770–1, 771 Mejı´a, Jose´ Maria Ramos, 801–2 melancholy, 17th Century, 103 Melbourne University, 796 Melkersson–Rosenthal syndrome, 664 membrane proteins, 363–6 membrane insertion, 363–4, 364 Mémoires sur la Nature Sensible et Irritable des Parties du Corps Animal (von Haller), 135 Mémoire sur l’électricité médicale (Marat), 630 memory assessment tests, 243–4 Binet, Alfred, 244, 244 Simon, Theodore, 244, 244 Milner, Brenda, 178 synaptic hypothesis, 180 Memory Scale, Wechsler, David, 243 Mendel, Lafayette, 439 Me´nie`re, Prosper, 495 meningioma, Ancient Egypt, 34 meningismus, 229–30 meningitis Ancient Egypt, 33 bacterial see bacterial meningitis epidemic, 421–2 Mesopotamia, 24 meningomyelocele, The Talmud, 45 mental retardation, children, 317–19 meridian system, traditional Chinese medicine (TCM), 756 Merritt, Houston anticonvulsants, 609 bacterial meningitis, 428 epilepsy therapy, 396 tuberculous meningitis, 425–6 Meryon, Edward childhood muscle disorders, 322 muscular dystrophy, 477, 479–81 Merzheevsky, Ivan Pavlovich, 743, 744 mesenteric tumor studies, Willis, Thomas, 282–3 Mesmer, Franz Anton, 110–11, 670 animal studies, 137–8 Mesopotamia, 15–27 anatomy, 18, 20 ãipu, 18–19 asû, 18–19 basal ganglia disorders, 24 brain, views of, 20 brain abscesses, 23 brain tumors, 23 cerebral malaria, 25 cerebral palsy, 24 coma, 21 cranial example, 22 diagnoses, 20 epilepsy, 21–2 floppy baby syndrome, 24 head, 20

INDEX Mesopotamia (Continued) headache, 20 health and healing theories, 16–18 demons, 17 external supernatural “hands”, 17–18 gods and deities, 17 quality of life, 17 historical context, 15–16 infantile seizures, 21 infectious neurological disease, 25 knowledge base, 19–20 medical texts, 17, 19 medical training, 18–19 meningitis, 24 motor impairments, 20–1 neurofibromatosis, 24 organs, 20 paralysis, 20–1 Parkinson’s disease, 24 pediatric neurology, 24 pharmacology, 19 “magic” vs., 18–19 rabies, 25 sakikku (symptoms), 19–20 seizures, 21–2 sensory impairments, 20–1 spinal cord trauma, 22–3, 23, 272 stroke, 23–4 tetanus, 25 Tourette’s syndrome, 24–5 Mestrezat, William, tuberculous meningitis, 424–5 Mesue, 64–5 Mesulam, M-M, 564 metabolic tremor, 528–9 metabolism, functional brain imaging, 259 metal poisoning, traditional Chinese medicine (TCM), 762 The Method of Physic (Barrough), 614 methotrexate, 459 methylenetetrahydrolate reductase, 461 Mettler, F A, 523 metu, Ancient Egypt, 31 Mexico, 810–11 Instituto Nacional de Neurologı´a y Neurocirugı´a de Mejico (INNN), 810, 811 Neolithic trepanation, 6–7 Meyer, Andre´, 681, 681 University of Strasbourg, 651 Meyers, R, 508 Meynert, Carlo, 165 Meynert, Theodor, 682 microneurography, 184 microscopy 18th Century, 108, 108–9 anatomical studies see anatomy Cajal, Santiago Ramo´n y, 159 Charcot, Jean-Martin, 206–7 development, 157 Dutrochet, Rene´ Joachim-Henri, 157 Ehrenberg, Christian Gottfried, 157 Golgi, Camillo see Golgi, Camillo

microscopy (Continued) Hannover, Adolph, 158 Malpighi, Marcello, 720 peripheral nervous system (PNS), 346 Purkinje, Jan Evangelista, 157–8 Remak, Robert, 158 Rosenthal, Joseph F, 157 Valentin, Gabriel, Gustav, 157 Virchow, Rudolf, 158 von Bru¨cke, Ernst Wilhelm, 674 microtomes, 157 Middle Ages Europe see Europe France, 629 hospitals, 305–6 Italy, 720 leprosy, 306 migraine 17th Century, 101 Ancient Egypt, 33 aura, first identification, 379 Galen, 377 Piso, Carolus, 92 The Talmud, 43–4 see also headaches Miller, Douglas, 789 Millington, Thomas, 96 Mills, Charles K agraphia studies, 216 aphasia rehabilitation, 857 cerebellar examination, 228 cranial nerve IV (trochlear nerve), 218–19 cranial nerve V (trigeminal nerve), 219 cranial nerve XI (accessory nerve), 221–2 hearing, 221 pupillary reaction testing, 217–18 temperature sensation testing, 227 visual field testing, 217 Milner, Brenda, 178 Minderhoud, J, 702 Mingazzini, Giovanni, 725 Mini-Mental State Examination (MMSE), 215, 251–2 Minor, Lazar’ Solomonovich, 742, 743 Minot, G R, pernicious anemia, 463–5 liver therapy, 464–5 Mintun, Mark, 262 Mir, Le´on, 808 mirror neurons, 173 miryachit, 530 Hammond, William A, 530 Mistichelli, Domenico anatomical studies, 155 apoplexy, 405 Mitchell, H K, 458 Mitchell, John K, 610 Mitchell, Silas Weir, 606, 607 athetosis, 520–1 Civil War, 607 phantom limbs, 493 Pickwickian syndrome, 549–50 professional specialization, 308 surgical neurology, 199

INDEX Mitsuyama, Y, 773 Miura, Kinnosuke, 772–3 Mo¨bius, Paul Julius, 680 modularity, 597–9 molecular biology, 361–72 Alzheimer’s disease, 369 biomembrane see biomembranes channelopathies, 180 definition, 361 gap-junction pathologies, 367 genome sequencing, 365–6 genomics, 369–70 multiple sclerosis (MS), 369 muscular dystrophy, 457–88 myasthenia gravis, 369 origins, 361–2 Parkinson’s disease, 369 prions/prion disease, 368–9 Schmitt, Francis O, 362 time line, 370 trinucleotide repeat expansion diseases (TREDS), 368 Mollaret, Pierre, 642 Mollin, D L, 466 Molotkov, Alexei, 746 Monakow, Constantin von see von Monakow, Constantin Mondino, Casimiro, 724 Moniz, Egas carotid artery studies, 410 prefrontal leucotomy, 562 psychosurgery, 725 monkeys, animal studies, 141 Monrad-Krohn, Georg Herman, 660, 660 cranial nerve VII (facial nerve), 220 pain testing, 227 Monte Alba´n, Neolithic trepanation, 6–7 Montevideo School of Medicine, 805, 806 Montpellier, 648–9 Montreal Neurological Institute, 610 Moore, D F, 817 Morbid Anatomy (Baillie), 406 The Morbid Anatomy of the Human Brain (Hooper), 423, 424 Morbis Artificum Diatriba (Ramazzini), 379 Morgagni, Giovanni Battista animal studies, 132 aphasia, 572–3 apoplexy, 405 De Sedibus et Causis Morborum per Anatomen Indagatis, 405 muscular dystrophy, 477 neuropathology, 720 post-mortem examinations, 573 Mori, Masamichi, 437 Morin, Georges, 653 morphine, 381 Morselli, Enrico, 724 Morton, Charles, 423 Morton, William, 191

Moruzzi, Giuseppe, 172 action potentials, 172 brainstem reticular formation, 175 sleep, 547–8 Moscati, Pietro, 722 Moscow School of Neuro(path)ology, 738–42, 739 Moss, Gerald Carew, 790 Mosso, Angelo, 171 brain blood circulation, 258 motion aftereffect, Aristotle, 491–2 motion parallax, 497 motivation, 566 medial frontal/anterior cingulate circuit, 565 motor circuits, 564 Hughlings Jackson, John, 623 motor cortex localization, 123 Ferrier, David, 123–4 Fritsch, Gustav, 123 Hitzig, Eduard, 123–4 Sherrington, Charles Scott, 171 Swedenborg, Emmanuel, 117–18 motor nerves, sensory nerves vs., 54 motor neuron disease (Madras type), India, 820 motor strength examination, 226 Mott, Frederick, 625 Mountcastle, V B, 172 Moutier, Franc¸ois aphasia cognitive assessment, 237 visuospatial/visuoconstructive skill tests, 245, 246 movement, analysis of Brown-Se´quard, Charles-E´douard, 293 Demeny¨, Georges, 295 Jendrassik, Erno¨, 295 Lund, Otto, 295 Marey, E´tienne-Jules, 293, 294–5 Marinesco, Georges, 295 Muybridge, Eadweard James, 293 Pepper, William, 293 photography, 293–5 Richter, Paul, 295 Stanford, Leland, 293 von Helmholtz, Hermann, 293 movement disorders, 501–46 19th Century, 501 Barbeau, Andre´, 502 cinematography, 297 clinical features, 501 Gowers, William Richard, 501–2 Scandinavia, 663 tremor see tremors see also basal ganglia Moxon, Walter, 844 Moyamoya disease, 775 MPTP, 512 Mudrov, Matvei Yakovlevich, 737 Muller, George, 710 Mu¨ller, Johannes, 672–3, 673 animal studies, 139 Handbuch der Physiologie, 673 phantom limbs, 494

937 Mu¨ller, Johannes (Continued) senses, 492 sensory examination, 227 Mu¨ller, Leopold, 771 Mu¨ller, L R, 351, 351 multiple labeling techniques, anterograde tract tracing, 165 multiple sclerosis (MS) Australia, 783 Charcot, Jean-Martin, 207, 210 molecular biology, 369 neural transplantation, 904 Parkinson’s disease vs., 207, 210 Scandinavia, 664–5 Multiple Sleep Latency Test (MSLT), 552 multisystem atrophy (olivo-pontocerebellar degeneration) (MSA), 514–15 Japan, 774 mummification Alexandrian medicine, 53 Ancient Egypt, 31–2 Municipal University of Amsterdam, 703 Munk, Hermann, 675 visual field testing, 216 Muratov, Vladimir Aleksandrovich, 741, 741 encephalitis, 741 epilepsy, 741 Murphy, J B, 887–8 Murphy, W P, pernicious anemia, 463–5 liver therapy, 464–5 muscle biopsy, Denny-Brown, Derek, 788 muscle disorders, child neurology, 321–2 muscle tendon reflexes, 222–4 Bowditch, Henry Pickering, 224 Erb, Wilhelm Heinrich, 222 Gowers, William Richard, 222, 223, 223 Jendrassik, Erno¨, 224 modifications, 224 Warren, Joseph W, 224 Wartenberg, Robert, 223 Westphal, Carl Friedrich Otto, 222 muscular dystrophy, 477–88 19th Century, 477 nomenclature, 487 early descriptions, 477, 479–84 Japan, 777 limb-girdle dystrophies see limb-girdle dystrophies molecular biology, 457–88 workers in Becker, Peter, 484 Canani, G B, 477, 478 Conte, Gaetano, 477, 479 Dejerine, Joseph Jules, 477 Erb, Wilhelm Heinrich, 477 Galvani, Luigi, 477 Gioja, L, 479 Gowers, William Richard, 479 Hoffmann, Edward, 477

938 muscular dystrophy (Continued) Meryon, Edward, 477, 479–81 Morgagni, Giovanni Battista, 477 Semmola, Giovanni, 477, 479, 479 Vesalius, Andreas, 477, 478 see also specific types Musculorum Humani Corporis Picturata Dissecto (Canani), 477, 478 Muskens, L J J, 696 Muybridge, Eadweard James analysis of movement, 293 Animal Locomotion, 294, 294 myasthenia gravis, 874–5 17th Century, 103 molecular biology, 369 pharmacological therapy, 180 Walker, Mary Broadbent, 874 Mycobacterium tuberculosis, bacterial meningitis, 427 myeloarchitectural subdivisions, cerebral cortex, 174 myelomeningocele, 459 myelopathy, Japan, 775–6 My Left Foot (Brown), 328 myoclonic epilepsy, 528 Lundborg, H, 528 myoclonic seizures, EEG classification, 396 myoclonus, 526–9 essential, 526, 528 secondary (symptomatic), 528 see also specific types myopathies, Japan, 777 myotonic dystrophy, 368

N Nachmansohn, D, 363 NAD (nicotinamide adenine dinucleotide), 457 NADP (nicotinamide adenine dinucleotide phosphate), 457 al-Nafı¨s, Ibn, 65 Naming and Recognition of Common Objects, Head’s Serial Tests, 238 Nansen, Fridtjof, 661 animal studies, 142 neuron doctrine, 162 narcolepsy, 552 Caton, Richard, 549 von Economo, Constantin, 547 narcotics, bacterial meningitis therapy, 428 National Institute of Mental Health and Neurological Sciences (NIMHANS) Bangalore, India, 819 Natrass, F J, 486–7 Natural Theology (Paley), 136 Nauta, Wally J H anterograde tract tracing, 164–5 sleep, 547 Nazi Germany, 313 euthanasia practices, 313 children, 328 forced sterilization practices, 313

INDEX Nazi Germany, (Continued) military medical service, 313 Negro, Camillo, 728 cinematography, 297–8 Nei Ching, 756, 757–8, 762 Neisseria meningitidis, bacterial meningitis, 426 Nelson, Cliff, 821–2 Nemesius, 63 Neolithic period, bacterial meningitis, 417 Neolithic period (New Stone Age), ancient trepanation, 3, 4–5, 6, 9 nerve(s)/neuron(s) Arabic/Islamic period, 66 Descartes, Rene´, 337 Forel, Auguste, 680 inborn connections/organization, 176 nerve conduction, 183–4 Arabic/Islamic period, 66 du Bois-Reymond, Emil, 493 Erlanger, Joseph, 609 Galvani, Luigi, 492 Gasser, Herbert Spencer, 609 United States, 609 Volta, Alessandro, 492–3 Nerve Injuries Committee of the British Research Council, 226–7 Nervenheilanstalten, German hospitals, 310–11 “nerves of voice”, Galen, 130 Nervous Diseases and Psychiatry (Kozhevnikov), 738–9 The Netherlands, 693–4 Central Institute for Brain Research (Amsterdam), 698 Netherlands Association of Psychiatry, 694 Netherlands Society of Neurology, 697 neurosurgery, 695–6 1907 Congress, 697–8 psychiatric care, 694 Society of Amsterdam Neurologists, 698–9 Universities, 700–5 Free University of Amsterdam, 702–3 Municipal University of Amsterdam, 703 Rotterdam University, 704 State University of Maastricht, 704–5 University of Groningen, 702 University of Leiden, 694, 700–1 University of Nijmegen, 704 University of Utrecht, 701–2 Netherlands Association of Psychiatry, 694 Netherlands Society of Neurology, 697 Neufeld, Friedrich, 426 neural pathways, anatomical studies, 164–5

neural plasticity, 180–1 neural transplantation, 885 neural transplantation, 885–912 aging animals, 899 Alzheimer’s disease, 904 animal models vs. human disease, 905 anterior eye chamber, 886–8, 895–6 autoradiographic studies, 894 axon sprouting, 893 brain as privileged site, 886–8 catecholaminergic system central grafting, 896–7 cell identification, 893 cell sources, 904 cerebellum grafts, 894–5 cholinergic system central grafting, 896–7 chronic vs. acute disease, 905 clinical trials, 904 early work, 885–6, 887 electron microscopy, 893 embryonic tissues, 896 functional recovery, 885, 894, 904–5 graft function mechanisms, 901, 901 hippocampal grafts, 899 Huntington’s disease, 903 hypothalamic neuroendocrine grafts, 899–900 intraocular grafts, 889–94 multiple sclerosis, 904 neural tissue into brain, 888–9 neuronal plasticity, 885 nigral grafts, 897–8 Parkinson’s disease, 901–3 adrenal grafts, 901–2 fetal nigral grafts, 903 spinal cord bridges and repair, 900–1, 904 spinal cord regeneration, 891–3 stroke, 904 visual system reconnection, 897 workers in Altobelli, R, 889 Arnold, H, 889 Bjo¨rklund, Anders, 896 Cajal, Santiago Ramo´n y, 888 D’Abundo, G, 889 Del Conte, G, 889 Dunn, Elizabeth, 888, 889, 890 Forssman, J, 888 Greene, H S N, 889 Murphy, J B, 887–8 Raisman, G, 890 Saltykow, S, 888–9 Sturm, E, 887–8 neural tube defects, 458–61 Hibbard, Brian, 459 Smithells, Richard, 459 therapy/prevention, folate administration, 459–61 see also folate, deficiency neuroanatomy see anatomy Neurobiologia, 804

INDEX neurochemistry frontal lobes, 567 Parkinson’s disease, 508 subthalamic nucleus, 523 neurodegeneration frontal lobes, 563 Huntington’s disease, 520 neuroembryology Edinger, Ludwig, 163 Magini, Giuseppe, 163–4 Remak, Robert, 163 von Baer, Karl Ernst, 163 Westphal, Carl Friedrich Otto, 163 neuroendocrinology, 335–60 Bargmann, Wolfgang, 339 current definitions, 335 early 20th Century, 348 neurons, 339–40 releasing factors, 341 see also specific releasing factors Scharrer, Ernst, 339 Speidel, Carl Casky, 339 see also specific hormones neurofibromatosis, Mesopotamia, 24 neurofibromatosis type 1 (von Recklinghausen’s disease), 369 neurofibromatosis type 2, 369 Neurographia Universalis (Vieussens), 105 neurohypophysis, 338–40 Collin, R, 338 Cushing, Harvey, 338–9 Dale, Henry, 339 Herring, P T, 338 neuroimaging see imaging neurolinguistics, 579–80 Alajouanine Th, 643, 643 Caramazza, Alfonso, 579 Chomsky, Noam, 579–80 Geschwind, Norman, 579 Goodglass, Harold, 579 Jakobson, Roman, 579 Zurif, Edgar, 579 see also language neurological diseases/disorders Aldini, Giovanni, 137 European Middle Ages, 85–8 traditional Chinese medicine (TCM), 762 Neurological Disorders and Stroke, (NINDS), muscle tendon reflexes, 223 neurological examinations, 213–33 agraphia, 216 aphasia, 215–16 cerebellar examination, 228–9 cranial nerves, 216–22 see also specific cranial nerves gait, 229 meningismus, 229–30 mental status examination, 214–15 motor strength, 226–7 neurological history, 214 reflexes, 222–3 see also specific reflexes

neurological examinations (Continued) sensory examination, 227–8 station, 229 textbooks, 213 workers in Binet, Alfred, 215 Charcot, Jean-Martin, 213 Church, Archibald, 214 Friedreich, Nikolaus, 214 Gowers, William Richard, 213–14 Hunter, John, 214 Huntington, George, 214 Jelliffe, Smith Ely, 215 Peterson, Frederick, 214 Sachs, Bernard, 214 White, William Alanson, 215 Worcester, William, 214 see also specific types neurological illustrations see illustrations Neurological Society of London, 613 Neurologie du Médecin Practicien (Van Gehuchten), 713 neuromodulators, central pathways, 341–4 neuronal channelopathies, 180 neuron doctrine anatomical studies, 159, 162–3 Cajal, Santiago Ramo´n y, 162–3 Forel, Auguste, 162 His, Wilhelm, 162 Nansen, Fridtjof, 162 Sherrington, Charles Scott, 162 neuronal hippocampal map, 173 neurons see nerve(s)/neuron(s) neuropathology ancient trepanation vs., 5–6 Australia, 785 Bianchi, Leonardo, 725 German-speaking countries, 677 Italy, 720 Japan, 773 Marchiafava, Ettore, 726 Morgagni, Giovanni Battista, 720 Scandinavia, 661–2 neuropathy, epidemic, 817 neuropeptides, 336 central pathway, De Wied, D, 342 Cushing, Harvey, 341–2 see also neuromodulators; neurotransmitters; specific neuropeptides neurophysins, early work, 340 neurophysiology, 169–88 Adrian, Edgar Douglas, 177 consciousness and memory, 177–8 event-related potentials, 182 evoked potentials, 182 German-speaking countries, 686–7 Holmes, Gordon, 169 imaging, 178 Japan, 773 Jasper, Herbert, 169

939 neurophysiology (Continued) neuron conduction studies see nerve conduction Pavlov, Ivan Petrovitsch, 171, 177 pharmacology, 180 Sherrington, Charles Scott, 170 subthalamic nucleus, 523 Vogt, Oskar, 684 neuropsychology Dejerine, Joseph Jules, 641 frontal lobes, 563 Goodglass, Harold, 563 Kaplan, Edith, 563 Quaglino, Antonio, 722 Vogt, Oskar, 684 neurosurgery see surgical neurology neurotransmitters, 869–83 amino acids, 877 Borelli, Giovanni Alfonso, 869 central pathways, 341–4 chemical neuroanatomy, 175 Descartes, Rene´, 869 du Bois-Reymond, Emil, 869 early work, 859 Eccles, John Carew, 869 frontal lobes, 567 Galvani, Luigi, 869 Matteucci, Carlo, 869 see also specific neurotransmitters Neville, A, 439 Newland, Henry, 788 Newman, Alfred Kingcombe, 783 Newton, Isaac anatomical studies, 155 color vision, 492 New Zealand, 792–3 geography, 782 niacin, 456 deficiency see pellagra Elvehjem, Conrad Arnold, 456 tryptophan metabolism, 457–8 nicotinamide adenine dinucleotide (NAD), 457 nicotinamide adenine dinucleotide phosphate (NADP), 457 nicotinic acetylcholine receptors (nAChRs), 363 diseases/disorders, 369 Nielsen, Johannes M cognitive assessment, 252, 252 language center localization, 596 Nigeria epidemic neuropathy, 817 Nigerian Society of Neurological Sciences (NSNS), 823 seasonal ataxia syndrome, 826 Nigerian Society of Neurological Sciences (NSNS), 823 night blindness, 437–8 see also keratomalacia nightmare (incubus), 17th Century, 102 nigral grafts, neural transplantation, 897–8 1907 Congress, The Netherlands, 697–8

940 nineteenth Century alexia, 583–5 animal studies, 138–40 anti-vivisectionist movement, 139 localization studies, 138 aphasia, 583–5 rehabilitation, 856 bacterial meningitis, 418–19, 420 beriberi, 445 cognitive assessment, 235 France, 633–40 frontal lobes, 559–61 headache see headaches hospitals, 306–8 intelligence tests, 241 Italy, 724–6 movement disorders, 501 muscular dystrophy, 477, 487 senses, 490, 492 speech production localization, 573 surgical neurology, 199 vitamins, 436 writer’s cramp, 526 Nissl, Franz, 679–80 stains, 157 nitrous oxide, general anesthesia, 191 Noguchi, Hideyo, 773 Nonne, Max, 311 non-REM parasomnias, 551 noradrenalin (norepinephrine), 872–3 identification as neurotransmitter, 179 norepinephrine see noradrenalin (norepinephrine) The Normal Child (Sachs), 324 Norse tradition, Scandinavia, 657–8 North, Elisha, 422 bacterial meningitis therapy, 428 epidemic meningitis, 422 Norway, 660–1 Nuovo et universale Theatro Farmaceutico (de Sgobbis), 380 nutritional value, pellagra, 453 Nyfeldt, A, 427 Nyle´n, C, 220 Nymann, Gregor, 404 nystagmus, 495–6

O Oaxaca Valley, Neolithic trepanation, 6–7 Obersteiner, Heinrich, 682 Object Forming Test, 249 Observationes Anatomicae (Falloppia), 152 Observationes Medico-practicae de Affectibus Capitis Internis & Externae (Wepfer), 572 Observations on Dropsy of the Brain (Whytt), 617 obstructive sleep apnea syndrome (OSAS), 550–1 occipital bone, Ancient Egypt, 31 occlusive stoke, Virchow, Rudolf, 408 occupational disorders, Russia, 750 occupational rehabilitation, 855–6

INDEX oculomotor circuits, 564 oculomotor nerve (cranial nerve III), 217–18 Odeku, E Latunde, 822–3 Odier, Louis, 420 Ogawa, Sieji, 264 Ogle, John William, 216, 586 Old Testament see The Bible olfactory nerve (cranial nerve I), 216 Olivecrona, Herbert, 659 Olivier, George, 870 olivopontocerebellar atrophy (OPCA), Japan, 774 Olsen, Lars, 895, 895 Olszewski, Jerzy, 515 On Anatomical Procedures (Galen), 56 On Chronic Disease see Soranus On Head Wounds, 52 On Nervous, Hypochondrial or Hysterical Diseases (Whytt), 617 On Paralysis from Brain Disease in its Common Forms (Bastian), 846 On the Fine Anatomy of the Central Organs of the Nervous System (Golgi), 161 On the Heart, 54 On the Sacred Disease see Hippocrates On the Senses (Theophrastus), 491 Oosterhuis, H, 702 Opere Minori (Semmola), 479, 480 Oporinus, Johannes, 274–5 Oppenheim, Hermann, 686 Babinski extensor toe reflex, 224 generalized primary tortion dystonia, 524 hospital development, 311 Oppenheimer, D R, 514–15 optic atrophy, pernicious anemia, 463 optic nerve see cranial nerve II (optic nerve) oral tradition, European Early Middle Ages, 80 orbitofrontal circuits, 564, 565 comportment, 565 organs Mesopotamia, 20 traditional Chinese medicine (TCM), 756–7, 757 Orientation–Memory–Concentration Test, 250–1 Osborne, Thomas aphasia rehabilitation, 856 vitamin A discovery, 439 Osler, William ancient trepanation, 11 Cerebral Palsies of Children, 846–7 cerebral palsy (Little’s disease), 322 Huntington’s disease, 518 infantile hemiplegia, 846–7, 847 Pickwickian syndrome, 549 Principles and Practice of Medicine, 847 Sydenham’s chorea, 517

Osuntokun, Benjamin, 823–4 Oto-Neuro-Ophthalmological Group, 699 Outline of Anatomy and Physiology (Hobson), 762 Overend, Walker, 225 Owen, Richard animal studies, 139 frontal lobes, 559 Oxford and Oxford University, 615, 796 17th century neurology, 91, 94, 95, 103, 104 oxytocin, 336 Du Vigneaud, Vincent, 340 early work, 340 food intake, 344 functions, 344 vasopressin relationship, 344 see also vasopressin

P Pacchioni, Antonio, 155 Padberg, George W A M, 704 Page, Irvine H, 876 serotonin, 876–7 Paget, James, 139 Paillas, Jean, 653 pain, 490 sensory examination, 227 Pakistan, lathyrism, 816 Paley, William, 136 palmomental reflex, 225–6 palsy 17th Century, 102–3 19th Century, 618 Great Britain, 618 see also epilepsy; seizures Pan African Association of Neurological Sciences (PAANS), 822–4, 823 Panama, 809–10 Pan American Congress, 811 Panizza, Bartolomeo anatomy, 722 neuronal pathways, 164 Panov, A G, 750 Papi, Federico, 802 Papp, M I, 515 papyri, Ancient Egypt, 29, 30 see also specific types Paracas Peninsula, Neolithic trepanation, 7 Paracelsus, 667 Paralysie pseudo-hypertrophique (Charcot), 140 paralysis Ancient Egypt, 32 Aretaeus, 56 Mesopotamia, 20–1 Paralysis and Other Diseases of the Nervous System in Childhood and Early Life see Taylor, James paramyotonia congenita (PC), 366 paraplegia, 19th Century Great Britain, 618 parasomnias, 551 parasympathetic autonomous nervous system, 335

INDEX paraventricular nucleus (PVN) microscopy, 339 neuropeptides, 342, 343 neurosecretions, 336 Pare´, Ambroise, 630 phantom limbs, 493 strabismus, 498 Ten Books of Surgery, 885–6 parietal bone, Ancient Egypt, 31 PARK1 gene, 510 PARK2 gene, 510–11 parkin, 511 Parkinson, James, 618 An Essay on the Shaking Palsy, 505–6, 618 gait examination, 229 tremors, 503 parkinsonism atypical, 512–16 see also specific diseases/disorders drug-induced, 512 Parkinson’s disease, 505–11, 873–4 17th Century, 99 Ancient Egypt, 34 clinical description, 505–7 computed tomography (CT), 508 empiric pharmacology, 507 genetics, 510–11 Japan, 774–5 Lewy bodies, 507, 510 Mesopotamia, 24 models, 874 molecular biology, 369, 510–11 multiple sclerosis vs., 207, 210 neural transplantation see neural transplantation neurochemistry, 508 pathology, 507 pharmacological therapy, 180 apomorphine, 509 bromocriptine, 510 catechol-O-methyltransferase (COMT) inhibitors, 509 L-DOPA, 508–9 dopamine agonists, 509–10 L-DOPA therapy, 509 subthalamic nucleus, 508 therapy, 507 pharmacological see above surgery, 508 workers in Backlund, E O, 901 Charcot, Jean-Martin, 207, 210–11, 503, 503, 506, 637 Cotzias, G C, 509 Erb, Wilhelm Heinrich, 507 Freed, Bill, 901 Gowers, William Richard, 506, 506–7 Madrazo, I, 901–2 Meyers, R, 508 Polymeropoulos, Mihael, 510 Parrenin, Dominique, 761, 761 partial seizures, EEG classification, 396

Partington Pathways Test, 249 Part–Whole test, 240 Passouant, Pierre, 649 Pasteur, Louis, 192 bacterial meningitis, 426 Pathologiae Cerebri et Nervosi Generis specimen in quo Agitur de Morbis Convulsus (Willis) see Willis, Thomas pathologic startle syndromes, 529–30 Patokrator Monastery, 305 Pauling, Linus, 264 Pavlov, Ivan Petrovitsch animal studies, 140 neurophysiology, 171, 177 Payne, A, 517 Pekelharing, Cornelius, 436 Pel, Pieter Klazes, 693 pellagra, 452–8 Carver, George Washington, 456 Casal, Gaspar, 452 cognitive manifestations, 457–8 dementia, 452–3 etiological theories, 453–4 Frapolli, Franscesco, 452 Goldberger, Joseph, 454–5 Lombroso, Cesare, 453 recognition of, 452 social issues, 455–6 Sydenstricker, Edgar, 455–6 treatment, 455, 456–7 brewer’s yeast, 455 United States, 452, 455–6 penetrating head injuries, The Bible, 39 Penfield, Wilder, 610 “centro-encephalic” epilepsy, 396 EEG, 395 penicillamine, Wilson’s disease therapy, 513–14 penicillin, bacterial meningitis therapy, 429–30 Penrose, Lionel, 326 Pen Tsao Kang Mu (The Great Herbal), 756–7 Pepper, William, 293 perceptual disorders, 489–500 peripheral nerves injury, The Bible, 38 Willis, Thomas, 153 peripheral nervous system (PNS) Bichat, Marie Franc¸ois Xavier, 346 early work, 346 neuropathies, Scandinavia, 663–4 pernicious anemia, 463 pernicious anemia, 461–2 folate, administration risks, 458 infectious theories, 463–4 optic atrophy, 463 peripheral nervous system, 463 therapy liver therapy, 464–5 Robscheit-Robbins, Freida, 464 Whipple, George H, 464 toxic theories, 463–4

941 pernicious anemia (Continued) workers in Addison, Thomas, 461–2 Bell, J R, 463 Castle, William B, 465 Ehrlich, Paul, 462 Hunter, John, 463 Hurst, A F, 463 Minot, G R see Minot, G R Murphy, W P see Murphy, W P Robscheit-Robbins, Freida, 464 Weigert, Carl, 462 Whipple, George H, 464 see also cyanocobalamin deficiency Peru, 806–7 ancient trepanation, 4, 4 Neolithic trepanation, 5, 7, 8, 8 Perusini, Gaetano, 724 Peters, Rudolph, 450 Peterson, Frederick language and cognitive development, 847 mental status examinations, 214 petit-mal epilepsy EEG, 182 original definitions, 393 Petty, William, 94 Pfeiffer, Richard, 427 Pflu¨ger, Eduard Friedrich Wilhelm, 675 phantom limbs, 493–4 Pharmaceutical-chemical Lexicon (Capello), 380–1 pharmacology epilepsy treatment, 396 Mesopotamia, 18–19 “magic” vs., 18–19 Pharmacopoeia Medico-Chymica (Schro¨der), 380 Phelps, Michael E, 260 phenobarbital, tremor therapy, 505 phenylketonuria, 326 Flling, Asbjrn, 326, 664 phenytoin, 609 Phillips, Gilbert Edward, 789 photography, 290–5 analysis of movement, 293–5 Bourneville, De´sire´-Magloire, 291–3 Charcot, Jean-Martin, 291–3 Diamond, Hugh Welch, 290 Duchenne de Boulogne, Guillaume Benjamin, 290–1 portraiture, 290, 290 Richter, Paul, 293 see also illustrations phrenology Flourens, Marie-Jean-Pierre, 633 France, 632–3 Gall, Franz Joseph, 632–3, 670, 672 German-speaking countries, 670, 672 Italy, 722 Spurzheim, Johann Caspar, 633 United States, 606

942 physical rehabilitation, 853–5 Great Britain, 853 Guttmann, Ludwig, 855 Kenny, Elizabeth, 854 Krusen, Frank H, 854 Rusk, Howard, 855 United States, 853, 855 World War I, 853, 854 World War II, 854–5 The Physiological Function of the Cerebellum (Jelgersma), 712 physiologic tremor, 504 Eschner, Augustus, 504, 504 physostigmine, 875–6 Piccolomini, Arcangelo anatomical studies, 152 Piccolomini, Francesco basal ganglia, 501 Pick, Arnold aphasia, 571 Die agrammatischen Sprachstörungen, 578 frontal lobes, 561 grammatic disorders, 577–8 Pickwickian syndrome, 549–50 Piercy, Malcolm, 252 pineal gland, 336–8 Arabic/Islamic period, 66–7 Pinel, Philippe, 632 Pinelli, Paolo, 730 Pines, Lev Yakovlevich, 745–6 Piper, H, 183 Piso, Carolus, 91–2, 92 Piso, Willem, 437 Pitres, Albert, 650 agraphia, 650 isolated agraphia, 591 University of Bordeaux, 649 pituitary gland, 336–8 blood supply, 340–1 Cushing, Harvey, 347 Descartes, Rene´, 336–7 van Rijnberk, G, 338 Vesalius, Andreas, 336, 336 plague, European Middle Ages, 86 Plato brain vs. heart controversy, 54–5 child neurology, 327 senses, 491 Platter, Felix, 494 Plinius, 376 Pliny the Elder, 55 Plutarch, 327 Pneumoencephalography (Robertson), 791 point-to-point correspondence, al-Haytham, Ibn, 71–2, 72 Poland, 748–9 poliomyelitis Ancient Egypt, 33, 34, 271 Australia, 784 epidemics, Scandinavia, 665 Pollak, Pierre, 508 polygraphic recordings, Gerardy, Werner, 550

INDEX Polymeropoulos, Mihael, 510 PolyQ diseases, 518 polysomnography, 183, 550 Ponto-geniculo-occipital, 652 rapid eye movement (REM) sleep, 548 Popesco, Constantin, 297 Poppelreuter, Walther, 859 aphasia rehabilitation, 857 cognitive rehabilitation, 858–9 frontal lobes, 561 visuospatial/visuoconstructive skill tests, 244–5, 245 Portal, Antoine, 406 Porterfield, William binocular vision, 497 phantom limbs, 493–4 Poser, Charles, 664 Posidonius, 63 positive feedback models, basal ganglia, 502–3 positron emission tomography (PET), 184, 259–63 epilepsy studies, 398 frontal lobes, 563 functional magnetic resonance imaging vs., 265 image analysis, 263 image averaging, 262 instrumentation, 259–61 metabolism vs. blood flow, 261 stereotaxy, 261–2 workers in Brownell, Gordon, 260 Cormack, Alan, 260 Cox, Jerome, 260 Donders, Franciscus C, 263 Guze, Sam, 262 Hoffmann, Edward, 260 Hounsfield, Godfrey, 260 Mintun, Mark, 262 Phelps, Michael E, 260 Reiman, Eric, 262 Snyder, Donald, 260 Sweet, William, 260 Wrenn, Frank, 260 post-encephalitic parkinsonism, encephalitis lethargica, 511–12 post-hemiplegic hemichorea, 520–2 post-mortem studies Macewen, William, 194–5 Morgagni, Giovanni Battista, 573 postsynaptic potentials, Eccles, John Carew, 362 potassium-aggravated myotonias (PAMs), 366 potassium bromide headache therapy, 381, 384 Locock, Charles, 393 Kþ channels, 365 Pourfour du Petit, Franc¸ois, 107, 630 anatomical studies, 155 animal studies, 133

Poynton, F, 517 Practica (John of Ardenne), 614 Practica copiosa in arte chirurgia (De Vigo), 572 praxis, assessment tests, 247–8 prefrontal leucotomy Lima, Almeida, 562 Moniz, Egas, 562 Prelectiones (Harvey), 616 Prick, J J G, 704 Prickett, C O, 451 primidone, 505 primitive (atavistic) reflexes, 226 Principles and Practice of Medicine (Osler), 847 Principles of Psychology (James), 258 prions/prion disease, molecular biology, 368–9 Prochaska, Georg, 670, 673 Procha´ska, Jiri, 222 professional specialization Great Britain hospitals, 308–10 Mitchell, Silas Weir, 308 progressive supranuclear palsy, 515–16 pronunciation, alexia, 598 propranolol, 505 protein crystallography, 363 Pseudo-hypertrophic Muscular Paralysis (Gowers), 479 psychiatry Africa, 822 Italy, 726–30 The Netherlands, 694 psychobiology, Meyer, Andre´, 681 psychology, Rossolimo, Grigory Ivanovich, 742 psychosurgery, Moniz, Egas, 725 Ptolemy developmental disorders, 496 vertigo, 494 publications/journals Argentina, 802 child neurology, 329–30 Chile, 808 headache, 385 Italy, 730–1 Mexico, 811 Peru, 807 Scandinavia, 665–6 Venezuela, 808–9 see also specific journals/publications public health interventions, vitamin A deficiency, 441–2 Puerto Rico, 811 Pulse Classic, 756 pulverulant cataract, 367 pupillary reaction testing, 217–18 Purcell, Edward, 264 pure alexia, Dejerine, Joseph Jules, 593 pure word blindness, Dejerine, Joseph Jules, 592–3, 594–5

INDEX Purkinje, Jan Evangelista illustrations, 284 microscopy studies, 157–8 neuron visualization, 159 microtome, 157 vertigo, 495 Purkinje shift, 489 Pussep, Lyudvig Martynovich, 746 Pussin, Jean-Baptiste, 632 Putnam, James J spinal cord subacute combined degeneration, 462 subthalamic nucleus, 523 Putnam, Tracey anticonvulsants, 609 epilepsy therapy, 396 Pythagorus, 50

Q Qi, traditional Chinese medicine (TCM), 756 Quaglino, Antonio, 722 quality of life, Mesopotamia, 17 Quastel, Juda Hirsch, 875 Queen Square Hospital, 309, 309–10, 620–2 Brown-Se´quard, Charles-E´douard, 310, 621 Collier, James Stansfield, 621 Gowers, William Richard, 310 Horsley, Victor, 310 Hughlings Jackson, John, 621 Kennedy, Robert Foster, 621–2 Ramskill, Jabez, 621 Russell, James Risien, 621 Querulantenwahnsinn (Hitzig), 679 Quijano, Andre´s Rosselli, 809, 809 Quincke, Heinrich, 426, 686 cerebrospinal fluid examination, 423–4 Quintus Serenus Sammonicus, headache, 377

R rabies Mesopotamia, 25 tropical neurology, 819 Racchetti, Vincenzo, 721 radiology, Robertson, Edward Graeme, 791 Radovici, Anghel, 225 Raisman, G, 890 Ramaer, J N, 693–4 Netherlands Society of Neurology, 697 Ramamurthi, B, 819 Ramazzini, Bernardino, 720 headache, 379 Morbis Artificum Diatriba, 379 Ramsay-Hunt, J, 410 Ramskill, Jabez, 621 Ranson, S, 352 Ranson, Walter, 547 Ranvier, Louis, 649–50 Raphael, 286

rapid eye movement (REM) sleep Jouvet, Michel, 548 Kleitman, Nathaniel, 548 Ponto-geniculo-occipital spikes, 548 sleep medicine, 548 Rapport, M M, 877 Rapports du Physique et du Moral de l’Homme (Cabanis), 631 Rasori, Giovanni, 722 al-Ra¯zı¯, Zakariyya¯’, pineal gland, 67 reading disorders see alexia Rebeiz, J J, 516 Recherches sur le Liquide CéphaloRachidien (Magendie), 139 Redfern, William, 782 redundancy theory, 834–5 Reflex Action of the Spinal Cord (Denny-Brown), 787–8 reflexes Astvatsaturov, Mikhail Ivanovich, 746 cutaneous see cutaneous reflexes Hall, Marshall, 619 Sherrington, Charles Scott, 625 testing, 222 Reflexes of the Brain (Reflexy golovnogo mozga) (Sechenov), 747 Refsum, Sigvald Bernhard, 660 rehabilitation, 851–67 American Civil War, 853 Ancient Egypt, 852 China, 852 cognitive rehabilitation see cognitive rehabilitation criticism of, 851 disorder characteristics, 851–2 early history, 852–3 Franklin, Benjamin, 853 Gall, Franz Joseph, 853 Greco-Roman World, 852 medical rehabilitation, 853–5 occupational rehabilitation, 855–6 physical rehabilitation see physical rehabilitation Renaissance, 852–3 stroke, 861–2 vocational rehabilitation, 855–6 Reil, Johann Christian, 670, 672 anatomical studies, 156 Reiman, Eric, 262 Reisner, E H Jr, 466 religion European Middle Ages, 80, 85 Greco-Roman World, 49–50 Mesopotamia, 17 Remak, Robert, 676 “cell theory”, 157 hospital development, 311 microscopy studies, 158 neuroembryology, 163 REM behavior disorder (RBD), 551 Rembrandt van Rijn Dr Deijman’s Anatomy Lecture, 337, 337 neurological illustrations, 285, 337

943 Re´mond, A, 649 REM sleep see rapid eye movement (REM) sleep Renaissance anatomical studies, 151–2 aphasia, 572 epilepsy, 387 headache, 378–9 hospitals, 305–6, 307 illustrations, 273–8 Italy, 720 rehabilitation therapies, 852–3 see also specific people Rennie, George Edward, 785 restless legs syndrome, 551 Restoration of Brain Functions after War Trauma (Vosstanovlenie funktsy posle voennoi travmy) (Luria), 751 restriction fragment length polymorphisms (RFLPs) HD gene, 368 Huntington’s disease, 518 rest tremors, 503–4 reticular theories anatomical studies, 158, 160–2 Butzke, Victor, 160 Flourens, Marie-Jean-Pierre, 161–2 Golgi, Camillo, 161–2 Ko¨lliker, A, 161 Leydig, Franz, 160 Rindfleisch, Georg Eduard, 161 Stricker, Salomon, 161 von Gerlach, Joseph, 161 Waldeyer, Wilhelm, 160 retiform plexus, Herophilius, 53 retinal pigments, Ku¨hne, Willy, 438–9 Rett’s syndrome, 324 Retzius, Gustav Magnus, 661 anatomical studies, 157 Rey, Andre´, 245 Reynolds, John Russell, 620 Epilepsy: Its Symptoms, Treatment and Relation to Other Chronic Convulsive Diseases, 393 Rhazes, pineal gland, 67 Rhodopsin, 436, 437, 438–9 Ribera, Jose´, 285 Ribot, T, 843 Ricaldoni, Ame´rico, 805 Richardson, J Clifford, 515 Richter, Paul analysis of movement, 295 photography, 293 Ridley, Humphrey, 615 The Anatomy of the Brain, 105, 155, 615 right hemispheric damage, Macewen, William, 195 Rijnberk, G van, 338 Rindfleisch, Georg Eduard, 161 Rinne, Heinrich, 220–1 Riquier, Giuseppe Carlo, 728 Riser, Marcel, 649 Rivers, Thomas, 428

944 Rivista di Patologia Nervosa e Mentale, 730–1 Rivista Sperimentale di Freniatria e Medicina Legale, 730 Robertson, Edward Graeme, 790–1, 791 Robertson, James, 362 Robo rats, 143–4 Robscheit-Robbins, Freida, 464 Rockwell, Alphonso, 526 Rokitansky, Carl, 407 Rolando, Luigi, 722 anatomical studies, 156 cerebellar examination, 228 Rolleston, Humphrey, 428 Roman World see Greco-Roman World Romberg, Moritz Heinrich, 229, 686 Romberg’s maneuver, 229 Rommel, Peter, 572 Rosa Anglica (John of Gaddesden), 614 Rosenbach, O, 226 Rosenberg, David, 429 Rosenthal, Joseph F, 157 Rossi, Ottorino, 728, 728 Rossolimo, Grigory Ivanovich, 741–2, 742 Rossolimo’s effect, 741 Rostan, Le´on, 407 rotation, nystagmus, 495–6 Rotch, Thomas, 847–8 Roth, Martin, 250–1 Roth, Vladimir Karlovich, 740–1, 741 Roth–Bernhardt’s syndrome, 741 Rotterdam, Jan Karel Van, 706 Rotterdam University, 704 Roy, Charles, 171 Royal Australian College of Physicians (RACP), 782, 789, 794 Royal Perth Hospital, 788 Royal Society, 17th Century, 94–5 Royle, Norman, 783 Rubens, Peter Paul, 286 Ruberti, R F, 823 Ru¨dinger, Nikolaus, 290 Rufus of Samaria, 42–3 Rulandus, Martinus, 391 Ru¨mke, H, 701 Rush, Benjamin, 605, 612 agraphia, 606 Rusk, Howard, 855 Russell, James Risien, 621 Russell, W Ritchie, 859 Russia, 737–54 All-Union Congress of Neuropathologists and Psychiatrists, 749 All-Union Society of Neuropathologists and Psychiatrists, 752 Great Patriotic War (World War II), 750–1 imperial Russia, 738–49 infections, 750 meetings, 478 Moscow School of Neuro(patho)logy, 738–42, 739 neurological care, 749–50

INDEX Russia (Continued) neurological chairs, 478 neurosurgery, 750 occupational disorders, 750 periodicals, 478 societies, 751–2 Soviet neuro(patho)logy (USSR), 749–52 St Petersburg School of Psychoneurology, 742–8 textbooks, 751–2 universities, 737 Ruysch, Frederick illustrations, 283 Municipal University of Amsterdam, 703

S Sachs, Bernard childhood brain damage, 324 language and cognitive development, 847 mental status examinations, 214 neurological examinations, 214 The Normal Child, 324 Treatise on the Nervous Diseases of Children, 324 Sadka, Marie, 794 Saint-Anne Dargassies, S, 324 Saint-Armand, Jean de, 83, 87 Sainte Anne Hospital (Centre Hospitalier Sainte Anne), 645–7, 646 sakikku (symptoms), Mesopotamia, 19–20 Sala, Guido, 728 Salernitan Medical School, headache, 378 Salerno animal studies, 131 Europe High Middle Ages, 80 Salpeˆtrie`re Hospital, 203, 204, 205, 635–43, 636 19th Century, 308 cinematography, 296 Freud, Sigmund, 637–8 photography, 291–2, 292 see also Charcot, Jean-Martin Saltykow, S, 888–9 San Lazzaro Asylum (Italy), 727 San Salvi Clinic (Florence), 727–8 Santorini, Giovanni, 155 Sauver, T D, 707 Scandinavia, 657–66 academic medicine, 657 cerebrovascular disorders, 663 clinical neurology, 658–61 clinical neurophysiology, 662–3 dementias, 665 epilepsy, 665 infections, 665 journals, 665–6 movement disorders, 663 multiple sclerosis, 664–5 national neurological associations, 666 neuroanatomy, 661 neurogenetics, 664 neuropathology, 661–2 Norse tradition, 657–8 peripheral neuropathies, 663–4

Scandinavia (Continued) poliomyelitis epidemics, 665 see also Denmark; Finland; Norway; Sweden Scarpa, Antonio anatomical studies, 155 clinical neurology, 721 cranial nerve VIII (acoustic-vestibular nerve), 220 Scha¨fer, Edward Albert, 870 Scharrer, Ernst, 339 Schiff, M, 346 schizophrenia, 873–4 chlorpromazine, 180 Schleich, Ernst Sauerbruch, 687 Schleiden, Matthias Jacob, 676 “cell theory”, 157 Schmidt, Carl, 258 Schmidt, Johann Baptist aphasia, 573 language comprehension localization, 575 Schmitt, Francis O, 362 Schneevogt, Gustaaf Eduard Voorhelm, 703 Schneider, Konrad Viktor, 153 Schoenberg, Bruce, 824 Scho¨nander, Georg, 659 Scho¨nlein, Roland Kuhn, 685–6 Schro¨der, Johann, 380 Schroeder, Alejandro, 805 Schuell, Hildred, 579 Schulte, Bento P M, 704 Schwalbe, Gustav, 524 Schwann, Theodor, 676 “cell theory”, 157 University of Lie`ge, 707 Schwartz, Michael, 466 Schwarz, Eduard, 437 Schwentker, Franc¸ois, 429 sciatic nerve neurapraxia, The Bible, 38 SCN4A gene, 366 Scott, Henry, 817 scrivener’s palsy see writer’s cramp scurvy, 17th Century, 99 seasonal ataxia syndrome, Nigeria, 826 seasonal (taiga) encephalitis, Panov, A G, 750 Sechenov, Ivan Mikhailovich, 747 secondary (symptomatic) myoclonus, 528 Secundus, Alexander Monro, 108 Sedillot, C E, 191 Sedleian lectures, Willis, Thomas, 95 seeing see vision Segawa disease, Japan, 775 Se´guin, Edouard child neurology, 327 intelligence tests, 242 surgical neurology, 193 Traitement moral hygiène et education (Aigu) des Idiots et des autres enfants, 327

INDEX seizures, 387–400 definition, 388 focal see focal seizures focus identification, 394 infant see infantile seizures Mesopotamia, 21–2 see also epilepsy Selby, George, 793–4 semantics, recovery of function, 839–40 semicircular canals, vertigo, 495–6 Sémiologie des Affections du Système Nerveux (Dejerine), 237, 641 Semmola, Giovanni muscular dystrophy, 477, 479, 479 Opere Minori, 479, 480 Semon, Richard, 675 senile dementia of the Alzheimer type (SDAT), 876 Senn, Louis, 422–3 sensations, Head, Henry, 625 senses, 489–93 17th Century, 101 19th Century, 490, 492 classification criteria, 491–3 workers in Alcmaeon of Crotona, 491 Anaxagoras, 491 Aristotle see Aristotle Bell, Charles, 492 Democritus, 491 Galen, 491 Hunter, John, 492 Mu¨ller, Johannes, 492 Plato, 491 Theophrastus, 491 Willis, Thomas, 101 see also specific senses sensory cortical neurons, response threshold, 172–3 sensory defects/disorders, 489–500 Brown-Se´quard, Charles-E´douard, 622 Mesopotamia, 20–1 Willis, Thomas, 489 sensory examination Head, Henry, 227–8 Holmes, Gordon, 227–8 Mu¨ller, Johannes, 227 Sherrington, Charles Scott, 227 von Frey, Max, 227 Weber, Ernest Heinrich, 227 sensory nerves 18th Century, 109–10 Arabic/Islamic period, 69 motor vs., Herophilius, 54 Seqenere, Pharoah, 304 serotonin, 876–7 headache, 384 Seutin, L, 708 seventeenth Century, 91–106 anatomical studies, 152–5 ‘animal spirits’, 92–3 aphasia rehabilitation, 856 apoplexy, 102 autonomic nervous system, 97–8

seventeenth Century (Continued) bacterial meningitis, 417–18, 428–9 biochemical fermentation doctrine, 92 blood–brain barrier (BBB), 98–9 brain connections, 97–8 cerebellum, 97–8 cerebral explanations, 91–2 comparative anatomy, 99–100 conscious activities, 97–8 cranial nerves, 98 delirium, 103 developmental disorders, 496–7 dissection, 96–7, 337 epilepsy, 98–9 excessive waking, 102 frenzy, 103 frontal lobes, 558–9 German-speaking countries, 669 Great Britain, 614–17 headache, 101–2 hypochondria, 98–9 hysteria, 98–9 illustrations, 278–83 insanity, 103 madness, 103–4 melancholy, 103 migraine, 101 myasthenia gravis, 103 neuroanatomy, 94, 95–6 neurological disorders, 101–4 see also specific diseases/disorders nightmare (incubus), 102 palsy, 102–3 Parkinson’s disease, 99 Royal Society, 94–5 ‘scurvy’, 99 senses, 101 sleep, 101, 102 stupidity/foolishness, 104 three parts of the soul, 93–4 vasomotor functions, 98 ventricles, role of, 97 vertigo, 102 Vertuosi, 94–5 waking, 101 see also specific people Sewell, Sidney Valentine, 785 Shanai, B T, 528 Sharpey-Schaefer, Edward Albert, 141–2 Shcherbak, Alexander Efimovich, 747, 747 Sheerer, M, 248 Shellsear, Joseph Lexden, 783 “shell-shock”, Campbell, Alfred Walter, 787 Shen Jin-ao, 763 Sherrington, Charles Scott, 171, 625 animal studies, vicariation, 838 brain blood circulation, 258 decerebrate rigidity, 170 The Integrative Action of the Nervous System, 170, 625 motor cortex localization, 171 neuron doctrine, 162

945 Sherrington, Charles Scott (Continued) neurophysiology, 170 nevous integration, 170–1 reflexes, 625 knee jerk, 170 sensory examination, 227 synapses, 870 Shiba, Ryoˆkai, 771 Shrift–Scalen visual acuity testing, 216 Shy, G M, 514 Shy–Drager syndrome (SDS), 774 Sibelius, Christian, 659–60 Sica, Roberto, 802 sickle cell anemia, 362 Siebold, Philipp Franz von, 770, 770 Siechenhäuser, German hospitals, 311–12 Siekert, Bob, 411–12 sight see vision Sigurdsson, Bjorn, 665 Simon, Theodore intelligence tests, 241 memory assessment tests, 244, 244 Singer, H Douglas, 452–3 Sinkler, Wharton, 846 sixteenth Century aphasia, 572, 856 German-speaking countries, 667 Skinhoj, Erik, 663 skin reflex, Rosenbach, O, 226 skull fractures Ancient Egypt, 31 ancient trepanation, 10 Skwortzoff, Nadine, 589 Sladek, J R, 900 sleep, 547–56 17th Century, 101, 102 deprivation, 552 EEG, 547, 651–2 epilepsy, 398 iatrogenic disorders, 552 neuroanatomy, 547–8 pathology, 549–51 pediatric breathing disorders, 551 rapid eye movement (REM) sleep, 548 thalamus, 551–2 workers in Aristotle, 547 Berger, Hans, 547 Cox, Leonard Bell, 790 Dement, William, 652 Gastaut, Henri, 549 Guilleminault, C, 549 Hess, Walter Rudolph, 547 Hippocrates, 547 Kleitman, Nathaniel, 651 Loomis, Lee, 547 Magoun, Horace, 547–8 Moruzzi, Giuseppe, 547–8 Nauta, Wally J H, 547 Ranson, Walter, 547 Steriade, Mircea, 548 von Economo, Constantin, 547 see also specific diseases/disorders

946 sleeping sickness, 818 smell, 489–90 17th Century, 101 Smith, E Lester, 466 Smith, Grafton Elliot, 625–6, 783 Smithells, Richard, 459 Smitt, W H Sillevis, 701 snake bites, Africa, 821 Snellen, Hermann, 216 snouting reflexes, 226 Snyder, Donald, 260 Sobue, G, 774 Soca, Francisco, 805 social medicine, Frank, Johann Peter, 721 Sociedad Mexicana de Neurologı´a y Psiquiatrı´a (Mexico), 810–11 Sociedad Neurolo´gica Argentina (SNA), 802 Sociedad Venezolana de Psiquiatrı´a, 808 Societa` dei Neurologi Ospedalieri (SNO), 731 Societa` Italiana di Neurologia (SIN), 731 Socie´te´ d’Anthropologie de Paris, Broca, Paul, 4 Socie´te´ Luxembourgeoise de Neurologie, Neuropsychiatrie et Electroencephalographie (SLNNE), 710 Society of Amsterdam Neurologists, 698–9 sodium (Naþ) channels, 365 sodium salicylate, 381 Soemmering, Samuel Thomas, 677 anatomical studies, 155 Solly, Samuel, 525 Soltmann, Otto childhood brain damage, 322–4 vicariation, 839 somatotropic organization, Ferrier, David, 124 SON see supraoptic nucleus (SON) Soranus, On Chronic Disease, 389–90 soul three parts of see three parts of the soul The Soul of Brutes (Willis), 133 souls, Willis, Thomas, 97 South America, 801–9 Neolithic trepanation, 6 South East Asia, 819–20 spatial navigation tasks, hippocampal grafts, 899 speech Broca, Paul, 4 disorders, Hippocratic neurology, 52 lack of see aphasia localization of, 573–5 19th Century, 572 Bouillaud, Jean-Baptise, 560, 573–4 Broca, Paul, 574–5 Brugnoli, Giovanni, 722 Dax, Gustave, 575 Dax, Marc, 560 Gall, Franz Joseph, 573

INDEX speech (Continued) Lavater, Johann Christian, 573 von Bru¨cke, Ernst Wilhelm, 674 speech blindness, Kussmaul, Adolf, 589 Speidel, Carl Casky, 339 Sperry, Roger Wolcott, 176 corpus callosum, 176–7 disconnection syndromes, 176 hemispheric specialization, 177 inborn neural connections/ organization, 176 split-brain studies, 598 spina bifida, 459 genetic polymorphisms, 461 spina bifida aperta, The Talmud, 45 spinal cord amyotrophic lateral sclerosis, 208–9 bridges and repair, 900–1, 904 diseases, The Talmud, 45 Galen, 56 injuries Ancient Egypt, 32 animal studies, 143 Mesopotamia, 22–3, 23, 272 The Talmud, 45 regeneration Cajal, Santiago Ramo´n y, 891–2 Clemente, C D, 892 Gerard, R W, 892 Le Gros Clark, W E, 892–3 neural transplantation, 891–3 Sugar, O, 892 subacute combined degeneration, 462–3 tumor removal, Horsley, Victor, 197 spinal injuries, Ancient Egypt, 31 spinal lesions, The Talmud, 45 ‘spin chairs’, Hallaran, William, 496, 497 spinobulbar muscular atrophy, 368 spinocerebellar ataxia, Friedreich, Nikolaus, 485 spinocerebellar ataxia type 1 (SCA1), 774 spinocerebellar ataxia type 6 (SCA6), 366 split-brain studies Bogen, Joseph, 597–8 Gazzaniga, Michael, 597–8 Sperry, Roger Wolcott, 598 Spring, Joseph A, 707 Spurzheim, Johann Caspar, 119, 672 anatomical studies, 156 animal studies, 138 frontal lobes, 559 phrenology, 633 Squier, Ephraim George, 3–4, 4 Sri Lanka, toxic neuropathy, 820 Stahl, Georg Ernst, 105, 669–70 stains anatomical studies, 157, 158 Nissl, Franz, 157 Stanford, Leland, 293 Starr, Moses Allen frontal lobes, 561

Starr, Moses Allen (Continued) visual field testing, 216 St Bartholomew’s Hospital, 307 Steele, John C, 515 Steensen, Niels (Stenon), 153–4 Stefansson, Kari, 664 Steinthal, Chaim aphasia, 571 grammatic disorders, 577 Stengel, Otto Christian, 664 Stensen, Niels, 658, 661 stereoscopic vision, 489 stereotaxy, positron emission tomography (PET), 261–2 Steriade, Mircea, 548 Sterling, W, 524 Sternberg, George, 426 Stewart, Thomas Grainger cerebellar examination, 228 Queen Square Hospital, 621 St George’s Hospital, 307 Stick Test, 249, 249 Still, G F attention deficit hyperactivity disorder (ADHD), 325 The History of Paediatrics, 317 Stilling, Benedikt, 687 tissue fixation, 157 stimulants, bacterial meningitis therapy, 428–9 Stolz, Friedrich, 871–2 The Story of Sinuhe, 32 St Petersburg School of Psychoneurology (Russia), 742–8 strabismus, 498 corrective devices, 498 Strachan, Henry, 816 Strasbourg, 650–1 Streptococcus pneumoniae, bacterial meningitis, 426 streptomycin, tuberculous meningitis therapy, 430 striatal dysfunction, 501 striatonigral degeneration (SND), 774 Stricker, Salomon, 161 stroke, 410–12, 861 Ancient Egypt, 30, 32, 33 angiography, 412 carotid artery science, 410 cerebrovascular disease, 861 Charcot, Jean-Martin, 209 computed tomography (CT), 412 definition, 401 Hippocratic neurology, 52 Mesopotamia, 23–4 neural transplantation, 904 rehabilitation, 861–2 Siekert, Bob, 411–12 as speciality, 411–12 subgroups, 402 Todd, Robert Bentley, 620 see also apoplexy Strong, Nathan Jr, 422

INDEX Stroop, Ridley, 249–50 Structure and Functions of the Nervous System (Secundus), 108 structure–function relationship, frontal lobes, 568 St Thomas’ Hospital, 307 A Study on Convulsions (Hughlings Jackson), 393, 623 Sturm, E, 887–8 subacute combined degeneration, spinal cord changes, 462–3 subacute myelo-optic-neuropathy (SMON), 776 subcortical nuclei cerebral cortex vs., 501–2 white matter vs., 501–2 substance P, 873 subthalamic nucleus, 522–4 Canfield, Ralph, 523 Forel, Auguste, 523 immunohistochemistry, 523–4 Luys, Jules, 522–3 neurochemistry, 523 neurophysiology, 523 Parkinson’s disease, 508 Putnam, James J, 523 sucking reflexes, 226 Sugar, O, 892 Sugita, Gempaku, 770 sulfachrysoidine, bacterial meningitis therapy, 429 sulfanilamide, bacterial meningitis therapy, 430 sulfonamides, Sydenham’s chorea, 517 Summaria Alexandrinorum, 62, 64 Sunderland, Sydney, 791 Sun Si-miao, 764 suprachiasmatic nucleus (SCN), neuropeptide central pathway, 342–3 supraoptic nucleus (SON) microscopy, 339 neuropeptides, 342 neurosecretions, 336 surgical neurology, 189–202 19th Century, 189, 199 antiseptic techniques see antiseptic techniques Australia, 788–9 basal ganglia, 502 cinematography, 296–7 complications, 189 development of, 312 epilepsy treatment, 396–7 European Early Middle Ages, 80 general anesthesia, 191 German-speaking countries, 687 head injuries, 192 interdisciplinary cross-fertilization, 200 localization theory, 125 the Low Countries, 695–6 The Netherlands, 695–6 Parkinson’s disease, 508

surgical neurology (Continued) Russia, 750 United States, 609 workers in Amidon, R W, 193 Ballance, Charles A, 199 Broca, Auguste, 199 Broca, Paul see Broca, Paul Brouwer, Bernardus, 696, 714 Chipault, Antony, 199 Cushing, Harvey, 189, 199–200, 609 Debaisieux, George, 695 Doyen, Euge`ne-Louis, 296–7 Durante, Francesco, 199 Ferrier, David, 193, 195, 197 Guldenarm, J A, 695 Keen, William W, 199 Krause, Fedor, 199 Lister, Joseph Jackson, 191–3 Martin, Paul, 695 Mitchell, Silas Weir, 199 Muskens, L J J, 696 Sedillot, C E, 191 Se´guin, Edouard, 193 von Bergmann, Ernst, 199 Weir, Robert F, 199 Yeo, Gerald, 193 Su wen, epilepsy, 763 Suzuki, Umetaroˆ, 773 Swammerdam, Jan, 109 animal studies, 134–5 Swank, Roy, 664–5 Sweden, 658–9 Swedenborg, Emmanuel, 117–18 anatomical studies, 155–6 frontal lobes, 558–9 Sweet, William, 260 Swieten, Gerard van, 408, 503 Switzerland see German-speaking countries Sydenham, Thomas, 516–17, 617 Sydenham’s chorea, 516–17 Sydenstricker, Edgar, 455–6 Sydney University, 796 Sylvius, Franciscus de la Boe¨, 94 anatomical studies, 152 tremors, 503 University of Leiden, 700 Symonds, Charles, 551 sympathetic autonomous nervous system, 335 synapses, 178–81 Dale, Henry, 179 Eccles, John Carew, 179 Hodgkin, A L, 178–9 Huxley, A F, 178–9 Katz, B, 178–9 Sherrington, Charles Scott, 870 Synopsis Nosologicae Methodica (Cullen), 406 Systematic Manual of Acupuncture, 756 Le Système Nerveux de l’Homme (Van Gehuchten), 712

947 A System of Dissection Explaining the Anatomy of the Human Body (Bell), 283, 618 Szenta´gothai, J, 899–900 Szymonowicz, Wladyslaw, 870

T Tabulae Anatomicae Sex (Vesalius), 152, 275–6 Taddeo Alderotti of Bologna, 83 Takaki, Kanehiro, 446 Takamine, Jokichi, 773, 871 adrenalin, 870–1 Talairach, Jean, 646–7, 647 The Talmud, 41–6, 42 brain, 43 cranial surgery, 45–6 definition, 41–6 epilepsy, 44–5 handedness, 45 headache, 43–4 head injuries, 43 medical knowledge, 43 meningomyelocele, 45 migraine, 43–4 spina bifida aperta, 45 spinal cord diseases/injuries, 45 spinal lesions, 45 structure, 41–2 tinnitus, 46 tremor, 44 see also The Bible Tamburini, Augusto, 724 Tanzi, Eugenio, 724 tardive dyskinesia, 512 taste, 489–90 17th Century, 101 Taylor, James, 837 Taylor Number Series, 249 teaching, Charcot, Jean-Martin, 636 temperature sensation testing, 227 temporal lobe epilepsy The Bible, 40 therapy, 397 Ten Books of Surgery (Pare´), 885–6 Ter Braak, J W G, 704 Terman, Lewis, 242 Terrenz, Johann, 760–1 Terzian, Hrayr, 729–30 tests see neurological examinations tetanus Chang Ching-yua, 762 Mesopotamia, 25 traditional Chinese medicine (TCM), 762 tropical neurology, 819 text blindness, Kussmaul, Adolf, 589 Text-book of Nervous Diseases by American Authors (Dercum), 294 textbooks child neurology, 329–30 neurological examinations, 213 Russia, 751–2 United States, 609

948 Textura del Sistema Nervioso del Hombre y los Vertebrados (Cajal), 163 thalamotomy, tremor therapy, 505 thalamus, sleep medicine, 551–2 Thales, 50 Thelwall, John, 327 Theophrastus, 491 thiamin as coenzyme, 451 deficiency, 445–52 see also beriberi; Wernicke– Korsakoff disease extraction, Japan, 773 Grijn, Gerrit, 448 isolation, 450 metabolic role, 450–1 Peters, Rudolph, 450 synthesis, 450 Thiebault, Franc¸ois, 651 Thomas, Andre´, 514 Thompson, W Gilman, 886 Thomsen, Asmus, 663 Three Paper Test, 236–7 three parts of the soul, 93–4 Descartes, Rene´, 93 thrombosis, apoplexy, 408 Thudichum, J W L, 361 Thurstone, Louis, 240 thyrotropin-releasing hormone (TRH), 336 early work, 341 tics, 530–2 Gilles de la Tourette, Georges, 530, 531–2 Itard, Jean, 530 Trousseau, Armand, 530–1 tinnitus, 46 Tissot, Samuel Avis au Peuple sur la Santé, 379 epilepsy, 392 headache, 379 tissue fixation, 157 Titus Flavius Vespasianus, 46 Toakley, Geoff, 788 Todd, Robert Bentley, 619–20 Token Test, 241 Tolosa, Adherbal, 804–5 Tomlinson, Bernard, 250–1 tonic–clonic seizures, EEG classification, 396 To¨nnies, Jan F, 685 Torkildsen, Arne, 660–1 torsin A gene, 525 touch, 489–90, 491 17th Century, 101 sensory examination, 227 Toulouse, 649 Tourette’s syndrome, 531–2 Mesopotamia, 24–5 toxic neuropathy, 820 toxins pellagra, 453 pernicious anemia, 463–4

INDEX Tractatus de Ventriculo et Intestinis (Glisson), 135 traditional Chinese medicine (TCM), 756–7 anatomical dissection, 757–60 anatomy books, 760–2 anesthetics, 764–5 beriberi, 763–4 brain, views on, 757, 758 carbon monoxide poisoning, 762 Doctrine of Five Elements, 756 ephedrine, 765 epilepsy, 762–3 general anesthesia, 764–5 Japan, 769 leprosy, 763, 764 meridian system, 756 metal poisoning, 762 nervous system, views on, 757 neurological diseases, 762 organ-orientation, 756–7, 757 Qi, 756 tetanus, 762 Yin/Yang principle, 756 Trail Making Test, 250 Traité d’Anatomie des Centres Nerveux (Dejerine), 641 Traité de Pathologie Médicale (Lhermitte), 643 Traité sur le Venin de la Vipère (Fontana), 110 Trallianus, Alexander, 377–8 transcranial magnetic stimulation, 184 transcription factors, anterograde tract tracing, 165 transient ischemic attacks (TIAs), 410–11 Traitement Moral Hygiène et Education (Aigu) des Idiots et des Autres Enfants (Se´guin), 327 traumatic brain injury (TBI) ancient trepanation, 11–12 common problems, 861 incidence, 861 traumatic cervical myelopathy, Ancient Egypt, 33 Traumatic Aphasia (Luria), 751 Treatise of Nervous Disease (Cooke), 401 A Treatise on Diseases of the Nervous System (Hammond), 608 A Treatise on Diseases of the Nervous System (Cooke), 618 A Treatise on the Human Body (Terrenz), 761 Treatise on the Nervous Diseases of Children (Sachs), 324 Trelles, Oscar Montes, 806, 812 tremors, 503–5 action tremors, 503–4 essential, 504–5 essential tremor, 504–5 Galen, 503 hereditary conditions, 505

tremors (Continued) Parkinson, James, 503 physiologic tremor see physiologic tremor rest tremors, 503–4 Sylvius, Franciscus de la Boe¨, 503 The Talmud, 44 therapy, 505 phenobarbital, 505 primidone, 505 propranolol, 505 thalamotomy, 505 van Swieten, Gerard, 503 trepanation, ancient, 3–14 copper/bronze knives, 8 cranial defects vs., 6 diagnosis/recognition, 5–6 geographic areas, 6–8 Bolivia, 5, 8 Central Mexico, 6–7 Europe, 6, 9 France, 4–5, 5 Inca, 5, 8, 9 Peru, 4, 4, 5, 7, 8, 8 group burials, 7 headache, 375–6 healing of, 5, 6, 8 multiple, 8, 9 new vs. old openings, 5–6 obsidian knives, 7 pathological conditions vs., 5–6 reasons for, 8–11 demon exorcism, 9 depressed skull fractures, 8, 9, 10 epilepsy, 10–11 infant convulsions, 9–10 traumatic head injury, 11–12 rehabilitation therapies, 852 survival, 3 The Talmud, 45–6 techniques, 6, 8 temporal survey, 6–8 Mesolithic period, 6 Neolithic period (New Stone Age), 3, 4–5, 6, 9 workers in Broca, Paul, 3–4, 9–10 Buckland, A W, 11 Horsley, Victor, 10 Hughlings Jackson, John, 10 Osler, William, 11 Squier, Ephraim George, 3–4, 4 trephination, United States, 606 Tre´tiakoff, C, 507 trigeminal nerve (cranial nerve V), 219 trimethadone, epilepsy therapy, 397 trinucleotide repeat expansion diseases (TREDS), 368 trochlear nerve (cranial nerve IV), 218–19 Troost, J, 705 tropical ataxic neuropathy (TAN), 824 tropical neurology, 815–30 20th Century, 817–27 Alzheimer’s disease, 826–7

INDEX tropical neurology (Continued) amyotrophic lateral sclerosis, 820 cassava, 817–18 Chagas’ disease, 818 dementia, 826–7 epidemic neuropathy, 817 gnasthosomiasis, 816 HIV infection, 826 human T-cell leukemia viruses, 825 HTLV-1-associated myelopathy (HAM), 825 infantile malnutrition, 818–19 Jamaican neuropathy (Strachan’s syndrome), 816 “konzo”, 818, 825 kuru, 820–1 kwashiorkor, 818 landmark years, 827–8 late-20th Century, 825–6 lathyrism, 816 leprosy, 819 marasmus, 818 pre-20th Century, 815–16 rabies, 819 sleeping sickness, 818 tetanus, 819 tropical spastic paraparesis (TSP), 825 trypanosomiasis, 818 under-nutrition, 818–19 World Federation of Neurology, 824–5 see also specific countries tropical spastic paraparesis (TSP), 825 Trousseau, Armand agraphia, 585–6 alexia, 585–6 aphasia, 635 cognitive assessment, 236 tics, 530–1 trypanosomiasis, 818 tryptophan metabolism, niacin, 457–8 tsalcha, 44 tuberculoma, Horsley, Victor, 198 tuberculosis, European Middle Ages, 86 tuberculous meningitis, 422–3 autopsy, 423 Fremont-Smith, Frank, 425–6 Gerhard, William, 423 Hooper, Robert, 423, 424 Louis, Pierre, 423 Merritt, Houston, 425–6 Mestrezat, William, 424–5 Senn, Louis, 422–3 therapy, 430 Tulp, Nicolaas, 703 Tu¨rck, Ludwig, 686 neuronal pathways, 164 Turner, Brian Baxter, 785 Turner’s Lane Hospital, 607–8 Twarog, Betty Mack, 877 twentieth Century animal studies, 143–4 antilocalizationist tendencies, 173 bacterial meningitis, 428 therapy, 429–30

twentieth Century (Continued) frontal lobes, 561–4 functional localization, 173–5 Great Britain, 625–6 headache, 384–5 hospitals, 312–13 intelligence tests, 241–2 Japan, 773–7 tropical neurology, 815–16, 817–27, 825–6 Tyler, H R, 528 Tyzzer, Ernest Edward, 142

U ubiquitin-proteasome proteolytic system, 511 Udagawa, Genzui, 770 Ueber die Erhaltung der Kraft (von Helmholtz), 675 unconsciousness, Ancient Egypt, 32 uncontrolled associations, aphasia cognitive assessment, 240 under-nutrition, tropical neurology, 818–19 United Kingdom see Great Britain United States of America (USA), 605–12 19th Century, 608–9 20th Century, 609–12 addiction therapy, 611 anticonvulsant therapies, 609 Great Depression, 610 imaging, 611 nerve conduction, 609 post-World War II, 610–11 Civil War, 606, 607–8, 853 rehabilitation therapies, 853 early days, 605–6 immigration, intelligence tests, 241–2 neurological institutions, 612 occupational rehabilitation, 856 organizations, 609 pellagra, 452, 455–6 phrenology, 606 physical rehabilitation, 853, 855 professional specialization, 308 textbooks, 609 trephination, 606 Turner’s Lane Hospital, 607–8 see also specific people Universite´ Catholique de Louvain La Neuve, 706 Universities Australia see Australia Belgium see Belgium Italy, 723 The Netherlands see The Netherlands Russia, 737 see also specific universities University of Antwerp, 709 University of Brussels, 708–9 University of Buenos Aires, 801 University of Ghent, 706–7 University of Groningen, 702 University of Leiden, 694, 700–1 University of Lie`ge, 707–8

949 University of Louvain, 705–6 University of Nijmegen, 704 University of Utrecht, 701–2 Unzer, Johann August, 670, 672 Uruguay, 805–6 School of Medicine of Montevideo, 805, 806 USSR see Russia

V vaccines, bacterial meningitis therapy, 430 vagus nerve (cranial nerve X), 221 Valentin, Gabriel Gustav, 157 valetudinarium, 305, 305 valproic acid, 397 Valsalva, Anton Maria, 720 Vampre´, Enjolras, 804 Van Bogaert, Ludo, 713, 713–14 multisystem atrophy (olivo-pontocerebellar degeneration), 514 Van Bogaert’s disease, 714 van Calear, Jan Stefan, 275 Van Crevel, H, 703, 704 Van Deen, Isaac, 702 Van der Drift, J H A, 703 Van der Eecken, Henri, 707 Van der Hoorst, Lammert, 703 Van der Kolk, J C Schroeder, 693 University of Utrecht, 701 Van der Lugt, Paul, 704 Van der Put, Nathalie, 461 Van der Scheer, W M, 702 Van Gehuchten, Arthur, 300, 695, 712, 712–13 cinematography, 299 Les Maladies Nerveuses, 299 University of Louvain, 705–6 Van Gehuchten, Paul, 706, 713 Van Gijn, J, 702 van Helmont, Jan Baptist, 92, 92 reception in Oxford, 94 van Leeuwenhoek, Antony, 154, 154 van Meerdervoort, J L C Pompe, 770–1, 771 van Rijnberk, G, 338 Van Rotterdam, Jan Karel, 706 van Swieten, Gerard, 408, 503 variant Creutzfeldt–Jakob disease (vCJD), 368 Varolio, Costanzo, 152 vascular anatomy cerebrovascular disease, 409–10 Duret, Henri, 409 Foix, Charles, 409–10 vascular dementia, Ancient Egypt, 33 vascular origins, apoplexy, 403–5 vasogenic vs. neurogenic “nerve storm” headache theory see headaches vasomotor functions, 17th Century, 98 vasopressin, 336 Du Vigneaud, Vincent, 340 early work, 340 oxytocin relationship, 344 pathways in brain, 343, 343 see also oxytocin

950 vasopressor agents, transient ischemic attacks (TIAs), 411 Velazquez, neurological illustrations, 285 venesection (bloodletting), Arabic/Islamic period, 69 Venezuela, 808–9 ventricles see brain Verga, Andrea, 723 Verhaart, W J C, 700 Vermeulen, Marinus, 703 vermis, Arabic/Islamic period, 66–7 vertigo, 494–6 17th Century, 102 18th Century, 495 cranial nerve VIII (acoustic-vestibular nerve), 220 semicircular canals, 495–6 workers in Aretaeus, 56 Breuer, Joseph, 495 Brown, Alexander Crum, 495 Darwin, Erasmus, 495 de Sauvages, Boissier, 495 Galen, 494 Hartley, David, 494 Herz, M, 494–5 Lucretius, 494 Mach, Ernst, 495 Nyle´n, C, 220 Platter, Felix, 494 Ptolemy, 494 Purkinje, Jan Evangelista, 495 Theophrastus, 494 Wells, William Charles, 495 Whytt, Robert, 495 Vertuosi, 17th Century, 94–5 Vesalius, Andreas, 274–7, 667, 720 anatomical studies, 151–2 animal studies, 131–2 basal ganglia, 501 De Humani Corporis Fabrica, 61, 132, 151, 271, 274 apoplexy, 403 frontal lobes, 558 illustrations, 272, 276, 277 muscular dystrophy, 477, 478 epilepsy, 391 pituitary gland, 336, 336 Tabulae Anatomicae Sex, 152, 275–6 University of Louvain, 705 vicariation, 835–6 age factor, 839 animal experiments, 837–8 Barlow, Thomas, 836–7 definition, 833 Ferrier, David, 838 Franz, Shepherd Ivory, 839 Hitzig, Eduard, 838 Kennard, Margaret, 839–40 Lashley, Karl, 838–9 redundancy theory vs., 833–4 Sherrington, Charles Scott, 838 Soltmann, Otto, 839

INDEX Vico, Giambattista, 720–1 Vicq-d’Azyr, Fe´lix, 631 Vieussens, Raymond anatomical studies, 154–5 Montpellier Medical School, 648 Neurographia Universalis, 105 Vieusseux, Gaspard, 421 epidemic meningitis, 421–2 Vignolo, Luigi, 241 Villemin, Jean-Antoine, 427 violence, frontal lobes, 568 Virchow, Rudolf Ludwig Karl, 408, 676 microscopy studies, 158 occlusive stoke, 408 vision, 489–90 17th Century, 101 acuity testing, 216 al-Haytham, Ibn see al-Haytham, Ibn cortical neurons Hubel, David, 172, 176 Hubel, D H, 172 Wiesel, T N, 172, 176 Hering, Ewald, 687 Leonardo da Vinci, 151 visual cycle, vitamin A, 440–1 visual field testing, 216–17 ‘visual image’ theory, 71 visual pigments Boll, Franz, 438 vitamin A, 436 vitamin A deficiency, 439–40 visuospatial/visuoconstructive skill tests, 244–7 Bender, Lauretta, 245 Goodenough, F L, 245 Head, Henry, 245 Moutier, Franc¸ois, 245, 246 Poppelreuter, Walther, 244–5, 245 Rey, Andre´, 245 vitalism German-speaking countries, 669–70 Montpellier Medical School, 648–9 vitamin(s), 435–44, 445–76 B vitamins, 445–76 overview and description, 435–6 see also specific types; specific vitamins vitamin A, 435–44 chemical synthesis, 440 deficiency, 436–42 public health interventions, 441–2 visual manifestations, 439–40 see also keratomalacia; night blindness discovery of, 439 hormone-like actions, 441 isolation, 440 Karrer, Paul, 440 structure, 440 visual cycle, 440–1 visual pigments, 436 Wald, George, 440–1

vitamin B1 see thiamin vitamin B12 biochemical reactions, 465–6 clinical studies, 466–7 isolation, 465–6 structure, 465–6 synthesis, 465–6 workers in, 466 see also cyanocobalamin deficiency vivisection, Alexandrian medicine, 53 vocational rehabilitation, 855–6 Vogt, Oskar, 684, 684 cerebral cortex studies, 165 Vogt-Mugnier, Ce´cile, 684, 684 voice production, Galen, 56 Volta, Alessandro animal studies, 137 nerve conduction, 492–3 voltage-gated channels, 179–80 von Baer, Karl Ernst, 163, 677 von Bergmann, Ernst, 199, 312 von Bru¨cke, Ernst Wilhelm, 673–4 von Calcar, Jan, 477, 478 von Economo, Constantin, 683 cerebral cortex studies, 165 encephalitis lethargica, 511 narcolepsy, 547 sleep, 547 von Euler, Ulf Svante, 873 von Ewarten, Sigmund Exner, 683 von Frey, Max, 227 von Fu¨rth, Otto, 870, 871 von Gerlach, Joseph, 161 von Gudden, Bernhard, 678, 678–9 von Haller, Albrecht see Haller, Albrecht von von Heine, Jacob, 687 von Helmholtz, Hermann see Helmholtz, Hermann von von Hubbenet, V, 437 von Koelliker, Rudolf Albert, 675 von Krafft-Ebing, Richard, 682 von Luschka, Hubert, 157 von Marxow, Ernst Fleischl, 682 von Monakow, Constantin, 680–1 language center localization, 596 neuronal pathways, 164 von Siebold, Philipp Franz, 770, 770 Vorderman, Adolphe, 447 Vulpian, Fe´lix Alfred, 636–7 adrenalin, 869–70 Vygotsky, Lev Semenovich, 751

W waking, 17th Century, 101 Wald, George, 440–1 Waldeyer, Wilhelm, 677 reticular theories, 160 University of Strasbourg, 650 Walker, Mary Broadbent, 874, 874 Wallenberg, Adolf, 311

INDEX Waller, Augustus Volney, 620 neuronal pathways, 164 Waller, G, 703 Walshe, Francis, 226 Walter, Grey, 183 Walton, J N, 486–7 Wang Ching-Jen, 757 warfare Middle Ages, hospitals, 306 see also specific wars Warren, Joseph W, 224 Wartenberg, Robert, 223 Watts, James, 562 Weber, Ernest Heinrich, 686–7 sensory examination, 227 Wechsler, David intelligence tests, 242–3 memory assessment tests, 244 Memory Scale, 243, 244 Wechsler Adult and Child Intelligence Scales, 215, 243 Wechsler–Bellevue Intelligence Scale, 242–3 Wechsler Memory Scale, 243, 244 Weichselbaum, Anton, 426 Weigert, Carl, 462 Weir, Robert F, 199 Weisenburg, Theodore H aphasia, 239, 240, 579 cinematography, 297 Weiss, Paul, 176 Wei Y-lin, Effective Prescriptions from Physicians of a Distinguished Medical Lineage, 765 wekhedu, Ancient Egypt, 31 Welander, Lisa, 664 Wells, Horace, 191 Wells, William Charles, 495 Welsh, John Henry, 877 Wepfer, Johann Jakob, 94, 94, 669 aphasia, 572 apoplexy, 403, 404–5 headache, 379 Observationes Medico-practicae de Affectibus Capitis Internis & Externis, 572 Wepman, Joseph, aphasia, 579, 857 Werman, R, 879 Wernicke, Karl, 575, 683 agraphia, 587, 589, 589 alexia, 587, 589, 589 aphasia, 215, 583, 587 conduction aphasia, 215 language center localization, 575–6, 596 Wernicke’s encephalopathy, 448–9 Wernicke–Korsakoff disease, 451–2 Wernicke’s aphasia, 236 Wernicke’s encephalopathy, 448–50 Korsakoff’s psychosis vs., 449–50 Wertheimer, Pierre, 651 West, Randolph, 466 West End Hospital for Diseases of the Nervous System, 310

Westminster Hospital, 307 Westphal, Carl Friedrich Otto, 683 muscle tendon reflexes, 222 neuroembryology, 163 reflex testing, 222 Wheatstone, C, 497 Whipple, George H, 464 White, William Alanson cerebellar examination, 229 mental status examinations, 215 Whittier, J R, 523 Whytt, Robert, 418, 617 animal studies, 136 bacterial meningitis, 418–19, 428 An Essay on the Vital and Other Involuntary Motion of Animals, 617 On Nervous, Hypochondrial or Hysterical Diseases, 617 Observations on Dropsy of the Brain, 617 pupillary reaction testing, 217 vertigo, 495 Wickman, Ivar, 665 Wiersma, C A G, 878 Wiesel, Torsten, 176 inborn neural connections/ organization, 176 visual cortical neurons, 172, 176 Wigan, Arthur Ladbroke, 834 Wilks, Samuel, 622 animal studies, 139 brain function localization, 844–5 Lectures on Diseases of the Nervous System, 622 pupillary reaction testing, 218 Williams, Edward, 821–2 Willis, Thomas, 95–101, 152–5, 614–16, 615 ‘animal soul’, 97, 99–101 ‘animal spirits’, 96 animal studies, 132–3 apoplexy, 403–4 ascending functions, 97 bacterial meningitis, 417–18, 428 basal arteries, 281 basal ganglia, 501 Cerebri Anatome (The Anatomy of the Brain), 91, 95–6, 278, 317, 615 anatomy, 153 animal experimentation, 133 apoplexy, 403–4 illustrations, 282 publication history, 98 cerebrum, 615 child neurology, 317–19, 318 autistic-like behaviors, 321 brain damage, 324 etiology, 318–19 parental risk factors, 318 pediatric epilepsy, 319 comparative anatomy, 99–100 cortical convolution studies, 153 cranial nerve studies, 153, 281

951 Willis, Thomas (Continued) cranial nerve IV (trochlear nerve), 218 cranial nerve V (trigeminal nerve), 219 criticism of, 104–5 De Anima Brutorum (The Soul of Brutes), 99–101, 133, 153, 317, 615–16 dissection, 338 headaches, 379 illustrations, 96 descending functions, 97 Diatribae duae Medico-Philosophicae, 615 dissection, 96–7, 338 epilepsy, 391 frontal lobes, 558 German-speaking countries, 669 influence of, 104–5 interactions of faculties, 97 mesenteric tumor studies, 282–3 nerve actions, 616 Pathologiae Cerebri et Nervosi Generis specimen in quo Agitur de Morbis Convulsus, 98–9, 153, 319, 615 dissection, 338 epilepsy, 392 illustrations, 319 peripheral nerves, 153 redundancy theory, 834 Sedleian lectures, 95 senses, 101 disorders of, 489 terminology, 615 ventricles, role of, 97 Wilson, Samuel A Kinnier, 626 aphasia cognitive assessment, 239 praxis assessment tests, 247 primitive (atavistic) reflexes, 226 transient ischemic attacks (TIAs), 410 Wilson’s disease, 512–14 Bramwell, B, 513 copper deposition, 513 Fleischer, Bruno, 513 genetic basis, 513 Kayser, Bernard, 513 therapy, 513–14 Wilson, Samuel A Kinnier, 512 Wing, Lorna, 321 Winkler, Cornelis, 710–11, 711 neuronal pathways, 164 psychiatry teaching, 694 University of Utrecht, 701 Wintrobe, M M, 458 Wintzen, Axel, 701 Wirtz, Felix, 667, 668 Wisconsin Card-Sorting Test, 249 Wising, Per Johan, 658 Wohlfart, Gunnar, 665 Wood, Anthony, 281 Worcester, William, 214

952 word blindness with agraphia, 591–2 Charcot, Jean-Martin, 590 Dejerine, Joseph Jules, 591–2 Kussmaul, Adolf, 589 Word Fluency Task, 240 working memory, 566 World Federation of Neurology, 824–5 World War I aphasia rehabilitation, 857 cognitive rehabilitation, 858–9 the Low Countries, 695 occupational rehabilitation, 855–6 physical rehabilitation, 853, 854 World War II aphasia rehabilitation, 857 cognitive rehabilitation, 859 physical rehabilitation, 854–5 Russia, 750–1 Wren, Christopher, 96 anatomical studies, 153 illustrations, 281, 282

INDEX Wrenn, Frank, 260 writer’s cramp, 525, 525–6 19th Century, 526 Beard, George, 526 Bell, Charles, 525 botulinum toxin, 526 Gowers, William Richard, 526 Kopp, J H, 525 Rockwell, Alphonso, 526 Solly, Samuel, 525 treatment, 526, 527 writing disorders see agraphia Wundt, Wilhelm, 676 Wyllie, John, 848 Wynter, Walter, 423

X Xavier, Francisco, 769 xenodochioi, 305 xenografts, 886 X-ray computed tomography see computed tomography (CT)

Y Yeo, Gerald, 193 Yerkes, Robert, 242 Yin/Yang principle, traditional Chinese medicine, 756 Yom Kippur War, cognitive rehabilitation, 860 Young, R R, 528 Young, Thomas, 492 Yuasa, R, 773

Z al-Zahra¯wı¯, Abu¯ al-Qa¯sim, 67 Zangwill, Oliver, 177 cognitive rehabilitation, 859 zeist theory, pellagra, 453 Zeman, Wolfgang, 524 Ziehen, Theodor, 701 zinc, Wilson’s disease therapy, 514 Zurif, Edgar, 579 zygomatic arch, Ancient Egypt, 31