Pediatric Neuroradiology

Pediatric Neuroradiology Brain Head and Neck Spine

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Paolo Tortori-Donati · Andrea Rossi In collaboration with Roberta Biancheri

Pediatric Neuroradiology

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Two-volume set consists of: Pediatric Neuroradiology Brain Pediatric Neuroradiology Head and Neck Spine

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Pediatric Neuroradiology Brain Paolo Tortori-Donati and

Andrea Rossi In collaboration with

Roberta Biancheri Foreword by

Charles Raybaud

With 1635 Figures in 4519 Separate Illustrations, 207 in Color and 202 Tables

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Paolo Tortori-Donati, MD Head, Department of Pediatric Neuroradiology G. Gaslini Children’s Research Hospital, Genoa, Italy

Andrea Rossi, MD Senior Staff Neuroradiologist Department of Pediatric Neuroradiology G. Gaslini Children’s Research Hospital, Genoa, Italy

Roberta Biancheri, MD, PhD Consultant Pediatric Neurologist Department of Pediatric Neuroradiology G. Gaslini Children’s Research Hospital, Genoa, Italy

Library of Congress Control Number: 2004118036

ISBN 3-540-41077-5 Springer Berlin Heidelberg New York This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitations, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer is part of Springer Science+Business Media http//www.springeronline.com © Springer-Verlag Berlin Heidelberg 2005 Printed in Germany The use of general descriptive names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every case the user must check such information by consulting the relevant literature. Medical Editor: Dr. Ute Heilmann, Heidelberg Desk Editor: Wilma McHugh, Heidelberg Production Editor: Kurt Teichmann, Mauer Typesetting: Verlagsservice Teichmann, Mauer Cover-Design: Frido Steinen-Broo, eStudio Calmar, Spain Printed on acid-free paper – 21/3150xq – 5 4 3 2 1 0

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Dedication

To my wife Lella, inseparable companion of my life, and to my son Raffaele for giving it a meaning.

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Foreword

Pediatric neuroradiology has always been a distinct entity within neuroradiology, because pathologies are different, more diverse and more often related to development than adult diseases. This has become still truer since the introduction of modern imaging modalities, in particular magnetic resonance imaging (MRI). In the past two decades entire fields of pathology have been made accessible to the physician on a daily basis: demyelinating and dysmyelinating diseases, malformations of cortical development, perinatal disorders and, moreover, prenatal brain disorders. The evaluation of tumors and malformations is now considerably more detailed. These changes are leading the pediatric neuroradiologist to develop much closer links with other specialists in neuropathology, genetics, neurophysiology and neurochemistry, to name but a few, to better comprehend the diseases she/he is dealing with. At the same time, the availability of an imaging modality practically devoid of noxious effects makes it possible to accumulate large series of patients studied in vivo, while more historical material has consisted only of a few specimens derived from autopsy or surgery. Easier patient surveillance has improved our understanding of the natural history of many diseases. Striking examples are the discovery of the transient nature of lesions (including some tumors) in neurofibromatosis type 1 and the routine observation of the relocation of cognitive functions after cortical injuries as a mechanism of brain plasticity. All this has given the pediatric neuroradiologist a unique opportunity to approach the central nervous system from a fresh, genuine point of view. She/he can now contribute significantly to the advances in clinical pediatric neurosciences, so much so that imaging has become the crucial step in diagnostic assessment, bringing information not only about structure (including the water sectors through DWI), but also about metabolism and function. With so many diseases and so much new knowledge, in such a short time: the need for comprehensive syntheses is immense, and Paolo Tortori-Donati, with his colleagues Andrea Rossi and Roberta Biancheri, has responded to the challenge with this new book. The 57 contributors of the 45 chapters are predominantly from Italy, and especially from Genoa, but also from France, the United States, Switzerland, the United Kingdom and Saudi Arabia. They represent more than 25 hospitals or universities and constitute a substantial representation of world pediatric neuroradiology. Despite the great number of contributors, the final result demonstrates a profound unity. The credit is to be given to Paolo Tortori-Donati and his colleagues. The book can be divided into three sections: brain (the largest), skull and neck, and spine. Each section begins with embryology. The three chapters written by Martin Catala (Chaps. 1, 28 and 38) do not only address the classical morphologic changes (descriptive embryology); they make up an exhaustive, state-of-the-art review of modern data regarding brain development: comparative embryology, tissue induction processes, neurulation, segmentation, migration, tissue interactions, cellular guidance, and specialization,

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all with their respective genetic control. These chapters are extremely rich and detailed, clearly written and easy to read. They help bridge the gap between disease, morphogenesis, and the general principles of the development. While most of the pathology rests upon MRI, chapters concluding each section deal extensively with sonography. Brain MR spectroscopy and diffusion, perfusion and functional MRI are also extensively dealt with, as these techniques have now become dedicated parts of the routine evaluation of patients. Each pathology chapter is an exhaustive review, each is lucidly didactic, beautifully illustrated, up to date, and written by eminent experts. It would take up too much space, and be tiresome for the reader, to analyze all of them. However, the chapter on metabolic disease, composed by Zoltan Patay (Chap. 13), deserves a mention as truly representative of the spirit and aims of the book. Being thoroughly documented and education-oriented, indeed it could be a book by itself. The neuroradiologists of my generation remember “the Taveras book” (J.M. Taveras and E.H. Wood: Diagnostic Neuroradiology) as being the bible in which they found most of their knowledge of and enthusiasm for neuroradiology. Since then, not all neuroradiology texts have attained that ideal, but a few have come close, having a similar impact on neuroradiologists in training, and they have set the standard of the subspecialty. I believe that the new Pediatric Neuroradiology elaborated by Paolo Tortori-Donati and his group will take its place among these major books. Toronto, January 2005

Charles Raybaud

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This book sees the light of day after 4 years’ gestation. The idea behind it originated in the early 1990s when, as I moved to the G. Gaslini Children’s Hospital, I realized the immense potential that was to be found there, both in terms of general pathologies and, more specifically, regarding central nervous system diseases, with a strong impact on diagnostic imaging, especially magnetic resonance imaging. The G. Gaslini Children’s Research Hospital in Genoa, Italy, where I hold the position of Head of the Department of Pediatric Neuroradiology, is a scientific institution and hospital dedicated to infancy and childhood, equipped with 400 beds for admission of patients under 14 years of age. Adults are not treated, with the sole exception of the Obstetrics and Gynecology department. All pediatric specialties are represented in the hospital. With particular regard to our field of interest, departments of Neurosurgery (with built-in spinal unit), Pediatric Hematooncology, Neurooncology, Infantile Neuropsychiatry, Ophthalmology, ENT, a Muscular Diseases Unit, and two Orthopedics Divisions are to be found. Moreover, special neuropathological competences are available within the Pathological Anatomy Unit. Within this environment, Neuroradiology has existed as an independent, individual unit since 1994. Very recently, the structural reorganization of the hospital has led to the definition of larger, “mother” departments. Within this new setting, Neuroradiology is housed within the Department of Diagnostic Imaging and is also functionally related to the Department of Neurosciences. Despite the unit’s relatively recent foundation, the neuroradiological experience in our hospital dates back to the introduction of CT in 1979 and MRI in 1988, as well as angiography, initially conventional and then digitalized, with neurovascular interventional activity since 1993. Ultrasound diagnosis has been developed, since its initial introduction, by the Department of Radiology, chaired by my friend Paolo Tomà, who also is a contributor to this book. The book is deliberately encyclopedic and was conceived to address pediatric neuroradiology in a different way from other existing publications in the field. I set out to create a book that would be useful not only to those who are directly involved with diagnostic imaging, but also to clinicians who care for infants and children with neurological conditions during their clinical practice. While the book retains a main diagnostic focus, clinical aspects, genetics, and treatment of the various conditions are also addressed. Embryology and neuropathology are also especially highlighted, the former being essential to the understanding of malformations and the latter because neuroradiology is nothing but the expression of the biological behavior of tissues. The book is divided into two volumes, one dedicated to the brain and the other to the head, neck, and spine. It is a long journey that starts from embryology, explores prenatal ultrasound and MRI diagnosis, reaches the fields of conventional CT, MRI and angiographic diagnosis, peers into the present and future of advanced imaging

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modalities and interventional techniques and then arrives at the clinical, metabolic, and genetic diagnosis. All the cases presented in this book have received a confirmed diagnosis, either pathological or clinical-metabolic, or genetic. Only those rare cases where a definite diagnosis could not be obtained are indicated as “presumed”. Many cases are presented globally, starting from the in utero appearance and extending to the final post-operative results and pathological features. Of the 45 chapters, about one third, the most relevant ones in terms of pathology and comprising the bulk of the book, were written by my group (except for the chapter on metabolic diseases), and belong to the listed authors in equal measure. The remaining chapters were written by leading, world-renowned authorities in the various fields. We undertook an enormous editorial revision of all contributions in other to give the book a homogeneous structure. This entailed editing the text, especially with regard to redundancies, and adding our own case material where I considered it useful to enrich the various presentations. I also made an extensive search, with the help of many friends and colleagues, for outstanding cases that could be added where we did not have sufficiently good demonstrations of individual diseases. Therefore, cases presented at various congresses or published in the literature were added to this book thanks to the gracious courtesy of these colleagues, who are individually acknowledged in the captions and to whom I extend my gratitude. The various clinical sections of the book were revised by one of my collaborators, specialized in Child Neurology, while a novice to the subject read the text to evaluate whether it was understandable at a basic level. We were fanatical about the quality of the illustrations. We drew most of the line drawings ourselves, and pathologic illustrations and anatomic preparations were included. Because the work on this book spanned several years, some illustrations from chapters submitted earlier were replaced with new, more recent and better ones obtained on modern imaging equipment. Furthermore, for the same reasons we also undertook a sometimes painful but hopefully thorough review of the more recent literature, so that I am confident the whole book embodies up-to-date knowledge on pediatric neuroradiology and the related fields. While a careful review of the existing literature was the foundation of this book, I also deliberately wanted to bring forth our own experience, based on our single-center case series, which I believe to be among the largest available. This experience, which has allowed me and my group to teach pediatric neuroradiology at various national and international congresses and courses, has eased the difficult task of putting together a clear, didactic and understandable text. I hope that the readers will appreciate this effort; only they will be able to judge whether I and my collaborators have succeeded in our goal. This book is dedicated not only to those who will use it in their everyday clinical practice, but especially to the children and their families who have had the ill luck to provide us with the material for our work.

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Acknowledgements I would like to thank all those involved with the production of this book, without whom this work would not have been completed. Professor Claude Manelfe needs no presentation, because everyone working in our field knows him. At the time when he was the President of the European Society of Neuroradiology, he believed in me and my project and introduced me to Springer. Prof. Lorenzo Moretta, Scientific Director of the G. Gaslini Children’s Research Hospital, assigned a grant to Roberta Biancheri, whose collaboration was crucial to the success of the project. The anesthesiologists of our hospital, and particularly Dr Giorgio Salomone, without whom we would be unable to obtain our results as most young children at our institution are imaged under general anesthesia. My technologists Piero Sorrentino (Chief), Eleonora Cioetto and Claudia Mancini, with whom I have been collaborating for many years and to whom I feel connected by bonds of affection, rather than merely work. My nurses Fausta Lucchetti, Patrizia Massabò, Armanda Piana, Wilma Ponta, Claudia Ricci, Michela Rollando and Candida Soro, who have lovingly taken care of these unlucky children. My brotherly friend and colleague Armando Cama, Chief Neurosurgeon of our hospital, his collaborators Gianluca Piatelli and Marcello Ravegnani, and the neurooncologists Maria Luisa Garrè and Claudia Milanaccio: how many fights, discussions, and laughs…. Without this everyday confrontation we would not have grown. Paolo Nozza, young and enthusiast neuropathologist, whose input was crucial especially for the chapters on neoplastic diseases. My good friend and colleague, Paolo Tomà, Chief of the Radiology Department of our hospital, for the friendship and esteem he always showed to me and for allowing neuroradiology to grow freely in our institution. All people at Springer in Heidelberg, Germany, and especially Dr Ute Heilmann, Ms Wilma McHugh, and Mr Kurt Teichmann, for the enduring kindness, patience, and trust that they bestowed in us, graciously accepting our too often controversial requests, believing that we would eventually succeed, and especially for their enthusiasm in pursuing a common goal. Dr Roberta Biancheri, Child Neurologist in love with Neuroradiology, outstanding contributor and “clinical soul” of this book, has been an invaluable support in our moments of discomfort and fear of not being able to finish this work and also has taught me and my group a lot regarding clinical correlations to neuroimaging. Last but not least, no words would be sufficient to thank Dr Andrea Rossi, a man of lofty human and professional talents, my first pupil and my major collaborator both in putting together this book and in everyday work activity, who shared and amplified my enthusiasm for our work. I am proud to say that Andrea is recognized both nationally and internationally as an authority in our field, and I believe he will hold high the torch of future development of pediatric neuroradiology. Genoa, January 2005

Paolo Tortori-Donati

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Contents

Contents

Brain 1 Embryology of the Brain Martin Catala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2 Myelination Cecilia Parazzini, Elena Bianchini, and Fabio Triulzi . . . . . . . . . . . . . . . . . .

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3 Malformations of the Telencephalic Commissures. Callosal Agenesies and Related Disorders Charles Raybaud and Nadine Girard . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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4 Brain Malformations Paolo Tortori-Donati, Andrea Rossi, and Roberta Biancheri . . . . . . . . . . .

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5 Magnetic Resonance Imaging of the Brain in Preterm Infants Luca A. Ramenghi, Fabio Mosca, Serena Counsell, and Mary A. Rutherford . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 6 Neonatal Hypoxic-Ischemic Encephalopathy Fabio Triulzi, Cristina Baldoli, and Andrea Righini . . . . . . . . . . . . . . . . . . . 235 7 Cerebrovascular Disease in Infants and Children Robert A. Zimmerman and Larissa T. Bilaniuk . . . . . . . . . . . . . . . . . . . . . . . . . 257 8 Arteriovenous Malformations: Diagnosis and Endovascular Treatment Laecio Batista, Augustin Ozanne, Marcos Barbosa, Hortensia Alvarez, and Pierre Lasjaunias . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 9 Capillary-Venous Malformations Paolo Tortori-Donati, Andrea Rossi, and Roberta Biancheri . . . . . . . . . . . 319 10 Brain Tumors Paolo Tortori-Donati, Andrea Rossi, Roberta Biancheri, Maria Luisa Garrè, and Armando Cama . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 11 Hemolymphoproliferative Diseases and Treatment-Related Disorders Paolo Tortori-Donati, Andrea Rossi, and Roberta Biancheri . . . . . . . . . . . . 437 12 Infectious Diseases Paolo Tortori-Donati, Andrea Rossi, and Roberta Biancheri . . . . . . . . . . . 469

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13 Metabolic Disorders Zoltán Patay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543 14 Neurodegenerative Disorders Ludovico D'incerti, Laura Farina, and Paolo Tortori-Donati . . . . . . . . . . . 723 15 Acquired Inflammatory White Matter Diseases Massimo Gallucci, Massimo Caulo, and Paolo Tortori-Donati . . . . . . . . . . 741 16 Phakomatoses Paolo Tortori-Donati, Andrea Rossi, Roberta Biancheri, and Cosma F. Andreula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 763 17 The Rare Phakomatoses Simon Edelstein, Thomas P. Naidich, and T. Hans Newton . . . . . . . . . . . . . . . 819 18 Sellar and Suprasellar Disorders Paolo Tortori-Donati, Andrea Rossi, and Roberta Biancheri . . . . . . . . . . . 855 19 Accidental Head Trauma Paolo Tortori-Donati, Andrea Rossi, and Roberta Biancheri . . . . . . . . . . . 893 20 Nonaccidental Head Injury (Child Abuse) Bruno Bernardi and Christian Bartoi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929 21 Hydrocephalus, Cysts, and Other Disorders of the Cerebrospinal Fluid Spaces Paolo Tortori-Donati, Andrea Rossi, and Roberta Biancheri . . . . . . . . . . . 951 22 Epilepsy Renzo Guerrini, Raffaelo Canapicchi, and Domenico Montanaro . . . . . . . 995 23 MR Spectroscopy Petra S. Hüppi and François Lazeyras . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1049 24 Diffusion-Weighted, Perfusion-Weighted, and Functional MR Imaging Ernst Martin-Fiori and Thierry A. G. M. Huisman . . . . . . . . . . . . . . . . . . . . . . . 1073 25 Brain Sonography Paolo Tomà and Claudio Granata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115 26 Prenatal Ultrasound: Brain Mario Lituania and Ubaldo Passamonti . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1157 27 Fetal Magnetic Resonance Imaging of the Central Nervous System Nadine Girard and Thierry A. G. M. Huisman . . . . . . . . . . . . . . . . . . . . . . . . . . 1219

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Head and Neck 28 Embryology of the Head and Neck Martin Catala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1255 29 Skull Development and Abnormalities Robert A. Zimmerman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1271 30 The Craniostenoses Cesare Colosimo, Armando Tartaro, Armando Cama, and Paolo Tortori-Donati . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1289 31 The Orbit Paolo Tortori-Donati, Andrea Rossi, and Roberta Biancheri . . . . . . . . . . . 1317 32 Disorders of the Temporal Bone Mauricio Castillo and Suresh K. Mukherji . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1361 33 Sinonasal Diseases Bernadette Koch and Mauricio Castillo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1391 34 Imaging of the Neck Zoran Rumboldt, Mauricio Castillo, and Suresh K. Mukherji . . . . . . . . . . . 1419 35 Cervico-Facial Vascular Malformations Jeyaledchumy Mahadevan, Hortensia Alvarez, and Pierre Lasjaunias . . 1459 36 Face and Neck Sonography Paolo Tomà . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1479 37 Prenatal Ultrasound: Head and Neck Mario Lituania and Ubaldo Passamonti . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1503

Spine 38 Embryology of the Spine and Spinal Cord Martin Catala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1533 39 Congenital Malformations of the Spine and Spinal Cord Paolo Tortori-Donati, Andrea Rossi, Roberta Biancheri, and Armando Cama . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1551 40 Tumors of the Spine and Spinal Cord Paolo Tortori-Donati, Andrea Rossi, Roberta Biancheri, Maria Luisa Garrè, and Armando Cama . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1609 41 Infectious and Inflammatory Disorders of the Spine Mauricio Castillo and Paolo Tortori-Donati . . . . . . . . . . . . . . . . . . . . . . . . . . 1653

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42 Spinal Trauma Paolo Tortori-Donati, Andrea Rossi, Milena Calderone, and Carla Carollo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1683 43 Spine and Spinal Cord: Arteriovenous Shunts in Children Siddhartha Wuppalapati, Georges Rodesch, Hortensia Alvarez, and Pierre Lasjaunias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1705 44 Spine and Spinal Cord Sonography Paolo Tomà . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1715 45 Prenatal Ultrasound: Spine and Spinal Cord Mario Lituania and Ubaldo Passamonti . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1725

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1737

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List of Contributors

Hortensia Alvarez, MD Diagnostic and Therapeutic Vascular Neuroradiology Unit Bicêtre Hospital Le Kremlin-Bicêtre, France

Roberta Biancheri, MD, PhD Consultant Child Neurologist Department of Pediatric Neuroradiology G. Gaslini Children’s Research Hospital Genoa, Italy

Cosma F. Andreula, MD Director, Diagnostic and Interventional Neuroradiology Unit Anthea Hospital Bari, Italy

Elena Bianchini, MD Department of Radiology and Neuroradiology V. Buzzi Children’s Hospital Milan, Italy

Cristina Baldoli, MD Department of Neuroradiology San Raffaele Scientific Institute Milan, Italy Marcos Barbosa, MD Diagnostic and Therapeutic Vascular Neuroradiology Unit Bicêtre Hospital Le Kremlin-Bicêtre, France Christian Bartoi, MD Department of Radiology Oakwood Hospital Dearborn, MI, United States of America and Department of Radiology Wayne State University and Michigan Children’s Hospital Detroit, MI, United States of America Laecio Batista, MD Diagnostic and Therapeutic Vascular Neuroradiology Unit Bicêtre Hospital Le Kremlin-Bicêtre, France Bruno Bernardi, MD Department of Neuroradiology Bellaria Hospital Bologna, Italy and Associate Professor, Department of Radiology Wayne State University and Michigan Children’s Hospital Detroit, MI, United States of America

Larissa T. Bilaniuk, MD Professor of Radiology, University of Pennsylvania Staff Neuroradiologist Children’s Hospital of Philadelphia Philadelphia, PA, United States of America Milena Calderone, MD Department of Neuroradiology Civic Hospital Padua, Italy Armando Cama, MD Head, Department of Pediatric Neurosurgery G. Gaslini Children’s Research Hospital Genoa, Italy Raffaello Canapicchi, MD Unit of Neuroradiology Clinical Physiology Institute National Council of Research Pisa, Italy Carla Carollo, MD Head, Department of Neuroradiology Civic Hospital Padua, Italy Mauricio Castillo, MD Professor of Radiology Chief of Neuroradiology University of North Carolina School of Medicine Chapel Hill, NC, United States of America Martin Catala, MD, PhD Laboratory of Histology and Embryology Pitiè-Salpêtrière School of Medicine University of Paris 6 Paris, France

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Massimo Caulo, MD Department of Radiology ITAB- University of Chieti Chieti, Italy

Renzo Guerrini, MD Chief, Division of Child Neurology and Psychiatry University of Pisa and IRCCS Stella Maris Foundation Pisa, Italy

Cesare Colosimo, MD Professor of Radiology Department of Radiology G. D’Annunzio University Foundation Chieti, Italy

PD Thierry A.G.M. Huisman, MD Radiologist-in-Chief and Chairman Department of Diagnostic Imaging Radiology and Neuroradiology University Children‘s Hospital Zurich Zurich, Switzerland

Serena Counsell, MSc Superintendent Radiographer Imaging Sciences Department, Robert Steiner MR Unit Hammersmith Hospital London, United Kingdom Ludovico D’Incerti, MD Department of Neuroradiology C. Besta National Neurological Institute Milan, Italy Simon Edelstein, MD Senior Fellow Diagnostic and Interventional Neuroradiology Head and Neck Radiology Advanced Clinical Neuroimaging The Mount Sinai School of Medicine New York, NY, United States of America Laura Farina, MD Department of Neuroradiology C. Besta National Neurological Institute Milan, Italy Massimo Gallucci, MD Professor of Radiology University of L’Aquila L’Aquila, Italy

Petra S. Hüppi, MD Director of Child Development Unit Department of Pediatrics University Children’s Hospital Geneva, Switzerland Bernadette Koch, MD Department of Radiology Cincinnati Children’s Hospital Cincinnati, OH, United States of America Pierre Lasjaunias, MD, PhD Head, Diagnostic and Therapeutic Vascular Neuroradiology Unit Bicêtre Hospital Le Kremlin-Bicêtre, France François Lazeyras, PhD Department of Radiology University Children’s Hospital Geneva, Switzerland Mario Lituania, MD Director of Center of Fetal and Perinatal Medicine Galliera Civic Hospital Genoa, Italy

Maria Luisa Garrè, MD Director of Neurooncology Unit Department of Pediatric Hematology and Oncology G. Gaslini Children’s Research Hospital Genoa, Italy

Jeyaledchumy Mahadevan, MD Diagnostic and Therapeutic Vascular Neuroradiology Unit Bicêtre Hospital Le Kremlin-Bicêtre, France

Nadine Girard, MD Associate Professor Department of Radiology Hospital Nord Université de la Méditerranée Marseille, France

Ernst Martin-Fiori, MD Head, Neuroradiology & Magnetic Resonance Department of Diagnostic Imaging University Children’s Hospital Zurich, Switzerland

Claudio Granata, MD Department of Pediatric Radiology G. Gaslini Children’s Research Hospital Genoa, Italy

Domenico Montanaro, MD Unit of Neuroradiology Clinical Physiology Institute National Council of Research Pisa, Italy

List of Contributors

Fabio Mosca, MD Consultant in Neonatal Medicine Head, Department of Neonatology Mangiagalli Clinical Hospital Milan, Italy Suresh K. Mukherji, MD Associate Professor of Radiology Chief of Neuroradiology University of Michigan School of Medicine Ann Arbor, MI, United States of America Thomas P. Naidich, MD Department of Radiology (Neuroradiology) The Mount Sinai School of Medicine New York, NY, United States of America T. Hans Newton, MD Professor of Radiology The Moffitt Hospital University of California at San Francisco San Francisco, CA, United States of America Augustin Ozanne, MD Diagnostic and Therapeutic Vascular Neuroradiology Unit Bicêtre Hospital Le Kremlin-Bicêtre, France Cecilia Parazzini, MD Department of Radiology and Neuroradiology V. Buzzi Children’s Hospital Milan, Italy Ubaldo Passamonti, MD Center of Fetal and Perinatal Medicine Galliera Civic Hospital Genoa, Italy Zoltán Patay, MD, PhD Consultant Neuroradiologist Department of Radiology King Faisal Specialist Hospital and Research Centre Riyadh, Kingdom of Saudi Arabia Luca A. Ramenghi, MD Consultant in Neonatal Medicine Department of Neonatology Mangiagalli Clinical Hospital Milan, Italy Charles Raybaud, MD Professor and Head, Neuroradiology CHU Timone, Université de la Méditerranée Marseille, France Andrea Righini, MD Department of Radiology and Neuroradiology V. Buzzi Children’s Hospital Milan, Italy

Georges Rodesch, MD Head, Department of Diagnostic and Therapeutic Neuroradiology Foch Hospital Suresnes, France Andrea Rossi, MD Senior Staff Neuroradiologist Department of Pediatric Neuroradiology G. Gaslini Children’s Research Hospital Genoa, Italy Zoran Rumboldt, MD Department of Radiology Medical University of South Carolina Charleston, SC, United States of America Mary A. Rutherford, MD, FRCR, FRCPCh PPP/Academy Senior Fellow in Perinatal Imaging Honorary Senior Lecturer and Consultant in Pediatric Radiology Imaging Sciences Department, Robert Steiner MR Unit Hammersmith Hospital London, United Kingdom Armando Tartaro, MD Department of Radiology G. D’Annunzio University Foundation Chieti, Italy Paolo Tomà, MD Head, Department of Pediatric Radiology G. Gaslini Children’s Research Hospital Genoa, Italy Paolo Tortori-Donati, MD Head, Department of Pediatric Neuroradiology G. Gaslini Children’s Research Hospital Genoa, Italy Fabio Triulzi, MD Head, Department of Radiology and Neuroradiology V. Buzzi Children’s Hospital Milan, Italy Siddhartha Wuppalapati, MD Diagnostic and Therapeutic Vascular Neuroradiology Unit Bicêtre Hospital Le Kremlin-Bicêtre, France Robert A. Zimmerman, MD Vice Radiologist-in-Chief, Department of Radiology Chief, Neuroradiology Division/MRI Children’s Hospital of Philadelphia Philadelphia, PA, United States of America

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Embryology of the Brain

1

Embryology of the Brain Martin Catala

1.1 Introduction

CONTENTS 1.1

Introduction

1.2

The Two Neural Inductions: Head and Trunk Inductions 2 Amphibian Chimeras and Neural Induction Genetic Regulation of Head Induction 3 Hesx1 and Septo-Optic Dysplasia 3

1.2.1 1.2.2 1.2.3 1.3 1.3.1 1.3.2 1.3.2.1

1.3.2.2 1.3.2.3 1.3.2.4 1.3.3 1.3.4 1.4 1.4.1 1.4.2 1.4.2.1 1.4.2.2 1.4.3 1.4.4 1.4.4.1 1.4.4.2 1.4.4.3 1.4.5 1.4.6 1.4.7 1.4.8 1.5 1.5.1 1.5.2 1.5.3

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Segmentation of the Neural Primordium into Neuromeres 3 The Genetic Control of Insect Segmentation 4 The Rhombomeres 4 The Motoneurons That Constitute One Branchial Nerve Are Located in Two or Three Adjacent Rhombomeres 4 Even-Numbered Rhombomeres Differentiate Earlier Than Odd-Numbered Rhombomeres 4 Rhombomeres Represent Relative Cell Lineage Restriction Compartments 5 The Genetic Control of Anteroposterior Identity of the Rhombomeres 6 Embryonic Origin of the Cerebellum 7 The Prosomeres, a Model of Rostral Segmentation 7 New Insights About Cerebral Cortex Development 8 Partitioning the Telencephalic Vesicle into Two Hemispheres 8 Asymmetric Division of Neuroepithelial Cells in the Ventricular Zone 9 Neuroepithelial Cells Divide at the Ventricular Zone of the Neural Tube 9 Asymmetric Mitosis and Neurogenesis 9 Formation of the Preplate 10 From the Ventricle to the Cortical Plate: The Migration of Neuroblasts 10 Radial Migration and Radial Glial Cells 10 Two Modes of Radial Migration 11 Radial Glial Cells Are Bipotential Progenitors 12 The Basal Telencephalon Participates in the Formation of Cortical Neurons 12 Subplate Neurons Control the Development of Thalamic Axons 13 The Ventricular Neuroblasts Are Not Fully Specified at the Time of Their Birth 13 Formation of Cerebral Gyration 13 Control of Formation of the Pyramidal Tract 14 Chemoattraction and Netrins 14 L1 Permits Crossing of the Midline 15 Epha4 and Ephrin B3 Prevent Pyramidal Axons from Recrossing the Midline at the Spinal Level 16 References

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The construction of the brain during embryonic life is a fascinating event. Indeed, the brain is the most complex organ of the whole body, and this is particularly evident in human beings. The human brain contains a huge number of cells, and each neuron is able to connect a great number of other neurons, leading to a very complex network of circuits. The development of such a complex structure is likely to be highly regulated in order to give rise to reliable anatomical regions that can perform their normal tasks after birth. Furthermore, the capacity for growth of the human brain is fantastic during fetal life; this can be illustrated by comparing the size of the brain at the beginning and the end of gestation (Fig. 1.1). In terms of anatomical segmentation, it is classical to distinguish the brain from the spinal cord. The brain is then divided into the hemispheres, the cerebellum, and the brainstem. The hemispheres are segmented into the cerebral cortex and the diencephalon, whereas the brainstem is separated into mesencephalon, metencephalon, and myelencephalon. This

Fig. 1.1. Comparison of the size of two human fetal brains at 10.5 weeks of gestation (arrow) and at 38.5 weeks of gestation (arrowhead) shows the tremendous capacity of growth of the brain

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anatomical classification has been extensively used in terms of embryological description. This explains why the segmentation of the primitive neural tube has been described according to the same classification with the different vesicles (telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon) (Fig. 1.2). Each embryonic vesicle was considered as the primordium for the adult region. This fixed and committed embryology is now really obsolete. First, it has been demonstrated that there are two separate regions in the neural tube: one rostral, comprising the telencephalon, diencephalon, and mesencephalon, and the other caudal. Indeed, the genetic regulations of these two regions are different.

another one, creating a chimera. After healing, it is thus possible to study the subsequent development of the chimera and to notice the consequences of such an operation. This was the beginning of the great American school with Ross Granville Harrison and the famous German school with Hans Spemann. In 1918, Hans Spemann described the peculiar property of the blastoporal lip of the amphibian gastrula (an early marker of the dorsal side of the gastrula in amphibians). Indeed, the graft of an extra lip on the ventral side of the gastrula leads to a duplication of the nervous system. However, it was impossible at that time to decipher between the tissues deriving from the host and those deriving from the donor. To address this question, it was necessary to have a perfect cell marker that can differentiate host tissues from donor ones. This was possible using two different species of Triton (T. taeniatus and T. cristatus), which can be differentiated thanks to the intrinsic pigmentation of the cytoplasm of their cells. These chimeras, in which donor and host embryos belong to different species, are called interspecific chimeras. This technique allowed the discovery of neural induction. This discovery was due to the experiments of Hilde Mangold (1924) in Hans Spemann’s laboratory [1]. Using the technique of interspecific chimeras, it was thus possible to note that the graft gives rise to the notochord, a part of the endoderm, the floor plate of the neural tube, and the medial part of the somites. In contrast, the remainder of the secondary neural tube was formed by the host (Fig. 1.3). This result allowed Spemann to describe the phenomenon of so-called Sek. D. R. sek. Pron. R. sek. Uw.

Fig. 1.2. Rostral extremity of a chick embryo (16-somite stage) showing the different vesicles: telencephalon (T), diencephalon (D), mesencephalon (M), rhombencephalon (R) or myelencephalon. Note that the eye vesicles (E) are developing and that the paraxial mesoderm is segmented into somites (S)

Sek Med. Pr. Med.

Sek. Ch.

1.2 The Two Neural Inductions: Head and Trunk Inductions 1.2.1 Amphibian Chimeras and Neural Induction At the end of the nineteenth century, experimental embryology was mainly based on the amphibian model, since it is possible to operate on the embryo and even to transplant a small part of one embryo to

Fig. 1.3. Section through an amphibian embryo after the graft of the dorsal lip of the blastopore (after Hans Spemann and Hilde Mangold, 1924). The cytoplasm of host cells is pigmented, whereas that of donor cells is not. Donor cells give rise to the secondary notochord (Sek. Ch.), the medial part of the somites (R. sek. Uw.), and the floor plate of the neural tube. The rest of the neural tube (Sek. Med.) derives from the host. [1]

Embryology of the Brain

neural induction. Neural induction means that the graft acts on the surrounding tissue and forces it to differentiate into neural fate. It is possible to reproduce the experiments of Spemann and Mangold in amniotes embryos by grafting Hensen’s node in birds [2] or the node in mice [3]. The problem of different inductors responsible for head and trunk induction was hypothesized by Spemann himself [1]. He distinguished three inductors: the head inductor, located in the upper blastoporal lip of the early gastrula; the trunk inductor in the same place of the advanced gastrula; and the tail inductor in the same place of the completed gastrula. These observations were at the origin of the concept of regionalized inductions.

1.2.2 Genetic Regulation of Head Induction The problem of head induction was recently strengthened by experiments performed in different models. The group of Eddy De Robertis [4] found that the secreted protein Cerberus is able to induce a head without inducing a trunk in the amphibian embryo. This experiment demonstrates that the formation of the head is independent of the formation of the trunk, and that the molecules involved in such a problem are different. In the mouse, two knock-out experiments selectively remove head structures while trunk and tail develop almost normally. This suggests that the genetic control of the head organizer is different from that of the trunk and tail organizer in the mouse. Lim1 is a gene coding for a protein carrying a LIM class homeodomain motif and two cyteine-rich domains. This gene is homologous to the Xenopus gene Xlim1 that is involved in the blastoporal functions. Heterozygous mice Lim1+/– are normal, whereas homozygous Lim1–/– died at embryonic day 10 [5]. Homozygous embryos showed a very abnormal neural plate with no neural structures anterior to rhombomere 3. Otx2 is one of the mouse cognates of the drosophila gene orthodenticle. This gene codes for a homeodomain containing protein and is particularly expressed in the rostral brain during development. The knockout of this gene in the mouse leads to very interesting results. First, heterozygous mice are either normal [6] or present a phenotype that is reminiscent of the otocephalic syndrome in humans [7]. The discrepancies between these results can be explained by the different genetic background in which the knock-out was performed. In the case of normal heterozygous, the background was CD1/129, whereas when the hetero-

zygous were abnormal, the background was C57Bl/6. These results show that there are other genes that can modify the phenotype of a single gene knock-out. In homozygous embryos, the head never develops and the embryos were truncated at the level of the third rhombomere [6–8]. Since Otx2 is expressed rostrally until the limit between the mesencephalon and the metencephalon [9], the absence of rhombomeres 1 and 2 (in which Otx2 is not expressed) is a secondary consequence of the absence of more rostral structures, indicating that these two rhombomeres need an interaction to survive or develop. In conclusion, from these two knock-out experiments, it can be proposed that the genetic control which is mandatory for the correct development of the head is different from that which is needed for the development of the body. It is thus possible to observe embryos lacking a head. The genetic control for the development of the head is probably complex, but it comprises both Otx2 and Lim1.

1.2.3 Hesx1 and Septo-Optic Dysplasia These experimental evidences lead to a tremendous amount of genetic work to try to decipher all the genetic markers involved in head development. I do not intend to make a thorough review of this field, but just to illustrate some important results. The pairedlike gene Rpx (now called Hesx1) is expressed very early during development in the most anterior part of the neural plate [10]. The knock-out of the gene leads in the homozygous mouse to a nervous phenotype which is reminiscent of septo-optic dysplasia (absence of the septum pellucidum, of the corpus callosum, microphthalmia, hypoplasia of the olfactory bulbs) [11]. This result prompted the authors to test the human homologue, HESX1, in familial cases of septo-optic dysplasia, and indeed they found a missense mutation in this gene [11].

1.3 Segmentation of the Neural Primordium into Neuromeres In insects, the body of the larva develops as separated and segregated repetitive units called compartments. This type of development is responsible for the metamerization of the adult body, and is considered a very ancestral mode of development. However, in vertebrates, including mammals, such repetitive units

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can be evidenced in the adult body: such is the case with the vertebrae and ribs. The search for a metamerization of the central nervous system is really an old story. The first description of repetitive units in the central nervous system can be credited to von Baer in 1828 [12]. These compartments were termed neuromeres by Orr in 1887 [13]. This theory was so popular that segmentation of the neural tube was presented in all textbooks of those times (Fig. 1.4).

Cm

ment no zygotic genes are expressed in drosophila. The first sets of zygotic genes to be expressed are gap genes. These genes are expressed in broad domains corresponding roughly to three future segments. Gap genes control the expression of pair-rule genes, which are expressed according to a zebra-like pattern (one segment expresses the gene, the adjacent does not express and the next one expresses). Pair-rule genes control the expression of segment polarity genes that are expressed only by a subregion of a segment, defining a polarity within each segment. Then, gap genes, pair-rule genes, and segment polarity genes interact to induce the expression of homeotic selector genes, which determine the developmental fate of each segment. These homeotic genes belong to the antennapedia and bithorax complexes, and are homologous to Hox genes of vertebrates.

1.3.2 The Rhombomeres I

I II III IV V

II III IV V

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The rhombencephalon is the neural tube region where segmentation is obvious with repetitive units, called rhombomeres. In higher vertebrates, seven rhombomeres can be perfectly identified. The most caudal rhombomere (or rhombomere 8) is less defined, and its caudal border is not as sharp as the frontiers of the others.

v v

Fig. 1.4. The rhombomeres (I, II, III, IV, V) in a section of a pig embryo as illustrated in the famous Prenant’s Eléments d‘Embryologie de l’homme et des vertébrés (1896). au otic vesicle, Cm midbrain, gv ganglion of the X cranial nerve, v X cranial nerve

1.3.1 The Genetic Control of Insect Segmentation The aim of this chapter is not to account for a thorough description of the genetic pathways involved in insect segmentation, but to describe the salient features of this issue that could be used for the understanding of vertebrate segmentation. The drosophila embryo is first patterned by maternal effect genes. The transcribed mRNA and the corresponding proteins accumulate and define the anteroposterior axis of the future larva. The genes Nanos, Caudal, and Bicoid belong to this family. These genes are only from maternal origin, since at this stage of develop-

1.3.2.1 The Motoneurons That Constitute One Branchial Nerve Are Located in Two or Three Adjacent Rhombomeres

The roots of the different cranial nerves can be traced by using a retrograde marker injected in the nerve pathway. This technique allows study of the nervous origin of each branchial nerve. It is interesting to note that adjacent rhombomeres participate in the formation of a single branchial nerve; motoneurons that form the motor part of one branchial nerve are located in adjacent rhombomeres. For example, in the chick embryo, the motoneurons of nerve V are located in rhombomeres 1, 2, and 3; those of nerve VII in rhombomeres 4 and 5; and those of nerve IX in rhombomeres 6 and 7 [14]. 1.3.2.2 Even-Numbered Rhombomeres Differentiate Earlier Than Odd-Numbered Rhombomeres

Neurons can be characterized by several markers. One of these is the intermediate filament, neurofila-

Embryology of the Brain

ment, that can be evidenced using different specific antibodies. In the chick embryo, the pattern of neurofilament expression is very specific in the developing hindbrain. Indeed, neurofilament-positive neurons are present earlier in even-numbered rhombomeres than in odd-numbered ones [15]. 1.3.2.3 Rhombomeres Represent Relative Cell Lineage Restriction Compartments Lrd, a Suitable Marker for Lineage Analyses

Lineage studies are based on experimental paradigms that allow labeling of one single cell and all its derivatives. The most-used technique consists of injecting lysinated rhodamine dextran (LRD) into the cytoplasm of one cell by iontophoresis. This marker is fluorescent and is transmitted to daughter cells during mitosis. Its molecular weight prevents the diffusion to neighbor cells through gap junctions, allowing its use for lineage studies. Because of dilution during successive mitosis, it is possible to observe daughter-cells until the eighth symmetrical division.

The Inter-Rhombomeric Boundary Is Established Through Interactions Between Even- and OddNumbered Rhombomeres

If an even-numbered rhombomere is grafted adjacent to an odd-numbered one, the cells of the grafted rhombomere will not mix with the cells of the host. In contrast, if a odd rhombomere is grafted adjacent to another odd rhombomere, the cells of the two rhombomeres intensively mix [18]. So, the boundaries between rhombomeres are established by interactions of one rhombomere with the adjacent ones. Furthermore, this experiment shows that even- and oddnumbered rhombomeres display distinct properties. To maintain these frontiers requires that the cells are both able to recognize each other within the same segment and to repulse each other between two adjacent segments. A repulsive molecular system that is involved in rhombencephalon segmentation is constituted by the Eph-ephrin system. Eph belong to a family of 14 members that are subdivided into two groups in vertebrates. Eph class A (A1–A8) are GPI (glycosylphosphatidylinositol)-anchored proteins. Eph class B (B1–B6) contain a transmembrane domain followed by a cytoplasmic tail with tyrosine hydroxylase activity. Eph class A bind to Ephrins A

Lineage Analyses of the Rhombomeres

The spreading of the progeny of one single cell has been extensively studied in the rhombomeres of the chick embryo. First, if LRD injection is performed before the 13-somite stage (the stage of appearance of the rhombomeric boundaries), the progeny of the injected cell is not always restricted to one rhombomere [16]. In contrast, if the injection is performed after this stage and if the embryo is observed at stages 18–19, the progeny of the injected cell is limited by the rhombomeric boundaries [16] (Fig. 1.5). This demonstrates that the boundaries between rhombomeres are established progressively during development. These results allow consideration of the rhombomeres as true cell-lineage restricted compartments, such as the developing compartments of insects. However, if the embryos are analyzed later during development (stages 18–25), the results appear a little bit different. Indeed, greater than 80% of the clones are located within the rhombomeric limits and greater than 5% of the clones expand across the rhombomeric boundaries [17] (Fig. 1.5). For the other clones, the results are equivocal. This shows that the rhombomeres are not strict compartments as defined in insects, but they can be considered as relative compartments in which cell mixing is very limited.

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Fig. 1.5a,b. Appearance of the rhombencephalic clones observed after a single cell injection. a If the injection is performed before boundary formation, some clones spread across the inter-rhombomeric limits (dark gray). b If the injection is performed after the formation of the boundaries, the majority of clones does not cross the limits (light gray). A few clones appear to cross the inter-rhombomeric limits (not shown)

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(except for EphA4, which can bind numerous Ephrins A but also Ephrins B2 and B3). Eph class B bind to Ephrins B. The Eph-ephrin system generates repulsive behavior between cells expressing these proteins. EphA4 is expressed by rhombomeres 3 and 5, whereas ephrin B2 by rhombomeres 2, 4, and 6 [19]. If EphA4 is forced to be expressed by a cell, it will adopt an odd position in the rhombencephalon. On the contrary, if the expression of ephrin B2 is forced, the cell will adopt an even position. This shows that the Eph-ephrin system is functionally involved in the formation of inter-rhombomeric frontiers. Adhesive molecules, such as cadherins, may play a role favoring cell adhesion within a rhombomere. However, functional evidences are lacking to support this model. 1.3.2.4 The Genetic Control of Anteroposterior Identity of the Rhombomeres Numerous Genes Are Expressed by the Rhombomeres

It is obviously out of the focus of this chapter to review all the genes known to be expressed in the rhombencephalon. It is convenient to decipher these genes into two classes (Fig. 1.6): 1) Some genes are expressed by a few rhombomeres. For example, Hox b1 is expressed by rhombomere 4 [20], Krox 20 is expressed by rhombomeres 3 and 5 [20], lunatic fringe is expressed by rhombomeres 3 and 5 in the mouse [21] but in rhombomeres 2, 4, and 6 in the zebrafish [22], kreisler in rhombomeres 5 and 6 [23]. 2) Other genes are expressed in a more broad domain, poorly limited at its caudal part but with a strict r1

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Hoxb 1

Krox 20

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This pattern of expression suggests that these genes may play a role in specifying the anteroposterior identity of the rhombomeres. Some Rhombomeres Are Missing in Mutant Mice

I will now present some illustrative mouse mutants to show that some genes are involved in the control of the development of the rhombomeres. The Kreisler Mouse

Kreisler is an X-ray-induced recessive mutation in the mouse. The gene that is impaired by this mutation (mafB) is expressed in rhombomeres 5 and 6. A careful analysis of this mutant shows that it lacks rhombomeres 5 and 6, which are replaced by an enlarged rhombomere 4 [23]. This result indicates that the Kreisler protein is mandatory for the acquisition of the identity of rhombomeres 5 and 6; in its absence, cells will adopt a r4 phenotype. Knock-Out of the Gene Coding for the Zinc Finger Protein Krox20

The knock-out of the gene coding for Krox20 leads to homozygous that die either in the first two weeks after birth [24] or shortly after birth [25]. In the two constructs, the hindbrain is severely affected with a dramatic reduction or disappearance of both rhombomeres 3 and 5, corresponding to the rhombomeres where the gene is expressed. Knock-Out of the Hox A1 Gene

r3

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anterior limit corresponding to an inter-rhombomeric boundary. Such is the case for Hox genes of the paralogues 1, 2, 3, and 4 (except for b1). For example, Hox a1 is expressed by the neural tube until the limit between rhombomeres 3 and 4.

Mice homozygous for Hox a1 invalidation present a marked rhombencephalic phenotype characterized by severe reduction of rhombomere 4 and absence of rhombomere 5 [26]. In this case, the phenotype is observed at the most rostral domain of expression of the gene. This is a quite general rule for Hox genes invalidation. Knock-Out of the Hox B1 Gene

c

Fig. 1.6a–c. Expression pattern of some genes expressed in the rhombencephalon; cells expressing the gene are represented in gray. a Hoxb1 is expressed by the sole rhombomere 4. b Krox 20 is expressed by both rhombomeres 3 and 5. c Hoxa1 is expressed by the neural tube up to a rostral limit corresponding to the boundary between rhombomeres 3 and 4

Mice homozygous for Hox b1 invalidation present a partial modification of r4 into r2 [27]. This change affects the territory of expression of the gene. Since the change is only partial, the protein Hox b1 is not mandatory for the acquisition of the r4 identity. This feature suggests that other genes are involved in such a control.

Embryology of the Brain

Interactions Between Rhombomeres

The situation is far from being so simple. Indeed, rhombomeres may be subjected to interactions that force them to change their fate. If rhombomeres are transplanted to the level of r7/8 in the chick embryo, their behavior is different according to their initial position. Rhombomeres 2, 3, and 4 do not change their fate in this new position, whereas rhombomeres 5 and 6 adopt a r7/8 identity [28]. The signals that induce this transformation are from two sources: the paraxial mesoderm [29, 30] and the posterior neural epithelium [29]. These results indicate that rostral rhombomeres differ from caudal ones for their genetic regulation. In this concept, it is interesting to note that quail embryos deficient for vitamin A present a very abnormal hindbrain with an absence of its caudal part [31] which is respecified into anterior hindbrain [32]. Such is also the case for the mouse embryos lacking the Raldh2 gene (which codes for one of the key enzymes involved in retinoic acid synthesis) [33]. These mutant embryos lack a caudal hindbrain, which is replaced by an abnormal r3–r4 identity. Raldh2 is expressed weakly by somites 1–3, whereas its expression is stronger from somite 4 caudalwards [34]. Furthermore, Hox b5, b6, and b8 are sensitive to retinoic acid, since they present a RARE (retinoic acid-response element) in their regulative sequences [35], indicating that these genes are direct targets for retinoic acid signaling. The action of retinoic acid on the caudal hindbrain is mediated through a gradient of concentration: higher concentrations lead to a caudal phenotype, whereas absence of signal leads to r4 identity [36]. These results in both quail and mouse embryos show that retinoic acid signaling is mandatory to promote the induction of the posterior hindbrain. Furthermore, FGFs are able to induce rhombomeric anterior markers in the hindbrain [37]. The patterning of the hindbrain is due to two antagonistic influences: FGF, which anteriorizes, and retinoic acid, which posteriorizes.

1.3.3 Embryonic Origin of the Cerebellum The classic conception is that the cerebellum is a pure rhombencephalic derivative. However, using the quail-chick chimera technique, a fate map of the cerebellum was constructed in the avian embryo at the 10–12-somite stage [38–41], which showed that both the mesencephalic and the metencephalic (upper rhombencephalon) vesicles contribute to the forma-

tion of the cerebellum. Furthermore, the results help to establish the exact origin of the different cell types of the cerebellum. Purkinje cells derive from progenitors located in the ventricular layer [39]. This is also the case with neurons of the molecular layer and small cells surrounding Purkinje cells. The external granular layer only yields the granule cells [39]. However, this conclusion of a dual origin of the cerebellum was challenged a few years later. The gene Otx2 coding for a transcription factor can serve as a reliable marker of the mesencephalo-metencephalic border [9] (Fig. 1.7). This gene enables the demon-

10-somite stage 40-somite stage

Fig. 1.7. Expression pattern of Otx2 in the mesencephalon during development of the avian embryo. Cells expressing the gene are represented in gray. At 10-somite stage, the caudal limit of expression does not correspond to the constriction between the two vesicles (arrows), whereas the concordance is perfect at 40-somite stage. This shows that the constriction is not a reliable anatomical marker for appreciating the limit between the mesencephalon and the metencephalon. [9]

stration that the constriction between the so-called mesencephalic and metencephalic vesicles is in fact not a fixed point, but moves rostrally during development. Therefore, at the 10-somite stage, the so-called mesencephalic vesicle is in fact formed by the mesencephalic vesicle itself and by the rostral part of the metencephalic vesicle. Using this new landmark, it is possible to demonstrate that the cerebellum is a pure metencephalic derivative [9]. The caudal limit of the presumptive cerebellar territory corresponds to the rostral limit of Hoxa2 expression [42]. The cerebellum arises precisely from rhombomere 1.

1.3.4 The Prosomeres, a Model of Rostral Segmentation The groups of Rubenstein at UCSF (United States) and Puelles in Murcia (Spain) carefully examined the

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expression pattern of numerous genes in the rostral part of the neural tube (prosencephalon) [43, 44]. From these aspects, it can be concluded that regionalization of the forebrain results from different mechanisms. First, the neural tube is separated into units according to the antero-posterior axis. This leads to the formation of separate domains, whose development is highly regulated. The second mechanism is the formation of longitudinal domains that are due to polarization of the neural plate according to the medio-lateral axis, and of the neural tube according to the ventro-dorsal axis. The convergence of these two types of regionalization could allow one to distinguish segments that the authors proposed to called prosomeres. However, the exact biological significance of this model remains to be strengthened in the future.

1.4 New Insights About Cerebral Cortex Development Writing a thorough paper on the tremendous amount of works published on cortical development would lead to the publication of a complete book! Here, I just want to give the reader some new insights about the results gained by experimental embryology. These results have sometimes changed our conceptions of cortical development.

1.4.1 Partitioning the Telencephalic Vesicle into Two Hemispheres The human telencephalon begins to be evidenced at Carnegie stage 14 (embryonic day 32, 4 weeks and 4 days of gestation) [45]. The interhemispheric fissure begins to form as early as at Carnegie stage 16 (embryonic day 37, 5 weeks and 2 days of gestation) [46]. This important landmark is obvious at Carnegie stage 17 (embryonic day 41, 5 weeks and 6 days of gestation) [47]. The falx cerebri differentiates during Carnegie stages 22–23 (8th week of gestation) [48]. The formation of two hemispheres from the single telencephalic vesicle is due to the induction by bone morphogenetic proteins (BMPs) of the midline roof plate [49]. The telencephalic midline roof plate is characterized by a low level of cell proliferation and a high level of apoptosis [50]. The limits between the cortical ventricular zone and the midline roof plate are called the cortical hems.

The defect of formation of two hemispheres leads to the development of holoprosencephaly. In humans, at least 12 genetic loci (HPE 1–12) have been linked with this pathological condition [50, 51]. Seven mutated human genes out of these 12 loci are associated with holoprosencephaly [51]. Three involved genes belong to the Sonic Hedgehog pathway, two genes to the nodal signaling pathway, and the two last genes are not yet related to the other molecular pathways. The first gene (corresponding to the HPE3 locus) whose mutation was linked with human holoprosencephaly is Sonic Hedgehog (SHH) [52], which codes for a secreted molecule acting as a morphogen. SHH is a diffusible molecule that acts on a membrane receptor, Patched-1. The consequence of the binding of SHH to Patched-1 is the inhibition of the membrane receptor. Since Patched-1 inhibits another membrane receptor, Smoothened, the effect of SHH will be to relieve the endogenous inhibition of Smoothened. The activation of Smoothened is mediated to the cytoplasm by the proteins Gli (Gli1, 2, and 3). These proteins will be translocated to the nucleus, where they will act as transcription factors. SHH is expressed in various tissues, including the prechordal mesoderm (the most rostral part of the axial mesoderm) and the ventral telencephalon [50]. Holoprosencephaly in SHH mutation is considered to be due to impairment of the prechordal mesoderm, and not to a defect of the ventral telencephalon [50]. Two other genes belonging to the SHH pathway have been associated with holoprosencephaly: PATCHED-1 [53], which codes for the receptor of SHH, and GLI2 [54], which codes for one of the cytoplasmic effectors of this pathway. Furthermore, Dispatched is required for long-range activity of Hedgehog in Drosophila. The mouse mutant line Dispatched A–/– displays holoprosencephaly [55]. The homologous human gene is located in chromosomal region 1q42, corresponding to the locus of HPE10. However, no human mutations of this gene have yet been reported in cases of holoprosencephaly. The second signaling pathway that has been linked with holoprosencephaly is the Nodal signaling. Nodal is a secreted molecule that belongs to the TGFβ superfamily. In absence of Nodal, the prechordal plate is not present and SHH is absent in the rostral part of the embryo [51]. Mutations of the TGIF gene are linked with the HPE locus situated in the chromosomal region 18p11.3 [56]. Another locus has been found to be associated with mutation of the TDGF1 gene (homologous to the Crypto gene) [57]. These two types of mutations lead to a loss of function of the proteins encoded by these genes. It is quite surprising to note that TGIF acts as negative regulator of SMAD2, an effector of Nodal signaling, whereas

Embryology of the Brain

TDGF1 is a coreceptor that is mandatory to mediate Nodal signaling. The SIX3 gene corresponds to the HPE2 locus (mapped on human chromosome 2p21) [58]. Six 3 (SIX3 for humans) is closely related to optix, a drosophila member of the sine oculis family of genes [58]. This gene is expressed by the anterior neural plate (which corresponds to the eye field domain). The exact role of this mutant in the generation of holoprosencephaly remains to be established [51]. The ZIC2 gene corresponds to the HPE locus in the chromosomal region 13q32 [59]. Zic2 (ZIC2 in humans) codes for a zinc finger gene homologous to the odd-paired gene of Drosophila [59]. The expression of this gene at the level of the forebrain is mainly dorsal [60]. Mutations of this gene lead to holoprosencephaly without any craniofacial involvement [50].

1.4.2 Asymmetric Division of Neuroepithelial Cells in the Ventricular Zone 1.4.2.1 Neuroepithelial Cells Divide at the Ventricular Zone of the Neural Tube

Fig. 1.8. Section through the neural tube of a chick embryo at the 6th day of incubation (Feulgen-Rossenbeck’s staining). The mitoses of neuroepithelial cells are concentrated at the ventricular side of the neural tube (arrows)

It has been well known for a long time that neuroepithelial cells divide at the ventricular border of the neural tube (Fig. 1.8). The first author to describe mitosis in the ventricular part of the neural tube was Wilhelm His in the middle of the nineteenth century. However, at that time, he considered that the neural tube was made of two types of cells: germinal cells, that are able to divide and give rise to neuroblasts, and epithelial cells (or spongioblasts), that are not. The latter were considered by His as the precursors of glial cells. Now, it is well established that neuroepithelial cells follow a cell cycle leading to a mitosis. This general movement of the nucleus from the periphery to the ventricular zone was described by Sauer [61] (Fig. 1.9) and is termed karyokinesis. 1.4.2.2 Asymmetric Mitosis and Neurogenesis

In a pioneer work, Martin [62] observed that the mitotic spindle of dividing neuroepithelial cells is orientated, and that this spindle is perpendicular to the surface of the neural tube only during the phase of neuroblast formation. The author concluded that the orientation of the mitotic spindle is linked with the differentiation program of neuroepithelial cells. Now, it is firmly established that two types of mitosis

Fig. 1.9. Diagram of the alar plate of a pig embryo from Sauer (1935). Nuclei follow a general movement from the basal part of the neural tube to its apical pole where they divide. [61]

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can take place in the ventricular zone of the neural tube. Symmetrical divisions lead to the formation of two identical daughter cells, whereas asymmetrical divisions lead to the formation of a young migratory neuron and a proliferative daughter cell. The difference between these two types of division is explained by the orientation of the mitotic spindle [63]. Asymmetric mitoses have been particularly well studied in Drosophila. They play a major role in generating neuronal cells. Different proteins, such as Glial-cells missing, Prospero, Numb, Miranda, Partner of Numb, Inscuteable, and Notch, are asymmetrically distributed in the dividing cell, leading to an asymmetrical repartition of these proteins in the two daughter cells [64]. In the mammalian telencephalon, asymmetric mitoses take place [63, 65–67]. However, the situation is far from simple. Indeed, there are differences according to the studied species: Numb is located at the apical part of the ventricular zone in the mouse [65], whereas it is located at the basal part of the ventricular zone in the chick [68]. Furthermore, the role played by Numb changes during development: this protein prevents cell differentiation during the early phase of neurogenesis [69], whereas Numb promotes neuronal differentiation during the late phase of neurogenesis [67]. In any case, all these results are highly suggestive for a pivotal role of asymmetric mitoses in the control of neurogenesis in the mammalian cortex.

1.4.3 Formation of the Preplate

term preplate was indeed coined to underscore that this layer is laid down before the formation of the cortex. The cells that compose the preplate derive from ventricular progenitors [70]. The role of the preplate has been firmly established by studying the reeler mutation in the mouse. In this case, the preplate is normally formed, but cortical organization is highly abnormal with an inverted outside-inside gradient. The reeler mutation affects the reelin gene, coding for a large extracellular protein synthesized by both Cajal-Retzius cells and granule neurons of the cerebellum [71]. Reelin interacts with Disabled-1, a cytoplasmic protein expressed by neurons of the cortical plate [72]. The couple Reelin–Disabled-1 is thus involved in the control of the end of migration of neuroblasts in the cortical plate. It is interesting to note that a human autosomal recessive disease, characterized by lissencephaly and cerebellar hypoplasia, has been associated with mutations in the human gene coding for Reelin [73]. Thus, Reelin also plays a role in the formation of the cortex in humans.

1.4.4 From the Ventricle to the Cortical Plate: The Migration of Neuroblasts 1.4.4.1 Radial Migration and Radial Glial Cells

Neuroblasts, generated by asymmetrical mitosis, must migrate from the ventricular zone to the superficial layer of the brain. This migration proceeds in the so-called intermediate zone (Fig. 1.11). When

The first-ever evidence of the future mammalian isocortex is the formation of the primordial plexiform layer, also known as the preplate (Fig. 1.10). This layer is composed of a superficial plexus, the CajalRetzius neurons, and the neurons of the subplate. The

Fig. 1.10. Section of the rostral neural tube of a human embryo (45 days post fertilization) showing the ventricular zone (VZ) and the developing preplate (Pre)

Fig. 1.11. Section of the telencephalic wall of a human embryo (12 weeks of gestation) showing a laminar organization orientated from the ventricle to the meninges (Me): the ventricular zone (VZ), the intermediate zone (IZ), the subplate (SP), the cortical plate (CP), and the molecular layer (M)

Embryology of the Brain

neuroblasts arrive at the level of the preplate, they stop their migration and split the preplate into two layers: the future layer I, i.e., the most superficial layer of the cortex, and the subplate. The first neurons to be generated are the future neurons of the deepest layers (i.e., layer VI) and, subsequently, neurons migrate and form more and more superficial layers. This mode of formation of the cortical plate has been termed the inside-outside gradient. Histological examination of developing cortex has shown the presence of radially orientated cells, i.e., radial cells (Figs. 1.12, 13), whose processes extend Fig. 1.13. Radial processes can be evidenced using the monoclonal antibody directed against GFAP (Glial Fibrillary Glycoprotein) (arrows)

of retrovirus [78], and construction of a transgenic mouse in which the lacZ gene is located on the X chromosome [79]. The discovery of nonradial migration of cells from the ventricle to the cortex is an important result, and shows that interpretations of malformative diseases in humans should be very careful and revisited using more modern data. 1.4.4.2 Two Modes of Radial Migration

It is possible to directly visualize the migrating cells by time-lapse imaging applied on brain slices. Using this technique, it was found that radial migration proceeds according to two different modes [80] (Fig. 1.14): Fig. 1.12. Reproduction of a drawing from Wilhelm His showing the radial cells (arrows) and the mitosis located in the ventricular zone (arrowhead)

from the ventricular pole to the brain surface. Migrating neuroblasts are preferentially apposed to the glial processes. These histological results lead to the proposal that ventriculo-cortical migration of neurons is strictly radial. This concept was so popular that the concept of radial unit is largely used in neuropediatric textbooks to explain cortical malformations. However, using defective retroviruses as cell markers, Walsh and Cepko [74, 75] found that clones arising from a single ventricular progenitor are widely dispersed across the cortex. This result leads to the proposal that the ventriculo-cortical migration is not solely radial. This conclusion is now firmly established by different techniques: marking cells on living slices [76], staining cells of telencephalic explants [77], use

a

Soma translocation

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Cell locomotion

Fig. 1.14a,b. The two modes of radial migration in the telencephalon. The neuroblasts are represented in light gray. a soma translocation and b cell locomotion

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1) Soma translocation: in this case, the neuroblast contains a long process that reaches the pial surface. The length of this process progressively shortens and the cell soma adopts a more superficial location. This movement is continuous, and is in fact independent of radial glial cells. 2) Cell locomotion: the neuroblast contains a leading edge apposed to glial radial cells that does not reach the pial surface. The length of this process is constant during migration. Migration is, in this case, discontinuous with periods of active movement and of pause, and is dependent upon radial glial cells.

the intermediate zone, and of the cortical plate [90] (Fig. 1.16). Cells coming from the medial ganglionic eminence follow a migration pathway located underneath the pia mater. This could correspond to the so-called subpial granular layer (Fig. 1.17), described by Brun in 1965 [91]. At last, the cells of the caudal ganglionic eminence participate in the formation of cortical GABAergic interneurons populating the layer V at the caudal level of the cortex [86]. In humans, the situation has been assessed by the group of Rakic [92]. Cortical GABAergic interneu-

1.4.4.3 Radial Glial Cells Are Bipotential Progenitors

It is now firmly established that radial glial cells can generate cortical pyramidal neurons and astrocytes [81–84]. During mitosis, the radial process persists and is asymmetrically inherited by daughter cells [85]. If the postmitotic neuroblast inherits the process, it will adopt the radial movement called soma translocation to reach the cortical plate. In contrast, if the postmitotic neuroblast is devoid of radial process, it will be guided by radial cells to reach the cortical plate. This can explain the two modes of radial migration observed on time-lapse microscopy.

Fig. 1.15. Organization of the embryonic telencephalon. OB olfactory bulb, CGE caudal ganglionic eminence, MGE medial ganglionic eminence, LGE lateral ganglionic eminence

1.4.5 The Basal Telencephalon Participates in the Formation of Cortical Neurons The existence of nonradial migration shows that the origin of cortical neurons is more complex that was commonly thought. In classic textbooks, it was thought that only the dorsal telencephalon is able to produce cortical neurons, whereas the ventral telencephalon gives rise to the striatum and pallidum. The ventral telencephalon is subdivided into three ganglionic eminences during development, i.e., lateral, medial, and caudal (Fig. 1.15). These three ganglionic eminences do not express the same subset of genes, indicating that they represent three different genetic compartments [86]. Staining the lateral ganglionic eminence allows to observe marked cells migrating in the intermediate zone of the dorsal telencephalon and then populating the cortical plate [87–90] (Fig. 1.16). These migrating cells differentiate into GABAergic neurons. Using the same technique, it is also possible to show that the medial ganglionic eminence gives rise to neurons that migrate and differentiate into GABAergic interneurons of layer I, of the subplate, of

Fig. 1.16. Frontal section of the telencephalon showing both the dorsal (DT) and the ventral telencephalon (VT). The dorsal telencephalon corresponds to the pallium, whereas the ventral telencephalon is composed of both medial and lateral ganglionic eminences (MGE and LGE). Neuroblasts originating from the two ganglionic eminences migrate to populate the pallium (arrows). These neuroblasts will eventually differentiate into GABAergic interneurons

Embryology of the Brain

1.4.7 The Ventricular Neuroblasts Are Not Fully Specified at the Time of Their Birth

Fig. 1.17. Section of the superficial layers of the telencephalic wall in a human embryo (13 weeks of gestation) showing the molecular layer (M) overlying the cortical plate (CP). The socalled subpial granular layer (SGL) corresponds to the most superficial part of the molecular layer, characterized by a higher cell density. Me meninges

rons arise from two different embryonic origins: the ganglionic eminences account for 35% of these interneurons, whereas 65% derive from the ventricular zone. Different behavioral cell movements have been associated with nonradial migration [93]: tangential pathways within the intermediate zone, branching cells that change the direction of their migration, and ventricle-directed migration in which a cell of the intermediate zone migrates to the ventricular zone.

1.4.6 Subplate Neurons Control the Development of Thalamic Axons The subplate is fated to disappear after birth, but its role during fetal development is crucial. During development, the neurons of the subplate develop axons which grow to reach subcortical targets, such as the internal capsule or the thalamus [94–96]. Furthermore, axons arising from subcortical nuclei form functional synapses with subplate neurons [97]. If occipital subplate neurons are destructed early during development by injection of kainic acid, the occipital cortex develops normally, but the axons arising from the lateral geniculate nucleus fail to enter the cortex and form a subcortical network [98, 99]. If the destruction of the subplate is performed later, the axons enter the cortex but make connections with wrong layers, showing that subplate neurons are necessary to control the correct cortical projection of geniculate axons [100].

Theoretically, it is possible to imagine two models for the ventricular zone. The protomap model postulates that the neuroblasts acquire their specification at the time they are generated [101]. In contrast, the protocortex model suggests that neuroblasts in the ventricular zone are still plastic and can change their fate according to their environment [102]. One experiment which can solve this discrepancy consists of transplanting ventricular cells from a donor into the ventricle of a host that has a different age (heterochronic transplantation). If the protomap model is correct, transplanted cells will not change their fate. After heterochronic transplantations, neurons belong to two populations: either they are fixed and do not change their fate or they adapt to this new environment [103]. The most striking result is that their adaptive behavior is dependent upon the phase of the cell cycle [104]. If the cells are very close to mitosis, they are specified and cannot change their fate. On the contrary, if the cells are transplanted during the S phase, they can adapt to their new environment. This shows that ventricular cells are sensitive to external clues, which can be conveyed by cortical neurons through their projecting axons [105]. In conclusion, even if cortical plate neurons develop far away from their progenitors, there are interactions between the two layers which can adapt the fate of the newly-generated neuroblasts to the cortical environment.

1.4.8 Formation of Cerebral Gyration One of the salient features of the development of human cortex is the progressive appearance of sulci and gyri during gestation. A gyrus is a cortical structure limited by either two sulci or a sulcus and a fissure. Sulci are classified according to their time of appearance. Primary sulci (i.e., Sylvian, calcarine, parieto-occipital, callosal, central, and olfactory sulci) develop after the 14th week of gestation [106]. It is important to note that primary sulci are quite invariant in all members of the species, suggesting that their development is highly regulated at the genetic level. The Sylvian and callosal sulci first appear during the 14th week of gestation (Fig. 1.18). Olfactory, parietooccipital, and calcarine sulci appear in the 16th week of gestation. Lastly, the central sulcus develops from the 20th week of gestation onwards [106] (Fig. 1.19).

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Secondary sulci (i.e., precentral, postcentral, lunate superior, frontal, and orbital sulci) arise later and show individual variations even in twins. The last to be formed are tertiary sulci, which present huge interindividual anatomical variations (Fig. 1.20).

Fig. 1.20. Lateral aspect of the right hemisphere of a human fetus at term. Note the complex development of the sulci and gyri

1.5 Control of Formation of the Pyramidal Tract

Fig. 1.18. Lateral aspect of the right hemisphere of a human fetus at 19 weeks of gestation. Note that the Sylvian fissure (arrows) is well developed

The pyramidal tract, as all fasciculi of the white matter and all white commissures, is composed of axons developing from neurons. These axons grow thanks to the development of their growth cone. The development of these cones is highly regulated, so that the tracts are packed and organized within the white matter. I will briefly review the three elementary mechanisms that are involved in the control of the development of the pyramidal tract. These elementary mechanisms are likely applicable also to other tracts or commissures.

1.5.1 Chemoattraction and Netrins

Fig. 1.19. Lateral aspect of the right hemisphere of a human fetus at 23 weeks of gestation. Note the developing central sulcus (arrows)

Some cerebral regions may play a chemoattractive role on growth cones derived from cortical neurons [107]. Such an effect is found for the basal pons [107], the ganglionic eminence [108], and the internal capsule and floor plate of the neural tube [109]. These results indicate that some neural regions are able to synthesize and secrete chemoattractant factors that direct the growth of axons (Fig. 1.21). What could be the chemical nature of these signals? From chick brains, it was possible to isolate two diffusible proteins, netrin 1 and 2 [110], which are homologous to UNC-6, a C. elegans protein. The latter is involved in the control of migration of commissural cells in this species. UNC-6 acts on two different receptors: one (unc-40) responsible for a chemoat-

Embryology of the Brain

Explant of the cortex

Growing axons

Floor plate of the neural tube Fig. 1.21. The axons that develop from the cortex converge to the floor plate, suggesting that chemoattractant proteins are secreted by the floor plate

tractant effect, and the other (unc-5) responsible for a chemorepellent effect. In vertebrates, the scenario is far from being so simple: netrins 1 and 2 act on two receptors [DCC (deleted in colorectal cancer) and neogenin] involved in chemoattraction, and two others (unc-5h2 and unc-5h3) involved in chemorepulsion. The role of netrins has been established in vitro. Transfected COS cells (a cell line derived for monkey kidney) secrete netrin 1 or 2 and play a chemoattractive role in growing axons from commissural neurons of the spinal cord [111]. Such a chemoattractive effect can be elicited for pyramidal axons [112]. Thus, netrins are excellent molecular candidates to account for the directional growth of pyramidal axons during development. To test in vivo the effect of netrin 1 on the development of the brain in mammalian embryos, the knock-out of this gene has been performed [113]. Homozygous mice die during the first postnatal days because they fail to eat. The study of the central nervous system in these mice shows that the white ventral commissure of the spinal cord is reduced, the corpus callosum is absent with formation of Probst’s bundles, the fimbria is malformed, the hippocampal commissure is practically missing, and the anterior white commissure is absent. In contrast, both the posterior white and the habenular commissures are normal. Furthermore, new commissures develop in aberrant anatomic positions (i.e., a commissure located at the junction between the mesencephalon and the metencephalon). These results show the pivotal role played by netrin 1 during the formation of some commissures of the central nervous system. It

is important to note that not all cerebral commissures are impaired by this knock-out, highlighting the fact that molecular mechanisms controlling the development of the different commissures are various, and differ according to their anatomical position. In the homozygous mice, the thalamo-cortical fasciculi are normal from the thalamus to the internal capsule, where the axons are disorganized leading to a dramatic reduction of the cortical projections [114]. The results concerning the effect of this knock-out on the pyramidal tract are surprising. Indeed, the pyramidal tract is normal from the cortex to the level of the medulla oblongata. However, pyramidal tracts fail to decussate, leading to a dramatic reduction of the total number of axons of the pyramidal tract in the spinal cord [115]. A similar phenotype is observed for mutations of the netrin receptors DCC and Unc5h3 [115]. In conclusion, netrin 1 plays a chemoattractive role in some growing axons, and its presence is mandatory for the correct decussation of the pyramidal tracts at the level of the medulla oblongata.

1.5.2 L1 Permits Crossing of the Midline Other molecular systems are involved in the control of the development of the decussation of the pyramidal tract at the level of the medulla oblongata. Such is the case for L1, an adhesion molecule belonging to the immunoglobulin superfamily. This molecule acts through both homo- and heterophilic interactions. Mutations of the human gene have been reported in association with the so-called CRASH syndrome (corpus callosum hypoplasia, mental retardation, adducted thumbs, spastic paraplegia, and hydrocephalus). This X-linked syndrome shows great interand intrafamilial variability. The pyramidal tract is frequently absent in patients with CRASH syndrome (Fig. 1.22). Such feature is not specific, but is highly evocative for this syndrome [116]. This indicates that L1 plays an important role during the formation of the pyramidal tract in humans. The exact role of L1 has been extensively studied in mice after knocking-out this gene [117, 118]. In these mice, the pyramidal tract appears normal from the level of the cortex to the medulla oblongata, where the axons fail to cross the midline. Caudally, the hypoplastic tract stops at the cervical spinal cord level. Furthermore, the corpus callosum can be hypoplastic. It is important to note that such a neuropathological feature is highly variable, and depends upon the genetic background of the mouse lines [119]. This suggests that other genes may have a modulatory

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Fig. 1.22. Section through the medulla oblongata of a human fetus (24 weeks of gestation) with CRASH syndrome. The pyramidal tract is hypoplastic (arrows), whereas the olives are hypertrophic (arrowheads)

role in L1 functions. The white anterior, posterior, and spinal commissures are normal in the knock-out mouse. The exact mode of action of L1 on pyramidal tract formation is still unknown. Three hypotheses may account for the observed phenotype [117]: (1) L1 could interact with CD24, one of its known ligands, expressed in the midline of the medulla oblongata; (2) axons of the pyramidal tract could interact with other L1 positive axons, such as those of the medial lemniscus that are formed earlier during development; and (3) formation of pioneer axons is independent of L1, but the subsequent growth of other axons requires the presence of L1. In conclusion, the adhesion molecule L1 plays a major role in controlling the crossing of pyramidal axons in the region of the medulla oblongata. The required interactions in terms of molecules are still unknown.

1.5.3 EphA4 and Ephrin B3 Prevent Pyramidal Axons from Recrossing the Midline at the Spinal Level The role of the Eph-ephrin system in the regulation of the development of the pyramidal tract has been demonstrated by studying the knock-out of the gene coding for EphA4 in the mouse [120]. EphA4 is expressed by growing axons of the pyramidal tract. Homozygous mice EphA4 -/- display an abnormal motor behavior (hesitation to move, lack of coordination, and abnormal synchronous movements of the hind limbs). Neuropathological examination of these mice shows that the pyramidal tract is severely impaired, with a lot of axons stopping at the level of the medulla oblongata. Furthermore, axons reaching

the spinal cord cross the midline in the spinal cord, in contrast to normal axons of the pyramidal tract that never cross the spinal midline. It is interesting to note that the white anterior commissure is absent. It is possible to copy the spinal phenotype by performing a deletion of the tyrosine kinase domain of the cytoplasmic tail [121]. In this case, the white anterior commissure is normal. This shows that tyrosine kinase activity is necessary for correct development of the pyramidal tract, whereas EphA4 controls the development of the white anterior commissure by kinaseindependent functions. Ephrin B3 is one of the ligands of EphA4. Axons expressing EphA4 interact with cells expressing Ephrin B3. EphA4-positive axons cannot grow, and cross a region of cells expressing Ephrin B3. Such a region forms a sort of molecular barrier. It is interesting to study the consequences of removal of the gene coding for Ephrin B3. This has been performed in the mouse [122]. Homozygous mice display the same abnormal locomotor behavior as EphA4 -/-. Neuropathological examination discloses that the decussation of the pyramidal tract crosses the midline at a more rostral position and the spinal pathway of the tract is normal in the dorsal bundle; however, at the level of the gray matter, axons cross the midline and contact contralateral motoneurons. The white anterior commissure is normal, indicating that another ligand of EphA4 is involved in the control of the formation of the white anterior commissure.

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Myelination

2 Myelination Cecilia Parazzini, Elena Bianchini, and Fabio Triulzi

CONTENTS 2.1 2.2 2.3

Introduction and Structure of Myelin Technical Aspects 21 Myelination Progression 23 References

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2.1 Introduction and Structure of Myelin Myelination is a very important process of brain maturation because it is essential for neural impulses transmission. It is a dynamic process that starts during fetal life and proceeds predominantly after birth, at least until the end of the third year, in a welldefined, predetermined manner [1–3]. Myelin is a cell membrane with a lamellar structure that wraps around the axon. It is composed of alternating lipids layers with large proteins. The lipidic component is higher than in other cellular membranes, and is formed mainly of cholesterol, glycolipids, and phospholipids. Cholesterol and glycolipids have functional groups interacting with the water and form the outer lipid layer, whereas hydrophobic phospholipids constitute the inner layer. Proteins mainly include myelin basic protein (MBP) and proteolipid protein (PLP). MBP is an intracytoplasmatic protein attached to the inner surface of the cell membrane. It is thought to stabilize the myelin spiral. PLP spans the lipid layer and interacts in the extracellular space with similar PLP chains from other myelin membranes, leading to close apposition of adjacent myelin spirals [4, 5]. As the formation of myelin by the oligodendrocytes and the progressive thickening and tightening of the myelin sheaths proceed, an increase in brain lipid concentration and a decrease in water content takes place [3, 6–9]. Other maturational changes include an increase in cellular and synaptic density and dendrite formation, involving mainly the gray matter and occurring simultaneously with myelination.

Such changes contribute to reduce the amount of free water in the brain [9–11]. This results in a modification of the magnetic resonance (MR) signal, characterized by shortening of both T1 and T2 relaxation times. It is thought that the deposition of lipid is the main factor accounting for the high signal on T1weighted images, whereas the decreased number of water molecules results in the diminished signal on T2-weighted images [4, 9, 12]. Lipid deposition is the main biochemical change in the first step of myelination, whereas subtle changes related to water density predominate in the later phase of the process. As a consequence, T1-weighted sequences detect contrast changes within the myelinating white matter earlier than T2-weighted sequences [13]. The white matter in the newborn is mainly unmyelinated; hence, it has lower signal intensity than gray matter on T1-weighted images, and higher signal intensity than gray matter on T2-weighted images. With advancing maturation, there is an inversion of signal intensity until the adult pattern is reached (white matter high and gray matter low signal intensity on T1; white matter low and gray matter high signal intensity on T2) (Fig. 2.1). On T1-weighted images, the adult appearance is reached at about 12–15 months of age, and minimal changes are seen after this time, whereas on T2weighted images maturation is complete at about 3 years [4, 14]. Maturation of the brain also includes dramatic volumetric growth. The increase in volume is mainly evident in the corpus callosum, the most important commissural system of the brain. The adult thickness is reached at about 9 months of age (Fig. 2.2).

2.2 Technical Aspects The process of myelination is better evaluated on a 1.5 T MR unit. Spin-echo or fast-spin-echo T2 sequences with long repetition time (TR:5500/6000) and echo time (TE:120/200), and spin-echo T1 (TR:500/600;

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Fig. 2.1a–d. Newborn and 3 years of age on T1-weighted images (a, c). Newborn and 3 years of age on T2 W images (b, d). The inversion of signal intensity of gray and white matter at two different ages is evident

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Fig. 2.2a–c. T1-weighted images. Increase in volume of the corpus callosum. a Newborn, b 6 months, c 9 months

Myelination

TE:10) or inversion-recovery T1 with short inversion time (TR:2000; TE:10; TI:750) should be used. Slice thickness should be 4–5 mm. At least axial and sagittal sections should be obtained. Dedicated coils with high signal-to-noise ratio, such as a knee coil for newborns, are preferred. A perfect immobility of the patient is important; hence, sedation for infants older than 3–4 months is requested. Recently, new MR techniques such as diffusionweighted images and the measurement of the apparent diffusion coefficient (ADC) have been applied to the study of normal brain development. The ADC of the normal neonatal brain is higher than that of the adult brain, and its value progressively decreases with age [15]. Moreover, ADC maps in newborns show a strong contrast between gray and white matter, with ADC white matter values being higher that those of gray matter. In the adult, ADC maps show essentially equal values for white and gray matter. The cause of such age-related ADC decrease is not understood, although it has been postulated that the rapid decrease observed between early gestation and term is due to the decrease in overall water content [16]. Relative anisotropy (RA) values also differ between adult and pediatric brain. RA values for white matter areas are relatively low in infants and increase with age in two different steps. The first increase takes place before the histological appearance of myelin, and has been attributed to changes in white matter structure which accompany the “premyelinating state.” The second, more sustained increase in RA is associated with the histological appearance of myelin and its maturation. Whereas RA values of cortical gray matter in adult brain are close to zero, they are transiently nonzero in premature brain for the earliest gestational age studied (26 weeks), and decreased nearly to zero by 32 weeks [17]. This change reflects microstructural modifications of the cerebral cortex. During the gestational ages for which anisotropy values are nonzero, cortical cytoarchitecture is dominated by the radial glial fibers spanning across the cortical strata and by the radially oriented apical dendrites of the pyramidal cells. With time, this architecture is disrupted by the addition of basal dendrites as well as of thalamocortical afferents, which tend to be oriented orthogonal to the apical dendrites.

2.3 Myelination Progression The myelination process begins very early during intrauterine life. Recent data on preterm newborns

suggest that the water content of the brain decreases between 24 weeks and term. Myelin is evident in numerous gray matter nuclei and white matter tracts of the brainstem and cerebellum around 28 weeks of gestational age (Fig. 2.3, 2.4). New myelin is not visualized anywhere between 28 and 36 weeks gestational age. At 36 weeks, myelin becomes evident in the typical regions of the term newborn (posterior limb of internal capsule, corona radiata, corticospinal tracts). After 37 weeks gestational age, the dorsal brainstem appears diffusely myelinated, probably as a combination of nuclei and white matter tracts; however, it is no longer possible to delineate specific structures [9, 11]. During the first postnatal year, myelin spreads throughout the brain according to a preordered scheme of chronological and topographic sequences. Myelination proceeds centrifugally, from inferior to superior, and from posterior to anterior. In the brainstem, myelination proceeds from the dorsal to the ventral areas. In the cerebral hemispheres, it proceeds from the central sulcus towards the pole and from the occipital and parietal lobes towards the frontal and temporal lobes. Sensory fibers myelinate before motor fibers, and projection pathways earlier than association pathways; sensitive, visual, and auditory tracts are already myelinated at birth. In detail, in the term newborn myelination is evident in the cerebellar flocculi, inferior and superior cerebellar peduncles, cerebellar vermis, dentate nuclei, dorsal brainstem (cranial nerves nuclei and sensitive tracts), decussation of the superior cerebellar peduncles, ventroposterolateral thalamic nuclei, globi pallidi, posterior putamen, posterior portion of the posterior limb of internal capsules, central corona radiata, pre- and postcentral gyri (Figs. 2.5–2.9). At 3 months of age myelination is evident in both T1- and T2-weighted images in cerebellar peduncles, deep cerebellar white matter, and optic radiation. The anterior limb of the internal capsule, splenium of the corpus callosum, and subcortical central white matter appear myelinated only on T1-weighted images. The different timing of the appearance of myelination in T1- and T2weighted sequences becomes evident at this age (Figs. 2.10, 2.11). Myelination proceeds at 5 months in the genu of the corpus callosum, subcortical parieto-occipital white matter, and central parietal lobes, and begins to appear in the frontal lobes on T1-weighted images (Fig. 2.12). At the same time, it is evident on T2-weighted images in the splenium of the corpus callosum and subcortical paracentral white matter (Fig. 2.13). In the following months, myelination proceeds on T1-weighted images involv-

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Fig. 2.3a–i. Preterm newborn (30 weeks gestational age): On T1-weighted images, myelin is evident in numerous white and gray matter structures. a gracile and cuneate fasciculi, b inferior cerebellar peduncles (short arrow), medial longitudinal fasciculus (long arrow), c superior cerebellar peduncles, d medial lemnisci, e lateral lemnisci, f subthalamic nuclei, g ventroposterolateral thalamic nuclei (VPL)

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Fig. 2.4a–f. Preterm newborn (30 weeks gestational age): On T2-weighted images, myelin is present in a dentate nuclei of the cerebellum (short arrow), cerebellar vermis (long arrow), inferior cerebellar peduncles, b lateral lemnisci (long arrow), medial lemnisci (short arrow), c inferior colliculi (long arrow), decussation of the superior cerebellar peduncles (short arrow), subthalamic nuclei (large arrow), e ventroposterolateral thalamic nuclei (arrow). No myelination is evident in the posterior limb of internal capsule

ing the ventral portion of brainstem, peripheral cerebellar white matter, and subcortical frontal white matter (Fig. 2.14); at about one year of age the pattern of myelination on T1-weighted images is very similar to that of adults. On T2-weighted images, the anterior limb of the internal capsules and genu of the corpus callosum appear myelinated at 9 months of age; at the same age myelination is evident in the parieto-occipital regions and extends in deep frontal areas. No significant difference between gray and white matter is evident in the cerebellum (Figs. 2.15, 2.16, 2.17). After 1 year of age, myelination proceeds in the temporo-frontal areas (Fig. 2.18), and during the second and third year of age the subcortical regions are involved. Myelination is complete on T2weighted images at about 3 years (Figs. 2.19, 2.20).

Initially, myelination increases at a high rate, but after the first year of life it proceeds more slowly [18]. The last areas to myelinate (so-called terminal zones) are commonly considered to be the peritrigonal regions, i.e., a triangular region posterior and superior to the trigones of the lateral ventricles characterized by persistent hyperintensity on T2-weighted images. However, recent data suggest that T2 high signal in these regions may in fact result from perivascular spaces (Fig. 2.21). On the contrary, the true terminal zones of myelination seem to be the subcortical areas of the frontal and temporal lobes, in accord with autopsy studies in which the subcortical associative fibers, connected with the highest intellectual functions, complete their myelination early in adulthood [12, 19–21] (Figs. 2.22, 2.23).

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Fig. 2.5a–i. Term newborn: On T1-weighted images, myelinated areas are bright. b cerebellar flocculi (short arrow), inferior cerebellar peduncles (long arrow), cerebellar vermis (large arrow), c superior cerebellar peduncles (arrow), d decussation of superior cerebellar peduncles (arrow), e ventroposterolateral thalamic nuclei (long arrow), globi pallidi (short arrow), f posterior portion of posterior limb of internal capsules (arrow), g central corona radiata (arrow), h precentral (short arrow) and postcentral (long arrow) central gyri, i precentral gyrus (arrow)

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Fig. 2.6a–i. Term newborn: On T2-weighted images myelinated areas are dark. b cerebellar flocculi (short arrow), inferior cerebellar peduncles (long arrow), c superior cerebellar peduncles (short arrow), dentate nucleus (long arrow), cerebellar vermis (large arrow), d decussation of superior cerebellar peduncles (arrow), e ventroposterolateral thalamic nuclei (short arrow) and posterior putamen (long arrow), f posterior portion of posterior limb of internal capsules (arrow), g central corona radiata (arrow), h, i precentral (short arrow) and postcentral (long arrow) gyri

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C. Parazzini, E. Bianchini, F. Triulzi Fig. 2.7a–h. Term newborn: T2-weighted images, sensitive pathway. a gracile and cuneate nuclei, b, c, d medial lemniscus through the brainstem, e ventroposterolateral thalamic nuclei, f posterior limb of the internal capsules, g thalamic radiation, h postcentral gyrus

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Fig. 2.8a–c. Term newborn: T2-weighted images, visual pathway. a optic tract, b lateral geniculate nucleus, c calcarine fissure

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Fig. 2.9a–c. Term newborn: T2-weighted images, acoustic pathway. a lateral lemniscus (dorsal pons), b medial geniculate nuclei, c inferior colliculi (short arrow), temporal cortex (long arrow)

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Fig. 2.10a–i. Three months. T1-weighted images. Myelination proceeds in a middle cerebellar peduncles (long arrow) and deep cerebellar white matter (short arrow), e anterior limb of internal capsule (short arrow) and optic radiations (long arrow), f anterior limb of internal capsules (short arrow) and splenium of corpus callosum (long arrow), g–i subcortical central white matter

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Fig. 2.11a–i. Three months: T2-weighted images show progression of myelination in a deep cerebellar white matter, b middle cerebellar peduncles, e Optic radiations

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Fig. 2.12a–c. Five months: FLAIR T1 images. Myelination proceeds in a, b subcortical parieto-occipital white matter (long arrow), genu of the corpus callosum (short arrow) and c paracentral areas, both parietal and frontal

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Fig. 2.13a–c. Five months: T2-weighted images. b Splenium of the corpus callosum is myelinated as well as c subcortical white matter of the paracentral area

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Fig. 2.14. Nine months: T1-weighted images. Myelination extends in ventral portion of brainstem, peripheral cerebellar white matter, and subcortical frontal region

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Fig. 2.15a–i. Nine months: T2-weighted images. Myelination is evident also in d anterior limb of internal capsules (long arrow), splenium of the corpus callosum (short arrow), genu of the corpus callosum (large arrow) e splenium of the corpus callosum (short arrow), subcortical parieto-occipital white matter (long arrow), g deep frontal region

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Fig. 2.16. One year: T1-weighted images. White matter is almost completely myelinated. The pattern of myelination is very similar to that of the adult

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Fig. 2.17a–i. One year: T2-weighted images. a subcortical cerebellar white matter is myelinated and myelination proceeds in f the frontal white matter

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Fig. 2.18a–f. Fifteen months. T2-weighted images. Myelination is evident peripherically in a temporal lobes and b–d frontal lobes

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Fig. 2.19. Three years. T1-weighted images. Myelination is complete

Fig. 2.20a,b. T2-weighted images. Linear hyperintensities in the peritrigonal areas, showing a radial course spanning from the ventricle wall towards the periphery, can be referred to perivascular spaces

a

b

Myelination

Fig. 2.21. Three years. T2-weighted images. Myelination is complete. The subcortical fronto-temporal white matter is myelinated

Fig. 2.22a,b. Twenty months. T2weighted images. Hyperintensity is recognizable in both subcortical temporopolar (a) and temporolateral (b) areas

a

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a

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c

Fig. 2.23a–c. T2-weighted images. Myelination of subcortical white matter at 21 (a), 33 (b), and 40 (c) months of age. a Subcortical white matter is bright in prerolandic area and along the first and second convolutions. b myelination is present in the prerolandic area. In c, T2 subcortical hyperintensity is no longer evident and myelination is complete

References 1. Dietrich RB, Bradley WG, Zaragoza EJ 4th, Otto RJ, Taira RK, Wilson GH, Kangarloo H. MR evaluation of early myelination patterns in normal and developmentally delayed infants. AJNR Am J Neuroradiol 1988; 9:69–76. 2. Martin E, Kikinis R, Zuerrer M, Boesch C, Briner J, Kewitz G, Kaelin P. Developmental stages of human brain: an MR study. J Comput Assist Tomogr 1988; 12:917–922. 3. Staudt M, Schropp C, Staudt F, Obletter N, Bise K, Breit A. Myelination of the brain in MR: a staging system. Pediatr Radiol 1993; 23:169–176. 4. Barkovich AJ, Kjos BO, Jackson DE, Norman D. Normal maturation of the neonatal and infant brain: MR imaging at 1.5T. Radiology 1988; 166:173–180. 5. Barkovich AJ. Concepts of myelin and myelination in neuroradiology. AJNR Am J Neuroradiol 2000; 21:1099–1109. 6. Hayakawa K, Konishi Y, Kuriyama M, Konishi K, Matsuda T. Normal brain maturation in MRI. Eur J Radiol 1990; 12:208–215. 7. Korogi Y, Takahashi M, Sumi M, Hirai T, Sakamoto Y, Ikushima I, Miyayama H. MR signal intensity of the perirolandic cortex in the neonate and infant. Neuroradiology 1996; 38: 578–584. 8. McArdle CB, Richardson CJ, Nicholas DA, Mirfakhraee M, Hayden CK, Amparo EG. Developmental features of the neonatal brain: MR imaging. Gray-white matter differentiation and myelination. Radiology 1987; 162:223–229. 9. Counsell SJ, Maalouf EF, Fletcher AM, Duggan P, Battin M, Lewis HJ, Herlihy AH, Edwards AD, Bydder GM, Rutherford MA. MR imaging assessment of myelination in the very preterm brain. AJNR Am J Neuroradiol 2002; 23:872–881. 10. Barkovich AJ: MR of the normal neonatal brain: assessment of deep structures. AJNR Am J Neuroradiol 1998; 19:1397–1403. 11. Battin M, Rutherford MA. Magnetic resonance imaging of the brain in preterm infants: 24 weeks’ gestation to term. In: Rutherford MA (ed) MRI of the neonatal brain. Edinburgh: WB Saunders, 2002:25–49.

12. Curnes JT, Burger PC, Djang WT, Boyko OB. MR imaging of compact white matter pathways. AJNR Am J Neuroradiol 1988; 9:1061–1068. 13. van der Knaap MS, Valk J. Magnetic resonance of myelin, myelination, and myelin disorders, 2nd ed. Berlin: Springer, 1995:31–52. 14. Bird CR, Hedberg M, Drayer BP, Keller PJ, Flom RA, Hodak JA. MR assessment of myelination in infants and children: usefulness of marker sites. AJNR Am J Neuroradiol 1989; 10:731–740. 15. Neil J, Miller J, Mukherjee P, Huppi PS. Diffusion tensor imaging in normal and injured developing human brain – a technical review. NMR Biomed 2002; 15:543–552. 16. Neil JJ, Shiran SI, McKinstry RC, Schefft GL, Snyder AZ, Almli CR, Akbudak E, Aronovitz JA, Miller JP, Lee BC, Conturo TE. Normal brain in human newborns: Apparent diffusion coefficient and diffusion anisotropy measured by using diffusion tensor MR imaging. Radiology 1998; 209:57–66. 17. Neil JJ, Mc Kinstry RC, Shiran SI, Snyder AZ, Conturo TE. Timing of changes on diffusion tensor imaging following brain injury in full-term infants. Ann Neurol 1998; 44:551. 18. van der Knaap MS, Valk J: MR imaging of the various stages of normal myelination during the first year of life. Neuroradiology 1990; 31:459–470. 19. Kinney HC, Brody BA, Kloman AS, Gilles FH. Sequence of central nervous system myelination in human infancy. Patterns of myelination in autopsied infants. J Neuropathol Exp Neurol 1988; 47:217–234. 20. Baierl P, Forster C, Fendel H, Naegele M, Fink U, Kenn W. Magnetic resonance imaging of normal and pathological white matter maturation. Pediatr Radiol 1988; 18:183– 189. 21. Parazzini C, Baldoli C, Scotti G, Triulzi F. Terminal zoneS of myelination: MR evaluation of children aged 20–40 months. AJNR Am J Neuroradiol 2002; 23:1669–1673.

Malformations of the Telencephalic Commissures

3

Malformations of the Telencephalic Commissures Callosal Agenesis and Related Disorders Charles Raybaud and Nadine Girard

3.1 Introduction

CONTENTS 3.1

Introduction 41

3.2

The Anatomy and Morphogenesis of the Forebrain Commissures 42 Normal Radiological Anatomy 42 Anterior Commissure 42 Corpus Callosum 44 Hippocampal Commissure 45 Septum Pellucidum 45 Limbic Structures 46 Midline Cysts 46

3.2.1 3.2.1.1 3.2.1.2 3.2.1.3 3.2.1.4 3.2.1.5 3.2.1.6 3.3

The Development of the Telencephalic Commissures 47

3.3.1 3.3.2

Comparative Anatomy 47 Morphogenesis: The Lamina Reuniens Forms Two Commissural Sites 47 The Role of the Specialized Glia: Glial Tunnel, Glial Sling, Glial Wedge, and Glia of the Indusium Griseum 48 Summary: A Practical Model of Commissuration 49

3.3.3

3.3.4

3.4

Imaging the Commissural Structures

3.4.1 3.4.2 3.4.2.1 3.4.2.2

Technical Issues 49 The Common Form of Commissural Agenesis 50 Classical Complete Commissural Agenesis 50 Classical Partial Posterior Commissural Agenesis 53 Commissural Agenesis with Meningeal Dysplasia 54 Commissural Agenesis with Interhemispheric Meningeal Cystic Dysplasia 55 Commissural Agenesis with Interhemispheric Lipomas 59 Agenesis of a Single Commissure 59 Isolated Agenesis of the Anterior Commissure 59 Isolated Agenesis of the Hippocampal Commissure 59 Isolated Agenesis of the Corpus Callosum 62 Other Commissural Defects 63 Septo-Commissural Dysplasia 64 The Case of the Commissure in Lobar Holoprosencephaly 65

3.4.3 3.4.3.1 3.4.3.2 3.4.4 3.4.4.1 3.4.4.2 3.4.4.3 3.4.5 3.4.6 3.4.7

3.5

Conclusions 66 References

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49

“Callosal agenesis” is a misnomer. Modern imaging with magnetic resonance (MRI) allows for a detailed anatomic study of the malformation, and demonstrates that in at least 90% of the cases, absence of the corpus callosum is only part of the disorder: typically, the hippocampal commissure is also missing or incomplete. Therefore, the term “commissural agenesis,” or “agenesis of the (forebrain) commissures” should rather be used [1]. In our experience, defects of the telencephalic commissures are the most common malformation of the central nervous system found by MRI in utero [2, 3]. This raises difficult problems of management, as the functional prognosis is uncertain. Many authors have long contended that absence of the corpus callosum per se (the hippocampal commissure was neglected) would not be responsible for any clinical disorder [4]. Only associated malformations would generate the clinical features [5, 6]. In those times, most patients were diagnosed by autopsy or by reluctantly applied radiographic methods, such as pneumoencephalography or angiography. This may have introduced a bias in the detection of affected patients. More innocuous modern imaging modalities are used more liberally in patients with neurological or psycho-intellectual deficits, and demonstrate quite a strong correlation between the pathology and the presence of clinical disorders; the latter, however, seem to be extremely diverse and unpredictable, while the name of “callosal agenesis” is univocal and lacks specificity. Today’s imaging provides exquisitely detailed depiction of morphologic abnormalities. One may presume that a more detailed classification of the abnormalities based on precise anatomical features might uncover more pertinent radiological-clinical correlates, and therefore would allow for more secure prognostic expectations. Although the interhemispheric commissures have seemingly been rediscovered in the 1980s thanks to the acquisition of midline sagittal cuts from MRI, their agenesis has been known for a long time.

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Bianchi [7] was the first to describe it (see Bull [8]) in 1749. Reil [9] produced the first detailed autopsy report of a woman with complete agenesis. Forel and Onufrowicz (quoted by Déjerine [10]) already emphasized that agenesis of the hippocampal commissure was associated with the agenesis of the corpus callosum. In 1892, Sachs [11] recognized that the bundle of fibers that run parallel and medial to the lateral ventricle is made of the rerouted fibers of the corpus callosum, and therefore considered it an “heterotopia of the corpus callosum,” rather than an agenesis. This was nine years before M. Probst [12] gave this bundle the name of Balkenlängsbündel, which was translated as the “longitudinal bundle of Probst,” or for simplicity “Probst’s bundle.” Later, the diagnosis became possible in vivo by pneumoencephalography, and Davidoff and Dyke [13] gave the first detailed radiological description of the malformation in 1934. More material was produced by Feld [14] on a pediatric series with clinico-radiologic correlates, and, in the same book, by Gross and Hoff [15] who reported on a large series of 40 autopsy cases, noting that even the longitudinal “heterotopic” bundle could be missing. Then, in 1968, Loeser and Alvord [16] gave a magisterial description of the malformation. In their paper, amongst other observations, they stressed the fact that the laminae of white matter which close the lateral ventricles medially are truly the leaves of the septum pellucidum (kept apart from the midline in the absence of commissuration and of the resulting interhemispheric approximation). This ill-located septal leaf contains the longitudinal bundle of Probst dorsally, and the longitudinal fornix ventrally. They noted that in rare cases, the corpus callosum alone could be missing, with a patent hippocampal commissure, and reported also on the total absence of callosal fibers, without a longitudinal bundle. The same year, Rakic and Yakovlev [17] reviewed the embryological concepts and provided their own analysis of the development of the telencephalic commissures, which after 35 years is still the reference paper. As clinically recognized cases were becoming more common, updates were published by Bull [8] and especially by F.P. Probst [18], whose sum is full of still valuable data. More recent works have mostly addressed modern imaging [19–22] and have attempted to organize the concepts about this malformation [1, 23]. For a clear understanding of the abnormalities encountered in the patients affected with commissural disorders, the following points will be addressed. Our description is based on the assumption that different morphologic types of commissural agenesis may represent different diseases.

● Radiological

anatomy, morphogenesis, imaging of the telencephalic commissures and midline cysts; ● Common form of commissural agenesis, either complete or partial; ● Commissural agenesis associated with meningeal dysplasias (either multicystic or more rarely lipomatous); ● Isolated agenesis of a single commissure; ● Other varieties of commissural dysplasias; ● Related malformations.

3.2 The Anatomy and Morphogenesis of the Forebrain Commissures 3.2.1 Normal Radiological Anatomy The telencephalic commissures are cortico-cortical bundles of white matter extending from one hemisphere to the other, typically but not absolutely in a symmetrical fashion (i.e., corpus callosum) (Fig. 3.1). Association bundles are cortico-cortical bundles of white matter extending from one area of the cortex to another area within one hemisphere (i.e., superior longitudinal bundle, arcuate fibers). Projection tracts are cortico-subcortical bundles of fibers extending between the cortex and subcortical structures (i.e., thalamocortical and corticospinal tracts). The interhemispheric (or telencephalic) commissures are the anterior commissure, the corpus callosum (the most prominent of all in humans), and the hippocampal commissure (or psalterium). An anterior commissure and a hippocampal commissure are found in all vertebrates, whereas the corpus callosum is found in placental mammals only. Surrounded by these commissures, the septum pellucidum also carries commissural fibers. Because the commissures have developed close to the limbic structures, they have special anatomic relationships with the cingulum and the cingular gyrus, and obviously with the hippocampus. 3.2.1.1 Anterior Commissure

The anterior commissure extends from one hemisphere to the other in the depth of the anterior portion of the basal ganglia, crossing the midline at the upper end of the lamina terminalis of the third ventricle (which belongs to the telencephalon: telencephalon medium, or impar) [24]. It relates mostly to the olfac-

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a

b

d

Fig. 3.1a–d. Normal anatomy of the commissures. a Midsagittal STIR image. Normal appearance of the commissural plate. The most prominent commissure is the corpus callosum with, from c the front to the back, its genu (G), trunk (T), isthmus (I), and splenium (S). Below the genu, the rostrum (R) points backward toward the anterior commissure (AC), thus forming the lamina rostralis (open arrow). The anterior commissure (AC) forms a round-to-oval section at the upper end of the lamina terminalis; it is joined to the fornix (F) and, together with it, forms the lower anterior margin of the foramen of Monro. The fornix (F) itself forms the lower limit of the septum pellucidum (sp), then it joins the under-surface of the corpus callosum at the isthmus. The line of attachment is at the midline of the hippocampal commissure. b Coronal STIR image, anterior. The anterior commissure (arrows) is well shown extending from one amygdaloid nucleus to the other, through the lower part of the basal ganglia, below the heads of the caudates. c Coronal T1-weighted 3D RFT image, posterior. The hippocampal commissure is seen extending transversely (arrows). It is attached at the corpus callosum on the midline, and laterally extends to the fornical crura, above the thalamus and the choroid fissure. It forms the roof of the cistern of the velum interpositum, whose floor is the third ventricular tela choroidea. d Coronal STIR image, midportion of the hippocampus. Using an animal comparison, it forms the image of a duck. The beak is the fimbria (F). The head is the cornu ammonis (CA). The neck and the upper torso are the subiculum (S). The anterior and lower torso is the parahippocampal gyrus (PHG). It contains the white matter of the inferior cingulum, the great limbic association tract that runs also under the cingulate gyrus around the corpus callosum (see Fig. 3.1a). (a courtesy of P. Tortori-Donati, Genoa, Italy)

tory system (olfactory bulbs) and to the paleo-pallium: extending the data from the monkey to the man, this includes the amygdaloid complex (cortex and nuclei), some of the insula (anterior-inferior), some of the orbito-frontal cortex (posterior-medial), and some entorhinal-perirhinal cortex [25]. The anterior commissure contains about 3.5 million fibers. On a

sagittal midline section of the brain, it is seen as a rounded or oval thickening of the upper portion of the lamina terminalis, in front of the anterior column of the fornix, in front of and slightly below the interventricular foramen of Monro. Its diameter is never greater than 6 mm (personal data). On coronal cuts, it extends from one amygdaloid nucleus to the other,

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forming an arch with an inferior concavity. On axial cuts, it sweeps from one hemisphere to the other through the anterior-inferior portion of the basal ganglia, looking like the handle-bar of a Dutch-style bicycle. It crosses the midline at the anterior end of the third ventricle, forming, together with the retrocommissural fibers of the fornix, the Greek letter π. 3.2.1.2 Corpus Callosum

The corpus callosum is the prominent commissure of advanced mammals with a large neocortex. In the human brain, it contains about 200 million fibers. It connects almost the entire neocortex of one side with the other side. Most fibers are homotopic reciprocal (two fibers are joining the cortex from one side to the other in a symmetric fashion). About 10% are homotopic and not reciprocal (a fiber joins two symmetric points in one way only). A few are heterotopic (a fiber joins two asymmetric parts of the brain, cortical or subcortical). Although the morphology of the corpus callosum varies among individuals, its general shape can be easily appreciated and described. Its size and thickness evolve in the first months of life [26], depending mostly on myelin content. It sweeps from the anterior commissure anteriorly to the hippocampal commissure posteriorly. It presents several segments, which seem to carry specific sets of commissural fibers. In spite of several studies in the monkey and in man [10, 27, 28], only broad rules of organization can be ascertained. Fibers are distributed from the front to the back according to the corresponding functional cortical areas, but irrespective of the strict lobar or gyral segmentation. ● The

lamina rostralis [29, 30] connects the anterior-inferior aspect of the corpus callosum to the lamina terminalis of the third ventricle and to the anterior commissure. This white matter lamina closes the space (real in fetuses and neonate, virtual afterwards) between the leaves of the septum pellucidum anteriorly. Although it is said not to contain any commissural fiber [28], its constituent white matter must be connected somewhere. It limits the paraterminal gyrus (of the septal area), to which the diagonal band of Broca is attached. ● The rostrum (the beak) is a thickening of the lamina rostralis where it joins the genu. It points backward to the lamina terminalis, below the callosal genu. It contains commissural fibers that are parallel, and contiguous to, the fibers of the anterior commissure [28], in front and below the ante-

rior putamen and nucleus accumbens. It connects the orbital aspect of the frontal lobes. ● The genu (the knee) is the anterior, rounded thickening of the corpus callosum, where it changes direction from inferior to posterior. Its fibers form the forceps minor (because of their shape as they come from the anterior frontal lobes); they connect the prefrontal cortices. The fibers connecting the ventro-medial portions of the prefrontal cortex are in the ventral genu; the fibers connecting the dorsolateral portions are in the dorsal genu [28]. The genu marks the anterior end of the septum pellucidum. Kier and Truwit [29] defined a “MAC line” (standing for mammillary body-anterior commissure-corpus callosum), which illustrates the anterior development of the corpus callosum during evolution. In the rat, rabbit, or cat, the genu is located behind or at the line. In the dog, monkey, and especially the normal human, it should be located in front of the line. If not, it is hypoplastic. ● The trunk (or body) is the portion of the corpus callosum that extends between the genu and the point where the fornix joins its inferior surface. It borders the septum pellucidum superiorly on the midline, and forms the roof of the body of the lateral ventricles laterally. It carries fibers from the precentral cortex, the supplementary motor area, the anterior cingulate gyrus, and the frontoparietal operculum, with the adjoining insular cortex. Laterally, the callosal fibers pass below (and around) the cingular bundle; then, as they diverge further, they cross and mingle with the other tracts of the centrum semiovale (superior longitudinal tract, occipitofrontal tract, corona radiata). ● The isthmus of the corpus callosum is a thinner portion where the corpus callosum is joined by the fornix. It carries fibers from the central, sensorimotor areas (except for the primary sensory representation of the hand and foot which are not interconnected). ● The splenium (the spleen) is the thickest part of the corpus callosum. It protrudes in the ambient cistern, and hangs above the collicular plate, with the great vein of Galen curving around it. Becoming more vertical, it marks a change in the general direction of the corpus callosum. The fibers of the splenium form the forceps major as they spread posteriorly. The upper portion of the splenium contains fibers from the inferior temporal cortex and parahippocampal gyrus, and from the peristriate cortex. Its lower portion contains fibers from the occipital striate areas. The primary visual cortex (area 17) is not connected.

Malformations of the Telencephalic Commissures

3.2.1.3 Hippocampal Commissure

3.2.1.4 Septum Pellucidum

The hippocampal commissure (or psalterium Davidi – the lyre of David) is part of the fornix (vault); it connects the hippocampi with one another. The fornix is made of longitudinal, ipsilateral fibers and of transverse, commissural fibers. The fimbria (the fringe) gathers the projection fibers of the hippocampus; these form a bundle that, coursing posteriorly and superiorly, becomes the crus, or posterior column, of the fornix, as it sweeps around the thalamus on each side. Both columns run toward the midline and meet under the isthmus of the corpus callosum, forming the trunk of the fornix by apposition. Then, the tracts continue forward along the lower margin of the septum pellucidum. In front of the interventricular foramen of Monro, they diverge again and form the anterior columns of the fornix, from which two tracts originate. One, the precommissural tract, continues forward above the anterior commissure to join the septal area. The other, the retrocommissural tract, turns down in front of the foramen of Monro, right behind the commissure (with which it forms the letter π, as described above), and courses within the wall of the third ventricle toward the mammillary body. Longitudinal fibers represent 80% of fornical fibers. Another 20% form the hippocampal commissure. This extends between the fornical crura (posterior columns) across the midline, under the corpus callosum and above the cistern of the velum interpositum. It has the shape of a trigone, with its tip behind the trunk of the fornix (below the callosal isthmus), its midline attached to the undersurface of the posterior corpus callosum, and two wings extending laterally toward the fornical crura. On the midline, it cannot be seen on a sagittal cut. It is best demonstrated on coronal cuts, posterior to the septum pellucidum. Its morphology gives the hippocampal commissure the appearance of a gothic “vault,” or “fornix” in Latin; the name of psalterium (lyre) comes from its striate, triangular shape. When the ventricles are enlarged, especially by hydrocephalus, these laminae tend to become vertical, pushed against the midline, prolonging posteriorly the appearance of the septum pellucidum. The hippocampal commissural fibers connect mostly the CA1 and CA3 sectors of the hippocampi in a symmetrical, homotopic fashion, but heterotopic fibers are also found, connecting CA3 on each side with the contralateral CA1 and dentate [31]. Together, the corpus callosum and the hippocampal commissure form what is commonly called the commissural plate.

The septum pellucidum is interposed between the corpus callosum and the body of the fornix. In the midline sagittal plane, its shape is roughly triangular, with the apex at the anterior commissure, the base at the trunk of the corpus callosum, one side at the lamina rostralis and rostrum, and another at the body of the fornix. Because of this close relationship with the commissures, it should be considered together with them. The septum pellucidum should not be confused with the septum granulosum, or septal area. The septal area is the posterior medio-basal part of the frontal cortex, associated with the septal nuclei. It is located anterior and inferior to, and is continuous with, the septum pellucidum; it prolongs the cingulate gyrus below the genu and the lamina rostralis, in front of the third ventricle. The septal area is part of the limbic structures, and is related to the olfactory tract. The normal septum pellucidum is made of the two apposed laminae of white matter which close medially the lateral ventricles, each belonging to the ipsilateral hemisphere. The upper and anterior margins of the septum pellucidum are attached to the trunk and genu, rostrum, and lamina rostralis of the corpus callosum, respectively. Its lower margin contains the fibers of the longitudinal fibers (columns) of the fornix, where they form the body of the fornix. It is covered with ependyma on its lateral, ventricular aspect, under which the septal veins can be identified, forming prominent subependymal afferents of the internal cerebral veins. The cellular lining of the medial aspect of the septal leaves is quite controversial, but its ventricular nature is no longer accepted. The septum pellucidum is devoid of any significant aggregates of neurons, and contains fibers only. Little is found in the literature about the connections of these fibers: hippocampal fibers diverging from the fornix [10], and/or medial subcallosal radiations of the cingulum, mostly toward and from the thalami [32]. The Fetal and Neonatal Septum Pellucidum

In fetuses and neonates, the leaves of the septum pellucidum are usually not apposed, and instead contain a cavum (Fig. 3.2). The meaning of this transitory cavity has been the subject of considerable controversy over the years [33]. Evidence from embryology and anatomy suggests that it is a remnant of the meningeal space that was isolated from the primitive interhemispheric fissure by the development of

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a

b Fig. 3.2a,b. Transient midline cava in fetuses and neonates. a, b Coronal T2-weighted images. a Cavum septi pellucidi. CSF filled space limited by the corpus callosum above, the third ventricular tela choroidea, and the septal leaves with the longitudinal fornices laterally (asterisk). It is an anterior extension of the cistern of the velum interpositum. b Cavum Vergae. It is a blind posterior blind extension of the cavum septi pellucidi between the corpus callosum and the hippocampal commissure (arrowheads). Both cava, together or separately, may become encysted (see Fig. 3.16b)

the commissures. In fetuses and young infants, this cavum septi pellucidi (or Duncan’s cave) is limited laterally by the leaves of the septum pellucidum, and dorsally by the trunk and the genu of the corpus callosum; it communicates with the ventricular lumen through the interspace between the anterior columns of the fornix at the foramina of Monro, and with the anterior interhemispheric fissure when the lamina rostralis is not completed yet. It may present a posterior expansion between the corpus callosum above and the hippocampal commissure below, which has been called the cavum Vergae (or cavum psalterii). These are normal features, limited by normally developed commissures and septal leaves. As the brain matures and grows, the cava recede and disappear, leaving only a small triangular space adjacent to the corpus callosum. 3.2.1.5 Limbic Structures

The limbic structures are anatomically related to the commissures in two ways, either because these are directly connected with them (amygdala-anterior commissure, hippocampus-hippocampal commissure) or because they are in close proximity (cingulate gyrus-corpus callosum). The corpus callosum is covered by the indusium griseum (or hippocampal rudiment) laterally, and is surrounded by the cingulate gyrus, that sweeps around it in the continuity of the parahippocampal gyrus. It overlies a large bundle of white matter, the cingulum (Latin for “belt,” “girth”), which is an association tract linking the whole limbic lobe together, from the septal area to the entorhinal cortex. It forms a circle that is concentric with, and outside of, the circle of the fornix. The corpus callo-

sum is separated from the limbic lobe by the callosal sulcus. 3.2.1.6 Midline Cysts

In rare cases, after a cavum has closed, fluid may slowly accumulate in it, forming a cyst with bulging walls (see Fig. 3.16). All commissures are present and anatomically normal. Usually, the cyst concerns the whole space comprised between the commissures and the septal leaves. More rarely, it concerns only the cavum septi pellucidi, sparing the more posterior cavum Vergae. Exceptionally, it concerns the cavum Vergae only [34], above the hippocampal commissure. These cysts are often asymptomatic but they may be a potential cause for headaches and slowly progressing hydrocephalus. Surprisingly, they are found quite commonly in some types of rare metabolic brain diseases (Alexander’s disease, spongiform encephalopathies). They are not really malformative, but just accumulations of CSF in spaces where it should not accumulate. They should not be confused with midline cystic tumors or with suprasellar cysts, which tend to expand upward between the leaves of the septum because this, anatomically, is a natural pathway. Moreover, they should not be confused with midline malformations in which the septal leaves stay apart because part of the commissural system is missing; these never present bulging walls. All midline cysts described above develop between the corpus callosum and the fornix; therefore, they are different from the cysts of the velum interpositum, which develop as accumulations of fluid between the fornix and the roof of the third ventricle (see Chap. 21).

Malformations of the Telencephalic Commissures

3.3 The Development of the Telencephalic Commissures 3.3.1 Comparative Anatomy Data from comparative anatomy [35-37] show that, although the anterior and hippocampal commissures are common to all vertebrates, a corpus callosum is found in placental mammals only. The most rudimentary brain would be composed of an olfactory bulb with its primitive cortex and nuclei only (septal cortex and nuclei attached to the medial olfactory root; amygdaloid complex attached to the lateral olfactory root). This is referred to as the paleopallium, whose commissure is the anterior commissure. Further evolutionary advance introduces a more sophisticated cortex, the hippocampus with the entorhinal cortex. This forms the archipallium, whose commissure is the hippocampal commissure (with some of the perirhinal cortex still depending on the anterior commissure). The neocortex (neopallium) develops later in evolution, becoming huge in humans; it is interposed between the paleopallium and the archipallium, and its specific commissure is the corpus callosum, similarly interposed between the anterior commissure and the hippocampal commissure. Some species, such as the marsupials, have a neocortex without a corpus callosum, and the neocortical commissural fibers pass though the anterior commissure. In some marsupials [35] part of the neocortical fibers can also pass together with, and above, the hippocampal commissure.

3.3.2 Morphogenesis: The Lamina Reuniens Forms Two Commissural Sites After decades of controversies, Rakic and Yakovlev in 1968 provided a magisterial description of the events leading to commissuration of the cerebral hemispheres [17]. This description was subsequently refined and complemented, but not challenged by more recent studies. The basic fact is that the commissures form not from one, but from two distinct sites, i.e., the lamina reuniens (within the lamina terminalis) for the anterior commissure, and the massa commissuralis (by interhemispheric fusion) for both the hippocampal commissure and the corpus callosum. By weeks 6–8, the upper portion of the lamina terminalis (or lamina commissuralis) of the third ventricle thickens; its densely cellular dorsal portion

forms a lamina reuniens, whereas its loosely cellular ventral portion forms the area precommissuralis, or prospective septal area. Together, they form the telencephalon medium, or impar [24]. By week 10, fibers coming from the ganglionic eminences are seen to approach the midline and cross within the lamina reuniens; these are the pioneer fibers of the anterior commissure. By week 11, a thick, definitive anterior commissure is present. In the meantime, a deep sulcus has developed on the dorsal aspect of the lamina reuniens, called the sulcus medianus telencephali medii (SMTM). The loosely cellular banks of the SMTM, clearly demarcated from the densely cellular isocortical plate that overrides it, form the primordium hippocampi on each side, with the primordia of the longitudinal fornices appearing by week 9. Intense proliferation of cells takes place within each primordium hippocampi, and a juxtaposition of the banks of the SMTM develops. The proliferating cells break through the lamina limitans and invade the meninx primitiva between the banks. This results in fusion of the medial walls of the hemispheres. This area of fusion, developed in the dorsal part of the lamina reuniens, is called the massa commissuralis; it is distinct and independent from the ventral lamina reuniens. By week 10, the pioneer fibers of the hippocampal commissure cross the midline through the massa commissuralis, and the hippocampal commissure is clearly completed by weeks 11–12. A well-defined callosal plate is obvious by weeks 12–13, distinct from the anterior commissure. The corpus callosum is virtually complete by week 20. From the initial massa commissuralis, its development follows the development of the cerebral hemispheres, both caudally and cephalically, following the expansion of the frontal and parietotemporo-occipital lobes. The relative growth of the callosal body is even during maturation. The growth of the genu is more important in the weeks before birth, whereas that of the splenium takes place mostly after birth. The anterior development of the genu, and then the inferior development of the rostrum and lamina rostralis, encloses the subcallosal pocket of the SMTM, which becomes the cavum septi pellucidi. This cavum is found in most adult mammals. It is also found in immature human brains, but not in adult brains of primates (including man) and cetaceans.

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3.3.3 The Role of the Specialized Glia: Glial Tunnel, Glial Sling, Glial Wedge, and Glia of the Indusium Griseum More recent experimental works on animal models have refined the understanding of the morphogenesis of forebrain commissures. It has been shown that four modalities exist to allow for crossing of the commissural fibers. ● through a “glial tunnel” in the upper lamina terminalis, for the anterior commissure; ● using the meninges of the interhemispheric fissure, for the hippocampal commissure; ● via an interhemispheric glial support (the “glial sling”), for the pioneer fibers of the corpus callosum in front of the hippocampal commissure; ● by fasciculation along the pioneer callosal fibers anteriorly and along the hippocampal fibers posteriorly, for the bulk of the corpus callosum. Silver et al. [38] and Katz et al. [39] demonstrated that in the mouse forebrain a “bridge-like” structure of specific glial cells, or “glial sling,” is required for commissuration. These cells originate from the germinal matrix medial to the lateral ventricles; they migrate medially through the fused walls of the cerebral hemisphere and form a bridge that extends from one hemisphere to the other across the medial interhemispheric meninx primitiva. The first callosal axons grow along its surface toward the contralateral hemisphere, above the anterior commissure. It has been shown that at least in rats, these pioneer fibers originate from the cingulate cortex [40]. This sling proceeds anteriorly and posteriorly as the brain grows. It should be noted that only the pioneer fibers of the corpus callosum need the sling to cross: later fibers follow and accumulate by a process of fasciculation, using early fibers as a support and mixing with them. This also occurs posteriorly, where the callosal fibers fasciculate along the hippocampal fibers to form the splenium. In a strain of acallosal mutant mice, other experiments have shown a delay in midline fusion and a failure of the sling to form. As a result, the would-be callosal axons form large “neuromas” adjacent to the interhemispheric fissure, similar to the longitudinal bundles of Probst. In other experiments on mouse embryos, surgical severing of the sling results in an acallosal brain that mimics the acallosal mutant; commissuration resumes if an artificial sling-like cellulose support is inserted. Wahlsten [41] and Livy and Wahlsten [42], in the same strain of acallosal mice, showed that the hippocampal fibers follow the pia at the bottom of the interhemispheric fissure without

using a glial sling. They confirmed that the posterior callosal fibers use the pre-existing hippocampal commissure as a support for their progression. More recently, Shu et al. [43, 44] further refined the understanding of the cellular processes of commissuration. Again in the mouse, they demonstrated a specialized “glial tunnel” guiding the anterior commissural fibers through the lamina reuniens of the lamina terminalis. They also demonstrated the repulsive role of two other glial structures to orient the callosal fibers toward the midline glial sling: one is a “glial wedge” located at the dorsomedial aspect of the lateral ventricles, the other is the glia of the indusium griseum which borders the lowermost cortex on the inner aspect of the hemisphere, at the margin of the primitive septum. These glial structures repel the commissural fibers toward the interhemispheric sling, at the level of the presumptive septum pellucidum. In knock-out mice lacking Nfia, the specialized glia of the glial wedge and of the indusium griseum is lacking; the cells of the glial sling migrate abnormally into the septum pellucidum instead of going into the interhemispheric fissure; therefore, the callosal fibers fail to cross, and course into the septum pellucidum instead. The hippocampal commissure is missing as well, whereas the anterior commissure is present but abnormally small, a fact that is noteworthy in that it reproduces the typical human malformation. The other fascinating point that was uncovered in recent years regards the role of the subplate. In the early embryo, the first neurons to migrate to the surface of the neural tube form a peripheral layer of gray matter, the preplate, which becomes split by the arrival of the neurons of the cortical plate into a superficial layer containing the Cajal-Retzius cells (future molecular layer or layer 1 of the cortex), and a deep, transient subcortical layer, the subplate. Mostly developed at the beginning of the third trimester, the subplate serves as a “waiting zone” for the incoming axons; temporary connections are established with associative and commissural axons, until the cortex is mature enough for permanent connections [45]. During the same period, many collateral branches of immature callosal axons are eliminated as the cortex matures [46, 47]. Other than these cellular guidance processes toward and along the sling and the fasciculation process, brain fiber pathfinding depends on many other factors. There is still much to be uncovered on the genic/molecular events controlling commissuration [48-51]. Factors involved in the formation of the cellular sling, the fasciculation process, the guiding of the axonal growth cones, and the control of midline crossing are complex and multiple. This is reflected in the fact that commissural disorders may be part of many different syndromes [52].

Malformations of the Telencephalic Commissures

Therefore, functional prognosis may depend not only on the anatomic disorganization but also on the failure of broader developmental processes.

3.3.4 Summary: A Practical Model of Commissuration From the morphogenetic data of classical embryology, using experimental observations in rodents and with the help of radiological evidence obtained from large clinical series in human patients, a model of commissuration can be proposed to classify the diverse disorders encountered in the clinical practice. Because the anterior commissure raises no real problem to this point, this model will only consider the other structures involved in the commissuration: the septum pellucidum, the hippocampal commissure, and the corpus callosum. The first step is a theoretical acommissural brain. No commissure is linking the two hemispheres and the interhemispheric fissure reaches the tela choroidea of the third ventricle. The medial walls of the lateral ventricles are composed of a medullary velum that extends from the medial cortical margin to the choroid fissure, behind the interventricular foramen of Monro, the primary septum pellucidum. Around the thalamus, it prolongs the fimbria hippocampi (which similarly closes the temporal horn between the hippocampus and the temporal choroid fissure). As the fimbria conveys the fibers leaving the hippocampus, the primary septum naturally also contains these fibers as they travel anteriorly toward the septal area and the mammillary body. It forms the longitudinal, ipsilateral columns of the fornix in the lower margin of the primary septum. The second step is hippocampal commissuration. To cross from one hemisphere to the other, both commissures use the massa commissuralis, representing the area of fusion of the medial walls of the hemispheres that corresponds to the primary septum, just below the indusium griseum. The hippocampal commissure first develops in the posterior part of the primary septum. The crossing fibers leave the crus fornicis at right angles, course within the leaves of the primary septum toward the fusion area, cross the midline, and continue symmetrically on the other side to join the contralateral crus, forming the transverse lamina of the hippocampal commissure. The third step is the initiation of the corpus callosum, starting more rostrally in the massa commissuralis. The fibers cross along the interhemispheric fusion line in the upper portions of the primary septum, below and adjacent to the indusium griseum. With the under-

lying portion of the primary septal leaves on each side, they isolate a space that forms the cavum septi pellucidi; eventually these leaves become apposed to form the mature septum pellucidum. The callosal commissuration process develops cranially as well as caudally [17], following the extension of the hemispheres. The fourth step is growth of the corpus callosum, with the later arriving fibers joining earlier ones by the process of fasciculation. Anteriorly, they follow the pioneer fibers above the septum pellucidum. Posteriorly, when reaching the earlier hippocampal commissure, they fasciculate along its fibers, forming with them the isthmus and the splenium. The consequences of this model are manifold: 1) Both the septum pellucidum and the wings of the hippocampal commissure derive from the same medullary velum that closes medially each lateral ventricle. If commissuration fails, the callosal fibers course longitudinally in the upper portion of this medullary velum (primary septum), forming the Probst’s bundle. Presumably, the hippocampal commissural fibers remain within the columns of the fornix in the inferior portion of the medullary velum. 2) The cavum septi pellucidi is a transitory space between the septal leaves and below the corpus callosum, which posteriorly is continuous with the space between the wings of the hippocampal commissure. Therefore, it is truly a portion of the interhemispheric fissure isolated by the development of the commissures. 3) If the anterior corpus callosum overrides posteriorly the hippocampal commissure before fusing with it, the cavum septi pellucidi extends between the two commissures as a cavity known as the cavum Vergae, enclosed by the septal leaves laterally, the corpus callosum above, and the hippocampal commissure below. 4) As the development of the commissure proceeds in different, successive interrelated stages, different types of malformations may result from the different possible combinations of developmental defects.

3.4 Imaging the Commissural Structures 3.4.1 Technical Issues Obviously, MR imaging is the only valuable method today to investigate the telencephalic commissural disorders. The goals of imaging are multiple: (i)

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assessing the morphology of all three commissures; (ii) evaluating the general morphology of the brain, i.e., cortical pattern and white matter as can simply be approached through ventricular morphology (future developments of tract imaging, such as diffusion tensor imaging, may improve on this); (iii) looking for disorders of cortical development; (iv) appreciating the hydrodynamics of contingent fluid collections within the brain and in the meningeal spaces; and (v) hopefully, appreciating the functionality and, as much as possible, the functional organization of this malformed brain. Imaging sequences should therefore demonstrate the morphology of the brain as well as the structure of the tissues. The signal of commissural tracts is usually somewhat different from that of the surrounding white matter, with shorter T1 and T2; this can be used as an aid for identification. In infants and neonates, tissue identity is more difficult to assess because of the immaturity of the brain. It is reasonable to wait for the infant to mature before investigating the brain unless there is a therapeutic need, such as fluid collection to drain or a cranial cleft to repair. The following basic sequences can be used: ● T1-weighted images, preferably inversion recovery

for its superb anatomic definition; ● T2-weighted images, for the anatomy and the iden-

tification of structural abnormalities (i.e., migrational disorders); ● FLAIR is helpful for identifying brain dysplasias in the mature brain; ● T1W 3DFT volumetric acquisitions (MPRAGE, SPGR, etc.) are extremely useful as they allow to reformat images in any desirable plane, and because of thin slice acquisition (about one millimeter). This yields greater anatomic details and minimizes partial volume artifacts. It also allows surface rendering, which can be useful in depicting abnormal sulcation patterns; ● Contrast injection may be useful to image vascular structures, especially the venous tree; ● Special sequences for CSF flow studies are needed to characterize the kinetics of CSF into cysts and cavities, in the brain or in the surrounding meninges; ● For research purposes, functional imaging would allow a better understanding of the organization of the cortex in a brain devoid of commissures and with an abnormal connectivity [53]. The anatomic diffusion tensor imaging depiction of the different fiber tracts could be associated with this functional imaging.

The plane of reference is a problem. The best suited one would be the bicommissural plane, which is roughly parallel to the plane of the corpus callosum in normal brains. However, the anterior commissure may be absent, and the morphology of the hemispheres may be altered by the presence of cystic masses or associated malformations. A rule-ofthumb is to use the plane parallel to the longest axis of the hemispheres. We prefer to obtain T2-weighted and inversion recovery images in a coronal plane, and other T1-weighted images (such as MPRAGE) in axial, coronal, and sagittal planes. Because of the high incidence of associated malformations, MR imaging of the spine should be performed in case of pelvic disorders or of neurological deficit. CT remains a very useful complementary tool in case of malformations of the face or of the base of the skull.

3.4.2 The Common Form of Commissural Agenesis The so-called classical form of commissural agenesis is the most common and typical, and the one usually described in the medical literature. It may be complete or partial. When complete, the corpus callosum, the hippocampal commissure, and in 50% of cases the anterior commissure are absent. When partial, the anterior commissure is always present, and a variable portion of the posterior corpus callosum is missing, together with the adjoining hippocampal commissure. The meninges are normal. Associated malformations are frequent. 3.4.2.1 Classical Complete Commissural Agenesis

Complete commissural agenesis is the most frequent type, representing a third of all cases (Fig. 3.3). By definition, in this form both the corpus callosum and the hippocampal commissure are totally lacking. In half the cases, the anterior commissure is also absent, but this does not seem to further significantly affect the general morphology of the brain. When present, the anterior commissure is often small, much smaller than in normal individuals. While it has frequently been stated that the anterior commissure can be enlarged (because some callosal fibers would use it to cross the midline), a thicker anterior commissure was never observed in our material, and was not reported in mice with experimentally created or genetic agenesis [38, 41, 43, 44]. A rudimentary callosal genu might have been mistaken for an enlarged anterior commissure in old reports. Moreover, absence of thickening

Malformations of the Telencephalic Commissures

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Fig. 3.3a–e. Classical, complete commissural agenesis. a Midsagittal T1-weighted 3D RFT image. Complete absence of the corpus callosum and of the hippocampal commissure. The anterior commissure in this case is present, albeit small (arrow). The roof of the third ventricle bulges upwards slightly. The usual pattern of the cingulate gyrus is not found. b Coronal T2-weighted image, anterior. There is no interhemispheric commissure. The medial cortex is rolled-in over the thalami. The lateral ventricles are away from each other, closed medially by the primordial septal leaves that contain the longitudinal bundles of Probst superiorly (thick arrow) (truly heterotopic, rerouted fibers of the corpus callosum) and the longitudinal fornix inferiorly (thin arrow). The temporal horns have an abnormal appearance, extending below the hippocampus into the parahippocampal gyrus (arrowhead), presumably because of the lack of cingulum. This lack of cingulum could also explain the loss of the normal pattern of the cingulate gyrus. c Axial T1-weighted 3D RFT image. The bodies of the lateral ventricles are wide apart, parallel to each other, separated by the Probst’s bundles (arrows), the rolled-in medial cortices and the interhemispheric fissure. d Coronal T2-weighted image, posterior. Major ventriculomegaly of the atrium, called colpocephaly as it has been assumed to be the persistence of the fetal anatomy. Yet, this ventriculomegaly is already present in young fetuses with the malformation, and is rather likely to reflect a lack of white matter fibers, especially under the medial and inferior occipital cortices. e Axial T2-weighted image (different patient). There is marked colpocephalic dilatation of the trigones. (e courtesy P. Tortori-Donati, Genoa, Italy)

of the anterior commissure is more consistent with the duality of the commissural beds for the anterior commissure on one hand, the corpus callosum and the hippocampal commissure on the other hand; as a consequence, the callosal fibers are not expected to change their path and mix with anterior commissural fibers. However, it is acceptable that a diffuse axonal guidance defect might affect both commissural beds.

Besides the absence of the commissures, the morphology of the medial aspect of the hemisphere is clearly abnormal. The interhemispheric fissure extends downwards to the roof of the third ventricle. The lower margin of the medial cortex is rolled in above the tela choroidea and the thalami. The cortical pattern is modified and no cingulate gyrus can be recognized; instead, there is an unusual arrangement of the median sulci, which more or less converge

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towards the third ventricle in the parietal area, and are roughly concentric with an upward concavity in the frontal area. The parieto-occipital sulci are shallow. The roof of the third ventricle bulges upward gently, but a significant expansion into the interhemispheric fissure is rare. When it occurs, it develops as a single cavity continuous with the lumen of the third ventricle and/or the lateral ventricle (type 1 of the classification of the callosal agenesis with cysts, see below). No meningeal abnormality is observed in these patients. The vascular anatomy is abnormal, especially regarding the anterior cerebral artery, reflecting the abnormal morphology of the brain; however, typically no vascular dysplasia is seen. The morphology of the ventricular system is modified as well. The lateral ventricles are shifted laterally. They are closed medially by a lamina of white matter that extends from the rolled-in cortex of the medial aspect of the hemisphere, to the choroid fissure on the dorsal aspect of the thalami, between the temporal horn and the septal cortex on the medial aspect of the frontal lobe. It prolongs the fimbria hippocampi. This lamina of white matter is actually what should have become, on each side, the leaf of the septum pellucidum [16]. In its lower margin, this “primary septum pellucidum” (like a normal septum pellucidum) contains the longitudinal fibers of the fornix, coursing anteriorly around the thalamus from the fimbria toward the anterior third ventricle. In its upper margin, it contains a conspicuously large longitudinal bundle of fibers: it has been known for a century [11, 12] to represent the callosal fibers which failed to cross and instead are rerouted parasagittally, parallel to the midline. This abnormal bundle is commonly called the “longitudinal bundle of Probst.” On coronal cuts it is identified at the superior-medial aspect of the body of the lateral ventricles, showing short T1 and T2 signal in mature brains. It is interesting to note that these fibers, which should have connected symmetrical areas of the cortex, instead connect cortical regions that are not directly connected in normal individuals. For that reason, it has been stressed that the malformation, rather than a callosal agenesis, could be called a callosal heterotopia [11]. This implies a significant alteration of the anatomy of the hemispheric connectivity, which to our knowledge has not been specifically studied. Beside the callosal commissure, it has been reported that at least in knocked-out mice, the hippocampal commissural fibers follow the callosal fibers in their abnormal course within the septum pellucidum [44]. Because the Probst’s bundles encroach on the ventricular lumen, the inner walls of the lateral ventricles are concave medially. Together with the lumen of the

third ventricle, this makes up the typical appearance of a “bull’s head” on coronal images. In about 10% of patients, the frontal horns are hypogenetic, with no apparent lumen, apparently because their walls are apposed; this also can be related to an abnormal arrangement of white matter tracts. On axial images, the bodies of the lateral ventricles are parallel to each other, away from the midline. From lateral to medial, the ventricular lumen, the longitudinal bundles of Probst, the medial cortex of the hemispheres with its underlying white matter, and the interhemispheric fissure are found. The temporal horns also are abnormal. In 80% of the patients, the hippocampus looks unusually rounded on coronal images. Still more strikingly, the ventricular lumen surrounds it and extends within the core of the parahippocampal gyrus, which is practically devoid of white matter. This missing white matter corresponds to the inferior, parahippocampal portion of the cingulum, the limbic fiber bundle that normally courses from the entorhinal cortex to the septal area, in the medial aspect of the brain around the hilum of the hemisphere. As the superior portion of the cingulum normally underlies the cingulate gyrus, its absence is likely to explain the abnormal appearance of the medial cortex, with no clearly demarcated cingulate gyrus. In itself, the cingulate cortex may not necessarily be abnormal, although the lack of commissural and cingular fibers should somewhat modify its connections. Posteriorly, the ventricular atria are markedly enlarged, which is wrongly named a colpocephaly. This term describes the relative atrial dilatation in the normal fetus, but in fetuses with commissural agenesis atrial enlargement is exceedingly pronounced. This ventriculomegaly is significant, occasionally huge, and sometimes asymmetrical. It occurs mostly at the expense of the medial and inferior white matter, and is associated with shallow sulci. It is likely to be related to a defect of the intrinsic association bundles of the occipital lobe. On occasion, a significant enlargement may reflect some degree of hydrocephalus. Many associated abnormalities can be observed (Fig. 3.4; see also Fig. 3.14). Hemispheric disorders may include periventricular or subcortical heterotopia (15%), cortical dysplasia resembling polymicrogyria, or even clefting. The rarely seen fusion of the anterior basal ganglia may suggest some relation with holoprosencephalies. Cerebellar abnormalities (10%) include cystic malformations (Dandy-Walkerlike) and vermian clefts (i.e., rhombencephaloschisis). Visual system abnormalities are common (20%), and include colobomas, microphthalmia, strabismus, Joubert syndrome, and congenital nystagmus. Skull

Malformations of the Telencephalic Commissures

3.4.2.2 Classical Partial Posterior Commissural Agenesis

Fig. 3.4. Complete commissural agenesis: associated lesions. Coronal STIR image. Complete commissural agenesis with malformed hippocampi and a large left temporal subcortical heterotopia (arrowheads). See also Fig. 3.14 for an associated Dandy-Walker malformation

and face defects (25%) include facial clefts, encephaloceles, bifid nose, bifid uvula, acromio-mandibular dysplasia, and Apert syndrome. In simple cases, the face appears large, with hypertelorism that may at least in part reflect the separation. Other disorders affect the heart (9%), the pituitary gland (6%), the spine (6%), and the extremities (6%). Neurological (i.e., epilepsy) and/or intellectual deficits are common (54%); in our series of 32 patients, only 2 could be said to be entirely normal, the malformation having been found incidentally for unrelated reasons. This point should be considered when commissural agenesis is discovered antenatally. In summary, the classical complete commissural agenesis is a compound and extensive defect. Beyond the absence of the telencephalic commissures (corpus callosum and hippocampal commissure, anterior commissure in half the cases), major association bundles, such as the cingulum and the intrinsic bundles of the occipital lobe, are also absent. Abnormal organization of the white matter may be present; the callosal and hippocampal commissural fibers are rerouted along the medial aspect of the lateral ventricle, thus forming the “heterotopic” Probst’s bundle, with abnormal intrahemispheric connections. The longitudinal fornices are presumably normal. All abnormalities (failed crossing process, missing cingulum, and missing intrinsic occipital bundles) are located in the medial part of the hemisphere. As no abnormality is observed in the interhemispheric fissure, this points to a histogenetic defect there, that prevented the proper organization of the fibers.

What is meant by “partial commissural agenesis” is difficult to define, and is probably the source of enduring confusion (Fig. 3.5). These disorders probably form an heterogeneous group, with diverse but still uncertain mechanisms. This difficulty has been emphasized by Rubinstein et al. [21]. To overcome at least part of the problem, two groups of partial defects should be distinguished. The term “partial agenesis” can clearly be used to describe cases in which a variable posterior portion of the corpus callosum and of the associated hippocampal commissure is missing, as if it were amputated. The term “partial hypoplasia” should instead be used for the wide spectrum of cases in which the commissural plate is too short but normally shaped, or shows a posterior tapering. This is to assume that an agenesis can be explained by a local failure of the commissuration process, while an hypoplasia, either global or partial, might be due to a more diffuse disturbance of fiber production or guidance. However, this distinction is made more difficult by the possible association of both. Our series of partial defects includes 28 cases. Of these, 15 presented with a typical partial agenesis affecting the splenium/isthmus. A normally shaped but short commissural plate was found in 6. Posterior tapering with a normal anterior commissural plate was found in 5. An extreme hypoplasia with a missing posterior part was found in 2. In the typical partial posterior commissural agenesis, the defect concerns the posterior portion of the commissural plate. Normally, the posterior end of the corpus callosum is made of a more or less rounded splenium located above the collicular plate, surrounded inferiorly and posteriorly by the vein of Galen, right in front of the attachment of the falx cerebri on the tentorium cerebelli. The extent of the partial posterior commissural agenesis may vary in different patients, i.e., the splenium only or the splenium and the isthmus, also a portion of the trunk, or even the whole trunk. In extreme cases, only an hypoplastic genu remains (possibly misinterpreted as an enlarged anterior commissure in the older literature). Together with the posterior corpus callosum, the related portion of the hippocampal commissure is also missing, with a cavum septi pellucidi anteriorly. This may point to a possible morphogenetic mechanism. To build up the splenium, the caudal fibers of the corpus callosum fasciculate along the fibers of the hippocampal commissure. One may assume that the primary defect here would be a missing hippocampal commissure. However, when the agenesis extends also anterior to the isthmus (i.e.,

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a

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Fig. 3.5a–c. Classical, partial commissural agenesis. a Sagittal T1weighted image. The anterior portion of the commissural plate is present and appears essentially normal (arrowheads). The posterior portion, including the posterior corpus callosum and the hippocampal commissure, is lacking. b Coronal T1-weighted 3D RFT image, anterior. Normal appearance of the brain section. c Coronal T1-weighted 3D RFT image, posterior. Appearance typical for a commissural agenesis, including the Probst’s bundles (arrow)

anterior to the hippocampal commissure), one should assume that the defect also affected part of the sling. An unifying alternative would be the existence of common defects of the medial hemispheric wall or of the leptomeninges, preventing both the hippocampal fibers (and the splenial fibers as well) to cross, and the sling to form properly. On midsagittal MR imaging sections, absence of the posterior segment of the commissural plate is obvious. The more the agenesis extends to the trunk of the corpus callosum, the more the septum pellucidum is hypoplastic, often too thick, with the fornices lying close to the present callosal segment. Often, this segment itself is hypoplastic. The rostrum and the lamina rostralis may be hard to identify. The anterior commissure is usually seen, and is sometimes extremely small. On coronal cuts, the brain looks normal where the corpus callosum is present, with separated septal leaves; where the commissures are lacking, the brain looks like a typical agenesis with Probst’s bundles, separated septal leaves, abnormal cortical pattern

of the medial aspect of the hemisphere, and missing cingulum. Both ventricular and white matter abnormalities are less marked than in complete agenesis. Yet, when most of the corpus callosum is missing, the brain looks like it does in complete agenesis except for a narrow callosal bundle above the anterior end of the third ventricle, in front of the foramina of Monro. Associated abnormalities are of the same type as those associated with complete commissural agenesis: migrational disorders, hypothalamo-pituitary defects (20%), visual defects (12%), cerebellar abnormalities, cranial clefts, etc. Epilepsy is common, and the neurologic/intellectual condition of the patients is frequently impaired (92%).

3.4.3 Commissural Agenesis with Meningeal Dysplasia The meninges are closely related to the brain, both anatomically and developmentally. The telencephalic

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meninges are derivatives of the anterior neural crest, together with the membranous skull, among others [54]. In the embryo, the meninx primitiva forms a solid connective tissue that surrounds the brain. At the end of the embryonic period, the meninx primitiva progressively differentiates to produce the compact dura mater by condensation, and the fluid-filled leptomeninges by vacuolization, whereas the fourth ventricle opens in the cisterna magna. The process of vacuolization starts at the ventral mesencephalon and from there proceeds over the entire central nervous system. The last region to differentiate is in the dorsal midline, the region to become the interhemispheric fissure and the velum interpositum [55]. The meninges seem to play a significant role in the development of the central nervous system, first allowing diffusion of nutrients in the embryo and later providing support to the vessels. Together with the Cajal-Retzius cells of the cortical molecular layer, the pial lining of the cortex prevents overmigration of the neuroblasts. In the interhemispheric fissure, the leptomeninges allow the glial sling to form and the hippocampal fibers to cross [42]. The cortex adjacent to a meningeal lipoma developing over the convexity is usually dysplastic [56]. Therefore, dysplasia of the interhemispheric meninges may interfere with the development of the telencephalic commissures. Two types of such dysplasia are commonly encountered: the common multicystic dysplasia of the interhemispheric meninges, and the less frequent interhemispheric lipomas.

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3.4.3.1 Commissural Agenesis with Interhemispheric Meningeal Cystic Dysplasia

The conspicuously frequent association of interhemispheric cysts with a commissural agenesis has been known since the first descriptions of the malformation [18, 57] (Fig. 3.6). It is not rare, accounting for 15% of cases in our series. In spite of the confusing terminology (i.e., arachnoid, neu-

Fig. 3.6a–c. Commissural agenesis with cystic meningeal dysplasia. a Sagittal T1-weighted image. No commissure is seen. There are multiple meningeal cystic, noncommunicating cavities; most are unrelated to the ventricles. Notice concurrent Chiari I malformation. b Axial T2-weighted image. There are multiple interhemispheric cavities. The right lateral ventricle is enlarged, whereas the left lateral ventricle is difficult to identify. The cortex of the medial aspect of the left cerebral hemisphere is dysplastic, with subcortical heterotopia. c Coronal T2-weighted image confirms cystic dysplasia of the interhemispheric fissure. (Case courtesy P. Tortori-Donati, Genoa, Italy)

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roepithelial, diencephalic cysts), these cysts have always been assumed to represent dorsal expansions of roof of the third ventricle, unrestrained in the absence of the overlying commissural plate. Histology in selected cases confirmed this hypothesis by showing tufts of choroid plexus or patches of ependymal lining. All these data rested upon air contrast studies, surgery, or autopsy. With the advent of modern imaging modalities performed without skull opening in large series of patients, things seem to be more complex. To better understand the different situations, a classification has been recently proposed [58]. In all patients presenting with an interhemispheric cyst, commissural agenesis is found. In the vast majority of patients studied with transfontanellar ultrasonography or MR imaging (especially with CSF flow imaging sequences), the cyst appears to be composed of multiple, noncommunicating cavities. This corroborates the neurosurgical observation that a single cystoperitoneal shunt usually fails to evacuate the whole cystic complex. MR studies may also show associated abnormalities of the adjacent dural structures, particularly the falx. The anterior third ventricle may communicate with the nearest cyst, but this is not always the case. Sometimes, the cyst is apparently single and close to, but separate from, the ventricle. In selected cases with follow-up, these cysts enlarge progressively over the years. Fluid shunting is indicated to correct compression of the adjacent brain. The real nature of the cystic walls is uncertain, as no craniotomy is ever performed in these patients. Ancient reports stated that the cysts were of neuroepithelial origin, and at least partly choroidal. The presence of these neuroepithelial tissues in the subarachnoid space cannot be explained by normal embryology. It has been postulated that it could result from abnormal migration into the leptomeninges of the cells of the tela choroidea [22]. However, the ependymal and pial layers that constitute the tela choroidea do not migrate; therefore a differentiation disorder seems more likely. These multiloculated cysts are clearly different from the huge interhemispheric expansion of the tela choroidea of the third and/or of one lateral ventricle, that can rarely be observed in patients with a common commissural agenesis (Fig. 3.7) and, more typically, in rare cases of global septal and commissural agenesis (see below, septocommissural dysplasia). In these, the fluid collection forms a single cavity that is continuous with the ventricle, and draining the cyst produces a global loss of volume of the cystic cavity and of the ventricles.

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c Fig. 3.7a–c. Commissural agenesis with upward expansion of the third ventricle. a Sagittal T1-weighted image shows complete agenesis of the commissural plate associated with expanded midline cerebrospinal fluid-filled space. b Axial T2-weighted image shows uniloculated interhemispheric cavity. The lateral ventricles have a typical parallel course. c Coronal T2-weighted image shows the “cyst” in fact results from upward expansion of the third ventricle. The appearance is otherwise typical for commissural agenesis. (Case courtesy P. Tortori-Donati, Genoa, Italy)

Malformations of the Telencephalic Commissures

Because the mass effect usually distorts the adjacent brain structure, the MR analysis of the hemispheric malformation is difficult. Agenesis of the commissures may be total or partial. The evaluation of the septal leaves, of the fornices, and even of the hippocampi is difficult, and their apparent condition varies from case to case. Shunting does not make this evaluation easier. The presence of the Probst bundles is hard to ascertain, and they may seem to be absent on the side of the cyst while present on the other side. Nevertheless, beyond the commissural agenesis, the brain is obviously dysplastic. The cortex lining the interhemispheric cysts is commonly dysplastic. Subcortical heterotopia are common, sometimes huge, as well as periventricular heterotopias. In some instances, cavities are found within the brain that seem to prolong the extracerebral cysts, but it is difficult to recognize whether such lesions are constitutive or, rather, they result from the deformity induced by the fluid masses. Affected children are usually referred for macrocephaly. Surprisingly, beside the problems with CSF dynamics, many seem to do better neurologically than patients affected with the common type of commissural agenesis. Some, however, are severely disabled, with mental deficits and/or severe epilepsy. Some present the features of the Aicardi syndrome (see below). In summary, it seems likely that interhemispheric multiloculated cysts are due to dysplasia of the interhemispheric meninges, and that this dysplasia might interfere with the development of the commissures and of the adjoining cortex. The mechanism of the frequent coexistence of subcortical gray matter heterotopia is uncertain. All these relate to different periods of the histogenesis, i.e., probably the 10th–12th week for the interhemispheric meninges, 8th–20th week for the gray matter heterotopia, and 18th–23rd week for the cortical dysplasia, although all abnormalities must obviously proceed from a common initial disorder. The Aicardi Syndrome

The Aicardi syndrome [59] was defined as an association of asymmetrical infantile spasms, agenesis of the corpus callosum, and chorioretinal lacunae, found in infant girls (Fig. 3.8). Since the first report, progresses with imaging have shown that, other than nonspecific commissural agenesis, the brains of affected patients always show a whole set of more characteristic, almost constant “migrational” disorders, including subcortical and periventricular nodular heterotopia, as well as cortical

polymicrogyria. Eye colobomas are also common. Single or multiple cyst formation in the choroid plexuses, especially in the ventricular atria and in the region of the posterior third ventricle, is characteristic, with a signal different from that of CSF expressing the absence of continuity with the subarachnoid space. These cysts have been reported to be of ependymal origin [59]. Other cysts may develop within the brain or in the posterior fossa. The incidence of the Aicardi syndrome is uncertain, perhaps accounting for 4% of infantile spasms. The prognosis is poor, with severe neurologic and mental impairment, persisting epilepsy, and a 40% survival rate at 15 years. Classification Proposals

Facing the obvious heterogeneity of these malformations, several authors have attempted to classify them. The simplest classification is that of Probst [18] who, using data from pneumoencephalography, simply distinguished between communicating and noncommunicating cysts. In 1998, using more detailed data from MR imaging, we proposed three types of malformations according to the nature of the meningeal and parenchymal dysplasias [1]: ● Type

1: the cysts are simple ventricular expansions, and therefore considered as hydrodynamic variants of the classical commissural agenesis. ● Type 2: a complex, multicystic meningeal dysplasia is associated with gray matter heterotopia and cortical dysplasias bordering the cystic cavity, together with the commissural agenesis. ● Type 3: the cysts are located not only in the meninges, but also within the parenchyma; they are dysgenetic or perhaps destructive, associated with gray matter heterotopia and cortical dysplasias (this type might include the Aicardi syndrome). In 2001, Barkovich et al. proposed a more detailed classification comprising two main groups, each with three subdivisions [58]: ● Type

1: the cyst is a diverticulation of the third and/or the lateral ventricle. This group is further subdivided into three subgroups: – Subtype 1a: macrocephaly, ventricular dilatation related to a simple communicating hydrocephalus, with or without Dandy-Walker malformation, parietal meningocele or falx hypoplasia; the corpus callosum is totally or partially absent. This group seems to concern boys only. – Subtype 1b: macrocephaly and hydrocephalus

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d Fig. 3.8a–d. Aicardi syndrome. a Sagittal T1-weighted image. The commissural plate is absent. There is a thick interthalamic mass (IM) and an interhemispheric cavity (asterisk). b Axial T1-weighted image. There is right microphthalmos with congenital cataracts. The interhemispheric cavity is also displayed (asterisk). c Axial T2-weighted image. There is diffuse cortical dysplasia involving both frontal lobes, albeit more markedly to the left. This dysplasia shows a variable combination of subependymal heterotopia, subcortical heterotopia, and polymicrogyria. The ventricles are distorted. d Coronal T1-weighted image. The frontal horns have a crescentic shape due to absence of the corpus callosum. However, there is distortion of the ventricles due to concurrent cortical dysplasia. (Case courtesy M. Rutherford, London, UK)

related to thalamic fusion; callosal agenesis is complete or partial; the falx is absent, or deficient in relation to meningoceles. This group raises the problem of the differential diagnosis with the holoprosencephaly spectrum, although thalamic fusion was not felt to be specific to this malformation.

– Subtype 1c: microcephaly (instead of macrocephaly), complete callosal agenesis, inferior vermian hypogenesis and brainstem kinking, cyst involving the tela choroidea of both the third and the lateral ventricles, unilaterally. This category could be related to either cerebral dysgenesis or a prenatal destructive process.

Malformations of the Telencephalic Commissures

● Type 2: the cysts are multiloculated and intraparenchymal. Three subtypes again are observed: – Subtype 2a: macrocephaly, multiloculated cysts with no associated brain anomaly other than callosal agenesis. – Subtype 2b: macrocephaly, multilocular cysts, callosal agenesis, polymicrogyria, and subependymal heterotopia. All patients are female. The cysts presumably do not communicate with the free CSF (showing different signal). The morphologic abnormalities of the Aicardi syndrome may fit into this subtype, as does the fact that all patients are female. – Subtype 2c: Multilocular, noncommunicating cysts, callosal agenesis, subcortical heterotopias (cerebellar cortical dysplasia in one case). 3.4.3.2 Commissural Agenesis with Interhemispheric Lipomas

Interhemispheric lipomas associated with commissural agenesis have been known for a long time, and the causal relationship between these abnormalities has been much debated (Fig. 3.9). Verga in 1929 [60] was the first to assume that meningeal lipomas, instead of being dysraphic inclusions, fatty tumor, meningeal degeneration, or misplaced heterotopia, were a maldifferentiation of the meninx primitiva. Truwit and Barkovich [61] carefully reviewed the arguments in favor of Verga’s hypothesis: the subarachnoid location, the absence of other mesodermal derivatives, and the intralesional location of vessels (often dysplastic) and nerves. This early meningeal dysplasia may presumably interfere with the development of the brain, and especially of the commissures, but the mechanism is uncertain. The hypothesis of the lipoma being a mechanical obstacle to posterior growth of the commissural plate is unlikely, as there are anterior lipomas associated with posterior partial commissural agenesis, or lipomas intermingled within callosal fibers. Yet, there is a relationship between the location of the lipoma and the commissural defect. It appears that anterior, bulky (i.e., tubulonodular) lipomas are more often associated with gross agenesis whereas smaller, posterior ribbonlike (i.e., curvilinear) lipomas are associated with more subtle commissural hypoplasia. This may be related to the time when the dysplasia occurred, in relation to the timing of the commissural development. Clinically, patients with anterior, bulky lipomas are more severely disabled than those with more posterior curvilinear lipomas [62]. Concurrent lipomas or extensions of the main lipoma may involve the choroid plexuses. Calcifications are relatively common. Angiography would show arterial dysplasias in the lipomatous segment of

the arteries. The lipoma is not a tumor, and therefore it does not expand. However, it does enlarge during the first weeks of life together with the physiological development of the body fat of the young infant. These midline lipomas are not common, accounting for 3% of our whole series of commissural defects. The most usual presenting feature is epilepsy, typically partial; some mental deficit and, on occasion, a cranio-facial malformation may be observed.

3.4.4 Agenesis of a Single Commissure These infrequent forms of commissural agenesis are not always diagnosed as such (i.e., agenesis of the hippocampal commissure is read as “persistent cavum septi pellucidi”), or are not diagnosed with anatomic certainty. It may be assumed that the causal defect is specific to the commissure concerned, or to its own particular commissuration mechanisms, and not to the general commissuration processes. A careful assessment of the anatomic features should be obtained though appropriate imaging sequences and planes. 3.4.4.1 Isolated Agenesis of the Anterior Commissure

Isolated agenesis of the anterior commissure is rare (3% of all commissural ageneses) (Fig. 3.10). The abnormality is obvious on the midline sagittal plane, where the commissure is not seen in the upper part of the lamina terminalis. It should be confirmed in axial and coronal planes as well, with thin, contiguous slices. On axial cuts, the anterior columns of the fornix are visible, but are widely splayed and lack the transverse anterior commissural band (neither the handle-bar of the Dutch bicycle nor the letter π). On coronal cuts, the commissure arching between the amygdaloid nuclei is not seen, whereas the leaves of the septum pellucidum diverge, the columns of the fornices staying wide apart. The rostrum and the lamina rostralis of the corpus callosum may be also abnormal, with a deformity of the corpus callosum. The clinical picture associates epilepsy and developmental delay. 3.4.4.2 Isolated Agenesis of the Hippocampal Commissure

Careful reading of the anatomic features of the commissures shows that a significant number of patients diagnosed at a first look as having a “persisting cavum septi pellucidi” actually lack a hippocampal commissure (Fig. 3.11). The idea of a “normal”

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e Fig. 3.9a–e. Commissural agenesis with interhemispheric lipoma. Three different cases. a Curvilinear lipoma in a 17-year-old girl. Sagittal T1-weighted image. There is a thin stripe of fatty tissue surrounding a mildly hypoplastic corpus callosum (arrows). b–d Tubulonodular lipoma. b Sagittal T1-weighted image at age 3 months shows lipoma overlying a thin, dysplastic corpus callosum. c Sagittal T1-weighted image at age 3 years shows the lipoma has significantly enlarged. The dysplastic corpus callosum also is thicker after completion of myelination. d Coronal T1-weighted image shows extension of the lipoma into both lateral ventricles. e Tubulonodular lipoma. Sagittal STIR image. The lipoma was associated with an anterior cranial cleft. It likely represents a meningeal dysplasia, which in turn may explain the commissural agenesis. As the lipoma is anterior, its action in preventing the callosal development was not simply mechanical. (a–d courtesy P. Tortori-Donati, Genoa, Italy)

Malformations of the Telencephalic Commissures

a

b Fig. 3.10a,b. Isolated agenesis of the anterior commissure. a Midsagittal T1-weighted 3D RFT image. Absence of the anterior commissure is associated with defect of the anterior corpus callosum, appearing somewhat small. b Coronal T1-weighted image. No image of the anterior commissure is seen between the amygdaloid nuclei. Diverging septal leaves as the fornices have lost the usual relationship with the commissure

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d Fig. 3.11a–d. Isolated agenesis of the hippocampal commissure. a Midsagittal T1-weighted 3D RFT image. Arched appearance of the corpus callosum; the fornix is not seen. b–d Consecutive coronal T1-weighted 3D RFT images cuts from the front to the back of the corpus callosum. Persisting space between the septal leaves (asterisk, b–d), which could be misread as a “persisting cavum septi pellucidi.” In fact, the fornices can be followed to the posterior part of the crura (arrows), and no transverse hippocampal commissure is found

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persisting cavum stems from the common finding in neonates of a nonfusion of the septal leaves (see above). However, in these normal neonates a close analysis of the posterior part of the commissural plate shows the transverse velum of the hippocampal commissure crossing below the posterior corpus callosum. On the contrary, in a significant number of older patients in whom the septal leaves are widely apart, no hippocampal commissure can be identified. Anteriorly, the fornices are separated as the septal leaves are. Posteriorly, the same pattern is found, with the septal leaves extending as far back as to the splenium, away from each other and perpendicular to the lower surface of the corpus callosum. On a midline sagittal cut, the appearance is still more striking, as no image of the fornix is found interposed between the corpus callosum and the third ventricular roof. Among our six patients (6% of cases), neurodevelopmental deficits were observed in five. In one of them there also was diencephalo-mesencephalic dysplasia, and the patient suffered with growth delay. In another, there was associated cortical dysplasia. These considerations imply that, in opposition to the classical ideas dating back to pneumoencephalography era, this is neither a persistent cavum septi pellucidi nor a normal variant, but a true developmental defect. This corroborates the fact that such feature was commonly observed in mentally retarded or epileptic patients [63]. The agenesis of such an important structure is more likely to explain this type of clinical feature. Identifying the hippocampal commissure, or on the contrary ascertaining its absence, is therefore extremely important while evaluating these patients. From an embryological point of view, agenesis of the hippocampal commissure without agenesis of the posterior portion of the corpus callosum is problematic in that, according to normal embryological data, the posterior corpus callosum requires a pre-existing hippocampal commissure to fasciculate. Possibly, callosal fibers are able to cross without the support of the hippocampal fibers, perhaps because the glial sling would extend posteriorly. In two additional patients, we found a combination of agenesis of both the anterior and the hippocampal commissure. These patients also had midline defects, pelvic disorders, developmental delay, and convulsions. 3.4.4.3 Isolated Agenesis of the Corpus Callosum

There are instances in which only the corpus callosum is missing, whereas the hippocampal commissure is present [1, 64] (Fig. 3.12). Such cases are commonly

a

b Fig. 3.12a,b. Isolated agenesis of the corpus callosum. a Midsagittal T1-weighted 3D RFT image. An hypoplastic lamina of white matter (arrows) is seen extending backwards from the region of the foramen of Monro, above the roof of the third ventricle. It could be misread as an hypoplastic corpus callosum, but its location is too low with respect to the medial hemispheric cortex. b Coronal T1-weighted 3D RFT image. The appearance of the brain is close to that of a complete commissural agenesis, except that the transverse lamina of the hippocampal commissure (arrowheads) is seen extending between the two fornices (open arrow), and not above where a normal corpus callosum should be. The callosal bundles indeed are present but form typical Probst’s bundles (black arrow). Only this variety of commissural disorder truly deserves the name of callosal agenesis

misread as hypoplastic corpus callosum, but a careful analysis of the anatomy corrects the diagnosis. This malformation is not frequent: it accounts for 11% of our material, the corpus callosum being totally (3%) or only partially (8%) agenetic. In the complete isolated agenesis of the corpus callosum (viz. with normal anterior and hippocampal commissures), the interhemispheric fissure is large, and the lateral ventricles are away from each other, in a way similar to complete commissural agenesis. Yet, on a midline sagittal cut, a band of white matter extends posteriorly from the upper lamina terminalis. It is located too low to be a corpus callosum, just above the roof of the third ventricle (from which it is separated by the normal cistern of the velum interpositum), but not above the foramina of Monro: this cannot correspond to the proper location of the corpus

Malformations of the Telencephalic Commissures

callosum. The coronal cuts are more explicit, in that the lateral ventricles are closed by the usual medial leaf of septal white matter, containing the Probst’s bundle above and the longitudinal fornix below. The interhemispheric band of white matter of the hippocampal commissure crosses the midline from one fornix to the other, in its right position. Partial segmental agenesis of the corpus callosum is not so uncommon, although still undescribed in the classical literature to our knowledge. We have seen it in eight patients (8% of our cases). It affects the midportion of the corpus callosum, the splenium being present. As the corpus callosum is said to develop from the front to the back, this defect of its middle portion is usually assumed to be destructive: for instance, bilateral posterior frontal schizencephalic clefts, or bilateral anoxic necrosis of the sensorimotor area in the neonate, may produce a closely related appearance. However, the segmental agenesis of the corpus callosum with preservation of the splenium can be observed in patients showing no other brain abnormality, and especially without destructive lesions likely to have affected the callosal fibers. Moreover, we have observed it in two siblings presenting the same clinical features (isolated spasticity of the lower limbs with normal intelligence). This familial occurrence with quite identical brain images obviously suggests a developmental origin; both exhibited a defect of the median portion of the corpus callosum (Fig. 3.13) with a preserved genu and a present, albeit hypoplastic, splenium. On coro-

nal cuts, the images of the brain were normal anteriorly and posteriorly, but at the level of the defect, the appearance was the same as that of complete callosal agenesis: no callosal fibers but a patent hippocampal commissure extending from one fornix to the other. No associated parenchymal dysplasia (especially without schizencephalic cleft) or gliotic scar was found. Six other similar nonfamilial cases have been seen. In one, the hippocampal commissure was also interrupted. In two there also was a small corresponding defect in the septum pellucidum. It should be noted that the clinical conditions of these patients may not be good; neurodevelopmental, visual, or endocrine disorders were observed in seven patients out of eleven (obviously there may be a referral bias). In view of the modern embryological data, this type of malformation is not in contradiction to developmental rules. The normal corpus callosum indeed develops from front to back; however, this occurs in two portions, first over the glial sling, then by fasciculation along both the pioneer frontal fibers and the hippocampal fibers. Obviously, the developmental defect prevented a normal fasciculation over the anterior hippocampal commissure, whereas the posterior splenium did develop more appropriately. According to this scheme, even an isolated splenium, without any corpus callosum, is conceivable. Conversely, in the typical partial posterior commissural agenesis, there is no posterior corpus callosum because there are no hippocampal fibers along which to fasciculate.

3.4.5 Other Commissural Defects Hypoplasia, Complete or Partial, Isolated or Associated with Agenesis

Fig. 3.13. Isolated partial agenesis of the corpus callosum with the splenium present. Midsagittal T1-weighted 3D RFT image. There is a defect of the posterior part of the callosal trunk (arrows). It is typically assumed to result from a destructive lesion in the hemispheres, but nothing abnormal was found in this group of patients, and a sibling of the patient illustrated here presented an identical defect. This is presumed to result from a defective development of the posterior portion of the callosal segment that uses the glial sling to cross, while the splenial fibers could fasciculate normally along the hippocampal commissure

This condition, in which the commissures are exceedingly small, is found in patients with an otherwise normal-looking brain, and is commonly observed in children investigated for neurodevelopmental delay. It may also be observed in association with partial commissural agenesis (Fig. 3.14). This entity is probably developmental, and should not be confused with atrophy of the commissures which is part of a global cerebral atrophy, or a result of a periventricular destructive process such as a periventricular leukomalacia. Hyperplasia

A hyperplastic, or rather an ill-shaped, thick corpus callosum lacking its normally well-delineated seg-

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sive telencephalic disorder. The corpus callosum is absent in some subgroups of lissencephalies. It may be thick and ill-shaped, or on the contrary thin, especially in cases of polymicrogyria (therefore likely to be destructive) or of microlissencephaly, of massive heterotopia, etc.

3.4.6 Septo-Commissural Dysplasia

Fig. 3.14. Global commissural hypoplasia. Sagittal T1-weighted 3D RFT image. Global hypoplasia of the commissures is here associated with posterior agenesis, affecting the corpus callosum more than the hippocampal commissure. Note associated Dandy-Walker malformation with communicating cyst

ments may be observed in some cases of neurofibromatosis type 1 (see Chap. 16). Its clinical significance is unclear. Also, a “fat,” often short corpus callosum is observed in some instances of pachygyria. This may possibly be attributed to a failure of the normal pruning process [39, 47] of the commissural fibers during the early childhood development. Finally, an enlarged corpus callosum is found in patients with Cohen syndrome, an autosomal recessive disorder showing nonprogressive psychomotor retardation, motor clumsiness and microcephaly, typical facial features, childhood hypotonia and hyperextensibility of the joints, ophthalmologic findings of retinochoroidal dystrophy and myopia in patients over 5 years of age, and granulocytopenia [65]. Dysplasia

Various types of dysplastic commissures are observed that have not been classified, in a variety of clinical conditions [22]: hypoplastic septum pellucidum with the fornix attached to the corpus callosum, thick septum pellucidum, either bilateral or unilateral. In hemimegalencephalies, a septal and commissural dysplasia associated with septal displacement toward the affected hemisphere is relatively common. Defects Associated with Gross Dysplasia of the Brain

Abnormalities of the corpus callosum are observed in association with massive dysplasias of the cerebral cortex [22]. They are not specifically studied in this chapter, as they are only part of a more mas-

It may seem surprising to include septo-optic dysplasia (or De Morsier syndrome) in a text on commissural agenesis. More usually, septo-optic dysplasia is assumed to be somewhat related to the groups of the holoprosencephalies [66] (see Chap. 4). Yet, there are reasons for doing so. Modern embryology demonstrates that commissural fibers cross at the level of the septum pellucidum [43, 44]. In our material, we found some anatomical and clinical overlap between septo-optic dysplasia and commissural agenesis. In our series of 18 cases of septo-optic dysplasia, total or partial commissural agenesis was observed in six. Moreover, both disorders have some of their associated features in common: among 99 cases of commissural agenesis, visual abnormalities were found in 12% (21% in case of complete agenesis), and endocrine disorders in 9% (personal data). The typical septo-optic dysplasia was first described histologically in 1956 by De Morsier [67], with more recent histological and radiological descriptions [66, 68, 69]. Its features include dysplasia of the hypothalamus, defective or absent septum pellucidum, and abnormal, atrophic or malformative anterior optic pathways. The MR imaging diagnosis is relatively easy (see Chap. 4); the septum pellucidum is entirely absent, or only a rudimentary portion is present anteriorly. Because the septum is absent, the fornix, often bulky, is not tethered to the inferior surface of the corpus callosum, and its course, straight or even concave superiorly, is well below it over the roof of the third ventricle, which itself is lowered. This is clearly visible on sagittal as well as on coronal cuts throughout the brain. In about half the cases, optic atrophy can be diagnosed from the small section of the optic chiasm on the midline sagittal cut. However, it should be confirmed with ophthalmoscopy. In four out of 18 cases from our series, an associated partial agenesis of the commissures (posterior corpus callosum and hippocampal commissure) was found. The splenium was missing in three, and the genu in one. This association does not seem to bear a poorer prognosis. In two cases (plus another one

Malformations of the Telencephalic Commissures

diagnosed in utero) there was a complete septo-commissural agenesis, represented by complete absence of commissures, as well as complete absence of the septal laminae (Fig. 3.15). The inner wall of the lateral ventricles is made of a membrane (tela choroidea?), which on one side may expand between the hemispheres and typically produces a huge interhemispheric cyst in continuity with the ventricular lumen at the atrium. This complex malformation has been initially reported by Sener in 1993 [70].

Fig. 3.15. Complete septo-commissural agenesis. a Coronal T1weighted image. No commissure is seen, no septal leaves, no Probst’s bundles, no fornix or hippocampal commissure. The right lateral ventricle is closed by a (choroidal?) membrane that extends from the lower margin of the medial cortex of the hemisphere to the dorsal aspect of the thalamus. On the left, large cystic expansion of the left ventricular atrium

3.4.7 The Case of the Commissure in Lobar Holoprosencephaly Holoprosencephaly is classically defined as a failure of development of the telencephalon. In the complete form (alobar holoprosencephaly), the single anteriorsuperior telencephalic vesicle remains undifferentiated from the diencephalon. The thalami and basal ganglia form a single basal mass. There is also a single ventricular cavity (instead of two lateral and a third ventricles), and therefore no septum pellucidum. However, in the same way as there is a posterior medullary velum bordering the posterior-inferior aspect of the cerebellum between the cerebellar cortex and the fourth ventricular choroid plexus, there may be a posterior medullary velum interposed between the holoprosencephalic cortex and the holoprosencephalic tela choroidea.

In the most differentiated form of holoprosencephaly (lobar holoprosencephaly), the two hemispheres have developed nicely except for a cortical continuity across the midline in their median portion. As in the more severe form, there is only one ventricle with no septum pellucidum and no apparent fornix associated to it; yet, the hippocampi, albeit abnormal, are present, well-differentiated, and have a fimbria. A bulky posterior bundle of white matter crosses the interhemispheric fissure from one side to the other behind the trans-hemispheric cortex, looking like a true splenium [69]; quite often, a similar commissure develops between the frontal lobes, but without continuity with the splenium. It has been hypothesized [71] that a well-developed interhemispheric fissure is necessary, and perhaps sufficient, for the development of a corpus callosum. In lobar holoprosencephaly with a normal division of most of the frontal lobes and of the occipito-temporal lobes, the normal interhemispheric meninges would initiate and/or allow the crossing of commissural fibers. It is certain that the meninges play a role for the crossing of the fibers and as a support for the glial sling (see above for embryology). In the frontal lobes, the specific leading glial cells of the medial portion of the frontal germinal matrix might differentiate, migrate, and build up the sling. However, this specific germinal matrix is located on the medial aspect of the frontal horns, which are fused even in the mildest form of holoprosencephaly. Therefore, other sites of origin have to be postulated. The mechanism of formation of the posterior splenium is possibly straightforward and simpler. It should be considered according to the peculiar anatomy of the holoprosencephalies. As indicated before, a medullary velum is interposed between the margin of the cortex and the tela choroidea, in the continuity of the fimbria which carries the outgoing fibers of the hippocampus. In an holoprosencephalic brain, this medullary velum follows the limit of the holoprosencephalic cortex, crossing the interhemispheric fissure behind it. The fibers it contains cannot be considered analogous to the columns of the fornix, as they are not directed toward the septal area or the mammillary bodies. However, they may well be considered to be the fibers of the hippocampal commissure. As in normal development, they may be used by the posterior callosal fibers to fasciculate toward the other side. Assuming that this model is valid, the “splenium-like” bundle of crossing white matter observed in lobar holoprosencephalies can be considered to be the true splenium of the corpus callosum.

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3.5 Conclusions Commissural (so-called “callosal”) agenesis can be re-evaluated thanks to the large clinical series and precise anatomic assessment allowed by modern imaging modalities. Several groups of malformations, likely to result from different mechanisms, can be identified. Morphologically, they can be represented by relatively simple schemes (Fig. 3.16). 1. The group of the common commissural agenesis, the most typical one (50%–60% of the cases), is characterized by a defect involving part, or the whole, of several commissures (callosal and hippocampal commissures always, anterior commissure less frequently), as well as major white matter bundles in the medial wall of the cerebral hemispheres. These abnormalities concern the brain parenchyma only, and spare the meninges; however, malformations of the skull may be associated. 2. In contrast, in a second group of about 15% of cases, multiple commissural agenesis is associated with major meningeal abnormalities in the interhemispheric fissure. In most instances, these abnormalities represent a multicystic dysplasia of the meninges. Other than the complete or

a

b

d

e

partial commissural defect, the brain malformation includes a dysplasia of the cortex bordering the meningeal cysts, gray matter heterotopia, and occasionally apparent parenchymal cavitations. It seems reasonable to assume that, in this form, the causal disorder can be extraparenchymal, within the interhemispheric meninges. Although different, the association of interhemispheric dysplastic meningeal lipomas with commissural defects may imply a similar mechanism. 3. A third group is composed of cases in which only one commissure is missing; this obviously points to an intrinsic defect of that commissure. The defect may concern either the anterior commissure, or the hippocampal commissure, or the corpus callosum, totally or in part. 4. A fourth group includes cases in which the commissures are present, but have an abnormal morphology, without any other abnormality of the brain. Most commonly, they are globally too small, but in other instances only the posterior or the anterior part fails to develop. This is, by definition, developmental, and should be differentiated from atrophic lesions. In neurofibromatosis type 1, on the contrary, the commissures may appear too thick. Although major abnormalities of cortical develop-

c

Fig. 3.16a–e. Schematic summary of commissural and septal abnormalities. a Complete commissural agenesis: no corpus callosum, no hippocampal commissure. The callosal fibers form a thickening in the upper portion of the septal laminae (the Probst’s bundles), and the longitudinal fornices form their lower margin. b Encysted cavum septi pellucidi/cavum Vergae. Cerebrospinal fluid accumulates in the normally absent space enclosed between the septal leaves and the commissures. c Isolated agenesis of the corpus callosum with the hippocampal commissure present. d Isolated agenesis of the hippocampal commissure with the corpus callosum present. e Isolated agenesis of the septal leaves with the corpus callosum and the hippocampal commissure present (typical septo-optic dysplasia)

Malformations of the Telencephalic Commissures

ment have been excluded from this study, it should be mentioned that such instances of dysmorphic commissures are common in agyria/pachygyria and in polymicrogyria. 5. Finally, the possible association of partial or complete commissural agenesis in cases of septo-optic dysplasias raises the problem of a possible continuity between the two groups of malformations, especially as visual and hypothalamo-pituitary disorders are quite frequent in both. In the same way, this could also apply to holoprosencephalies, as a fusion of the anterior basal ganglia may be observed in commissural agenesis. All three types of malformations are concerned with the genetic processes of basal induction and dorsal interhemispheric differentiation. This classification is purely descriptive, and although it points to a general “location” for the causal disorders (intracerebral versus meningeal, multi- or unicommissural defect, isolated or associated with other cerebro-meningeal disorders), it does not assign a single specific, causal mechanism for each group. For example, the commissuration of the corpus callosum implies, among others, the formation of the sling anteriorly, the fasciculation with the hippocampal fibers posteriorly, and an anatomical relationship with the septum pellucidum. Yet, absence of the septum does not prevent the formation of normal commissures in septo-optic dysplasia. The classical types of commissural agenesis, either total or partial, may logically be related to a guidance defect intrinsic to the medial wall of the hemisphere, given that other intrahemispheric fiber tracts are concerned as well. Reciprocally, the presence of huge dysplastic abnormalities of the interhemispheric meninges may be sufficient to prevent the crossing of the commissures. Hippocampal and callosal fibers may cross independently (isolated callosal agenesis, and conversely, isolated agenesis of the hippocampal commissure; septo-optic dysplasia), although they normally fasciculate together. With the multiplicity of factors involved in the commissuration processes, a multiplicity of single or associated defects may explain such diverse phenotypes. Encouragingly, the accumulation of embryologic data in the last decades has, on the whole, confirmed the primordial paper of Rakic and Yakovlev [17], but also brought much additional information. Moreover, the links between commissural agenesis, septo-optic dysplasia, and at least some types of holoprosencephaly may become further elucidated with the accumulation of knowledge on the role of the genes controlling the complex development of the derivatives of the anterior neural plate.

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pal commissure in embryos from mouse strains lacking a corpus callosum. Hippocampus 1997; 7:2–14. 43. Shu T, Richards LJ. Cortical axon guidance by the glial wedge during the development of the corpus callosum. J Neurosci 2001; 21:2749–2758. 44. Shu T, Butz KG, Plachez C, Gronostzjski RM, Richards LJ. Abnormal development of forebrain midline glia and commissural projections in Nfia knock-out mice. J Neurosci 2003; 23:203–212. 45. Kostovic I, Rakic P. Developmental history of the transient subplate zone in the visual and the somatosensory cortex of the macaque monkey and human brain. J Comp Neurol 1990; 297:411–470. 46. O’Leary DDM, Stanfield BB, Cowan WM. Evidence that the early postnatal restriction of the cells of origin of the callosal projection is due to the elimination of axonal collaterals rather than to the death of neurons. Develop Brain Res 1981; 1:607–617. 47. Kadhim HJ, Bhide PG, Frost DO. Transient axonal branching in the developing corpus callosum. Cerebral Cortex 1993; 3:551–566. 48. Serafini T, Colamarino SA, Leonardo ED, Wang H, Beddington R, Skarnes WC, Tessier-Lavigne M. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 1996; 87:1001–1014. 49. Qiu M, Anderson S, Chen S, Meneses JJ, Hevner R, Kuwana E, Pedersen RA, Rubenstein LR. Mutation of the Emx-1 Homeobox Gene Disrupts the Corpus Callosum. Dev Biol 1996; 178:174–178. 50. Flanagan JG, Van Vactor D. Through the looking glass: axon guidance at the midline choice point. Cell 1998; 92:429–432. 51. Lanier L, Gates MA, Witke W, Menzies S, Wehman AM, Macklis JD, Kwiatkowski D, Soriano P, Gertler FB. Mena is required for neurulation and commissure formation. Neuron 1999; 22:313–325. 52. Norman MG, McGillivray BC, Kalousek DK, Hill A, Poskitt KJ. Congenital Malformations of the Brain. New York: Oxford University Press, 1995:309–331. 53. Quigley M, Cordes D, Turski P, Moritz C, Haughton V, Seth R, Meyerand ME. Role of the corpus callosum in functional connectivity. AJNR Am J Neuroradiol 2003; 24:208–212. 54. Couly GF, Le Douarin NM. Mapping of the early neural primordium in quail-chick chimeras. II. The prosencephalic neural plate and neural folds: applications for the genesis of cephalic human congenital anomalies. Dev Biol 1987; 120:198–214. 55. Osaka K, Handa H, Matsumoto S, Yasuda M. Development of the cerebrospinal fluid pathways in the normal and abnormal embryos. Childs Brain 1980; 6:26–38. 56. Britt PM, Bindal AK, Balko MG, Yeh HS. Lipoma of the cerebral cortex: case report. Acta Neurochir (Wien) 1993; 121:88–92. 57. Zingesser L, Schechter M, Gonatas N, Levy A, Wisoff H. Agenesis of the corpus callosum associated with an interhemispheric cyst. Brit J Radiol 1964; 37:905–909. 58. Barkovich AJ, Simon EM, Walsh CA. Callosal agenesis with cysts. A better understanding and new classification. Neurology 2001; 56:220–227. 59. Aicardi J. Aicardi syndrome. In: Guerrini R, Andermann F, Canapicchi R, Roger J, Zifkin BG, Pfanner P (eds) Dysplasias of Cerebral Cortex and Epilepsy. Philadelphia: Lippincott Raven, 1996:211–216. 60. Verga P. Lipoma ed osteolipomi della piamadre. Tumori 1929; 15:321–357 (quoted by Truwit and Barkovich, 1990).

Malformations of the Telencephalic Commissures 61. Truwit CL, Barkovich AJ. Pathogenesis of intracranial lipomas: an MR study in 42 patients. AJNR Am J Neuroradiol 1990; 11:665–674. 62. Tart RP, Quisling RG. Curvilinear and tubulonodular varieties of lipoma of the corpus callosum: an MR and CT study. J Comput Assist Tomogr 1991; 15:805–810. 63. Bodensteiner JB, Schaefer GB. Wide cavum septum pellucidum: a marker of disturbed brain development. Pediatr Neurol 1990; 6:391–394. 64. Barkovich AJ. Apparent atypical callosal dysgenesis: analysis of MR findings in six cases and their relation to holoprosencephaly. AJNR Am J Neuroradiol 1989; 11:333–339. 65. Kivitie-Kallio S, Autti T, Salonen O, Norio R. MRI of the brain in the Cohen syndrome: a relatively large corpus callosum in patients with mental retardation and microcephaly. Neuropediatrics 1998; 29:298–301. 66. Fitz CR. Holoprosencephaly and septo-optic dysplasia. Neuroimag Clin N Am 1994; 4:263–281.

67. De Morsier G. Agénésie du septum lucidum avec malformation du tractus optique. La dysplasie septo-optique. Schweiz Arch Neurol Psychiat 1956; 77:267–292. 68. Roessmann U, Velasco ME, Small EJ, Hori A. Neuropathology of “septo-optic dysplasia” (de Morsier syndrome) with immunohistochemical studies of the hypothalamus and pituitary gland. J Neuropathol Exp Neurol 1987; 46:597– 608. 69. Barkovich AJ, Fram EK, Norman D. Septo-optic dysplasia: MR imaging. Radiology 1989; 171:189–192. 70. Sener RN. Septo-optic dysplasia associated with total absence of the corpus callosum: MRI and CT features. Eur Radiol 1993; 3:551–553. 71. Oba H, Barkovich AJ. Holoprosencephaly: an analysis of callosal formation and its relation to development of the interhemispheric fissure. AJNR Am J Neuroradiol 1995; 16:453–460.

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Brain Malformations

4

Brain Malformations Paolo Tortori-Donati, Andrea Rossi, and Roberta Biancheri

CONTENTS Introduction

4.3.5

72

4.1

Cephaloceles 72

4.1.1 4.1.2 4.1.3 4.1.4 4.1.5

Background 72 Embryology 74 Clinical Features 74 Classification and Neuroradiological Features 75 Syndromes Associated with Cephaloceles 82

4.2

Defects of the Mediobasal Prosencephalon

Holoprosencephalies and Related Entities 4.2.1 4.2.1.1 4.2.1.2 4.2.1.3 4.2.1.4 4.2.1.5 4.2.2

86

4.2.2.1 4.2.2.2 4.2.2.3 4.2.3 4.2.3.1 4.2.3.2 4.2.3.3 4.2.3.4 4.2.4 4.2.4.1 4.2.4.2

Holoprosencephaly 86 Background 86 Embryogenesis and Pathogenetic Theories 87 Clinical Features 88 Associated Conditions 88 Imaging Studies 89 Syntelencephaly (Middle Interhemispheric Holoprosencephaly) 92 Background 92 Pathogenesis and Relationship with HPE 93 Imaging Findings 94 Septo-Optic Dysplasia 95 Background 95 Pathogenesis 95 Clinical Findings 96 Imaging Findings 96 Kallmann Syndrome 97 Background 97 Pathogenesis 99

4.3

Malformations of Cortical Development

4.3.1 4.3.2 4.3.3 4.3.4 4.3.4.1 4.3.4.2 4.3.4.3 4.3.4.4 4.3.4.5 4.3.4.6 4.3.4.7

100

Background 100 Normal Cortical Development 100 Classification of MCD 103 Malformations Due to Abnormal Neuronal/Glial Proliferation or Apoptosis 103 Microcephaly 103 Microlissencephaly 105 Megalencephaly 106 Tuberous Sclerosis Complex 108 Focal Transmantle Dysplasia (Taylor’s Focal Cortical Dysplasia) 108 Hemimegalencephaly 112 Neoplasms 116

4.3.7.1 4.3.7.2 4.3.7.3

Malformations Due to Abnormal Neuronal Migration 116 Lissencephalies 116 The Cobblestone Complex 121 Heterotopia 126 Malformations Due to Abnormal Cortical Organization 130 Polymicrogyria 130 Schizencephaly 134 Non-Taylor’s Focal Cortical Dysplasia (Architectural and Cytoarchitectural) 136 Malformations of Cortical Development, not Otherwise Classified 138 Zellweger Syndrome 138 Mitochondrial Disorders 138 Sublobar Dysplasia 138

4.4

Malformations of the Posterior Cranial Fossa

4.4.1 4.4.2 4.4.3 4.4.3.1 4.4.3.2 4.4.3.3 4.4.3.4 4.4.3.5 4.4.4 4.4.4.1 4.4.4.2 4.4.4.3

Embryology 138 Classification of Malformations 140 Cystic Malformations 142 Dandy-Walker Malformation 142 Dandy-Walker Variant 146 Persistent Blake’s Pouch 147 Mega Cisterna Magna 150 Arachnoid Cysts 152 Noncystic Malformations 155 Paleocerebellar Hypoplasia 156 Neocerebellar Aplasia and Hypoplasia 161 Isolated Brainstem Hypoplasia/Dysplasia 170

4.5

Chiari Malformations

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4.5.1 4.5.2 4.5.3 4.5.4

Chiari I Malformation Chiari II Malformation Chiari III Malformation Chiari IV Malformation

172 178 184 186

4.3.5.1 4.3.5.2 4.3.5.3 4.3.6 4.3.6.1 4.3.6.2 4.3.6.3 4.3.7

References

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Introduction Brain malformations are extremely polymorphous, and individual cases very often escape rigid categorization. Moreover, several malformations are frequently associated with one another in individual patients, and many are comprised within complex multiorgan syndromes. Although some believe that a purely descriptive diagnostic approach is advantageous [1], classifications are useful to practicing clinicians to make sense of what they see and to approach their patients on the basis of a logical framework. Neuroradiologists have a wellknown propensity for classifications, basically because MRI has proved to be a very powerful and effective tool to attempt radiologic-pathologic correlations. However, classification schemes are continuously challenged by new advances in the understanding of the pathologies they attempt to describe. This has been the case with many disease processes involving the central nervous system (CNS), and especially with brain malformations. Knowledge of the basic molecular and genetic processes that direct normal brain development and, when deranged, result in congenital abnormalities has literally boomed in the past decade. For this reason, we are now witnessing a delicate transition from a purely morphological [2] to a molecular genetic (Table 4.1) [3, 4] approach to brain malformations. At present, both perspectives are probably equally unsatisfactory, basically because the molecular and genetic background is well known for a few entities, but is still unavailable for many others. In fact, causes of malformations can be divided into four groups, i.e., chromosomal abnormalities, single gene mutations, environmental agents, and unknown; unfortunately, the last category is the largest [1]. Therefore, neuroradiological classifications are still mostly based on morphology [5, 6] or on a combination of morphologic and biochemical data [7]. MRI is the single best modality for imaging brain malformations. There is little point in describing here the several advantages of MRI over other imaging modalities, as they are well known and have been widely described elsewhere. However, CT is still widely used in centers where MRI is not readily available. Advanced MRI techniques, such as diffusion-weighted imaging, perfusion-weighted imaging, and MR spectroscopy are not particularly useful. A notable exception is the role of diffusion-weighted imaging in the differentiation of arachnoid cysts from dysontogenetic masses [8]. Ultrasounds play a crucial role as a screening modality in neonates, and are credited for revealing many abnormalities that are subsequently investigated in detail with MRI (see Chap. 25). Before proceeding with the description of the various entities, a short premise on semantics is required [9].

Agenesis (synonym: aplasia) indicates failure of development of a whole organ or of a part of it, whereas hypoplasia (synonym: hypogenesis) involves incomplete formation. On the contrary, atrophy implies degeneration occurring after achievement of complete development; on this basis, atrophy can secondarily involve hypoplastic structures. Dysplasia indicates abnormal histogenesis, basically represented, in the CNS, by migrational anomalies (i.e., cortical dysplasia). The term dysgenesis is a generic synonym of malformation (i.e., corpus callosum dysgenesis). Use of semantically correct terms is important to develop a common language and to favor interaction between clinicians. In the following discussion, brain malformations have been somewhat arbitrarily categorized into five broad groups, i.e., cephaloceles, defects of the mediobasal prosencephalon, malformations of cortical development, malformations of the posterior cranial fossa, and Chiari malformations. Abnormalities of the telencephalic commissures, including corpus callosum abnormalities, have been discussed elsewhere in this book (see Chap. 3).

4.1 Cephaloceles 4.1.1 Background Cephaloceles are characterized by evagination of brain and/or leptomeninges through a congenital defect of the skull and dura, usually located on the midline. Cephaloceles affect 0.8–3:10,000 viable newborns [10, 11]. There are significant geographic variations in their location, incidence, and gender predilection. In Western populations, the majority of these lesions involve the occipital bone and occur in females, whereas anterior cephaloceles involving the frontal, nasal, and orbital bones are more frequent in male patients of Asian descent. These variations suggest that different genetic assets play a causal role. In cephaloceles, the meninges form the wall of a sac that is filled with CSF and, in some cases, nervous tissue. Depending on the contents of the herniation [10], cephaloceles are categorized as follows (Fig. 4.1): ● Meningocele: cerebrospinal fluid (CSF) collection lined by partially epithelized meningeal wall; ● Meningoencephalocele, or encephalocele: meningeal, variably epithelized sac containing brain; ● Meningoencephalocystocele: an encephalocele containing a portion of the ventricles;

Brain Malformations Table 4.1. Proposed new etiological classification of human nervous system malformations based upon patterns of genetic expression I. Genetic mutations expressed in the primitive streak or node A. Upregulation of organizer genes 1. Duplication of neural tube B. Downregulation of organizer genes 1. Agenesis of neural tube II. Disorders of ventralizing gradient in the neural tube A. Overexpression of ventralizing genes 1. Duplication of spinal central canal 2. Duplication of ventral horns of spinal cord 3. Diplomyelia (and diastematomyelia?) 4. Duplication of neural tube 5. Ventralizing induction of somite a. Segmental amyoplasia B. Underexpression of ventralizing genes 1. Fusion of ventral horns of spinal cord 2. Sacral (thoraco-lumbo-sacral) agenesis 3. Arrhinencephaly 4. Holoprosencephaly III. Disorders of dorsalizing gradient of the neural tube A. Overexpression of dorsalizing genes 1. Duplication of dorsal horns of spinal cord 2. Duplication of dorsal brainstem structures B. Underexpression of dorsalizing genes 1. Fusion of dorsal horns of spinal cord 2. Septo-optic dysplasia (?) IV. Disorders of the rostrocaudal gradient and/or segmentation A. Increased homeobox domains and/or ectopic expression 1. Chiari II malformation B. Decreased homeobox domains and/or neuromere deletion 1. Agenesis of mesencephalon and metencephalon 2. Global cerebellar aplasia or hypoplasia 3. Agenesis of basal telencephalic nuclei 4. Agenesis of the corpus callosum (some forms: Emx 1)

B. Neoplastic 1. Medullomyoblastoma 2. Dysembryoplastic neuroepithelial tumors 3. Gangliogliomas and other mixed neural tumors VI. Disorders of secretory molecules and genes that mediate migrations A. Neuroblast migration 1. Initial course of neuroblast migration a. Filamin-1 (X-linked dominant periventricular nodular heterotopia) 2. Middle course of neuroblast migration a. Doublecortin (DCX; X-linked dominant subcortical laminar heterotopia or band heterotopia) b. LIS1 (type I lissencephaly or Miller-Dieker syndrome) c. Fukutin (type II lissencephaly; Fukuyama muscular dystrophy) d. Empty spiracles (EMX2; schizencephaly) e. Astrotactin 3. Late course of neuroblast migration; architecture of cortical plate a. Reelin (pachygyria of late neuroblast migration and cerebellar hypoplasia) b. Disabled-1 (DAB1; also VLDL / Apoe2R?App recep tor defect; downstream of reelin, EMX2 and DCX) c. L1-NCAM (X-linked hydrocephalus and pachygyria with aqueductal stenosis) B. Glioblast migration C. Focal migratory disturbances due to acquired lesions of the fetal brain VII. Disorders of secretory molecules and genes that attract or repel axonal growth cones A. Netrin downregulation B. Keratan sulfate and other glycosaminoglycan downregulations C. S-100? protein downregulation or upregulation (?)

V. Aberrations in cell lineages by genetic mutation A. Non-neoplastic 1. Striated muscle in the central nervous system 2. Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos) 3. Tuberous sclerosis 4. Agenesis of the corpus callosum (some forms: Emx 1) 5. Hemimegalencephaly (also VIII. Disorders of symmetry)

VIII. Disorders of symmetry A. Hemimegalencephaly (also see V. Aberrations of cellular lineages) 1. Isolated hemimegalencephaly 2. Syndromic hemimegalencephaly a. Epidermal nevus b. Proteus c. Klippel-Trénaunay-Weber d. Hypomelanosis of Ito B. Hemihyperplasia of the cerebellum

An additional variant is the atretic cephalocele, a rudimentary form composed by a small fibrolipomatous nodule. The degree of epithelization of the herniated sac is variable in individual cases. When the arachnoidal lining becomes exposed to the environment, ulceration and infection may ensue. As with other neural tube defects, the skin overlying the abnormality may exhibit birthmarks, such as hairy tufts, hemangiomas, dyschromic patches, and dimples. The neural tissue contained within the sac usually

is disorganized, and includes zones of necrosis, calcifications, and vascular proliferation [9]. The size of the cephalocele may vary from a small nodule to an enormous sac that may be larger than the head itself. However, size does not predict the severity of the dysgenesis of the portion of the brain remaining within the cranium [9]. Instead, there is a direct relationship between the amount of herniated neural tissue and the degree of microcephaly. This correlates with the eventual degree of mental retardation [12].

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a

b

c

Fig. 4.1a–c. Schematic drawing of the different types of cephaloceles. a Meningocele: herniation of the meninges only. b Meningoencephalocele (or encephalocele): herniation of the meninges and nervous tissue through a skull defect. c Meningoencephalocystocele: a portion of the ventricular system herniates into the sac

4.1.2 Embryology The etiology of cephaloceles remains incompletely determined. Multiple defects of brain maturation, such as neuronal migration, axonal projection, and synaptogenesis, may be found, but none appears to play a key pathogenetic role. The relationship between cephaloceles and neural tube closure defects is the key point in the etiopathogenetic debate. Based on the traditional bidirectional, “zipper-like” neural tube closure model, cephaloceles have been related to defects of closure of the anterior neuropore [13]. However, intermediate defects, such as occipital or frontal cephaloceles, remained difficult to explain. Recently, a multisite neural tube closure model was proposed [14]. The multisite model suggests that cephaloceles and other neural tube closure defects, such as myelomeningoceles, anencephaly, and craniorachischisis, can be explained by failure of fusion of one of the closures or their contiguous neuropore [14]. A striking correlation between the neural tube defects observed in clinical cases and the location of the closure sites and their neuropores is believed to exist by these authors [14]. However, other authors [15] believe that cephaloceles should be considered postneurulation defects. The primary event should be traced to failure in the bony covering of the neural tube, and cephaloceles would be caused by events not associated with neurulation, but with distortion and crowding of a rapidly growing brain through the defect. It is still controversial whether cephaloceles result from primary neural tube nonclosure or from secondary reopening. The absence of a membrane coverage to the malformation is probably the single most significant indicator of primary failure of

neural tube closure. Conversely, it is difficult to determine whether skin-covered cephaloceles result from incomplete neural tube closure or secondary reopening. Lateral (i.e., off-midline) cephaloceles most likely result from secondary neural tube reopening, and are usually seen in association with disruptive disorders [14].

4.1.3 Clinical Features The degree of neurological and developmental damage associated with cephaloceles is variable, and depends on the amount of herniated neural tissue, the presence of hydrocephalus, and the association with hindbrain lesions or cerebral hemisphere dysplasias which result from the associated disorder of cellular migration and organization [13]. Some patients are only mildly impaired. Mental retardation, spastic diplegia, and cognitive disorders may not become evident until childhood. Patients with meningoceles or atretic cephaloceles have an essentially normal neurological picture, and their prognosis is favorable provided there is neither hydrocephalus nor associated congenital abnormalities. Conversely, children with encephaloceles show a complex clinical picture that depends on variably combined factors such as the size, contents, and location of the herniation, as well as the presence of hydrocephalus, perinatal injury, apneic crises, seizures with consequent hypoventilation, hypoxia, and acidosis [16]. In general, occipital cephaloceles are associated with a unfavorable prognosis compared to that of skull base cephaloceles. Severe occipital cephaloceles are often associated with distortion of the brainstem

Brain Malformations

and cranial nerves leading to visual disturbances, neurovegetative disorders (apnea, bradycardia, sialorrhea), and cranial nerve deficit (strabismus, nystagmus, dysphagia). Hydrocephalus is often progressive and manifests with increased intracranial pressure, opisthotonus, and hypertonic limbs. Ulceration of the sac may be complicated by local infection or meningoencephalitis. Associated anomalies are especially important, as they often influence the clinical picture more severely than the cephalocele itself. Agenesis of the corpus callosum is found in 80% of cases. Occipital cephaloceles are also often part of complex abnormalities such as the Chiari III malformation and tectocerebellar dysraphia, and are found in a host of inherited syndromes (see below). Associated abnormalities account for a variable degree of developmental and psychomotor delay, blindness, superior functions compromise (symbolic functions, language, learning, memory), motor incoordination, and seizures [16]. Skull base cephaloceles usually are characterized by severe cranio-facial dysmorphism with cleft lip and palate, coloboma, and microphthalmos. Sphenoidal cephaloceles usually become manifest either with signs of upper airway obstruction or with endocrine and visual dysfunction, due to prolapse of the pituitary gland and optic chiasm into the herniated sac. Visual disturbances may also be due to associated abnormalities, such as holoprosencephaly and septo-optic dysplasia. Anosmia may result from compromise of the olfactory nerves and bulbs in patients with sincipital cephaloceles. Ascending infections of the CNS with recurrent meningitides may be caused by occult connections between unsuspected skull base cephaloceles and the nasal and paranasal cavities, rhinopharynx, and inner ear [16].

Cephaloceles of the Convexity

Occipital Cephaloceles

Depending on the relationship of the calvarial defect with anatomic landmarks, such as the external occipital protuberance and the posterior lip of the foramen magnum, occipital cephaloceles are categorized into three subsets: (i) occipito-cervical: the defect involves the occipital squama, foramen magnum, posterior arch of the atlas, and often the neural arches of the upper cervical vertebrae; (ii) inferior occipital: the defect lies at or below the external occipital protuberance and above the posterior lip of the foramen magnum (Figs. 4.2–4); and (iii) superior occipital: the defect lies above the external occipital protuberance (Fig. 4.5). Occipital cephaloceles are obvious at birth and are usually diagnosed antenatally. In newborns, the differential diagnosis includes cephalohematomas, caput succedaneum, and cystic lymphangiomas. The majority (80%) are meningoencephaloceles that contain either cerebral tissue, cerebellar tissue, or both [12, 19]. However, the content of the sac is not predictable based on the site of the cranial defect [10]. The occipital lobes are the single most common portion of brain that is included within the herniation. Dural sinuses and other venous structures may also lie close to or within the sac, generating a risk for hemorrhage and subsequent brain damage during surgery. The overall size of the cephalocele is usually large, exceeding 5 mm in diameter in 72% of cases [10].

4.1.4 Classification and Neuroradiological Features Cephaloceles are usually categorized according to their location into convexity, skull base, and internal cephaloceles [10, 17]. Their neuroradiological evaluation aims to assess: (i) their exact location; (ii) the morphology, size, and content of the sac; (iii) possible associated abnormalities, such as callosal dysgenesis [18] and the Chiari II malformation, that portend a poorer prognosis; and (iv) the anatomic relationship with vascular structures, especially the dural sinuses, whose inadvertent damage during surgery may cause profuse bleeding. MR angiography is valuable to identify the location and course of the major venous structures.

Fig. 4.2. Inferior occipital meningocele. Sagittal T1-weighted image. Small occipital meningocele covered by dystrophic skin (arrow)

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a

b Fig. 4.3a,b. Occipital meningocele. a. Sagittal T1-weighted image; b. Three-dimensional CT scan. A complex malformation is associated with an occipital meningocele (asterisk, a). CT scan clearly shows the skull defect (arrows, b)

a Fig. 4.4a,b. Occipital meningoencephalocystocele. a Sagittal T1weighted image; b Axial T1-weighted image. Large occipital cephalocele, characterized by herniation of meninges (arrow, a), nervous tissue (arrowheads, a, b), and a portion of the ventricular system (asterisk, a, b) that communicates with the left atrium. The herniated ventricle is well separated from the adjacent herniated subarachnoid space (M, b). (Case courtesy Dr. Z. Patay, Riyadh, Saudi Arabia)

b

Brain Malformations

Simple meningoceles are usually isolated (Fig. 4.2). Conversely, meningoencephaloceles can be associated with other malformations (Figs. 4.3, 4.4), such as holoprosencephaly, callosal dysgenesis, myelomeningocele, Klippel-Feil syndrome, and hydrocephalus. Some of these associations are considered as autonomous entities. The presence of signs of Chiari II malformation (small posterior fossa, tectal beaking, enlarged interthalamic mass) in a child with an occipital cephalocele is designated “Chiari III malformation.” The cephalocele is occipito-cervical or, more rarely, inferior cervical [20]. The coexistence of an occipital cephalocele, agenesis of the vermis, and marked deformation of the tectum is called “tectocerebellar dysraphia.” These entities are described in detail elsewhere in this chapter. a

Sagittal (Interparietal) Cephaloceles

These rare cephaloceles are located between the parietal bones in the midline (Fig. 4.6), and may be associated with callosal dysgenesis and arachnoid cysts. Lateral Cephaloceles

Lateral (i.e., off-midline) cephaloceles are very rare (Fig. 4.7). They are found along the coronal and lambdoid sutures, and at the pterion or asterion. They are believed to result from secondary reopening of the neural tube. Therefore, they are considered secondary, disruptive disorders [14]. Bregmatic Cephaloceles

Cephaloceles located at the anterior fontanel must be differentiated from dermoids, which are much more common. Computerized tomography (CT) may be useful to demonstrate the calvarial defect that is associated with cephaloceles.

b

Interfrontal Cephaloceles

They are found between the glabella and the bregma, and the defect lies along the metopic suture. Portions of the frontal lobes may herniate into the sac. Skull Base Cephaloceles

c Fig. 4.5a–c. Superior occipital meningocele. a Sagittal T1weighted image; b Gd-enhanced sagittal T1-weighted image; c 2D TOF MRA. Huge occipital meningocele (a, b). The venous sinuses are not herniated into the sac (c). A falcine sinus is associated (arrow, a, b)

Anterior cephaloceles (Fig. 4.8) usually are found in children with little or no neurological impairment. However, they may be associated with callosal agenesis, interhemispheric cysts, and interhemispheric lipomas; the latter usually belong to the tubulonodular variety and can be partially calcified. Cortical dysplasia and holoprosencephaly may also be associated, whereas hydrocephalus, albeit possible, is rare. Cephaloceles of the skull base may be accompanied by midline facial defects, such as hypertelorism, cleft

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b a Fig. 4.6a,b. Interparietal cephalocele. a Sagittal T2-weighted image; b 3D TOF MR angiography. Small posterior interparietal meningocele (arrow, a). The venous sinuses are not herniated into the sac (b). A large falcine sinus is recognizable (arrowheads, a, b)

a

b Fig. 4.7a,b. Parietal meningocele. a Coronal T2-weighted image; b Axial T2-weighted image. Large meningocele containing septa in the right parietal region. Widespread cortical malformations, represented by subependymal heterotopia (arrowhead, a) and multiple bilateral polymicrogyric infoldings (arrows, a, b) are recognizable. (Case courtesy Dr. Z. Patay, Riyadh, Saudi Arabia)

lip, and cleft palate [21]. Contrary to occipital cephaloceles, they may be clinically occult [22] and discovered later in life. Sincipital Cephaloceles

Sincipital or fronto-ethmoidal cephaloceles are categorized according to their relationship with the frontal bone, nasal bones, and ethmoid.

Nasofrontal or glabellar cephaloceles: The defect lies between the frontal and nasal bones at level of the “fonticulus nasofrontalis,” a small transient fontanel corresponding externally to the glabella [23, 24]. These lesions may be in the midline or lie slightly off the midline, and can be associated with other abnormalities such as callosal dysgenesis, lipomas, holoprosencephaly, and cortical malformations (Fig. 4.9).

Brain Malformations

a

b

d

e

c

f

Fig. 4.8a–f. Schematic representation of sincipital (a–c) and naso-pharyngeal (d–f) cephaloceles. Asterisks or arrows indicate the bony schisis. E, ethmoid bone; F, frontal bone; N, nasal bones; S, sphenoid bone; V, ventricles. a Naso-frontal cephalocele: The skull defect involves the glabella, being located between the frontal bone superiorly and the ethmoid and nasal bones inferiorly. b Nasoethmoidal cephalocele: The skull defect is located between the frontal and nasal bones superiorly and the ethmoid inferiorly. The cephalocele creeps into the nose between the nasal bones and cartilage. c Naso-orbital cephalocele: The skull defect involves the ethmoidal lamina papyracea, lacrimal bone, and frontal process of the maxillary bone. The facial extremity of the defect is localized at level of the medial orbital wall, and the ostium involves the internal canthus. d Trans-ethmoidal cephalocele: Skull defect involves the ethmoid, with resulting intranasal mass. e Spheno-ethmoidal cephalocele: Skull defect is between the ethmoid and sphenoid bones, with resulting mass in the posterior nasal cavity. f Spheno-nasopharyngeal cephalocele: Sphenoidal bone defect with nasopharyngeal mass

Nasoethmoidal cephaloceles: The congenital defect is located between the nasal bones and the cartilage. The cephalocele can develop either on the surface of the nasal pyramid or in the inner canthus of the eye. Nasoorbital cephaloceles: The defect lies at the junction between the frontal, ethmoidal, lacrimal, and maxillary bones. The cephalocele develops either externally on the face or internally in the orbit. These cephaloceles are believed to result from incomplete regression of a dural outpouching that normally crosses the fonticulus nasofrontalis during fetal life, and is subsequently obliterated [23, 24], resulting in the foramen caecum. The enlargement of this foramen is a hallmark of these lesions, and is well demonstrated by CT [23].

Sincipital cephaloceles must be differentiated from nasal gliomas and dermoids, which share a common embryological mechanism. Nasal gliomas (Fig. 4.10) are also called nasal brain heterotopia [24, 25]. The term “nasal glioma” is a dreadful, confusing misnomer, as it implies a neoplastic condition with malignant potential, which it is not. Nasal glioma is a rare developmental abnormality, and should be differentiated from glioma, which is a tumor of the brain, and from a primary encephalocele, which is herniation of the cranial contents through a bone defect in the skull, through which it retains an intact connection with the CNS [25]. Nasal gliomas are composed of dysplastic brain tissue located into the nasal fossae or in the subcutaneous tissues of the glabella. They are not connected with the CNS. Embryologically, nasal gliomas are similar to sincipital cephaloceles in that both entities are believed to result from nervous

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a

b

c

Fig. 4.9a–d. Sincipital encephalocele. a. Photograph of the patient; b. Sagittal T2-weighted image; c. Axial T1-weighted d image; d. 3D CT scan. Patient has large, slightly left-sided subcutaneous mass at the nasal root, and is hyperteloric (a). MRI shows herniation of dysplastic nervous tissue, originating from the left frontal lobe, through the fonticulus frontalis (arrow, b, c). A falcine sinus is associated (arrowhead, b). 3D CT scan shows location of bony defect, involving the caudal portion of the frontal bone at the glabella (arrow, d)

tissue herniating through the foramen caecum along a dural outpouching. If the proximal portion of the dural stalk regresses, sequestration of distal nervous tissue produces a nasal glioma, whereas preservation of the connection at the level of the foramen caecum results in a cephalocele. The differentiation between the two entities is obviously important in view of the inherently different surgical strategy. Dermoids are dysontogenetic masses that usually are associated with a dermal sinus tract (Fig. 4.11). The latter arises at an external ostium situated along the midline of the nose and extends deeply for a variable distance, sometimes crossing the

foramen caecum to reach the intradural intracranial space [21]. The differentiation of dermoids from nasal gliomas is based on their density on CT, which parallels that of fat, and signal behavior on MRI. Sphenoidal Cephaloceles

Sphenoidal cephaloceles usually are not clinically evident at birth, and require time to become manifest with either exophthalmos or upper airway obstruction. Therefore, they are generally recognized later in infancy, or even in adulthood. Physical examination in these children often reveals a pulsatile rhinopha-

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Brain Malformations

a

c

b

Fig. 4.10a–c. Nasal glioma. a Sagittal T1-weighted image; b Gd-enhanced sagittal T1-weighted image; c Axial T2-weighted image. Large mass involving both the nasal cavity (asterisk, a, b) and the subcutaneous tissue of the nasal pyramid (arrow, a–c). The lesion is isointense on T1-weighted images (a), hyperintense on T2-weighted images (c), and shows inhomogeneous enhancement (b)

b

a Fig. 4.11a,b. Nasal dermoid. a Sagittal T1-weighted image; b Sagittal T2-weighted image. A small mass (arrowhead, a, b) extends intracranially through the foramen caecum (white arrow, a, b). A dependent fluid-fluid level is recognizable (black arrow, a)

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ryngeal mass covered by nasal mucosa that expands with a Valsalva maneuver. Spontaneous fistulas are rare, but may be complicated by ascending meningitis. Sphenoidal cephaloceles are further divided into several groups. Spheno-orbital cephaloceles: The defect may involve the superior orbital fissure, the great sphenoidal wing [26], the optic canal, and the walls of the orbit. Exophthalmos may result from chronic mass effect within the rigid orbital cavity [27]. Spheno-maxillary cephaloceles: The cephalocele herniates through the inferior orbital fissure into the pterygopalatine fossa, and usually contains portions of the temporal lobe. Naso-pharyngeal cephaloceles: This category includes several forms, depending on the relationship between the bony defect and the ethmoid, sphenoid, and basiocciput [28]. Transethmoidal cephaloceles (Fig. 4.12) cross a defect in the cribroid plate and extend into the ethmoidal cavities, which are deformed and remodeled; sometimes the sac protrudes into the nasal cavity, vestibule, and rhinopharynx. Spheno-ethmoidal cephaloceles pass between the body of the sphenoid and the ethmoid, and occupy the posterior nasal cavity or the rhinopharynx [29]. Spheno-nasopharyngeal cephaloceles develop through the body of the sphenoid bone and represent the more typical form of sphenoidal cephalocele, classically presenting as a submucosal pharyngeal mass (Fig. 4.13). When the defect involves the floor of the pituitary fossa, the pituitary gland, hypothalamus, and optic chiasm may herniate into the sac [30]. Basioccipital-nasopharyngeal cephaloceles are exceedingly rare and develop through a midline clival defect at the level of the spheno-occipital synchondrosis. The sac may contain a portion of the prepontine cistern, brainstem, and even fourth ventricle [31].

a

b

Internal Cephaloceles

These very rare cephaloceles are different from both calvarial and skull base cephaloceles in that they are acquired forms that result from positional rearrangement of the nervous structures secondary to major trauma or surgery [10, 16]. c

4.1.5 Syndromes Associated with Cephaloceles Cephaloceles may be part of malformative complexes, whose pattern of genetic transmission has been estab-

Fig. 4.12a–c. Transethmoidal encephalocele. A Reconstructed sagittal image from T1-weighted 3D sequence; b Coronal T1weighted image; c Coronal T2-weighted image. A large portion of the basal portion of the right frontal lobe herniates through an ethmoidal defect into the nasal cavities (asterisk, a–c). (Case courtesy Dr. Z. Patay, Riyadh, Saudi Arabia)

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Brain Malformations

a

b Fig. 4.13a,b. Spheno-nasopharyngeal encephalocystocele. a. Sagittal T1-weighted image; b. Coronal T1-weighted image. The anterior third ventricle herniates through the sellar floor in the sphenoidal region (asterisk, a, b). The two portions of the pituitary gland (anterior and posterior lobe) are recognizable, although the gland is flattened against the clivus (arrowheads, a)

lished in some cases [32]. Cephaloceles may represent either a constant or a possible finding, depending on the nature of the syndrome (Table 4.2). The association with other congenital CNS anomalies accounts for the often severe psychomotor compromise exhibited by affected children. Genetic counseling is obviously very important in view of the severe prognosis which is often associated with these syndromes.

underdeveloped premaxilla, median cleft of the secondary palate, widely separated nasal halves, extreme asymmetrical orbital hypertelorism with strabismus, widow’s peak, enlarged ethmoidal air cells, low cribriform plate, thickened nasal septum, duplication of the frenulum, nose or teeth, and intracranial-associated anomalies, such as holoprosencephaly, lipomas of the interhemispheric fissure, and callosal agenesis.

Frontonasal Dysplasia

Tecto-Cerebellar Dysraphia

Frontonasal dysplasia (also called frontonasal dysostosis or median cleft face syndrome) [33] comprises ocular hypertelorism, median facial cleft affecting nose and/or upper lip, unilateral or bilateral cleft of the alae nasi, anterior cranium bifidum occultum, or a widow’s peak (the strip of hairline at the top of the forehead sticks out, as opposed to being horizontal). It usually is a sporadic disorder, although a few familial cases have been reported, suggesting either autosomal dominant or X-linked dominant transmission [34]. The embryological origin of this syndrome is in the period prior to the 28 mm stage. It is due to deficient remodeling/differentiation of the nasal capsule which causes the future fronto-naso-ethmoidal complex to freeze in the fetal form [35]. This syndrome has a range of severity in its manifestations. There is an increased incidence of basal/ fronto-ethmoidal/transsphenoidal encephalocele with pituitary herniation. Other deformities that may be present are [21] a bifid nose tip/dorsum with or without a median notch/cleft of the upper lip, bifid or

This abnormality is characterized by absent vermis, kinking of the brainstem, marked tectal beaking, and herniation of the cerebellum into an occipital encephalocele (see below, malformations of the posterior cranial fossa). Chiari III Malformation

This rare abnormality is defined by the association of a high cervical/low occipital encephalocele and signs of Chiari II malformation, that may include a small posterior fossa, tectal beaking, and low bulbo-medullary junction. Other features include hypoplasia of the low and midline aspects of the parietal bones, petrous and clival scalloping, cerebellar hemisphere overgrowth, cerebellar tonsillar herniation, hydrocephalus, dysgenesis of the corpus callosum, posterior cervical vertebral agenesis, and spinal cord syringes. The encephalocele may contain varying amounts of brain (either cerebellum and occipital lobes or cerebellum only), ventricles (fourth and lateral), cisterns, and brainstem [20].

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P. Tortori-Donati, A. Rossi, and R. Biancheri Table 4.2. Syndromes associated with cephalocele Syndrome

Cephalocele location

Frequency of asso ciated cephalocele

Transmission modality

Frontonasal dysplasia

Frontal

100%

Heterogeneous

Tecto-cerebellar dysraphia

Occipital

100%

Sporadic

Chiari III malformation

Occipital, occipito-cervical

100%

Sporadic

Von Voss-Cherstvoy

Occipital

100%

Autosomal recessive

Iniencephaly

Occipital

Frequent

Sporadic

Meckel-Gruber

Occipital

80%

Autosomal recessive

Knobloch

Occipital

80%

Autosomal recessive (presumed)

Joubert

Occipital

30%

Autosomal recessive

Walker-Warburg

Occipital

30%

Autosomal recessive

Dyssegmental dwarfism

Occipital

20%

Autosomal recessive

Cryptophthalmos

Occipital

10%

Autosomal recessive

Klippel-Feil

Occipital

Rare

Heterogeneous

Pseudo-Meckel

Occipital

Rare

Chromosomal; t(3p+)

Roberts

Frontal

Rare

Autosomal recessive

Goldenhar

Occipital

Rare

Heterogeneous

Early amniotic rupture

Anterior (other)

Rare

Sporadic

Fetal warfarin

Occipital

Rare

Iatrogenic

Apert

Frontonasal

Rare

Autosomal dominant

von Voss-Cherstvoy Syndrome

Iniencephaly

This entity, also known as DK-phocomelia syndrome, is characterized by radial ray defects, occipital encephalocele, and urogenital abnormalities [36, 37]. Other possible CNS findings include callosal agenesis, partial vermian agenesis, and hypoplasia of the olivary nuclei and pyramids [16]. Both sexes are affected, and parental age is not increased. The inheritance pattern may be heterogeneous, but autosomal recessive inheritance has been suggested in at least some instances [36].

Iniencephaly is a rare neural tube defect of the craniocervical junction [1:1000–1:100,000 births] [39] involving the occiput and inion, combined with rachischisis of the cervical and thoracic spine. It is characterized by marked, fixed retroflection of the skull on the cervical spine due to thick fibrous bands, representing hypoplastic trapezius muscles and a thick ligamentum nuchae [39]. Occipital bone defect and spina bifida of the cervical vertebrae are other distinguishing features of this abnormality [40]. The neck is often absent, and the skin is continuous with the scalp, face, and chest. The abnormal and retroflexed occiput may join the vertebrae of the spine. The cervical spine is always severely deformed and shows multiple anomalies, such as a block or deficiencies. Posterior midline schises may include cleft occipital bone, wide foramen magnum, and vertebral anomalies affecting the cervical and thoracic spine with anterior/posterior spina bifida. The pedicles may be short and the laminae absent. The overlying skin and dorsal soft tissues may be intact or completely deficient, exposing the neural tissue to the environment [39]. Although the cause of this abnormality is unknown, low parity and socioeconomic status probably play a role [41]. There is a marked female predilection (90% of cases). Most iniencephalic fetuses are stillborn;

Joubert Syndrome

Occipital cephaloceles are found in 30% of patients with Joubert syndrome. Clinically, hyperpneic/ apneic spells, ataxia, nystagmus, and psychomotor delay represent the classical tetrad. Radiologically,the “molar tooth” malformation is a typical feature (see below). Walker-Warburg Syndrome

Walker-Warburg Syndrome is an autosomal recessive disorder showing characteristic brain and eye malformations (cobblestone complex, cerebellar and brainstem malformations, retinal abnormalities) in patients with congenital muscular dystrophy. Occipital cephaloceles occur in 24% of cases [38].

Brain Malformations

however, a limited number of viable newborns has been described in whom surgery allowed correction of the abnormal position of the head. Iniencephaly is subdivided into iniencephaly clausus and iniencephaly apertus, depending on the presence of an associated occipital cephalocele that may contain the occipital lobes, cerebellum, and brainstem. Although the morphological appearance of iniencephaly may resemble a large occipital cephalocele, the huge occipital bone defect and rachischisis of the cervical vertebrae are distinctive features [40]. Associated malformations of the CNS include anencephaly, hydrocephalus, callosal dysgenesis, microcephaly, holoprosencephaly, atresia of the ventricular system, and malformations of the cerebral cortex [16, 39, 40]. Systemic malformations include cyclopia, cleft lip and palate, bifid uvula, deformed ears, fusion or deficiency of ribs, abnormal lobation of the lungs, diaphragmatic hernia, single umbilical artery, omphalocele, situs inversus, horseshoe or polycystic kidneys, imperforate anus, club feet, and congenital heart disease. Meckel-Gruber Syndrome

Also called dysencephalia splanchnocystica or simply Meckel syndrome, it is a rare, lethal syndrome characterized by occipital cephalocele, postaxial polydactyly, and dysplastic cystic kidneys. It can be associated with several other conditions, including fibrotic lesions of the liver. The incidence varies from 0.07 to 0.7 per 10,000 births, but in Finland the disorder is unusually frequent and reaches 1.1 per 10,000 births [42]. It is also estimated that this syndrome corresponds to 5% of all neural tube defects [43]. Inheritance is autosomal recessive, and the genetic locus has been mapped on the long arm of chromosome 17 [44]. Occipital cephaloceles are present in 60%–80% of cases. Other possible CNS abnormalities include microcephaly, holoprosencephaly, cerebral and cerebellar hypoplasia, hypoplasia of pituitary gland, and the Dandy-Walker malformation. Eye anomalies (microphthalmos, cataract, coloboma), cleft lip and palate, and facial abnormalities (Potter-like face) can also be found [16]. Pseudo-Meckel Syndrome

Pseudo-Meckel syndrome is characterized by congenital absence of the rhinencephalon, callosal agenesis, Chiari I malformation and a variable association of cardiac defects, cleft palate, club feet, and hammer toes; occipital cephalocele occurs rarely [16]. Knobloch Syndrome

Knobloch syndrome is an autosomal recessive syndrome of hereditary vitreoretinal degeneration with

retinal detachment, severe myopia, and occipital encephalocele in children with normal intelligence [45]. However, congenital occipital scalp defects, rather than true encephaloceles, may accompany Knobloch syndrome in some cases [46]. Dyssegmental Dwarfism

Dyssegmental dwarfism is an autosomal, recessively inherited, lethal, generalized chondrodysplasia, characterized by micromelia, cleft palate, and variable limited mobility at the elbow, wrist, hip, knee, and ankle joints. In some cases, occipital encephalocele, inguinal hernia, hydronephrosis, hydrocephalus, and patent ductus arteriosus are found [47]. Cryptophthalmos

Cryptophthalmos is a condition that results in failure of eyelid formation. It is divided into three types: the complete, incomplete, and symblepharon variety. The complete variety is the most common; the eyelids do not form and the eyelid skin grows continuously from the forehead to the cheek, covering the underlying globe which is usually abnormal. Cryptophthalmos is associated with several other congenital anomalies, including abnormal hairline, syndactyly, and an occipital cephalocele in 10% of cases [16, 48]. Klippel-Feil Syndrome

The Klippel-Feil deformity is a complex of osseous and visceral anomalies that includes low hair line, platybasia, fused cervical vertebrae with short neck, and deafness. The classical clinical triad consist of short neck, limitation of head and neck movements, and low set posterior hairline. Bony malformations may entrap and damage the brain and spinal cord. The disorders of the lower vertebral region may become symptomatic in adolescence or adult life. The pathogenesis has been related to anomalous somitic segmentation between gestational weeks 4 and 8 [16]. Associated CNS abnormalities include occipital cephalocele, Chiari I malformation, syringes, microcephaly, and hydrocephalus [16]. Several associated abnormalities, such as scoliosis, posterior bony spina bifida, absence of ribs, conductive hearing loss, mirror movements, unilateral renal ectopia with dilated collecting system, microtia, and preaxial polydactyly have also been reported. The pattern of bony fusion may involve more than one level, producing the “wasp waist sign” when two adjacent levels are involved [49]. Cervical spondylosis, disk herniation, and secondary degenerative changes are more common at levels adjacent to fused vertebrae [50]. Spontaneous and progressive neurological sequelae and neurological injury may follow minor neck trauma.

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Roberts Syndrome

Roberts syndrome (also known as pseudo-thalidomidic syndrome) is a rare genetic disorder characterized by pre- and postnatal growth retardation, limb defects, and craniofacial anomalies. Affected individuals have variable malformations that involve symmetric reduction in the number of digits and length or presence of bones in the arms and legs. Craniofacial malformations include hypertelorism, hypoplastic nasal alae, and a high incidence of cleft lip and palate. Familial and sporadic cases have been reported, consistent with an autosomal recessive mode of inheritance [51]. Cephaloceles occur occasionally in the frontal region. Goldenhar Syndrome

The main features of this condition are unilateral underdevelopment of one ear associated with underdevelopment of the jaw and cheek on the ipsilateral side of the face (hemifacial microsomia), possibly associated with vertebral anomalies and an epibulbar dermoid. The muscles of the affected side of the face are underdeveloped and there often are skin tags or pits in front of the ear, or in a line between the ear and the corner of the mouth. Often, there are abnormalities of the middle ear, and the ear canal may be completely absent. Unilateral deafness is extremely common. Cephaloceles (both anterior and posterior), plagiocephaly, and intracranial dermoids are occasionally associated [16, 52, 53]. Amniotic Band Syndrome

Severe fetal malformations, including neural tube defects, may be secondary to early amniotic rupture followed by formation of fibrous bands that cause fetal malformation, deformation, and compression. Most of the craniofacial defects (encephaloceles and/ or facial clefts) occurring in these fetuses are believed to result from a vascular disruption sequence, with or without cephalo-amniotic adhesion [54]. Fetal Warfarin Syndrome

In utero exposure to warfarin between gestational weeks 6 and 9 produces a constellation of nasal hypoplasia, punctate epiphyses, optic atrophy, mental retardation, hydrocephalus, and occasionally occipital cephalocele [16]. Apert Syndrome

It is characterized by craniosynostosis and syndactyly, and may be associated with hydrocephalus and naso-frontal cephalocele. The inheritance is autosomal dominant, although a number of sporadic cases have been reported [16]. (see Chap. 30).

4.2 Defects of the Mediobasal Prosencephalon Holoprosencephalies and Related Entities

4.2.1 Holoprosencephaly 4.2.1.1 Background

Holoprosencephaly (HPE) was defined by Yakovlev [55] as “a median holosphere with a single ventricular cavity instead of two hemispheres with symmetrical lateral ventricles.” HPE is a complex developmental abnormality of the forebrain that is related to anomalous differentiation and separation of the prosencephalic vesicle, the cranialmost of the three primitive vesicles that appear at the anterior end of the neural tube shortly after the end of primary neurulation. Anatomically, the basic defect involves incomplete separation of the eye fields and developing forebrain into distinct left and right halves [56]. Therefore, HPE may be viewed as a developmental field defect, with impaired cleavage of the embryonic forebrain as its cardinal feature. The prevalence is about 1 in 16,000 live births [57], but the incidence in conceptuses obtained through induced abortion is much higher (approximately 1 in 250) [58], reflecting early spontaneous loss of the majority of the abnormal fetuses. In most cases, craniofacial abnormalities are associated (Fig. 4.14), and reflect in 80% of cases the degree of severity. Their severity is variable, ranging from cyclopia to minimal craniofacial dysmorphism, such as mild microcephaly with a single central incisor [59]. HPE is characterized by hypoplasia of the most rostral portions of the neural tube, resulting in fused cerebral hemispheres and absence of midline structures, such as the rhinencephalon, corpus callosum, and septum pellucidum. In the past, HPE was confused with “arhinencephaly,” thereby stressing the absence of olfactory structures. Subsequently, DeMyer and Zeman [60] introduced the term HPE, which identifies more clearly the lack of cleavage and differentiation of the prosencephalon as the main causal factor. HPE is classically divided into alobar, semilobar, and lobar types according to the severity of the malformation, which follows an anterior-to-posterior gradient. In general, the basal forebrain, in the region of the hypothalamus and subcallosal cortex, is most severely affected. As one goes posteriorly in the cerebrum, the involvement becomes progressively less [61]. However, a precise boundary among the three groups does not exist, and intermediate cases may

Brain Malformations

be identified. Therefore, HPE should be viewed as a continuous spectrum ranging from the most severe alobar forms, in which the fetus is usually nonviable, to the milder lobar forms, in which the abnormality may be discovered incidentally [62]. An exception to this anterior-to-posterior rule is syntelencephaly, or middle interhemispheric holoprosencephaly (MIH) [63], which could represent a separate form [61]. 4.2.1.2 Embryogenesis and Pathogenetic Theories

a

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Traditionally, HPE has been related to absent cleavage of the prosencephalon, which results in fusion of the cerebral hemispheres along the midline associated with a number of midline abnormalities, such as absence of the olfactory system, septum pellucidum, and corpus callosum. The etiology of HPE is very heterogeneous and comprises environmental factors (i.e., maternal diabetes mellitus) [64], teratogens, and genetic causes. HPE can occur as apparently sporadic or as familial cases. Approximately 50% of cases are associated with a cytogenetic abnormality, of which trisomy 13 is the most common. Other chromosomal aberrations include partial deletion of the long arm of chromosome 13, ring chromosome 13, trisomy 18, partial deletion of the short arm of chromosome 18, ring chromosome 18, and partial trisomy 7. Based on recurrent cytogenetic abnormalities, there are at least 12 genetic loci that likely contain genes implicated in the pathogenesis of HPE. Currently, four human HPE genes are known: HPE1 on chromosome 21, HPE2 on chromosome 2, HPE3 on chromosome 7, and HPE 4 on chromosome 18 [56, 59, 65]. Because of such heterogeneity, it probably is incorrect to think of a gene “for” HPE, but rather, it is the action of a gene or genes with the environment of the developing embryo that determines the outcome [56]. The HPE3, or sonic hedgehog (shh) gene, maps on human chromosome 7q36 and is responsible for an autosomal dominant form of HPE that has been well described. Penetrance in families with HPE3 mutations approaches 88%. Shh encodes proteins that are implicated in ventral embryonic patterning, suggesting that HPE is a disorder of ventral induction. Shh is expressed during gastrulation in

Fig. 4.14a–c. Facial dysmorphism in holoprosencephaly. a Cyclopia: complete fusion of orbits and eyes. The nose is absent, while there is a midline proboscis above the single orbital cavity. b. Ethmocephaly: Separation of the orbits, albeit with marked hypotelorism. A single or double proboscis originates between the eyes. The nose is absent. c. Cebocephaly: Small, rudimentary nose with a single nostril. The orbits are small and hypoteloric

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several locations. In the spinal cord, the main source of ventralizing signals is the notochord, whereas in the forebrain ventralization is chiefly regulated by the prechordal plate, a region of foregut mesoderm underlying the embryonic hypothalamus and thalamus that lies cephalad to, and is induced by, the cranial extremity of the notochord. In normal embryonic development, an interplay of dorsalizing molecules (emanating from the roof plate) and ventralizing molecules (emanating from the prechordal plate and floor plate) modulates regional identity of tissues along the dorsoventral axis of the neural tube. Either a lack of production of ventralizing factors or an overproduction of dorsalizing factors can result in noncleavage (commonly called fusion) of structures that normally lie just lateral to the midline. This is the presumed mechanism by which HPE develops [66, 67]. Accurate characterization of the longitudinal (i.e., segmental) organization of the forebrain along the anteroposterior axis indicates that the hypothalamus is not part of the diencephalon, as classically conceived, but is grouped with the telencephalon in an anterior domain known as the secondary prosencephalon [66]. Thus, the structures most consistently malformed in HPE (i.e., the cortex, striatum, and hypothalamus) all belong to the same embryonic anteroposterior domain—the secondary prosencephalon—but occupy different dorsoventral positions within it. In this light, HPE may be best viewed as a disorder of dorsoventral patterning affecting the secondary prosencephalon [66]. Interestingly, cases of associated HPE and caudal agenesis, also known as the caudal regression syndrome, have been reported in the recent literature [68, 69]. This association could perhaps indicate a common embryogenetic background for these abnormalities. Caudal agenesis results from a disorder of notochordal formation, and has been thought to relate with cellular depletion at the level of the Hensen’s node (see Chap. 38). The neural tube that forms in chick embryos in which the caudal part of the Hensen’s node has been removed does not express ventral markers such as Shh, and is subsequently removed by apoptosis; however, grafting with Shhsecreting fibroblast rescues the caudal neural tube [70]. The effect of Shh on cell survival in the early neuroectoderm could reveal a common pathogenetic ground for caudal agenesis and HPE.

crine dysfunction [60]; however, symptoms may vary depending on the severity of the malformation. Also, HPE is typically associated with facial abnormalities (Fig. 4.14) that vary according to the severity of the abnormality. This occurs because the paired nasal and optic placodes are induced by the prosencephalon, and these in turn induce the maturation of the frontonasal and maxillary processes, which are ultimately responsible for the formation of the face [71]. Cyclopia, ethmocephaly, and cebocephaly are the most severe forms of facial derangement, and are usually associated with alobar HPE. Cyclopia is characterized by complete fusion of the ocular globes and orbits [72]. There is absence of a nose, with a midline appendage or “proboscis” usually present above the single orbit, and trigonocephaly is usually associated. Ethmocephaly exhibits marked hypotelorism. A bulky, single or double proboscis grows in between the two orbits along the midline, whereas the nose is absent. Cebocephaly is characterized by a short, flat nose with a single nostril. The orbits are small and hypoteloric. Less severely affected individuals may show agenesis of the premaxillary segment of the face, cleft lips and palate, hypotelorism, or trigonocephaly. In mild (i.e., lobar) forms, facial abnormalities usually are absent, and the clinical picture is one of mild to moderate psychomotor delay, hypothalamic-pituitary dysfunction, and visual disturbances [61]. The occurrence of a solitary median maxillary central incisor is a very rare condition, and may be a sign of a mild degree of HPE [73].

4.2.1.3 Clinical Features

The Genoa syndrome involves HPE, craniosynostosis, and multiple congenital anomalies including cloverleaf skull, Dandy-Walker malformation, bilateral microphthalmia, cleft soft palate, congenital scoliosis, hypoplastic nails, and coarctation of aorta [76].

The neurologic picture includes mental retardation, spastic quadriparesis, athetosis, epilepsy, and endo-

4.2.1.4 Associated Conditions

HPE may represent a part of several complex syndromic associations. Neural tube defects [74] and anterior cephaloceles [16] are much greater associations than is commonly thought. Smith-Lemli-Opitz syndrome is an autosomal recessive disorder of cholesterol biosynthesis. The syndrome involves poor growth, developmental delay, and a common pattern of congenital malformations including cleft palate, genital malformations, polydactyly, and HPE [75]. Because cholesterol is required for proper spatial restriction of Shh signaling [56], mutations of cholesterol synthesis may result in HPE.

Brain Malformations

CHARGE (Coloboma, Heart Anomaly, Retardation, Genital and Ear anomalies) has been rarely described in association with HPE [77]. 4.2.1.5 Imaging Studies

The MRI diagnosis of HPE is based on a careful assessment of the telencephalic structures, particularly in the basal regions, for noncleavage [61]. This can be difficult, especially in microcephalic newborns and when superimposed hydrocephalus further distorts the anatomy. Thin coronal sections, both on T1- and T2-weighted images, are especially important, and reassessment following decompression of the ventricular system may improve diagnostic accuracy [61]. The traditional classification into alobar, semilobar, and lobar HPE [60] reflects the graded severity of the malformation with respect to both the brain and face. Although this categorization is useful to give an idea of the severity of the picture, it has become apparent that several important features, such as cortical malformations and variations in separation of deep gray nuclei, cannot be incorporated into this classification scheme, and neurodevelopmental outcome cannot always be predicted accurately by this rather inflexible system [66]. As was previously stated, HPE should be viewed as a continuous spectrum of abnormality ranging from mild (i.e., lobar) to severe (i.e., alobar) forms, without precise boundaries among the three varieties. This concept is reflected clinically in a continuous phenotypic spectrum ranging from cyclopia at one extreme to clinically unaffected carriers of an HPE mutation at the other [56]. Several specific features have been used to assess the severity of the abnormality using MRI. These have included, traditionally, the degree of anterior extension of the corpus callosum [78, 79] which, however, is prone to subjective evaluation. Barkovich et al. [80] have proposed using the determination of the so-called sylvian angle to evaluate the severity of HPE. The sylvian angle is defined as the anterior intersection of two lines drawn to connect the anterior and posterior extremity of the insula in the axial plane. The sylvian angle progressively increases with the severity of the malformation; the mean value is 15° in normal individuals, 39° in lobar HPE, 63° in mild semilobar HPE, 101° in severe semilobar HPE, and 122° in alobar HPE [80]; in the most severe forms, no sylvian fissures are developed, thus identifying a category of “asylvian” HPE, which represents the most severe end of the HPE spectrum. The same authors found that as the severity of the malformation increases, the sylvian fissures are located more and more anteriorly with respect to the front of

the brain, and the amount of cerebral tissue that is comprised between them progressively diminishes [80]. More recently, noncleavage of the deep gray matter nuclei has been extensively analyzed by Simon et al. [66]. Contrary to other reports [81], these authors found that the degree of noncleavage of the deep gray matter nuclei is not always in direct proportion to the severity of the cerebral hemispheric malformation. Hypothalamic noncleavage was present in all cases, caudate noncleavage was found in 96% of cases, and 85% of cases showed some noncleavage of the lentiform nuclei. Noncleavage of the thalami occurred in 67% of patients in the same study, and abnormalities in orientation of the long axis of the thalamus were associated with the degree of thalamic noncleavage. Some degree of mesencephalic noncleavage, associated with the presence of thalamic noncleavage, was found in 27% of cases. These results show that the frequency of noncleavage in HPE is dependent on proximity to the midline and to the ventricular system. Structures normally located adjacent to the midline and/or ventricles (such as the cingulate cortex, caudate nucleus, and medial hypothalamus) are more frequently noncleaved than are structures normally located further from the midline or ventricles (such as the globus pallidus). Also, the involvement of more posterior brain structures, such as the thalamus (diencephalon) and midbrain (mesencephalon), decreases with distance from the anterior pole. This gradient of involvement in HPE may be related to the relative effectiveness of ventralizing signals from the notochord and prechordal plate [66]. In conclusion, it seems likely that the traditional classification into alobar, semilobar, and lobar HPE will sooner or later be dropped in favor of other more valuable classification schemes; however, we still believe it is useful to maintain the traditional classification in the present textbook, for didactic purposes. Alobar Holoprosencephaly

Alobar HPE traditionally designates complete failure of cleavage of the two cerebral hemispheres. The diagnosis of alobar HPE is usually made antenatally by ultrasounds (see Chap. 26), and may be confirmed by fetal MRI (see Chap. 27). Neonates are usually stillborn or have a very short life-span. Therefore, they are rarely imaged by MRI. Survivors can present with neonatal seizures and/or infantile spasms, profound mental retardation, rigidity, apnea, and temperature imbalance. Generalized epilepsy may develop during childhood [82]. Facial anomalies usually are severe and result from absence or hypoplasia of the premaxillary segment of the face [71].

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a Fig. 4.15a,b. Alobar holoprosencephaly. a Sagittal T1-weighted image; b. Axial T2-weighted image. There is a single rudimentary b ventricle that is continuous with a large dorsal CSF-filled cavity, the dorsal sac, which extends cranially to the calvarium (a, b). The brain is extremely rudimentary and uncleaved, i.e., midline structures such as the interhemispheric fissure and falx cerebri are thoroughly absent, while the deep white matter is continuous across the midline (b). The septum pellucidum is also absent. The posterior fossa is normal. (Case courtesy Dr. E. Simon, Philadelphia, PA, United States)

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Fig. 4.16a–d. Alobar holoprosencephaly. a Sagittal T2-weighted image; b Axial T2-weighted image; c Coronal T2-weighted image; d 3D TOF MRA, coronal MIP. The brain is reduced to a flattened pancake of tissue anteriorly (a). The holoventricle (asterisk, a, b) communicates widely with a large dorsal cyst (DC, a, b). The fused thalami are visible on coronal image (arrows, c). MRA shows agenesis of both anterior cerebral arteries (d)

Brain Malformations

The MRI picture reflects the pathological appearance of the malformation (Figs. 4.15, 4.16). The definition of alobar HPE involves absence of distinct temporal lobes and temporal horns of the lateral ventricles, and absent interhemispheric fissure [80]. The cerebrum is rudimentary, may be shaped like a pancake, cup, or ball [60], and is located in the cranialmost aspect of the calvarium. There is continuation of gray and white matter across the midline with absence of both interhemispheric fissure and falx cerebri. The brain surface may be smooth or have a few, broad gyri with shallow, abnormally oriented sulci; however, cortical thickness is normal. The only cortical malformation that has been found in alobar HPE in a large series was subcortical heterotopia [80]. Midline structures, such as the superior sagittal sinus, septum pellucidum, corpus callosum, third ventricle, pituitary gland, and olfactory bulbs, are absent; the optic nerves and chiasm are usually hypoplastic and poorly myelinated. The thalami, hypothalamus, and basal ganglia are not separated, resulting into absence of the third ventricle; usually, these rudimentary nuclei form a bilobed mass that abuts a single, rudimentary, crescent-shaped ventricle (“holoventricle”). The dorsal-most part of the rudimentary brain usually encompasses the holoventricle. When the dorsal lip of the brain does not roll over the holoventricle, the ependymal lining bulges dorsally and extends upward to the calvarium. This so-called “dorsal sac” or “dorsal cyst” is really the holoventricle itself. The presence of a dorsal cyst correlates with the presence and degree of thalamic noncleavage; it has been speculated that the unseparated thalamus mechanically blocks egress of cerebrospinal fluid from the third ventricle, resulting in ballooning of the posterior third ventricle to form the cyst [83]. The brainstem is usually grossly normal, except for absence of the pyramidal tracts. The cerebellum may be normal or small. If normal, it appears relatively large compared to the small cerebrum. The vascular system is commonly composed of a network of vessels arising from the internal carotid and basilar arteries [61]. The main differential diagnosis is with agenesis of the corpus callosum associated with large interhemispheric cysts. The diagnosis is mainly based on the assessment of the falx cerebri, which is absent in alobar holoprosencephaly and present, albeit usually displaced, in callosal agenesis with interhemispheric cysts.

Semilobar Holoprosencephaly

In semilobar HPE (Fig. 4.17), facial abnormalities are milder or even absent. The interhemispheric fissure and falx cerebri are present in the posterior regions of the brain, whereas there is failure of cleavage of the frontal and parietal lobes anteriorly. The brain is less dysmorphic than in alobar HPE, but is invariably smaller than normal. The holoventricle shows development of rudimentary temporal horns, although the hippocampus is usually incompletely formed; the frontal horns are not present. The thalami may be partially separated and a rudimentary third ventricle. The dorsal sac usually is absent. When present, it is usually smaller than in alobar HPE, and may be difficult to differentiate from an enlarged interhemispheric fissure. The corpus callosum is absent in the uncleaved regions, whereas a rudimentary commissure is present where the two cerebral hemispheres are separated. This so-called pseudosplenium gradually extends anteriorly as the severity of the forebrain malformation lessens, and has been considered a marker of the severity of the abnormality [78, 79]. It represents a notable exception to the rule of anterior-to-posterior development of the corpus callosum. HPE is the only anomaly in which isolated agenesis of the anterior segments of the corpus callosum is present, whereas it is the posterior aspect of the corpus callosum that is malformed in partial callosal agenesis [71]. Lobar Holoprosencephaly

Lobar HPE is the mildest form, usually found in asymptomatic or mildly retarded individuals. Lobar HPE (Fig. 4.18) implies the presence of the interhemispheric fissure with midline continuity of the neocortex [84] and some degree of formation of the frontal horns. Failure of cleavage usually involves the anterior and basal regions of the frontal lobes, other than the basal ganglia. The thalami usually are separate or may be joined by a broad interthalamic mass. The lateral ventricles are rather well-formed as compared with semilobar HPE. Abnormal vertical orientation of the hippocampal formation is a possible associated finding. An arrest of the normal process of hippocampal inversion was found in all patients with HPE in one study [85]. An azygous anterior cerebral artery is usually found. The septum pellucidum is constantly absent and the frontal horns are uncleaved, resulting in a rudimentary box-

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Fig. 4.17a–c. Semilobar holoprosencephaly. a Axial T2-weighted image; b Coronal STIR image; c Sagittal T2-weighted image. There is complete uncleavage of the frontal lobes (a, b) with absence of both the interhemispheric fissure and falx cerebri. Notice that both the interhemispheric fissure and falx are formed posteriorly (arrows, a), consistent with normal cleavage of the posterior regions of the brain. Correspondingly, the trigones of the lateral ventricles, albeit rudimentary, are formed, whereas there is agenesis of the frontal horns (a, b). There is an azygous anterior cerebral artery (arrowheads, a, c) that courses abnormally into a deeper median sulcus over the surface of the brain. The corpus callosum is absent except for the splenium (arrow, c). Notice concurrent Dandy-Walker variant (c)

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like shape on coronal sections, a feature in common with septo-optic dysplasia. Isolated absence of the septum pellucidum probably represents the mildest form of lobar HPE, and must be differentiated from septo-optic dysplasia. Assessment of the optic nerves does not reveal abnormalities in lobar HPE, unlike in septo-optic dysplasia. Differentiation between semilobar and lobar HPE can be difficult, as no clear-cut boundary exists between the two abnormalities. The degree of anterior extension of the “pseudosplenium” may be used as an approximate indicator of the severity of the noncleavage. If the third ventricle is fully formed, some frontal horn formation is present, and the splenium and posterior half of the callosal trunk are formed, the abnormality can be classified as lobar HPE [61].

4.2.2 Syntelencephaly (Middle Interhemispheric Holoprosencephaly) 4.2.2.1 Background

Syntelencephaly, or middle interhemispheric holoprosencephaly (MIH), was first described by Barkovich and Quint in 1993 [63]. Although initially considered a variant of semilobar HPE, MIH is typically characterized by failure of cleavage of the posterior frontal and parietal regions of the brain, in spite of separation of the rostrobasal forebrain, with presence of an interhemispheric fissure anteriorly. This represents a crucial difference from classical HPE, in

Brain Malformations

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Fig. 4.18a–c. Lobar holoprosencephaly. a Axial STIR image; b Coronal STIR image; c Sagittal T1-weighted image. Cleavage of the cerebral hemispheres is greater than in semilobar holoprosencephaly. In this case, there are rudimentary frontal horns. The anterior portions of the frontal lobes are uncleaved (asterisks, a, b), and the anterior interhemispheric fissure is absent; the bottom of an aberrant sulcus can be seen in this axial image (arrowhead, a). Notice that the septum pellucidum is absent (a), a constant feature of all variants of holoprosencephaly. On the midsagittal image, the corpus callosum is more developed and extends far more anteriorly than in semilobar forms (compare with Fig. 4.17); the degree of anterior extension of the corpus callosum (arrow, c) can be used as a rough indicator of the severity of the malformation.

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which the rostrobasal forebrain typically is involved. Another difference is the possible presence of the septum pellucidum [86]. MIH currently is viewed as a unique form of HPE [61], but could in fact represent a different malformation. Affected patients are usually severely developmentally retarded, but they have no facial deformities and either normal interorbital distance or, even, hypertelorism, contrary to typical HPE patients. However, we saw a patient with MIH and normal intelligence (IQ = 102). 4.2.2.2 Pathogenesis and Relationship with HPE

Although MIH and classical HPE share a number of similarities, including noncleavage of a substantial

portion of the cerebral hemispheres, abnormal anterior cerebral arterial circulation, and abnormal orientation of the sylvian fissures, significant differences exist between the two entities. This raises the question whether MIH should be regarded as a variant of HPE or, rather, as a separate entity. As was previously stated, classical HPE is regarded as a disorder of dorsoventral patterning due to excessive ventralization of the neural tube at level of the floor plate. Instead, MIH can be viewed as excessive dorsalization of the neural tube at level of the roof plate. Interestingly, a mutation of the ZIC2 gene has been found in a patient with MIH [87]. ZIC2 plays an important role in differentiation of the roof plate and in the development of the interhemispheric fissure, thereby explaining the prevalence of abnormalities at the level of the

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dorsal portions of the brain in MIH. These data seem to support the hypothesis that MIH is an abnormality of dorsal induction, contrary to classical HPE, which is produced by abnormal ventral induction. As such, a future genetic classification scheme could lead to a separation of these entities into different categories. 4.2.2.3 Imaging Findings

MIH is characterized by defective cleavage of the two cerebral hemispheres at the level of the posterior frontal and parietal lobes, with resulting “fusion” across the midline at the level of the oval centers and absence of the corresponding part of the interhemispheric fis-

sure. The corpus callosum is typically hypoplastic. A thinned genu and anterior trunk are present in some cases (Fig. 4.19). In others, the corpus callosum is separated in two distinct anterior and posterior portions (Fig. 4.20). The nervous tissue that bridges the midline may be represented by a heterotopic nodule or by cortical dysplasia [88]; in the majority of cases, the sylvian fissures are abnormally connected across the midline [87]. In MIH, cleavage of deep gray nuclei occurs differently than in classical HPE; significantly, the hypothalamus (which is consistently involved in classical HPE) is always cleaved with intervening formation of the third ventricle [87]; the lentiform nuclei are also consistently cleaved, whereas the caudate nuclei are separated in the majority of cases. Failure

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d Fig. 4.19a–d. Syntelencephaly. a Sagittal T1-weighted image; b Sagittal T2-weighted image; c, d Coronal T2-weighted images. Cerebral hemispheres are uncleaved in the parietal region, where cortical dysplasia is seen to connect the two hemispheres (arrowheads, a–d). Anteriorly, the corpus callosum is reduced to a thin lamina (arrows, a, b). An azygous anterior cerebral artery is present (open arrows, a, b)

Brain Malformations

a

b Fig. 4.20a–c. Syntelencephaly in a mildly hypotonic patient with normal intelligence (IQ = 102). a Axial T2-weighted image; b Coronal STIR image; c Sagittal T1-weighted image. On axial images, lateral ventricles have a rudimentary shape and the septum pellucidum is absent; however, normally developed interhemispheric fissure both anteriorly and posteriorly (arrows, a) would not suggest holoprosencephaly at first glance. However, coronal images clearly show a thin sling of normal-appearing cortex bridging the midline just below the callosomarginal sulcus (arrowheads, b); notice that cortex should never be found between the commissural plate and the callosomarginal sulcus in normal individuals. This bridging cortex represents the site of uncleavage of the two cerebral hemispheres. On sagittal images, partial intermediate agenesis of the corpus callosum is found, with both the genu (G) and splenium (S); and an intervening thin hyperintense commissural structure (arrows, c). One could speculate that the developmental defect prevented normal fasciculation of the callosal fibers over the hippocampal commissure, whereas both the genu (whose development follows the glial sling) and posterior splenium did develop more appropriately (see Chap. 3 for thorough discussion)

c

of cleavage involves more commonly the thalami, and the mesencephalon in a minority of patients [87]. The arterial tree is nearly normal, although an azygous anterior cerebral artery is usually present [61].

4.2.3 Septo-Optic Dysplasia 4.2.3.1 Background

Septo-optic dysplasia (SOD), first described by De Morsier in 1956 [89], is characterized by the association of optic nerve hypoplasia and absence or hypoplasia of the septum pellucidum. As knowledge

evolved, it gradually became clear that SOD is, in fact, a constellation of lesions that can also include pituitary-hypothalamic dysfunction, olfactory aplasia, and brain abnormalities, such as schizencephaly, cortical dysplasia, and agenesis of the corpus callosum. This apparent heterogeneity has resulted in some disagreement as to whether SOD should be regarded as a single precisely defined entity or, rather, a group of heterogeneous cases [1]. 4.2.3.2 Pathogenesis

Recent studies by Dattani et al. [90] led to the identification of a homeobox gene, Hesx 1, whose absence is believed to be related with SOD. Hesx1, which encodes

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a pituitary transcription factor, is first expressed during gastrulation in the mouse embryo. Hesx1 expression begins in prospective forebrain tissue but later becomes restricted to the Rathke’s pouch, the primordium of the anterior pituitary gland. Transgenic mice lacking Hesx1 exhibit a phenotype comprising variable anterior CNS defects, such as a reduced prosencephalon, abnormalities in the corpus callosum and septum pellucidum, anophthalmia or microphthalmia, defective olfactory development, and bifurcations of the Rathke’s pouch with pituitary dysplasia. A comparable and highly variable phenotype in humans is SOD. In the Dattani et al. study, two siblings with SOD were homozygous for a missense mutation within the HESX1 homeobox, suggesting a vital role for Hesx1 in forebrain and pituitary development, and hence in some cases of SOD, in humans [90]. Other authors [91] postulated that SOD could result from vascular disruption, possibly involving the proximal trunk of the anterior cerebral artery. SOD was also described in association with maternal exposure to valproic acid throughout pregnancy [92]. 4.2.3.3 Clinical Findings

The clinical picture exhibited by children with SOD is highly variable. Visual disturbances may range from blindness to nystagmus to normal vision [93]. Hypothalamic-pituitary dysfunction, mainly represented by growth deficit, is seen in approximately two thirds of patients [62, 79]. About half of patients have schizencephaly, and usually present with seizures [62, 79, 93]. Spastic motor deficits may be related to other malformations of cortical development, such as polymicrogyria. Developmental delay is also found in patients with associated cortical malformations. Anosmia is present in cases with associated abnormalities of the olfactory pathways. On the basis of the spectrum of associated abnormalities and the corresponding clinical features, SOD can be categorized into [94]: (i) isolated SOD, presenting with endocrine dysfunction, and (ii) SOD-plus, in which schizencephaly or other cortical malformations are associated; these patients usually present with seizures and/or spastic motor deficit associated with neurodevelopmental delay.

4.2.3.4 Imaging Findings Isolated SOD

Absence of the septum pellucidum is easily recognized in both axial and coronal MR images (Fig. 4.21). In the latter, the frontal horns may display a box-like squared shape that resembles that seen in mild forms of holoprosencephaly. The septum pellucidum is not confidently assessed in the sagittal plane; however, an indirect sign of its absence is a lowering of the fornix, which adjoins the corpus callosum only at the level of the inferior surface of the splenium. Moreover, the anterior columns of the fornix may be fused along the midline. The septum pellucidum is usually thoroughly absent in patients with isolated SOD [93]. One should note that septal agenesis may seldom be isolated, in which case patients usually are asymptomatic. Therefore, all patients with an apparently isolated agenesis of the septum pellucidum should be actively scrutinized for other abnormalities of the SOD spectrum. Hypoplasia of the optic nerves is readily assessed with high-resolution, thin-slice MR images, and is confirmed at ophthalmological examination. Only one nerve may be involved in some cases. Hypoplasia of the optic chiasm causes enlargement of the anterior recesses of the third ventricle, and may be associated with a small pituitary gland. White matter hypoplasia of the cerebral hemispheres may be restricted to the optic radiations or may be diffuse, in which case ventriculomegaly results. Diffuse white matter hypoplasia is characteristically associated with isolated SOD (83% of cases), whereas it typically is absent in SOD-plus [93]. SOD-Plus

Unlike isolated SOD, a remnant of the septum may be found in patients with SOD-plus [93] (Fig. 4.22). The spectrum of brain malformations that are found in SOD-plus is probably wider than was initially suspected. Schizencephaly is the most consistent among these malformations; gray-matter lined holohemispheric clefts may be unilateral or bilateral, and may be multiple in a minority of cases. Clefts may vary in size from fused to open lips. The corpus callosum may show focal thinning correlating to cleft location [93], and may rarely be thoroughly absent [95].

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Brain Malformations Fig. 4.21a–c. Isolated septo-optic dysplasia. a Sagittal T1weighted image; b Coronal T1-weighted image; c Axial T2weighted image. There is moderate hypoplasia of the optic chiasm (arrow, a–c) and both optic nerves (arrowheads, c). Notice marked hypertelorism (c). There is agenesis of the septum pellucidum (asterisk, b). Notice that the fornix (open arrows, a) adjoins the corpus callosum at the inferior surface of the splenium, a typical indicator of septal agenesis

a

b

c

Polymicrogyria has been recently recognized as a possible component of the SOD-plus spectrum [94, 96]; it can be isolated or coexist with schizencephaly, possibly involving the contralateral hemisphere in case of unilateral clefts.

4.2.4 Kallmann Syndrome 4.2.4.1 Background

Kallmann syndrome (KS) is a form of congenital hypogonadotropic hypogonadism associated with

hyposmia or anosmia [97]. The olfactory disturbance is caused by hypoplasia or aplasia of the olfactory bulbs and tracts, whereas hypogonadism is related to deficient incretion of gonadotropin-releasing hormone (GnRH), resulting in failure of adenohypophyseal stimulation to synthesize and secrete luteinizing and folliculo-stimulating hormones. KS is more frequent in males, and can be transmitted with X-linked, autosomal recessive, or autosomal dominant modes of inheritance. Mutations of the KAL gene, located at Xp22.3, have been demonstrated to cause X-linked KS [98, 99]. The Kal protein is involved in both neuronal migration of the olfactory placode and axonal pathfinding. Moreover, KAL expression is also required for the normal development of the kidney in the first

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d

a

b

c

e

Fig. 4.22a–e. Septo-optic dysplasia plus. a Sagittal T1-weighted image; b, c Coronal STIR images; d Axial T2-weighted image, e Axial STIR image. Marked hypoplasia of the optic chiasm (white arrow, a) and both optic nerves (arrowheads, c, d), associated with agenesis of the septum pellucidum (asterisk, b, e). Also in this case, the fornix adjoins the corpus callosum at the inferior surface of the splenium (open arrows, a). There is a schizencephalic cleft in the right fronto-basal region (arrow, c). Diffuse abnormalities of cortical organization are also visible (arrowheads, b, e)

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trimester of pregnancy, accounting for frequent concurrent renal abnormalities in X-linked KS [100]. 4.2.4.2 Pathogenesis

KS is considered a migrational abnormality involving the olfactory placode. In normal conditions [101], cells and fibers originating from the olfactory placodes in the cephalic nasal fossa migrate towards the telencephalic vesicles to form the olfactory nerves laterally, and the terminal and vomeronasal nerves medially. In response, the telencephalic vesicles are induced to form the olfactory bulbs, which represent ventricular diverticula around which the olfactory nerve fibers wrap. Thus, neuronal migration from the olfactory placode to the telencephalon is required to induce formation of the olfactory bulbs. In addition, the terminal and vomeronasal nerves form a scaffold along which GnRH-secreting neurons originating from the medial olfactory placode migrate into the forebrain to their eventual hypothalamic and septal locations. In KS, projections from the lateral olfactory placode to the brain are insufficient to induce adequate formation of the olfactory bulbs [101]. Aplasia of the olfactory bulbs results in lack of formation of the olfactory sulci over the inferomedial surface of the frontal lobes. Moreover, there is failed migration of GnRHsecreting neurons to their eventual location in the hypothalamus [102], resulting into inability of the adenohypophysis to synthesize and secrete luteinizing and folliculo-stimulating hormones.

a

Imaging Findings

b

High resolution, thin-slice coronal MRI sections covering the anterior cranial fossa (i.e., from the back of the frontal sinus to the hypothalamus) on both T1and T2-weighted images must be obtained in order to adequately display the abnormality of the olfactory system. Sagittal T1-weighted images are also mandatory to study the sella turcica. The MRI diagnosis of KS involves [101, 103, 104] (Fig. 4.23):

Fig. 4.23a,b. Kallmann syndrome. a Coronal T2-weighted image, b Sagittal T1-weighted image. Absence of the olfactory sulci (arrows, a) and bulbi (arrowheads, b) is shown on coronal planes. Global hypoplasia of the pituitary gland is recognizable on sagittal image (b). The pons is also hypoplastic

1) olfactory bulb, tract, and sulcus aplasia/hypoplasia. There is absent visualization of the olfactory bulbs associated with flattened gyri recti due to lack of formation of the corresponding sulci. In case of olfactory bulb hypoplasia, smaller than normal bulbs associated with rudimentary sulcal formation are visualized [101]. Asymmetry of the two sides is possible, and correlates with asymmetric olfactory function [101].

2) Hypothalamic-hypophyseal abnormalities. Because of the small contribution to the overall size of the hypothalamus by GnRH-releasing cells, the hypothalamus is macroscopically normal [101]. However, a small anterior pituitary lobe can result from insufficient adenohypophyseal stimulation. The posterior pituitary lobe is normal.

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4.3 Malformations of Cortical Development 4.3.1 Background Malformations of cortical development (MCD) encompass a large amount of abnormalities that result from interruption of the orderly process of generation and maturation of the cerebral cortex. Until recently, the concept of MCD basically implied that neurons failed to complete their journey from their site of origin in the periventricular germinal matrix to their final resting place in the cortical mantle, and therefore remained somewhere along their migratory route [1]; therefore, MCD were usually referred to as “disorders of neuronal migration.” However, neuronal migration is one of a host of extremely complex, partially overlapping maturational processes that can be basically grouped into three major steps, i.e., (i) neuronal/ glial proliferation, (ii) neuronal migration, and (iii) cortical organization. As a consequence, current classification of MCD basically rests on the attribution of individual malformations to malfunction of one of the above processes [7, 105]. MCD are the single category of CNS malformation whose understanding has changed more dramatically in the past decade. A substantial part of this development must be credited to MRI, which has allowed identification of MCD with increasing frequency in patients with apparently heterogeneous conditions such as epilepsy, developmental delay, cognitive dysfunction, and congenital neurologic disorders; recent evidence suggests that greater than 50% of children referred for intractable seizures to epilepsy centers have different forms of developmental pathology [105]. Moreover, biochemical and genetic research has made it possible to accumulate knowledge regarding both normal and abnormal cortical development, to identify new clinico-pathologic entities, and to elucidate specific genetic and acquired etiologies [106, 107]. A detailed description of this immense body of knowledge is beyond the scope of this paper. Here, a primer on normal cortical development will be followed by a discussion of the main entities, based on the framework of the updated classification of MCD published by Barkovich et al. in 2001 [7].

4.3.2 Normal Cortical Development At least a basic understanding of the complex events that ultimately lead to the formation of the six-layered human cerebral cortex is essential in order to understand the disorders of its development [108]. The normal cerebral neocortex is a thin ribbon whose thickness does not exceed 4.5 mm, organized into six layers [109]. The main events that characterize cortical development can be organized in three basic steps, as was previously stated. However, one should not forget that cortical development is, in fact, a continuous process. Its separation into three periods, albeit somewhat artificial, is useful to understand both normal and abnormal development. Knowledge of the factors involved in these mechanisms is far from complete. To date, over a dozen molecules that are peculiar to cortical development have been reported [110, 111]. Mutations of genes encoding some of these molecules have been demonstrated to cause MCD in humans (Table 4.3). Cell Proliferation and Apoptosis

Neurons that will eventually rest in the cortical mantle are generated in the germinal matrix along the ventricular margins of the embryonic cerebral wall. Stem cells of the germinal matrix are common progenitors to neurons and glia. Programmed cell death, or apoptosis, plays an important role in forebrain growth by modulating the production of certain stem cell populations while sparing others, i.e., modulating the number of early progenitors before the onset of neurogenesis; about 25%–50% of all generated neuroblasts are eliminated by apoptosis [112]. Stem cells in the germinal matrix undergo rapid mitosis which results in exponential increase of the founder cell population [113]. In the human neocortex at week 6 of gestation, proliferation is confined to the ventricular zone, or neuroepithelium. Cell division is symmetric, with both daughter cells re-entering mitosis. At week 7, the subventricular zone, a secondary proliferative zone, appears. It mainly gives rise to local circuit neurons and glial cells. Around week 12, the ventricular and subventricular zones are thickest, indicating that proliferation peaks at this stage [114]. Thereafter, asymmetric division becomes the predominant mode of proliferation, with one daughter cell re-entering mitosis and the other one migrating out into the cortical mantle. As neuronal proliferation proceeds, the germinal matrix progressively recedes. Eventually, it is transformed into a germinal source for ependymal cells [108]. Generation of neurons basi-

Brain Malformations Table 4.3. Genetic basis of human MCD (modified from references # 4 and 111) Gene

Locus

Encoded molecule

DISORDERS OF NEURONAL/GLIAL PROLIFERATION/APOPTOSIS TSC1 9q34 Hamartin

TSC2

16p13.3

Tuberin

DISORDERS OF NEURONAL MIGRATION (initial course) FLM1 Xq28 Filamin-1 DISORDERS OF NEURONAL MIGRATION (middle course) LIS1 17p13.3 Platelet activating factor acetylhydrolase 1bl (Pafah1bl)

Suspected role

Human mutation phenotype

Growth inhibitory (tumor suppressor) protein

•Tuberous sclerosis complex 1 •Focal cortical dysplasia, Taylor balloon cell type

Growth inhibitory (tumor suppressor) protein

Tuberous sclerosis complex 2

Actin crosslinking phosphoprotein

Bilateral periventricular nodular heterotopia

Signaling/tubulin cytoskeletal dynamics

•Miller-Dieker syndrome •Lissencephaly (isolated lissencephaly sequence) (class LISa1-4) •Lissencephaly with cerebellar hypoplasia (LCH) (class LCHa)

DCX/XLIS

Xq22.3-q23

Doublecortin

Microtubule associated protein-cytoskeletal dynamics

•Double cortex or subcortical band heterotopia •X-linked lissencephaly (class LISb1-4) •LCH (class LCHa)

FCMD

9q31

Fukutin

Putative extracellular matrix molecule

Fukuyama congenital muscular dystrophy

POMGNT1

1p34-p33

Protein 0-mannose β-1, 2-N-acetylglucosaminyltransferase

Putative extracellular matrix molecule

Muscle-eye-brain disease

POMT1

9q34.1

Protein 0-mannosyltransferase 1

Endoplasmic reticulum molecule – required for cell integrity and cell wall rigidity

Walker-Warburg syndrome

ASTN

1q25

Astrotactin

Neuronal adhesion molecule

LCH? (mouse model)

KAL1

Xp22.3

Anosmin

Extracellular matrix molecule

Kallmann syndrome

Extracellular matrix molecule

LCH (class LCHb)

DISORDERS OF NEURONAL MIGRATION (late course) RELN 7q22 Reelin DAB1

1p32-p31

Disabled

Docking protein for cAbl tyrosine kinase, intracellular signaling

LCH? (predicted, based on similarity of RELN and DAB mutant mice)

L1-NCAM

Xq28

Neural cell adhesion molecule L1

Neural recognition molecule

X-linked hydrocephalus and pachygyria

Transcription factor

Schizencephaly (rare cases)

DISORDERS OF CORTICAL ORGANIZATION EMX2 10q26.1 Empty spiracles

MALFORMATIONS OF CORTICAL DEVELOPMENT, NOT OTHERWISE SPECIFIED PEX1, 2, 3, 5, 6

7q21 (PEX1) 8q (PEX2) 6q (PEX3) 12 (PEX5) 6p (PEX6)

Peroxisomal proteins

Zellweger syndrome

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cally occurs in two bursts, the first from 8 to 10 weeks and the next from 12 to 14 weeks [115]. By 16 weeks, most of the neurons have been generated and have started their migration into the cortex [1]. Neuronal Migration

Migrating cell Nucleus

Neuronal migration basically consists of two different mechanisms according to the involved cell type. Excitatory glutamatergic projection neurons are generated from the germinal matrix in the ventricular zone by a process of radial migration, whereas most inhibitory gamma-aminobutyric acid (GABA)ergic interneurons (as well as oligodendrocytes) are elaborated from ventral forebrain stem cells that undergo tangential migration [116].

Leading process Radial fiber

Trailing process

Radial Migration

Radial migration is the better known and most widely studied of the two mechanisms. According to the radial unit hypothesis, the ependymal layer of the embryonic cerebral ventricle consists of proliferative units that provide a proto-map of prospective cytoarchitectonic areas [115]; the columnar organization of the cortex arises through large numbers of neuronal precursors using a “point to point” radial migration from the ventricular zone to the cortical plate [117]. Neuronal migration is initially simple, and involves cell elongation with displacement of the nucleus to the cell end farthest from the ventricular lining, followed by detachment of the cell from the ventricular surface. As the thickness of the cerebrum increases, migration becomes more complex. Subsequent waves of migrating neurons migrate to their final destination along radial glial cells that extend long, unbranched processes from the ventricular zone lining the lateral ventricle out to the cortical pial surface (Fig. 4.24). Groups of 4–10 radial glial cells form glial fascicles that provide a scaffold and supply metabolites for the migrating neurons, and organize the vertical lamination of the developing neocortical plate [118]. Regulatory mechanisms for neuronal migration probably involve [111]: (i) a “go” signal; (ii) regulation of adhesive and contractile elements producing a net cell movement when the cytoskeleton contracts; (iii) determination of direction or vector of movement; and (iv) a “stop” signal when the final destination into the cortex has been reached. Development of the neocortex starts with the establishment of a primordial plexiform layer (PPL), representing a primitive cortical organization which is shared by amphibians, reptiles, and mammals [119, 120]. The molecular layer (layer 1) and the transient

Fig. 4.24. Schematic of radial neuronal migration. Neurons migrate from the germinal matrix to their final cortical destination along radial glial cells that extend long, unbranched processes from the ventricular zone lining the lateral ventricle out to the cortical pial surface. (Modified from [1])

layer 7, or subplate, derive from the PPL. The formation of the PPL is required for subsequent formation of the cortical plate, from which the remaining layers of the neocortex derive. Specialized layer 1 neurons, called Cajal-Retzius (CR) cells, secrete reelin, a glycoprotein which attracts the migrating neurons toward layer 1 and determines their detachment from the radial glia. All migrating neurons, guided by the radial glia, must reach layer 1, establish contacts with CR cells, develop an apical dendrite, and become pyramidal cells [119, 120]. Without losing either their original contact with layer 1 or their cortical level, each neuron elongates its apical dendrite to accommodate the arrival of subsequent neurons [119, 120], so that each newly generated cohort of neurons migrates past the previously formed neurons. This accounts for the orderly “inside-out” formation of subsequent layers, beginning from layer 6 and ending with layer 2 [108]. In the meantime, proliferation occurring in the subplate results in formation of glial cells [114]; other astrocytes develop from the radial glia. Tangential Migration

Recent data on the development of the mammalian neocortex show that cells originating from the gan-

Brain Malformations

glionic eminences in the subpallium (future basal ganglia) migrate tangentially into the pallium. These tangentially migrating cells are a significant source of cortical inhibitory GABAergic interneurons, accounting for approximately 15%–30% of the total neuronal population, and possibly other cell types such as oligodendrocytes [117, 121]. Cells undergoing tangential migration must travel long distances to their sites of residence. While some attach to the existing neocortical radial glial scaffold after having entered the cortical plate [122], others probably interact with their migrating neighbors to provide a foothold for their movement [123]. Alternatively, these migrating cells may use as yet uncharacterized modes of migration to facilitate their movement [117]. In contrast to radial migration, where genetic analyses have provided a framework for the underlying molecular mechanisms, much remains unknown about the cues that guide nonradial migration, although a role for the same guidance molecules used to guide the outgrowth of neuronal growth cones is suspected [117]. Although many questions regarding tangential migration in the developing telencephalon are still unresolved, it is already apparent that this type of migration is extremely widespread, and that there probably are further pathways of migration yet to be discovered [117]. Cortical Organization

After proliferation and migration have occurred, local intracortical growth of cells and processes will determine the final appearance of the cortex [1]. The laminated cortical pattern becomes evident around 23–25 weeks of gestation, the age at which large neurons can first be seen within layer 5 [1]. Subsequent events involve growth in size of the neurons, axonal sprouting, formation of the dendrites, and development of synapses. Growth of neuron cell bodies and their processes, as well as of glia, is related to formation of the gyri and sulci. Gyrus formation is also associated with the arrival of thalamo-cortical and cortico-cortical axons into the cortex [124]. The molecular forces that underlie the invasion by axons into specific cortical layers followed by activity-dependent maturation of synapses are poorly understood. An important role in cortical target selection and ingrowth is played by subplate neurons. These are the first postmitotic neurons in the neocortex, located in the transient layer 7, or subplate. Afferent axons accumulate in the subplate before selecting their final destination in the cortical plate, and their close association to subplate neurons is crucial for this process [125].

Subplate neurons are also likely to provide important cues that aid the process by which cortical axons grow toward, select, and invade their subcortical targets [126].

4.3.3 Classification of MCD Barkovich et al. [105] are credited for conceiving the first modern classification scheme of MCD. This scheme is based upon categorization into three main groups according to the developmental step that is preferentially involved, plus a fourth group of unknown etiologies. These authors introduced an updated version in 2001 [7], whose framework will be used here to describe individual malformations (Table 4.4). Because new data are rapidly added to the already consistent body of knowledge regarding normal and abnormal cortical development, it is likely that further revisions will be introduced in the near future. Controversies in classification still exists, and will also tentatively be addressed here.

4.3.4 Malformations Due to Abnormal Neuronal/Glial Proliferation or Apoptosis

4.3.4.1 Microcephaly

Microcephaly is defined as head circumference 2 standard deviations or more below the age-matched norm [7]. At present, classification of microcephalies is, to say the least, nebulous. Differentiation from microlissencephaly (MLIS) is based on cortical thickness, which is normal to reduced in microcephaly and increased in MLIS. Microcephaly is basically classified in three categories [7], i.e., (i) primary microcephaly, or microcephalia vera (Fig. 4.25); (ii) extreme microcephaly with simplified gyral pattern (defined as occipitofrontal circumference of at least 3 standard deviations below the mean at birth) (Fig. 4.26); and (iii) extreme microcephaly associated with either polymicrogyria (Fig. 4.27) or corpus callosum agenesis and cortical dysplasia. This categorization is probably rather arbitrary, and overlap among the various entities is likely to exist [7]. Furthermore, it should also be considered that, in the event of an association with polymicrogyria, it may be difficult to assess whether microcephaly or polymicrogyria

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P. Tortori-Donati, A. Rossi, and R. Biancheri Table 4.4. Classification scheme for MCD [7] I. Malformations due to abnormal neuronal/glial proliferation or apoptosis A. Decreased proliferation/Increased apoptosis: Microcephalies 1. Microcephaly with normal to thin cortex 2. Microlissencephaly (extreme microcephaly with thick cortex) 3. Microcephaly with polymicrogyria/cortical dysplasia B. Increased proliferation/decreased apoptosis (normal cell types): 1. Megalencephalies C. Abnormal proliferation (abnormal cell types): 1. Non-neoplastic a. Cortical hamartomas of tuberous sclerosis b. Cortical dysplasia with balloon cells c. Hemimegalencephaly 2. Neoplastic a. DNT (dysembryoplastic neuroepithelial tumor) b. Ganglioglioma c. Gangliocytoma II. Malformations due to abnormal neuronal migration A. Lissencephalies 1. Classical lissencephaly-subcortical band heterotopia spectrum 2. X-linked lissencephaly with agenesis of the corpus callosum 3. Lissencephaly with cerebellar hypoplasia 4. Lissencephaly, not otherwise classified B. Cobblestone complex 1. Congenital muscular dystrophy syndromes a. Walker-Warburg syndrome b. Fukuyama congenital muscular dystrophy c. Muscle-eye-brain disease 2. Isolated cobblestone complex C. Heterotopia 1. Subependymal (periventricular) 2. Subcortical (other than Band Heterotopia) 3. Marginal glioneuronal III. Malformations due to abnormal cortical organization (including late neuronal migration) A. Polymicrogyria and schizencephaly 1. Bilateral polymicrogyria syndromes 2. Schizencephaly (polymicrogyria with clefts) 3. Polymicrogyria with other brain malformations or abnormalities 4. Polymicrogyria or schizencephaly as part of multiple congenital anomaly/mental retardation syndromes B. Cortical dysplasia without balloon cells C. Microdysgenesis IV. Malformations of cortical development, not otherwise classified A. Malformations secondary to inborn errors of metabolism 1. Mitochondrial and pyruvate metabolic disorders 2. Peroxisomal disorders B. Other unclassified malformations 1. Sublobar dysplasia 2. Others

a

b

c Fig. 4.25a–c. Primary microcephaly (microcephalia vera). a. Sagittal T1-weighted image; b, c. Axial STIR images. The brain is smaller than normal, but shows normal convolutional pattern and cortical thickness. Small frontal horns and slightly receding frontal convexity indicate underdevelopment of the frontal lobes

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are the primary event in the determination of the eventual picture. Microcephaly is believed to result from early exhaustion of the germinal matrices or abnormal apoptotic events [7]. Primitive microcephaly must be differentiated from microcephaly secondary to congenital TORCH infection [127], in which polymicrogyria also may be associated (Fig. 4.28). Clinically, patients with microcephalia vera are less severely affected than those with extreme microcephaly. The former have a normal prenatal course and present with developmental delay and mild corticospinal tract signs in infancy. Normal intelligence has been rarely reported [128]. The latter are severely hypotonic at birth and rapidly develop myoclonic seizures [129]. Early death is common in this patient group. On neuroimaging studies, microcephaly is characterized by a markedly small brain with a normal to thin, smooth cortex, surrounded by enlarged CSF spaces [128]. The gyral pattern is normal in primary microcephaly (Fig. 4.25), and simplified in extreme microcephaly (i.e., oligogyria) [129] (Fig. 4.26). The degree of cerebral gyration and sulcation can be difficult to assess; the van der Knaap score [130] may be helpful. Associated polymicrogyria (Fig. 4.27) or callosal dysgenesis can be found.

a

4.3.4.2 Microlissencephaly

The definition of MLIS [7] involves extreme microcephaly (i.e., occipitofrontal circumference of at least 3 standard deviations below the age-matched norm) associated with thick cortex. As such, cortical thickness is the main determinant in the differentiation between microcephaly and MLIS. Thus, the term MLIS is presently used less loosely than in the recent past [7, 131]. As with other microcephalies, MLIS is believed to result from early exhaustion of the germinal matrices, resulting in reduced progenitor cell proliferation, possibly associated with increased or abnormal apoptotic events. Clinically, affected patients seem to be very similar to those with extreme microcephaly belonging to the microcephaly group. The neonatal course is typically abnormal, with either severe hypotonia or hypertonia, myoclonic seizures, and possible early death. Delayed myelination can be associated in some patients [131]. A categorization of MLIS into five patient groups based on combined clinical and imaging features [131] was published before the reorganization of microcephalies and microlissencephaly into different groups [7]. Therefore, further investigations are awaited

b Fig. 4.26a,b. Extreme microcephaly with simplified gyral pattern. a Sagittal T1-weighted image; b Axial T2-weighted image. There is marked decrease in head circumference; notice the slanted frontal convexity with size preponderance of the face with respect to the calvarium (a). The gyral pattern is simplified with too few, rudimentary convolutions; however, cortical thickness is normal (b). Notice marked thinning, but not dysgenesis, of the corpus callosum (arrows, a). (Case courtesy of Dr. Z. Patay, Riyadh, Saudi Arabia)

to shed light on clinical and prognostic differences between the two entities. Clinical entities showing a microlissencephalic appearance of the brain include the Norman-Roberts syndrome, characterized by microcephaly, bitemporal hollowing, low sloping forehead, slightly prominent occiput, widely set eyes, broad and prominent nasal bridge, and severe postnatal growth deficiency. Hypertonia, hyperreflexia, seizures, and profound mental retardation are also present [132].

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a Fig. 4.28. Microcephaly secondary to congenital TORCH infection. Axial CT scan. There is diffuse bilateral polymicrogyria associated with widespread calcified foci in the deep white matter

MRI detects a markedly small brain; the gyral pattern is simplified, with few gyri and shallow sulci or even complete agyria [131, 133]. The corpus callosum may be absent, and the cortical mantle is variably thickened (Fig. 4.29). MLIS can coexist with cerebellar hypoplasia within the heterogeneous group of lissencephalies with cerebellar hypoplasia (LCH). According to current classifications, six subgroups of LCH are recognized, called a to f [134]. All these groups are characterized by microcephaly, that is extreme (greater than 3 standard deviations from norm) in LCH types c, d, and f. According to Barkovich’s definition [7], these types meet the criteria for MLIS. In these types, MLIS is associated with moderate to severe cerebellar hypoplasia and mild to moderate brainstem hypoplasia. Cortical thickness is increased. The corpus callosum is absent in LCH type f. LCH is discussed in greater detail in a following section.

b

c Fig. 4.27a–c. Extreme microcephaly with polymicrogyria. a Sagittal T1-weighted image; b Axial T2-weighted image; c Coronal STIR image. There is extreme microcephaly. The brain is small and shows diffuse perisylvian and parietal polymicrogyria (b, c). The corpus callosum is macroscopically normal; however, it apparently lies more posteriorly than normal on sagittal views (a), consistent with underdevelopment of the posterior brain as opposed to some preservation of the frontal lobes. The posterior fossa is grossly normal. The extreme degree of microcephaly differentiates this entity from syndromic bilateral polymicrogyria

4.3.4.3 Megalencephaly

Megalencephaly is defined as a brain volume which exceeds the mean by more than twice the standard deviation or is above the 98th percentile [135]. Primary (i.e., anatomic) megalencephaly results from increased proliferation of normal cell populations [7]. As such, it must be differentiated from other condi-

Brain Malformations

tions in which megalencephaly represents a secondary condition, such as metabolic megalencephalies [7, 136]. Megalencephaly affects the brain as a whole. This represents a notable difference from hemimegalencephaly (HME), in which volume increase is unilateral. Classification of anatomic megalencephaly is difficult. Familial and sporadic forms exist; in the familial forms, a benign, autosomal dominant form and a symptomatic, autosomal dominant or recessive form are identified [1]. Clinical syndromes with megalencephaly are numerous. Some will be briefly discussed here. Sotos Syndrome (Cerebral Gigantism)

This autosomal dominant syndrome is characterized by excessively rapid growth, acromegalic features, advanced bone age, and a nonprogressive cerebral disorder with mental retardation [137]. A 5q35 microdeletion, encompassing the NSD1 gene, was reported as the major cause [138, 139]. As with other overgrowth syndromes, children with Sotos syndrome are at risk for subsequent development of cancer [140]. MRI shows a large brain with normal gyration (Fig. 4.30) except for rare gray matter heterotopia. Prominence of the whole, or parts of, the ventricular system is common, as well as thinning of the posterior portions of the corpus callosum, possibly as a result of deficient or inadequate development of the posterior cerebral white matter.

a

Megalencephaly with Megalic Corpus Callosum b

Gohlich et al. [141] described three patients with head circumference above the 97th percentile at birth, who completely lacked motor and speech development and showed very little intellectual progress. Frontal bossing, low nose bridge, and large eyes resulted in a characteristic facies. MRI showed bilateral megalencephaly with a broad corpus callosum, enlarged white matter, and focally thick gray matter, resulting in a pachygyric appearance of the cortex. Sylvian opercularization was incomplete. Megalencephaly-Polymicrogyria-Hydrocephalus Syndrome

c Fig. 4.29a–c. Microlissencephaly. a Sagittal T1-weighted image; b Axial T2-weighted image; c Coronal T2-weighted image. Head circumference is markedly reduced. The cerebral cortex is thickened, with a pachygyric appearance (b, c). There is associated agenesis of the corpus callosum (a). (Case courtesy of Dr. Z. Patay, Riyadh, Saudi Arabia)

Hayashi et al. [142] described the autopsy finding of hydrocephalus, brain overweight after complete CSF removal, and bilateral frontoparietal polymicrogyria in a child with severe growth failure, frequent hypoglycemia, and cardiac malformations.

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lesions, usually angiomyolipomas, and cardiac rhabdomyomas. Two genetic forms of the disease exist, TSC1 and TSC2, caused by mutations in the TSC1 gene on chromosome 9 and the TSC2 gene on chromosome 16, respectively. The products of these genes, hamartin and tuberin, are growth inhibitory proteins playing a crucial role in tumor suppression [143, 144]. Brain manifestations of TSC include cortical tubers, subependymal nodules, white matter abnormalities, and subependymal giant cell astrocytomas. Histologically, cortical tubers are characterized by the presence of balloon cells, representing a common histologic feature with other malformations due to abnormal proliferation, such as Taylor’s focal cortical dysplasia and HME. Therefore, the cortical tubers of TSC are included in this category of malformation [7]. TSC is discussed in greater detail in Chap. 16. a

4.3.4.5 Focal Transmantle Dysplasia (Taylor’s Focal Cortical Dysplasia) Background

b Fig. 4.30a,b. Megalencephaly in a 12-month-old boy. a Sagittal T1-weighted image; b Axial T2-weighted image. Diffuse, homogeneous increase in brain volume. Frontal bossing is prominent, contrary to microcephaly. The cortex is normal, and myelination is normal for age

4.3.4.4 Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC), or Bourneville disease, is a dominantly inherited disease of high penetrance, characterized pathologically by the presence of hamartoma in multiple organ systems. The typical clinical triad is represented by (i) skin lesions, such as depigmented spots and adenoma sebaceum; (ii) seizures; and (iii) mental deficiency. However, this triad is not present in all patients. Many patients have renal

Focal cortical dysplasias (FCDs) display a broad spectrum of structural changes, reflecting abnormal proliferation, migration, differentiation, and apoptosis of neuronal precursors and neurons during cortical development. In the past, the term “cortical dysplasia” was used loosely by neuroradiologists [145], because it was difficult to differentiate among the various types of MCD with low-field MRI units and histologic correlation was not always available. Therefore, radiologic classification of cortical dysplasias has traditionally been problematic and largely unsatisfactory. The advent of new technology and the progressive development of epilepsy surgery have enabled researchers to attempt histologic-radiologic correlations of cortical dysplasia and to identify new subtypes [146, 147]. A subtype linked to chronic intractable epilepsy, showing distinct clinical and phenotypic features and characterized histologically by abnormally large dysplastic cells, has been called Taylor’s focal cortical dysplasia because the first description of this entity was made by Taylor et al. in 1971 [148]. Because the histologic abnormality, which is reflected in corresponding MRI features (see below) involves not only the cortex, but rather the whole thickness of the cerebral mantle (i.e., from the ventricular to the pial surface), this entity has also been called focal transmantle dysplasia (FTD) [149]. Clinically, affected patients present with intractable partial epilepsy, whose onset is usually in childhood or young adulthood. Intellectual impairment may be present [146].

Brain Malformations

Pathology

Histopathologic analysis shows a glioneuronal malformation with striking similarities to the cortical tubers of patients with TSC. The close relationship between FTD and TSC is reinforced by the presence of sequence alterations of the TSC1 gene product in both the pathologic tissue and adjacent normal cells of patients with histologically documented FTD [150]. However, patients with FTD lack additional features of neurocutaneous syndromes, especially regarding development of CNS or systemic tumor. Therefore, FTD is sometimes regarded as a forma frusta of TSC. Histologically, FTD is characterized by the association of heterotopic neurons in white matter, derangement of cortical lamination, giant neurons, and dysmorphic neurons; the possible presence of balloon cells, i.e., large cells containing a large cytoplasm volume that may express neuronal markers, glial markers, or both, identifies two subtypes of FTD (i.e., FTD with or without balloon cells) [147]. Balloon cells coexist with megalic and dysmorphic neurons within a focally enlarged cortical region that shows subverted lamination and organization (“cortical chaos”). Both cell types are also disseminated along a diffuse front throughout the subjacent white matter, resulting in loss of demarcation between gray and white matter [144]. The gray-white matter junction contains the larger proportion of balloon cells and typically is blurred. The subcortical white matter shows hypomyelination with astrogliosis. Unlike cortical tubers, calcification is exceptional [151, 152]. Cortical epileptogenicity is probably accounted for by an increased number of excitatory neurons and a decreased number of inhibitory neurons [153, 154]. Imaging Findings

Although cortical dysplasia may occur anywhere in the cerebrum, the frontal lobe is affected more frequently in case of FTD [155, 156]. This represents a notable difference from nonballoon-cell FCDs, which tend to be more common in the temporal lobes. The sensitivity of MRI in the detection of FTD is not 100% [146, 147, 155], even when an adequate technique, including highresolution volumetric techniques with thin partition size and curvilinear reconstructions, is used [147, 157, 158]. Because identification of subtle dysplastic areas with this technique is time-consuming, prior identification of the seizure focus with both clinical and electrical criteria is helpful to concentrate one’s attention to the likely lesion site [158]. Phased array surface

coils may improve lesion detection [159]. As will be described in a following section, FLAIR images are of crucial importance in order to detect the subtle signal abnormalities typical of FTD, whereas lack of delineation of the gray-white matter junction is best appreciated with high resolution T2-weighted fast inversion recovery sequences [160]. The site of the lesion often correlates with the stereo-electroencephalographic focus, although the size of the epileptogenic zone is frequently larger than the anatomic abnormality detected by MRI, probably as a result of pathologic connections or membrane hyperexcitability of normally differentiated neurons [144]. MRI detects a highly characteristic triad of signs, as follows [144, 147, 152, 156, 161, 162] (Figs. 4.31, 4.32): 1) Focal cortical thickening: Enlargement of the affected gyri can be best demonstrated on 3D surface rendering. There usually is mild to moderate focal thickening of the cortex, generally in the range of 5–8 mm. Careful assessment of cortical thickness with respect to adjacent normal cortical areas is crucial, because the malformation may be subtle. The signal from the cortex can be variably increased, mixed, or normal on T2-weighted images [156, 161], whereas it is slightly increased on FLAIR images. Spin-echo T1-weighted images show isointense cortical signal with respect to normal gray matter [156]. However, slight signal increase can be detected by means of thin-slice gradient-echo imaging. This sign has been regarded as a potentially specific feature of FTD, and could result from increased cortical cellularity [161]. 2) Blurred gray-white matter junction: The gray-white matter junction is blurred with disappearance of subcortical white matter digitations [144, 161, 163]. Loss of gray-white matter demarcation has been attributed to the presence of ectopic neurons and bizarre glial cells, dysmyelination, and a reduction in the number of myelinated fibers [163]. 3) Funnel-shaped high T2/FLAIR signal intensity in the subcortical white matter: The subcortical white matter is homogeneously hyperintense on T2weighted and FLAIR images, and slightly hypointense on T1-weighted images, possibly reflecting spongiolytic changes [162, 164, 165]. High signal intensity tapers as it extends inward from under the thickened cortical ribbon to the lateral ventricle [147, 152], reflecting involvement of the entire radial glial-neuronal unit. The distinct three-dimensional geometry of this lesion is best appreciated on FLAIR images, and is thought to represent a neuroradiological hallmark of FTD [156].

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Differential Diagnosis

a

b

c Fig. 4.31a–c. Focal transmantle dysplasia (Taylor’s focal cortical dysplasia). a Coronal STIR image; b and c Coronal FLAIR images. Notice gyral enlargement (arrow, a) and hyperintense signal on FLAIR images (arrow, b) that tapers towards the lateral ventricle (arrows, c)

Owing to the common histological background, differentiation of FTD from isolated cortical tubers of TSC may be problematic (Fig. 4.32). In our experience, the single most useful differential feature has been calcification, which is extremely common in tubers and very uncommon, if at all existent, in FTD. Two consequences derive from this observation, i.e., (i) calcification involves a differential diagnosis between tubers and tumor, whereas it makes FTD a very unlikely diagnosis; and (ii) CT plays a key role in the differential diagnosis of tumoral and nontumoral conditions affecting the cortex of children, and should therefore be employed as an useful adjunct to MRI in the diagnostic workup. Another point that has been advocated by some authors is that identification of an apparently single FTD should prompt a Wood light skin examination and abdominal ultrasounds in search of possible occult manifestations of TSC. Distinguishing FTD from tumors, such as dysembryoplastic neuroepithelial tumors (DNTs) or gangliogliomas, is usually not particularly problematic based on MRI findings. However, cortical dysplasia and tumor often coexist [166]. Contrast enhancement, while more common with tumor, has rarely been reported also in FTD [144, 152, 161]. In one investigation [152], statistically significant MRI findings suggesting FTD rather than tumor were frontal lobe involvement, gray matter thickening, homogeneous T2 hyperintense signal in the subcortical white matter, and ventricular extension of signal; on the other hand, temporal lobe involvement, especially when medial, significantly favored the diagnosis of tumor. Although in that study calvarial remodeling did not reach the level of statistical significance, we nevertheless believe it also strongly suggests tumor rather than cortical dysplasia. To date, no large studies have ultimately assessed the value of MR spectroscopy for differentiating FTD from tumor. Decreased NAA/Cr ratio in the affected cortex, possibly reflecting the presence of dysfunctional cells with abnormal synaptic activity and connectivity, has been described in at least three major studies [167–169]. However, the spectral findings alone are nonspecific, because NAA decrease may also be observed in low grade neoplasms. In a recent study, greater diffusion abnormalities and more marked NAA decrease were found in a patient harboring a low grade neoplasm within an area of cortical dysplasia than in one with cortical dysplasia alone [170].

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b

a

d

c Fig. 4.32a–d. Focal transmantle dysplasia (Taylor’s focal cortical dysplasia) versus forma frusta of tuberous sclerosis. a Coronal T2-weighted image; b Axial T2-weighted image; c. Axial T1-weighted image; d Axial CT scan. There is focal cortical thickening (arrow, a, b). The involved convolution is slightly hyperintense on T1-weighted image (arrow, c), with blurred gray-white matter junction. There is corresponding slight hyperdensity on CT (arrow, d), that may indicate calcification

Classification Issues

Balloon cells are a common feature of FTD, TSC, and hemimegalencephalies. Failure of these cells to commit to or differentiate into a specific phenotype suggests they originate from abnormal stem cell differentiation [105, 152]. This assumption led Barkovich et al. to classify FTD among disorders of cell proliferation [7, 105]. Thereby, FTD was separated from nonballoon cell FCDs, which are characterized histologically by clear-cut neuronal differentiation and are separately categorized by the same authors among

disorders of cortical organization [7]. On the other hand, histopathologic studies support the view that FTD represents the severe end of a spectrum of abnormality that also includes other forms of FCD (i.e., architectural and cytoarchitectural FCDs) [146, 147, 153] (Table 4.5). The latter classification is valuable in that it correlates with epilepsy surgery outcome; in fact, an inverse correlation between histologic grade and percentage of seizure-free patients after one year of follow-up has been found [146, 156]. These consid-

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Histology

Architectural FCD (microdysgenesis)

•Heterotopic neurons in white matter •Derangement of cortical lamination

Cytoarchitectural FCD

•Heterotopic neurons in white matter •Derangement of cortical lamination •Giant neurons

Taylor’s FCD without balloon cells

•Heterotopic neurons in white matter •Derangement of cortical lamination •Giant neurons •Dysmorphic neurons

Taylor’s FCD with balloon cells

•Heterotopic neurons in white matter •Derangement of cortical lamination •Giant neurons •Dysmorphic neurons •Balloon cells

FCD: focal cortical dysplasia

erations illustrate the controversies that still exist in the classification of FCD, the rapid evolution of classification schemes in the recent years, and especially the difficulties one finds when attempting to correlate histological diagnoses with MRI findings. Hopefully, disclosure of the genetic background will shed further light on the true nature of this elusive group of disorders and improve our approach to them, both from a diagnostic and a therapeutic perspective. 4.3.4.6 Hemimegalencephaly Background

HME, or unilateral megalencephaly, is an uncommon condition characterized by hamartomatous growth of one cerebral hemisphere. This condition is presently categorized among disorders of neuronal/glial proliferation and apoptosis, together with FTD and TSC, on the basis of the common presence of balloon cells in this group of disorders (see above). It has been recently suggested that HME could be a genetically programmed disorder related to cellular lineage and/or establishment of symmetry [171]. However, these genetic abnormalities have not yet been demonstrated. Affected patients present during the first days or weeks of life with medically intractable seizures; there also is severe psychomotor delay and contralateral hemiparesis [171, 172]. Management of these children is difficult. Seizure control may not be achieved by pharmacologic treatment in all cases, and adverse side effects may complicate the picture. Hemispherectomy has been advocated as a treatment method for

patients with frequent, refractory, and intractable seizures [173]. Pathology

On pathologic examination, all or part of the involved hemisphere is larger and heavier than the contralateral one. Concomitant ipsilateral enlargement of a cerebral hemisphere, half of the brainstem, and cerebellar hemisphere is called total hemimegalencephaly [174]. Histologically, the cortex shows lack of alignment in the horizontal layers and an indistinct demarcation from the underlying white matter. Giant, dysplastic neurons and balloon cells identical to those seen in FTD (see above) are scattered throughout the cortex and subcortical white matter. Striking demyelination of the centrum semiovale is seen in some cases [175]. Imaging Findings

HME occurs on either side of the brain. There is gross asymmetry with enlargement of all or part of one hemisphere and possible concomitant enlargement of the ipsilateral half of the brainstem and cerebellar hemisphere (Fig. 4.33). Midline shift can be present, either total or limited to the posterior region, a condition called the occipital sign [171]. The cerebral cortex is thickened and shows a variable spectrum of abnormalities, including lissencephaly, pachygyria, polymicrogyria, and, rarely, schizencephaly [171], probably reflecting the fact that what we call “hemimegalencephaly” probably represents a spectrum of, rather than a single, disorder. The most severe end of this spectrum has been termed hemilis-

Brain Malformations

a

b

Fig. 4.33a–c. Hemimegalencephaly. a Coronal T2-weighted image; b, c Axial T2-weighted images. There is global increase in size of the whole right cerebral hemisphere (a, b) and homolateral cerebellar hemisphere (c). Diffuse cortical dysplasia involves the frontoinsulo-temporal regions (arrowheads, a,b). There also is abnormally increased signal intensity within the white matter. The right lateral ventricle is dysmorphic, although size is not significantly different than contralaterally. Infratentorially, abnormal foliation of the right cerebellar hemisphere (arrowheads, c) is associated with dilatation of the homolateral recess of the fourth ventricle

c

a

b Fig. 4.34a,b. Hemimegalencephaly in a newborn. a Coronal T1-weighted image; b Axial T1-weighted image. General increase in size of the right cerebral hemisphere, showing cortical thickening with a lissencephalic appearance and hypermyelination of the residual white matter (arrowheads, a, b). Notice marked dilatation of the lateral ventricle. The homolateral cerebellar hemisphere is also larger than the contralateral one (a). (Case courtesy of Dr M. Rutherford, London, UK)

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sencephaly [176] (Fig. 4.34). The gyri are broad and flat, and the sulci are shallow. The gray-white matter junction is blurred [164]. The affected white matter shows abnormal signal intensity that varies with patient age. In neonates and small infants, these signal changes are characterized by T1 and T2 shortening, reflecting abnormally advanced myelination for the age [177] (Fig. 4.34). In older children, the white matter of the involved hemisphere becomes hyperintense on T2weighted images (Fig. 4.33). This correlates histologically with lack of myelin [164]. White matter volume is usually increased. Calcification may involve both the cortex and the white matter, and is better demonstrated by CT. There is a roughly inverse relationship between the severity of the malformation and the size of the involved hemisphere, with polymicrogyric

hemispheres appearing larger than lissencephalic ones [178]. The lateral ventricle in the affected hemisphere shows variable abnormalities, including a straightened or collapsed frontal horn, colpocephalic dilatation of the occipital horns, and global dilatation of the ventricle [171]. In some cases, only a portion of one cerebral hemisphere, usually corresponding to one lobe, is enlarged (Fig. 4.35). Serial imaging studies may show progressive atrophy of the involved hemisphere [179], so that the “megalic” hemisphere may actually become smaller than the unaffected one in the long run. A grading system for HME has been proposed based on the severity of the detected abnormalities [171] (Table 4.6). Proton MR spectroscopy shows marked decrease of NAA/Cr ratio in the involved white matter [180].

a

b

c

d Fig. 4.35a–d. Focal megalencephaly. a Axial CT scan; b Axial T1-weighted image; c Sagittal T2-weighted image; d Coronal STIR image. The left occipital lobe is diffusely slightly hyperdense on CT scan (a). The occipital horn is larger than the contralateral (a, b). The occipital lobe is slightly hyperintense on T1-weighted images (b) and markedly hypointense on T2-weighted images (c); its morphology is abnormal, with a lissencephalic appearance. On STIR images (d), the involved regions show mild signal intensity changes

Brain Malformations Table 4.6. Grading system for hemimegalencephaly [172]

Klippel-Trenaunay-Weber Syndrome (KTWS)

Grade I

KTWS is one of the hemihypertrophy syndromes. It is characterized by a constellation of anomalies that includes cutaneous capillary malformation, usually affecting one limb, abnormal development of the deep and superficial veins resulting in multiple varicosities, and limb asymmetry due to osseous and soft tissue hypertrophy [185]. Mixed vascular malformations may include capillary, venous, arterial, and lymphatic systems [186]. Affected patients are at risk for thromboembolic episodes and bleeding from multiple sites. HME is the most frequently reported brain abnormality in patients with KTWS [187]. Other reported CNS findings include brain atrophy, calcifications, enlarged choroid plexus, and leptomeningeal angiomatosis, similar to Sturge-Weber syndrome [185].

• Mild hemispheric enlargement • Straight midline/minimal displacement • Ventricular asymmetry with straightened frontal horn • Hyperintense white matter • No apparent cortical dysplasia Grade II • Moderate hemispheric enlargement • Moderate dilatation or reduction of lateral ventricle, or colpocephaly • Slight/moderate midline displacement • Moderate focal cortical dysplasia Grade III • Marked hemispheric enlargement • Marked midline displacement/occipital sign • Marked dilatation and distortion of lateral ventricle • Severe, extensive cortical dysplasia including hemilissencephaly

Associated Conditions

HME can be isolated or associated with several hemihypertrophic syndromes or phakomatoses. There are no imaging differences between isolated and syndromic HME. The main entities will be briefly discussed here; some are discussed in greater detail in Chaps. 16 and 17. Organoid Nevus Syndrome (ONS)

ONS, also called epidermal nevus syndrome, consists of sebaceous nevus of the face or scalp (nevus sebaceous of Jadassohn) associated with ipsilateral defects of the brain, eye, and connective tissue [181]. A lipoma of the cheek is usually found in association with HME. It has been suggested that ONS may be caused by mosaic mutation of a gene which would be lethal if expressed in all cells [181]. CNS abnormalities described in the setting of ONS include HME, DandyWalker malformation, and corpus callosum agenesis [182].

Proteus Syndrome (PS)

PS is named after the Greek god Proteus, “the polymorphous”, who could change his shape at will to avoid capture. PS involves partial gigantism of the hands and/or feet, pigmented nevi, hemihypertrophy, subcutaneous hamartomatous tumors and macrocephaly, and/or other skull anomalies [188]. The suggested cause is an as yet unknown dominant lethal gene surviving by mosaicism [189]. Mandatory diagnostic criteria include mosaic distribution of lesions, progressive course, and sporadic occurrence. When present, connective tissue nevi are almost pathognomonic for PS [190]. HME is the typical intracranial abnormality seen in patients with PS [191, 192]. Other CNS abnormalities include migrational disorders, Dandy-Walker malformation, callosal anomalies, and calcified subependymal nodules [191, 192]. Meningiomas, pinealomas, and optic nerve tumors have also been reported [193]. Neurofibromatosis Type 1 (NF1)

HME has rarely been reported in association with NF1 [194, 195]. The prognosis is apparently better than with isolated HME, with later onset and better therapeutic control of seizures and absence of focal neurologic signs [195].

Hypomelanosis of Ito (HI)

Tuberous Sclerosis Complex (TSC)

HI does not represent a distinct entity, but is rather a symptom of many different states of mosaicism [183]. Affected patients have unilateral or bilateral macular hypopigmented whorls, streaks, and patches with variably associated eye, musculoskeletal, and CNS abnormalities, such as HME and other migration disorders [184].

There is a close histologic relationship between TSC and HME in that balloon cells are found in both conditions. Hemispheric enlargement may be diffuse [196–198] or focal [196]. When a large calcification is found within a hemimegalencephalic cerebral hemisphere, associated TSC must be suspected [198].

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4.3.4.7 Neoplasms

perspective, in view of the significant differences in their neuroimaging features.

The inclusion of tumor conditions, such as DNT, gangliocytoma, and ganglioglioma, in a classification of MCD must be considered judiciously. The possible presence of dual pathology, i.e., association of cortical dysplasia with tumor, is commonly found in histological studies of resected cortical specimens, both from the temporal lobe [199] and other locations [199, 200]. While there is basically no question concerning the neoplastic nature of gangliocytomas and gangliogliomas, controversies still exist concerning DNTs. These entities are described in Chap. 10.

Genotype-Phenotype Correlations

4.3.5 Malformations Due to Abnormal Neuronal Migration 4.3.5.1 Lissencephalies The Lissencephaly-Subcortical Band Heterotopia Spectrum Background

The term “lissencephaly” refers to a smooth brain with total absence of cortical convolutions. As such, it is synonymous with agyria. Pachygyria refers to a simplified convolutional pattern with few, broadened gyri and shallow sulci. There is a spectrum of variability in the phenotypic expression of lissencephalies, accounting for the denomination “agyriapachygyria,” which is still widely used in the everyday practice. Subcortical band heterotopia (SBH), or double cortex, is characterized by a poorly organized band of arrested neurons residing beneath a relatively normal cortex. Lissencephaly and SBH were once categorized separately. However, there is etiological intersection between the two conditions, represented by the fact that subcortical band heterotopia (SBH) can be caused by less severe mutation in the same genes, LIS1 and DCX, that are responsible for classical lissencephaly (formerly known as type 1 lissencephaly) [7]. Strictly speaking, all malformations in this group are heterotopia in that there is arrested neuronal migration with failure of achievement of the cortical plate, resulting in a band of arrested neurons beneath the cortical mantle. Separation from other entities, such as subependymal and subcortical heterotopia, is justified from a neuroradiological

The LIS1 gene [201] is located on 17p13.3 and encodes a noncatalytic subunit of platelet activating factor acetylhydrolase 1bl (Pafah1b1), or Lis1 protein, which in turn regulates platelet activating factor (PAF). PAF is involved in a variety of biologic and pathologic processes; however, it is not yet proven whether LIS1 influences neuronal migration through regulation of PAF [111]. More importantly, the Lis1 protein has been implicated in the organization of microtubule dynamics, which is needed for neurite extension and nuclear translocation [202, 203]. Mouse models inactivating LIS1 display slowed neuronal migration [111]. The DCX/XLIS gene [204, 205] is on the X chromosome (Xq22.3-q23) and encodes a protein called doublecortin. DCX is expressed in migrating neurons throughout the central and peripheral nervous system during embryonic and postnatal development, and is believed to direct neuronal migration by regulating the organization and stability of microtubules [206]. Miller-Dieker Syndrome (MDS)

MDS is manifested as lissencephaly with characteristic facial abnormalities and profound psychomotor retardation [207, 208]. MDS is a contiguous gene deletion syndrome; deletion of or mutation in the LIS1 gene causes the lissencephaly, whereas facial dysmorphism and other anomalies result from deletion of additional genes distal to LIS1. Affected patients display profound psychomotor retardation, intractable epilepsy generally presenting before age 6 months, and progressive spastic paraplegia [202]. The MDS facial phenotype includes bitemporal hollowing, prominent forehead, short nose with upturned nares, prominent upper lip, thin vermilion border of the upper lip, and small jaw [209]. Isolated Lissencephaly Sequence (ILS)

ILS corresponds to lissencephaly without facial abnormalities. Mutations in both LIS1 and DCX/XLIS genes may cause ILS. Together, these account for 76% of classical lissencephaly [210]. LIS1 mutations are generally represented by point mutations or intragenic deletions; they are less extensive than those causing MDS, and do not involve contiguous genes. LIS1-related ILS has no gender predilection. DCX/XLIS-related ILS, also called X-linked lissencephaly, is typically found in hemizygote males, whereas the same mutation causes SBH in heterozygous females. Failure of lyonization

Brain Malformations

(i.e., random X-inactivation) accounts for exceptional female cases of X-linked lissencephaly [211]. The clinical manifestations of the two forms of ILS are not remarkably different, and basically comprise seizures, mental retardation, difficult feeding, and aspiration. Differentiation from MDS is easy on the basis of the facial phenotype, which only involves mild bitemporal hollowing and slightly small jaw [212]. On the other hand, there are remarkable differences in the pathological features, in that the brain malformation due to LIS1 mutations is more severe over the parietal and occipital regions, whereas DCX mutations produce more severe involvement of the frontal cortex [212]. Subcortical Band Heterotopia (SBH)

SBH is the least severe end of the malformation spectrum. It typically is found in females harboring mutations in DCX. This phenotype arises because lyonization, i.e., random inactivation of one X chromosome early in embryogenesis, results in roughly half of neurons expressing the mutated allele. SBH has also exceptionally been demonstrated in males. In these cases, it occurs as a consequence of minor missense mutations of DCX/XLIS or LIS1 [213, 214]. Affected patients are far less severely affected than those with classical lissencephaly. Although they may manifest seizures and a variable degree of cognitive impairment, about 25% possess normal or near normal intelligence [111]. There is a relationship between the degree of disability and the thickness of the heterotopic band of neurons [215]. Pathology

Lissencephaly is characterized by a smooth hemispheric surface with absent primary fissures. As such, it is synonymous with agyria. Complete lissencephaly is very rare. More often, at least a few broad, coarse gyri with shallow sulci are present, in which case the term pachygyria is more correct. The cortex is much thicker than normal, and there is a corresponding reduction of white matter volume. Microscopically, there is a four-layered cortex composed of [17, 108]: (i) a molecular layer with an excess of nerve fibers; (ii) a disorganized outer cellular layer corresponding to the would-be cortex, containing the few neurons that have completed their migration; (iii) a sparse-cell layer, formed by a tangential plexus of myelinated fibers containing few neurons; and (iv) a thick inner cell layer, composed of heterotopic neurons whose migration has been arrested. As such, this malformed cortex is remarkably similar to the normal migration pattern seen in

the 11th–13th week fetus. The ventricles are variably enlarged. In SBH, the heterotopic band consists of a superficial zone of disorganized neurons, an intermediate zone of small neurons with tentative columnar organization, and a deep zone of nodular conglomeration of the heterotopic neurons [106]. Imaging Findings

From a neuroimaging perspective, there is a continuous spectrum of variability that ranges from complete lissencephaly to localized forms of SBH. A six-tiered grading system for lissencephaly and SBH has been proposed [212] (Table 4.7). For practical purposes, only the basic pictures will be discussed here. Table 4.7. Grading system for classical lissencephaly and subcortical band heterotopia [213] 1. Diffuse agyria 2. Diffuse agyria with a few shallow sulci 3. Mixed agyria and pachygyria 4. Diffuse or partial pachygyria only 5. Mixed pachygyria and subcortical band heterotopia 6. Subcortical band heterotopia only

Lissencephaly (Agyria) (Dobyns Grade 1)

The size of the brain is smaller than normal, and the brain surface is smooth with complete lack of sulci; the sole exception is relative sparing of the orbitofrontal and anterior temporal zones. The brain has a figure-of-eight shape resulting from wide, vertically oriented Sylvian fissures [108] (Fig. 4.36). Cortical thickness is greater than 10 mm. MRI detects a three-layered pattern. The outer stripe corresponds to the molecular and outer cellular layers. The median stripe is characterized by T1 and T2 prolongation and corresponds to the sparse-cell layer [108, 216]. The deep stripe is the thickest, and corresponds to the inner layer of arrested neurons. The gray-white matter junction is linear, and the white matter is greatly reduced in volume. The lateral ventricles are enlarged. Other signs include hypoplasia of the pyramidal tracts or of the brainstem as a whole, corpus callosum dysgenesis, and eversion of the hippocampi [108, 144]. Lissencephaly associated with cerebellar hypoplasia is presently categorized separately from classical lissencephaly (see below). Agyria-Pachygyria (Dobyns Grades 2-4)

Complete lissencephaly is rare. More often, there is diffuse or localized presence of shallow sulci sub-

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a

b Fig. 4.36a,b. Classical lissencephaly. a Axial T2-weighted image; b Coronal T2-weighted image. On axial sections, the brain has a “figure of eight” appearance (a) due to shallow, vertically oriented Sylvian fissures, whereas on coronal planes it resembles a “chicken brain” (b). The malformation is almost complete except for minimal, rudimentary sulcation in the frontal region. The brain surface is totally smooth. Thickness of the cortex is much greater than that of white matter. The sparse cells layer, separating the thin outer cortical layer from the thick layer of arrested neurons, is clearly recognizable as a hyperintense stripe (arrowheads, a, b). Dilated perivascular spaces are visible in the periventricular regions as well as below the sparse cell layer (arrows, b)

dividing the cortical mantle into broad, coarse gyri (Figs. 4.37, 4.38). In the less severe cases, no completely agyric portions are found. There is a clearcut correspondence between the gyral pattern and the gene mutation which is responsible for the malformation. Mutations of LIS1 are associated with a posterior-to-anterior gradient of lissencephaly, with a more severe malformation in the parieto-occipital regions of the brain. Conversely, mutations of DCX/ XLIS are associated with an anterior-to-posterior gradient, with regional prevalence over the frontal regions of the brain [212]. In the LIS1 group, patients with MDS are more likely to have a high-grade picture than those with ILS [212]. SBH (Dobyns Grades 5-6)

There is a symmetric, circumferential band of heterotopic gray matter deep to the cortical mantle, separated by well-defined, smoothly marginated layers of normal-appearing white matter from both the overlying cerebral cortex and the underlying ventricle [217] (Fig. 4.39). The overlying gyral pattern can be normal, may have normal thickness with shallow sulci, or can be frankly pachygyric. Patients with pachygyria have thicker heterotopic bands [215]. SBH may coexist with other regions of frank pachygyria in the most severe cases, whereas involvement may be incomplete with sparing of either frontal or posterior regions in less severe cases, depending on the involved gene [212]. Asymmetric involvement of the two hemispheres has also been described [218].

X-Linked Lissencephaly with Abnormal Genitalia (XLAG)

XLAG is found in genotypic males with neonatalonset intractable epilepsy, hypothalamic dysfunction including deficient temperature regulation, and ambiguous or underdeveloped genitalia. Brain manifestations of this syndrome involve a consistent association of lissencephaly and agenesis of the corpus callosum [219, 220]. Additional clinical features include severe hypotonia, poor responsiveness, and early death [106, 221]. There is X-linked inheritance; the involved gene, ARX, has been mapped on Xp22.13 [222]. Carrier female relatives of affected patients have isolated, complete or partial agenesis of the corpus callosum; however, they do not harbor cortical abnormalities [221]. Histologically, there is a 3-layered cortex lacking a sparse-cell zone [221]. MRI findings [221] include a posterior-to-anterior gradient of severity consisting of posterior agyria and frontal pachygyria, associated with corpus callosum agenesis. Remarkably, this pattern of lissencephaly is the opposite of DBX/XLIS lissencephaly, and similar to that of LIS1-related lissencephaly. Cortical thickness is in the range of 6–7 mm, i.e., thinner than in classical lissencephaly. Additional findings include poor delineation of the nucleocapsular regions, ventricular dilatation, and an abnormal signal intensity in the periventricular white matter, probably related to gliosis and richness of heterotopic neurons [221].

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b Fig. 4.38a,b. Focal pachygyria. a Axial STIR image; b Sagittal T1weighted image. Focal pachygyria in the fronto-rolandic regions (arrows, a), associated with vertically oriented, shallow Sylvian fissure. An associated persistent Blake’s pouch, causing tetraventricular hydrocephalus, is recognizable (b). The brainstem is hypoplastic

c

Fig. 4.37a–c. Classic lissencephaly: incomplete form. a Axial T2-weighted image; b Coronal STIR image; c Sagittal T1weighted image. The brain is totally lissencephalic in the posterior regions, whereas it is pachygyric in the fronto-temporal regions (a). In the most severely abnormal areas, there is a complete loss of arborization of the white matter, with a smooth gray-white matter interface (b). The corpus collosum is mildly dysmorphic, and thickened anteriorly (arrows, e). Perivascular spaces are dilated in the para-artrial regions (arrowheads, a). The brainstem is hypoplastic, and there is concurrent mega zisterna magna (c)

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a

b Fig. 4.39a,b. Subcortical band heterotopia: two different cases. a, b Axial STIR images. a In this case, a thick layer of heterotopic neurons (arrowheads, a), located deep to a grossly normal-appearing cortex, extends continuously along both hemispheres bilaterally. The band is separated from the cortex by a layer of myelinated white matter. Notice that the convolutions are somewhat coarse, and the gyral pattern is probably simplified. b In another case, heterotopia is incomplete, forming a thin band (arrowheads, b) that involves the hemispheres asymmetrically. (b courtesy Dr R. Devescovi, Trieste, Italy)

Lissencephaly with Cerebellar Hypoplasia (LCH)

LCHb

The association between lissencephaly and cerebellar hypoplasia has recently emerged as a separate class of malformations [134] that, for the largest part, result from different genetic abnormalities rather than classical lissencephaly. The affected cortex shows variably increased cortical thickness. The convolutional pattern varies from frank agyria to gyral simplification. In some cases, the cortical malformation may be better defined as microlissencephaly, because of associated marked brain size decrease [133]. Cerebellar involvement ranges from mild vermian hypoplasia to diffuse cerebellar underdevelopment. Six subtypes of LCH (LCH a-f) have been identified based on phenotype [134]. Causative gene mutations have been identified for two of them, whereas they remain undetermined for the remaining four.

LCHb is associated with mutations of the RELN gene, located on 7q22 [223]. RELN encodes reelin, a protein implicated in the process of detachment of migrating neurons from the radial glia, which terminates neuronal migration. The LCHb phenotype is characterized by pachygyria with mild cortical thickening and anterior predominance, hippocampal abnormalities, and severe cerebellar hypoplasia with absent foliation.

LCHa

LCHd

LCHa is, for all purposes, a subtype of classical lissencephaly characterized by associated midline cerebellar hypoplasia [134]. The genetic background is mutation of either LIS1 or DCX/XLIS. Accordingly, the severity of the cortical malformation follows a posterior-toanterior or an anterior-to-posterior gradient, respectively. Cortical thickness is in the 10–20 mm range.

LCHd is characterized by variably severe lissencephaly with microcephaly (i.e., microlissencephaly) associated with moderate to severe hypoplasia of both the hemispheres and the vermis. Cerebellar foliation, albeit simplified, is preserved. Cortical thickening is in the 10–20 mm range.

LCHc

Microlissencephaly with associated severe cerebellar hypoplasia and cleft palate has been described in a family [224]. Histologically, there is a thickened, unlayered cortex. MRI studies of this entity have not been published yet.

Brain Malformations

LCHe

In LCHe, there is a distinctive cortical pattern represented by an abrupt transition from frontal agyria with 10–20 mm cortical thickening to a simplified gyral pattern with near normal cortical thickness posteriorly [134]. Cerebellar hypoplasia predominately involves the vermis. LCHf

This entity displays a characteristic association of agyria-pachygyria, cerebellar hypoplasia with greater involvement of the vermis than the hemispheres, and agenesis of the corpus callosum. There is mild brainstem hypoplasia.

4.3.5.2 The Cobblestone Complex Background

Abnormalities belonging to this group were once considered to be part of the lissencephaly spectrum [105]. The typical cortical malformation was once called lissencephaly type II [225]. However, the surface of the brain is not always smooth in this group of pathologies; rather, it usually appears irregularly bumpy and knobbed. Therefore, the descriptive term “cobblestone complex” was introduced [7]. Separation from lissencephalies is also justified in view of the different pathogenetic mechanism, involving neuronal migration beyond layer 1 into the leptomeninges through gaps in the glial limiting membrane [7, 111], and the characteristically disorganized, unlayered appearance of the cortex on histopathologic examination. Imaging Findings

On imaging studies, the cobblestone complex is characterized by cortical thickening with an irregular, pebbled external surface comprising an irregular mixture of agyria, pachygyria, and polymicrogyria, with severely reduced sulcation. The white matter is abnormal due to dysmyelination or edema, resulting in a bright signal on T2-weighted MR images. The ventricles can be enlarged either because of dysmorphic ventriculomegaly (i.e., colpocephaly) or true hydrocephalus. The posterior fossa is consistently abnormal in the cobblestone complex. The brainstem can be hypoplastic and deformed. The cerebellum is also hypoplastic, usually with a greater degree of involvement of the vermis than the

hemispheres, and/or dysplastic (cerebellar polymicrogyria) [226]. Classification

The cobblestone complex is typically found in patients with congenital muscular dystrophy (CMD). CMDs are a heterogeneous group of disorders characterized by hypotonia of prenatal onset, weakness, and frequent congenital contractures, associated with histological findings of muscular dystrophy [227, 228]. CMDs may show isolated muscular involvement or be associated with brain and ocular abnormalities. Three conditions share the combination of CMD and brain abnormalities: Walker-Warburg syndrome (WWS), Fukuyama congenital muscular dystrophy (FCMD), and muscleeye-brain disease (MEB). Ocular abnormalities are typically associated in WWS and in MEB, whereas they are distinctly uncommon in FCMD. Recently, the cobblestone complex has been reported as an isolated finding in patients without muscle or ocular involvement [229]. These entities must be differentiated from merosin-deficient CMD, in which brain involvement is restricted to the white matter without cortical abnormalities [230]. There are striking similarities between these entities both on pathological and imaging studies. From a broad perspective, one can conceive a spectrum of severity ranging from the more severe WWS to the milder MEB, with FCMD showing intermediate severity and partially overlapping features with both WWS and MEB. MRI can play an important role in the differentiation among these entities, but genetic studies are required for an ultimate diagnosis. A brief discussion of these entities follows. Walker-Warburg Syndrome (WWS)

WWS is a lethal autosomal recessive developmental disorder characterized by CMD and complex brain and eye abnormalities, previously known as HARD±E (hydrocephalus, agyria, retinal dysplasia, with or without encephalocele). WWS is caused by mutation in the gene encoding protein O-mannosyltransferase (POMT1), located on 9q34.1 [231]. WWS is the most severe entity among CMD with coexistent CNS involvement, with a life span that is usually not longer than a few months. Rare survivors display profound mental retardation, intractable seizures, failure to thrive, and hypotonia [232]. In WWS, the cobblestone pattern prevailingly comprises diffuse agyria blended with bumpy-surfaced pachygyria (Fig. 4.40). Cortical thickening is in the order of 7–10 mm, i.e., thinner than in clas-

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sical lissencephaly. However, the cortex may be secondarily thinned when hydrocephalus is present. Irregular subcortical heterotopic foci are often present. Obliteration of the interhemispheric fissure, often detected on MRI, results from leptomeningeal thickening due to neuronal overmigration [232]. Diffuse T1 and T2 prolongation in the white matter is a consistent feature of WWS, and correlates histologically with hypomyelination and edema. There can be associated callosal dysgenesis [228]. Hydrocephalus, albeit frequent, is not a necessary diagnostic criterion; when present, it is caused either by fusion of the cortical surfaces with the overlying leptomeninges, as a result of neuronal overmigra-

tion causing obstruction to CSF circulation [233], or by concurrent aqueductal stenosis [230]. Cerebellar hypoplasia is usually greater in the vermis than in the hemispheres. A full-blown Dandy-Walker malformation is found in 50% of cases [111, 232]. The cerebellar cortex is dysplastic. An occipital cephalocele is associated in 25%–50% of cases [232]. The brainstem is hypoplastic, with a striking size reduction of the pons. The brainstem also shows a typical posterior kink, resulting in a broad inverted S shape on sagittal MR images [228]. Microphthalmia, cataracts, congenital glaucoma, persistent hyperplastic primitive vitreous, retinal detachment, and optic nerve atrophy are seen [228,

Fig. 4.40a–c. Walker-Warburg syndrome. a. Sagittal T1-weighted image; b, c. Axial T2-weighted images. There is marked supratentorial hydrocephalus associated with corpus callosum agenesis. Notice Dandy-Walker malformation (c), with rotation of the hypoplastic vermis (arrow, a). The brainstem is dysmorphic with an italic S appearance (arrowheads, a). The quadrigeminal plate is hypertrophic with aqueductal stenosis. The cerebral cortex is flat and markedly thinned, with shallow, verticalized Sylvian fissures (arrow, b). Multiple subependymal neuronal heterotopic nodules are visible (arrowheads, b, c). There is left microphthalmos with persistent hyperplastic primitive vitreous (c). (Case courtesy Dr. F. Triulzi, Milan, Italy)

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Brain Malformations

232]. These abnormalities are readily depicted by MRI. Retinal malformations are universally present [232]. Fukuyama Congenital Muscular Dystrophy (FCMD)

FCMD has been reported almost exclusively in the Japanese. Although a diagnosis of FCMD in non-Japanese patients still requires caution [230, 234], there is increasing evidence that the distribution of FCMD may be more widespread. FCMD is an autosomal recessive entity caused by mutation of a gene located on 9q31 [235] and encoding fukutin, a putative extracellular matrix molecule. FCMD differs from WWS and MEB basically because eye abnormalities are usually absent [236]. Affected children show progressive facial and limb weakness, congenital and progressive joint contractures, and markedly elevated serum creatine kinase [237]. Clinical presentation is usually in the neonatal period with hypotonia and diminished tendon reflexes. The clinical course is less severe than in WWS, with most patients surviving beyond infancy and remaining relatively stable afterwards. Brain MRI shows two basic patterns of cortical involvement (Fig. 4.41). A cobblestone appearance prevails in the temporal and occipital lobes, whereas MRI imaging characteristics consistent with polymicrogyria are preferentially found in the frontal and parietal lobes [227, 228]. This peculiar distribution may assist in the differentiation from WWS or MEB. In the vast majority of cases, there is either diffuse or patchy T1 and T2 prolongation in the central white matter of the cerebral hemispheres that may lessen with age, possibly in relation to an extreme form of delayed myelination [227]. The cerebellum is usually not severely hypoplastic; however, there is disorganized cerebellar foliation corresponding to cerebellar polymicrogyria, with associated small, multiple subcortical “cysts” that are isointense with CSF in all sequences (Fig. 4.41). These “cysts” are believed to result from entrapment of the subarachnoid space from superficial fusion of the dysplastic cortex and leptomeninges in the boundary between the normal and polymicrogyric cortex [238]. The brainstem may be normal; however, a variable degree of pontine hypoplasia with flattened anterior surface, similar to MEB, has been described in some cases [227, 228] (Fig. 4.41). Muscle-Eye-Brain Disease (MEB)

MEB is the least severe entity in the cobblestone complex spectrum. This autosomal recessive entity is caused by mutations in the O-mannose β-1, 2-Nacetylglucosaminyltransferase gene (POMGNT1), located on 1p34-p33 [239]. The protein encoded by

POMGNT1 participates in O-mannosyl glycan synthesis. As such, MEB is closely related to WWS, although it is less severe from both clinical and neuroimaging standpoints. MEB is distinctly frequent in Finland [240]. Affected patients present with congenital hypotonia, muscle weakness, and elevated serum creatine kinase. Ophthalmologic findings include severe visual failure, uncontrolled eye movements associated with severe myopia, and progressive retinal degeneration associated with giant visual evoked potentials [240]. Most patients have severe psychomotor delay. On the whole, pathologic and imaging findings are less severe than in WWS regarding both the severity and extent of cerebral cortical dysplasia and the extent of white matter abnormalities [230]. MRI shows a less severe cobblestone pattern than in the other entities, with remarkable differences of severity and extent in individual cases (Fig. 4.42). The appearance of the cortex is prevailingly polymicrogyric with a variable pachygyric appearance [230]. Complete agyria is not encountered [241]. Cortical involvement prevails in the frontal, temporal, and parietal lobes, and thickness of the cortical mantle is normal or slightly increased [241], whereas the posterior regions of the brain usually show a normal cortical pattern. Unlike WWS, the gray-white matter interface shows interdigitations. The white matter is either normal or shows patchy areas of T1 and T2 prolongation, lacking the diffuse involvement found in WWS [240]. When present, ventricular dilatation is basically ex-vacuo, not hydrocephalic [230], and may be associated with absence of the septum pellucidum. The corpus callosum is thinned or dysplastic. Typically, there is cerebellar polymicrogyria with multiple subcortical cysts [241], similar to those found in FCMD and, rarely, in WWS. Isolated vermian hypoplasia is also present. There is a striking hypoplasia of the pons, with a flat brainstem in sagittal images due to absence of the anterior pontine bulge [241, 242] (Fig. 4.42). Isolated Cobblestone Complex (ICC)

ICC is believed to be an allelic variant of WWS and MEB which does not fulfill the diagnostic criteria for these syndromes [229]. ICC is characterized by a cobblestone complex with normal eyes and muscles. Affected patients have moderate to severe psychomotor delay. MRI shows generalized pachygyria with a cobblestone surface, flattened gray-white matter interface, and ventriculomegaly. The white matter shows scattered areas of bright signal on T2-weighted images. The brainstem and cerebellum are hypoplastic, and there may be an associated retrocerebellar cyst [229].

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Fig. 4.41a–e. Fukuyama congenital muscular dystrophy. a,c,e Axial T2-weighted images; b Coronal T2-weighted image; d Sagittal T1-weighted image. Diffuse, bilateral frontal cortical dysplasia without signal changes of the underlying white matter (a, b). There is marked ventriculomegaly with absence of the septum pellucidum (asterisk, b) and fusion of the anterior pillars of the fornix (arrow, b). The pons is hypoplastic (arrows, d), there is mega cisterna magna (d), and diffuse subcortical cerebellar cysts, indicating cerebellar polymicrogyria (arrowheads, c). There also is right microphthalmos with persistent hyperplastic primitive vitreous (arrowhead, e)

Brain Malformations

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d Fig. 4.42a–d. Muscle-eye-brain disease. a and c Axial T2-weighted images; b Sagittal T1-weighted image; d Axial STIR image. There is diffuse cortical dysplasia involving both frontal lobes (a); with coarse interdigitation between the thickened cortex and the underlying white matter, which is diffusely T2 hyperintense (a). Hyperintensity involves also the paratrigonal regions bilaterally. On sagittal images, a Dandy-Walker variant is associated with hypoplasia of the pons (arrows, b). Diffuse cortico-subcortical cerebellar microcysts, indicating polymicrogyria (arrowheads, c), result in a spongy appearance of the cerebellar surface (arrowheads, d). Left buphthalmos (asterisk, d)

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4.3.5.3 Heterotopia

of FLN1 [249]. These observations indicate that several syndromes with BPNH exist [247].

The term heterotopia refers to normal cells occupying an abnormal position within their organ of origin [4]. In the CNS, heterotopia implies arrested migration of normal neurons along the radial glial path between the ependyma of the lateral ventricles and the cortex. Heterotopia are best classified according to location into subependymal and subcortical heterotopia. A third group, marginal glioneuronal heterotopia, implies overmigration of neurons and glial cells into the leptomeninges through gaps in the pial-glial border. Because marginal glioneuronal heterotopia are usually detected only microscopically [144], these will not be further dealt with. SBH, or double cortex, was once classified together with other heterotopia, but has been recently reclassified to the lissencephaly category based on a common genetic background [7] (see above, lissencephalies). On imaging studies, heterotopia are isointense with normal gray matter on all MRI sequences and lack enhancement on postcontrast scans [108].

Pathology

Subependymal Heterotopia Background

Subependymal heterotopia are the most common form of heterotopia [243]. They comprise subependymal nodules of gray matter that can be unilateral or bilateral, localized or diffuse. While unilateral and localized, heterotopia are usually sporadic and show no sex predilection. Bilateral periventricular nodular heterotopia (BPNH) is an X-linked dominant disorder with marked predominance in females due to near total male lethality during early embryogenesis [244]. The affected gene in BPNH, FLN1, is located on Xq28 [245] and encodes filamin-1, an actin-binding protein that promotes cell motility [245, 246]. Filamin-1 also plays a role in vascular development and blood coagulation, which may account for male lethality during early embryogenesis [245]. In females, random inactivation of one chromosome X, or lyonization, results in a milder phenotype that is compatible with life. Affected patients are often grouped into pedigrees with multiple miscarriages [106]. Heterozygous females usually have normal intelligence to borderline mental retardation, epilepsy of variable severity, and coagulopathy [244]. Presentation is usually in the second to third decade, accounting for the distinct rarity of BPNH in the pediatric age group. Recently, BPNH has been observed in unusual settings, such as in male patients with mental retardation [247, 248]. Some of these cases are probably explained by partial loss-of-function mutations

Pathologically, subependymal nodular collections of well differentiated neurons, often bulging into the ventricular cavity, are found. Neurons show random orientation and size distribution, and may assemble into laminar patterns [250]. In BPNH, these neurons represent those cells expressing the X chromosome that carries the mutation, and are located symmetrically along the ventricular body. Imaging Features

MRI shows nodular, subependymal masses that are isointense with gray matter in all sequences and do not enhance with gadolinium administration [251]. These nodules are typically located along the lateral wall of the lateral ventricles. Their number and distribution is variable, ranging from one (Fig. 4.43) or few scattered, prevailingly peritrigonal nodules in sporadic cases to bilateral near-continuous heterotopic nodules in FLN1related BPNH (Fig. 4.44) [109, 144, 252]. The surrounding white matter shows normal signal intensity, and the overall appearance of the cerebral hemispheres is not significantly distorted, with a normal thickness and gyral configuration of the cortical mantle. We have also seen a case of “laminar” subependymal heterotopia, in which the heterotopia has a flat, rather than bumpy, appearance, and was associated with radially oriented transmantle heterotopia (Fig. 4.45). The main differential diagnosis is with the subependymal nodules of TSC. However, the latter usually have an elongated shape, are not isointense with gray matter due to calcification, and may enhance with gadolinium [108]; moreover, other brain manifestations of TSC are typically present. Subcortical Heterotopia

Subcortical heterotopia are irregular lobulated masses of gray matter located in the subcortical white matter of the cerebral hemispheres [250]. Unlike SBH, subcortical heterotopia are essentially always contiguous to the overlying cortex and the underlying ventricular surface, i.e., without intervening well-defined white matter layers [253]. Most reported cases have been males [254], suggesting an as yet unproven X-linked mechanism of inheritance, as is the case with several other migrational disorders. The etiology of subcortical heterotopia is unknown, but it could be related to a secondary, heterotopic germinal zone abnormally

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b Fig. 4.43a,b. Isolated subependymal heterotopia. a Axial T2weighted image; b Axial STIR-weighted image. Small heterotopic nodule in the lateral wall of the left atrium (arrow, a, b) is isointense with gray matter

a

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b Fig. 4.44a,b. Diffuse subependymal nodular heterotopia. a Axial T1-weighted image; b Axial T2-weighted image. Numerous, diffuse subependymal heterotopic nodules (arrowheads, a, b) are evident. A further small heterotopic nodule is recognizable in the left frontal region (arrow, a, b). All heterotopia are isointense with gray matter on both T1- and T2-weighted images. (Case courtesy Dr. C. Hoffmann, Tel-Hashomer, Israel)

located deep in the cerebral hemisphere, as shown in some rat models [67, 253]. Affected patients have hemiparesis in the contralateral body half, developmental delay, normal or near-normal intelligence, and simple partial motor seizures presenting any time between birth and the second decade [254]. MRI shows irregularly lobulated conglomerations of gray matter extending from the ventricular surface into the hemispheric white matter and, sometimes, to

the cerebral cortex (Fig. 4.46) [251, 253, 254]. The size of the heterotopia is variable. Some cases are relatively localized and are better defined as nodular, whereas in other cases there is a curvilinear appearance that extends to a large part of, or the whole, cerebral hemisphere [253]. The cortex overlying the heterotopia is thin with abnormally shallow sulci. Sometimes the cortex appears continuous with the heterotopia, which may contain engulfed vessels and CSF [251]. In these

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a

b Fig. 4.45a,b. Laminar subependymal heterotopia. a Sagittal T2-weighted image; b Axial T2-weighted image. There is diffuse laminar arrangement of neurons in the right periventricular occipital region (arrowheads, a, b). The lateral ventricle is sectorially dilated. Radial stripes of transmantle heterotopia (arrows, a, b) are recognizable. The corresponding cortical mantle is somewhat thickened and flat. This patient also had persistent hyperplastic primitive vitreous in his right eye

a

b Fig. 4.46a,b. Subcortical heterotopia in a newborn with Aicardi syndrome. a Axial T2-weighted image; b Sagittal T1-weighted image. This newborn has gross heterotopic islets in the left frontal subcortical region (thin arrows, a), surrounded by abnormally myelinated white matter. In the corresponding frontal areas, the cortical mantle appears abnormally flattened and perhaps thinned. Subcortical heterotopia is also visible in the contralateral frontal lobe (arrowhead, a). Subependymal heterotopia is also visible along the right atrium (open arrow, a). Colpocephaly and agenesis of the corpus callosum are also present. Notice multiple associated arachnoid cysts (asterisks, a, b). Congenital pharyngeal tumor (T, b) caused demise a few months after this examination; histology remained unascertained

cases, subcortical heterotopia may resemble cortical infoldings. There is a high prevalence of associated corpus callosum dysgenesis, probably resulting from failure of the heterotopic neurons to extend normal interhemispheric commissural axons [67, 243]; some cases are actually consistent with the definition of Aicardi syndrome (Fig. 4.46) (see Chap. 3). The basal

ganglia homolateral to the heterotopia are small and dysplastic, and the white matter is reduced, probably as a result of a reduction of intrahemispheric association axons [67]. As a consequence, the affected hemisphere is smaller than the contralateral one [251, 254]. In rare instances, giant heterotopic nodules may replace a whole cerebral hemisphere (Fig. 4.47) [255].

Brain Malformations

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d

c Fig. 4.47a–d. Giant subcortical heterotopia. Two different cases. Case #1 (a, b): a Coronal T1-weighted image; b Sagittal T1-weighted image. There is a huge heterotopic nodule in the right temporo-parieto-occipital region (asterisk, a, b). The frontal cortex anterior to the heterotopia is also dysplastic. A second subependymal heterotopic nodule is recognizable al the level of the temporal horn (arrowhead, b). (Case courtesy of Dr. G. Fariello, Rome, Italy.) Case #2 (c, d): c Axial T2-weighted image; d Coronal T1-weighted image. There is a severe abnormality of the migrational process, resulting in subverted organization of the right hemisphere. Individual lobes are no longer recognizable. The whole width of the hemisphere is occupied by a single-nodule giant subcortical heterotopia. CSF spaces are trapped within the lesion (arrow, c), suggesting the lesion may be at least partly explained as a large cortical infolding. Only on coronal images, a thin white matter layer separating the heterotopia from the normal cortex is recognizable (arrow, d). (Case courtesy of Prof. G. Scotti and Dr. A. Falini, Milan, Italy)

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Transmantle Heterotopia

This descriptive term, not to be confused with focal transmantle dysplasia (see above), indicates a column of heterotopic gray matter that extends through the full thickness of the cerebral mantle, i.e., from the subependymal to the pial surfaces (Fig. 4.48). Careful analysis must be performed to differentiate this abnormality from fused lips schizencephaly; absence of a ventricular dimple is an useful clue. Furthermore, the abnormality is differentiated from a polymicrogyric cortical infolding because the superficial sulcation, while usually abnormal, is shallow.

4.3.6 Malformations Due to Abnormal Cortical Organization 4.3.6.1 Polymicrogyria Background

Polymicrogyria (PMG) refers to an abnormal cortical pattern characterized by an excess of small, irregular convolutions without intervening sulci, with obliterated sulci due to fusion of the molecular layers, or with intervening shallow sulci [108, 256]. PMG is thought to result from events occurring during late neuronal migration and early cortical organization [7]. Causes of PMG involve both genetic and acquired events. Several bilateral PMG syndromes have been described in which either X-linked or autosomal modes of inheritance are contemplated [257]. In some cases, the causal genetic mutations have been identified [258, 259]. Environmental causes of PMG include prenatal cytomegalovirus infection [260] and in utero ischemic events [1, 261]. Remarkably, cytomegalovirus-related brain damage is caused by cerebral ischemia through angiitis or transient systemic perfusion failure, rather than by a direct cytopathic effect [262]. Pathology

a

PMG can be unilateral or bilateral. Owing to the common pathogenesis, PMG can be associated with schizencephaly (see below). The cortex is characterized by a flat external surface that results from adhesion of multiple small adjacent gyri, often with complete fusion of the superficial layers and obliteration of the intervening sulci. As a result, the cortical mantle appears macroscopically thicker, even though microscopically there is, in fact, cortical thinning, owing to reduction of the neuronal population. Histologically, two major forms of PMG exist, i.e., unlayered PMG and four-layered PMG. However, because the two forms cannot be distinguished by means of imaging, this categorization is not particularly useful for neuroradiologists.

b Fig. 4.48a,b. Transmantle heterotopia. a Axial STIR-weighted image; b Coronal STIR image. Cortical dysplasia involves the whole thickness of the right cerebral hemisphere in the temporo-parietal lobes (black arrowheads, a, b), extending from the pia to the ependymal lining. On coronal image, association with diffuse cortical dysplasia of the mesial aspect of the hemisphere (white arrowhead, b) is clearly recognizable. Notice there is neither cleft nor ventricular dimple, thereby ruling out schizencephaly

Unlayered PMG is characterized by a disorganized cortex with absent lamination, and results from earlier, genetically determined or exogenous events [10th–18th gestational week]. Four-layered PMG arises later [13th–24th gestational week] and is basically associated with perfusion fail-

Brain Malformations

ure causing laminar cortical necrosis that preferentially involves cortical layer 5 [202, 256, 263, 264]. Clinical Findings

Clinical presentation varies significantly among patients, depending on the extent and location of cortical involvement as well as on associated abnormalities. The spectrum of clinical manifestations ranges from severe encephalopathy with intractable epilepsy to near-normal patients with limited cognitive impairment [202]. Definite clinical syndromes with PMG have been described, as detailed below. Regardless of the morphologic abnormality, involvement of the central sulcus, operculum, or sylvian fissure is more likely to be associated with neurologic signs than abnormalities in other cortical regions [109]. Imaging Findings

PMG can be uni- or bilateral, localized or diffuse, and results in an irregular contour of the hemispheric surface. The cortex has an irregular appearance with multiple, tiny gyri lining a folded region. The flattened or bumpy appearance of the cortical surface results from the individual gyri merging with one another as a result of fusion of the superficial layers. This results in an apparent thickening of the cortical ribbon, simulating pachygyria on thick MRI sections [265]. The gray-white matter interface is typically corrugated [256], reflecting the multiple subcortical white matter interdigitations in the depth of the microgyri. The extent of the cortical abnormality is variable in individual cases. Bilateral, symmetric PMG is typically found in genetic syndromes, and the perisylvian regions are most commonly involved (see below). In these cases, there is failure of sylvian opercularization with abnormally shallow, verticalized sylvian fissures that extend posteriorly into the parietal regions. Unilateral PMG (Fig. 4.49) can be variably severe. The involved hemisphere is usually smaller than the contralateral one, and there is concurrent dysmorphic ventriculomegaly. Localized polymicrogyric areas may involve the cortex surrounding abnormally deep, large sulci, forming cortical infoldings that may reach the ependymal surface (Fig. 4.50). Volumetric MRI techniques with thin partition size and curvilinear and surface reconstructions are especially useful to fully depict the cortical abnormality. CT plays an important role in detecting associated cerebral calcification, suggesting underlying congenital cytomegalovirus infection. Prominent vascularity is typically detected in the enlarged sub-

arachnoid space superficial to the dysplastic cortex, and represents abnormal venous drainage related to persistence of tributaries of the embryonic dural plexus [256]. Syndromes with PMG

Unilateral PMG

The severity of the clinical picture correlates with the extent of the abnormal cortex, its location, and the presence of associated anomalies. The affected hemisphere is invariably smaller than the contralateral one. The regions of the brain around the sylvian fissure are the most common location (Fig. 4.49). Affected patients usually present with congenital hemiparesis or hemiplegia that involves the contralateral body. Seizures, often complex partial, developmental delay, and neurologic signs are other well-known presenting signs [244, 266]. The contralateral hemisphere can be normal or show associated abnormalities, most notably schizencephaly. Although most cases of unilateral PMG have been sporadic, a genetic basis has also been suspected (A.J. Barkovich, personal communication). Bilateral PMG

Bilateral, symmetric hemispheric involvement of the cerebral hemispheres with PMG has been increasingly recognized in the past few years [257]. Distribution of PMG regionally involves discrete, nonoverlapping brain portions. Bilateral perisylvian PMG is the most common of these syndromes. In this disorder, PMG involves the perisylvian regions with variable extent among patients [257, 267]; typically, the sylvian fissures have an abnormally verticalized orientation and extend far more posteriorly than normal into the parietal regions. Affected patients display a typical clinical syndrome consisting of facial, lingual, and masticatory diplegia (developmental Foix-ChavanyMarie syndrome), associated with mental retardation and seizures [268-270]. Bilateral perisylvian PMG is probably genetically heterogeneous [271]. However, X-linked inheritance is predominant [272]. A locus for bilateral perisylvian PMG has been mapped to Xq28 [259]. Bilateral parasagittal parieto-occipital PMG. The cortical abnormality is centered around the mesial parieto-occipital regions bilaterally (Fig. 4.51). Affected patients basically present with seizures, often complex partial, and significant developmental delay. Age

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a

b Fig. 4.49a,b. Unilateral polymicrogyria. Two different patients, both presenting with congenital hemiplegia involving the contralateral body half. Case #1: a Axial STIR image. The right hemisphere is smaller than the contralateral, unaffected hemisphere. The cortical mantle is apparently thickened, resulting from fusion of multiple adjacent small gyri. Such condition becomes apparent when one considers the corrugated gray-white matter interface, resulting from subcortical white matter interdigitations within the core of the microgyri. The sylvian fissure is shallow, verticalized, and somewhat displaced posteriorly from its normal location; it contains a few large veins (arrow, a). Case #2: b Sagittal STIR image. Diffuse polymicrogyria involves the fronto-temporo-insular regions. Note the smooth outer cortical surface, whereas the gray-white matter interface is irregular due to multiple fine interdigitations resulting from tightly packed abnormal convolutions. The malformative condition has caused defective sylvian opercularization. Notice large veins within the sylvian fissure (arrow, b). Case courtesy of Dr. C. Capellini, La Spezia, Italy

a

b Fig. 4.50a,b. Cortical infoldings. a Axial STIR image; b Coronal STIR image. a cortical infolding is recognizable in the anterior left frontal region (white arrowheads, a). The infolding reaches the surface of the lateral ventricle (black arrowhead, a). Coronal image shows a large infolding of thickened cortex (black arrows, b), associated with subcortical heterotopia (white arrow, b). It is difficult to determine the nature of the dysplasia involving the cortex, that appears thickened and smoothly marginated

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a

b

c

d

e

Fig. 4.51a–e. Diffuse polymicrogyria. Case #1: a Axial STIR image, b Sagittal STIR image. Bilateral parieto-rolandic polymicrogyria. Both the inner and outer surfaces are irregular, although the outer is more gross. Adjacent subarachnoid spaces and ventricular portions close to the malformation are dilated. Case #2: c Axial T1-weighted image; d, e. Axial T2-weighted images. There is absent opercularization of both sylvian fissures. Polymicrogyria involves the perisylvian regions, extending cranially to both the frontal and parietal lobes

at presentation is highly variable. Although reported cases have been sporadic, a genetic basis is suspected [273]. Bilateral posterior parietal PMG. The abnormality involves the lateral portions of the parietal lobes over the convexity. Affected patients display minor speech difficulties; seizures are not a typical manifestation in this patient group [274]. Bilateral frontal PMG. There is involvement of the frontal lobes, from the frontal poles anteriorly to the precentral sulcus posteriorly and the frontal operculus inferiorly. Affected patients present in early childhood with delayed development and mild spastic quadriparesis, whereas seizures usually appear later [263]. Possible autosomal recessive inheritance has been suggested [263].

Diffuse PMG

Not surprisingly, affected patients display a more severe clinical compromise that presents earlier than in children with more localized pathology. In many cases, bilateral extensive involvement of the cerebral hemispheres likely results from a combination of the discrete regions described above (Fig. 4.51) [257]. However, PMG involving widespread cortical areas more likely has epigenetic causes, such as exposure of the fetus to viral or toxic agents. Diffuse PMG has also been described in several syndromes, including the Aicardi syndrome [275] (see Chap. 3), Zellweger disease (see below), and in association with hydrocephalus, craniosynostosis, severe mental retardation, and facial and genital anomalies [276].

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4.3.6.2 Schizencephaly Background

The term schizencephaly refers to a uni- or bilateral, full-thickness cleft in the brain that connects the lateral ventricles to the subarachnoid space through the cerebral mantle. The definition of schizencephaly has long been controversial, and pathologists have often disagreed on its real significance, basically because of uncertainties regarding its etiology [1, 277, 278]. Differentiation from purely clastic lesions (i.e., porencephaly) is based on the fact that the schizencephalic cleft is consistently lined by gray matter in the form of unlayered PMG [108]. Thus, PMG and schizencephaly are presently grouped together (“polymicrogyriaschizencephaly spectrum”) [7]. In fact, there probably is a spectrum of severity in the causal event that correlates with the extent of the resulting abnormality, which can vary from flat PMG to cortical infoldings lined by PMG, to full thickness schizencephaly [108, 279]. This categorization is reinforced by the observation that PMG and schizencephaly may coexist in individual patients, for instance with schizencephaly in one hemisphere and PMG affecting the other (Fig. 4.52).

a

As is the case with PMG, schizencephaly could be the end result of a variety of insults resulting in abnormal cortical organization. In utero ischemic events probably account for the majority of cases [107, 280]. Mutations of the EMX2 homeobox gene, located on 10q26.1, have been rarely found in patients with large schizencephalic clefts [281]. The role of the Emx2 protein has not been fully established, but it may be related with cell fate determination. Classification

Schizencephaly is categorized on the basis of the degree of separation of the cleft lips, which grossly correlates with the severity of the clinical picture. Open lips schizencephaly is characterized by a variable degree of separation of the cleft walls, resulting in a well-defined holohemispheric cleft filled with CSF (Figs. 4.52, 4.53). Patients with open lips schizencephaly are more severely impaired, with moderate to severe developmental delay, seizures, hypotonia, spasticity, inability to walk or speak, and blindness. The incidence of contralateral hemiparesis and the severity of developmental delay and mental retardation correlate significantly with the size of the cleft, a

b Fig. 4.52a,b. Unilateral open lips schizencephaly. a Axial STIR image; b Coronal STIR image. In the left frontal region, a deep fissure involves the whole thickness of the cerebral hemisphere, allowing direct communication between the pial surface and the lateral ventricle, that is sectorially dilated. Polymicrogyric cortex surrounds both lips of the fissure, that are widely separated from one another (arrowheads, a, b). The septum pellucidum is absent (b). Polymicrogyria also involves a portion of the contralateral hemisphere (black arrow, a). Large drainage veins are visible into the dilated CSF spaces corresponding to the cortical malformations on both sides (white arrows, a, b)

Brain Malformations

a

b Fig. 4.53a,b. Bilateral schizencephaly in a patient with septo-optic dysplasia. a Coronal STIR image; b Axial STIR image. A large fissure is recognizable in the left hemisphere, surrounded by dysplastic cortex (white arrowheads, a, b). The large CSF cavity (white asterisk, b) causes asymmetric macrocrania. A narrower fissure is visible contralaterally (black arrowheads, a), and a third is seen in the left temporal region that allows communication between the hemispheric surface and the temporal horn (black arrowheads, a). Also these narrower fissures are surrounded by dysplastic cortex. Transmantle cortical heterotopia involves the posterior portion of the right frontal lobe (black asterisk, b). Notice absence of the septum pellucidum

location involving the rolandic region, and the presence of bilateral defects [278, 279]. Seizures appear earlier and are more likely to be intractable in open lips schizencephaly than in closed lips schizencephaly [202]. Closed lips schizencephaly is characterized by apposition of the walls of the cleft with a variable degree of fusion of the opposed cortical surfaces, resulting in a narrow, variably obliterated furrow that extends from the pial surface to a dimple located along the lateral ventricular wall (Fig. 4.54). Patients with unilateral closed lips schizencephaly can be almost normal, although they may have seizures and spasticity. Imaging Findings

MRI depicts schizencephaly as a CSF-filled cleft bordered by gray matter, extending from the pial surface to the ventricular wall [108] (Figs. 4.52–54). Schizencephalic clefts may be unilateral or bilateral; in the latter case, they are usually almost symmetric in location, but not necessarily in size [202, 279, 280]. Unilateral and bilateral clefts probably occur with a similar incidence in the general population [280]. Multiple clefts are exceptional; however, we observed cases with multiple bilateral clefts and associated septooptic dysplasia.

Open-lipped defects are more readily appreciated than closed-lipped ones. When large, open-lips schizencephaly may cause enlargement of the skull as a result of CSF pulsations (Fig. 4.53) [279, 280]. Differentiation from porencephalic cavities is based on the presence of gray matter lining both sides of the cleft. Large vessels are often seen within the CSF into open-lipped clefts [108]. A single case report has described open lips schizencephaly in conjunction with an intracranial arteriovenous malformation [282]. An important clue to the presence of a fused cleft is a dimple along the lateral ventricular wall, corresponding to the site where the cleft enters the ventricle [108] (Fig. 4.54). This sign can be particularly useful with CT, as recognition of a fused-lipped cleft may not be easy due to insufficient contrast resolution. Associated cortical malformations are common. These typically include PMG and subependymal heterotopia extending for variable distances from the superficial and deep extremities of the cleft, respectively. Moreover, cortical malformations (typically PMG) often involve the contralateral hemisphere in cases of unilateral schizencephaly, usually in a symmetric location (Fig. 4.52) [279]. The septum pellucidum is absent in the majority of patients with schizencephaly [280, 283]. Some patients also have associated optic nerve hypoplasia and are best categorized as having “septo-optic dys-

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4.3.6.3 Non-Taylor’s Focal Cortical Dysplasia (Architectural and Cytoarchitectural) Background

Non-Taylor’s focal cortical dysplasia (NFCD) is believed to result from a localized insult to the developing cortex occurring during the process of cortical organization [7]. As such, it is currently separated from FTD (see discussion, Taylor’s FCD). However, such separation is questionable on the basis of histological findings. In fact, there is a histological spectrum of severity ranging from mild forms of NFCD with essentially normal cell populations to full-blown FTD with balloon cells [146, 147]. According to this classification (Table 4.5), NFCD is categorized into two subsets [146, 147]:

a

[1] Architectural FCD (formerly microdysgenesis): The affected cortex shows mildly to moderately abnormal lamination without malformed or giant neurons, associated with heterotopic neurons in the underlying white matter; [2] Cytoarchitectural FCD: Moderately to severely abnormal cortical lamination is associated with giant neurons distributed throughout the cortex and heterotopic neurons in the white matter.

Clinical Findings b Fig. 4.54a,b. Closed lips schizencephaly. a Axial T2-weighted image; b Axial STIR image. Two thin, full-thickness clefts are visible in the occipital regions bilaterally (arrowheads, a, b). An ependymal dimple, corresponding to the orifice of the cleft, is clearly visible on the left (thin arrow, a, b), whereas a cortical depression, corresponding to the outer orifice of the cleft, is detected to the right (thick arrow, a, b). Both sequences, but especially STIR, clearly show both clefts are surrounded by abnormal cortex

plasia plus” (Fig. 4.53) [94] (see “septo-optic dysplasia”). There is a relationship between location of the cleft and involvement of septum, in that absence of the septum correlates with frontal clefts, whereas presence of the septum is found with clefts involving the parietal, occipital, and temporal lobes; however, clefts involving the rolandic regions do not show an equally well-defined relationship with septal defects [284].

Clinically, patients basically present with seizures. Epilepsy onset is generally in the first decade. Seizure frequency is high, typically with one or more episodes a day, and increases with the histological grade [146]. Mild mental retardation and abnormal neurological examination are found in a minority of patients. Imaging Findings

The role of MRI in the identification of NFCD is not completely known. A significant proportion of cases (probably as many as one third) remains undetected even with high resolution MRI, and is only detected by postsurgical histological examination. Moreover, the boundaries of the lesion identified with MRI are often maldefined, thereby providing an imperfect guide to surgical resection [146]. Architectural FCD is characterized on MRI by normal cortical thickness and pattern of gyration

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[147]. This represents a notable exception from most other MCD. Significant findings [147] are focal brain hypoplasia, white matter core atrophy, and moderate white matter hyperintensity on T2weighted images. Typical location is in the temporal lobe (Fig. 4.55) [147]. A blurred gray-white matter junction, best appreciated on fast inversion recovery sequences, may also be seen, although it is less marked than in FTD [147, 160]. An association with the typical MRI features of hippocampal

sclerosis is found in about 55% of cases (Fig. 4.55) [147]. Cytoarchitectural FCD was only rarely commented upon in the literature. MRI is normal in about 50% of patients. In the remainder, MRI are not characteristic, being either undistinguishable from FTD (Fig. 4.56) or showing isolated frontotemporal hypoplasia without signal abnormalities. The diagnosis was histological in all these cases [147].

a

b Fig. 4.55a,b. Architectural focal cortical dysplasia associated with hippocampal sclerosis (dual abnormality). a Coronal STIR image; b Coronal T2-weighted image. There is hypoplasia of the left temporal pole, with blurred gray-white matter junction (arrow, a). Hippocampal sclerosis is also detected (arrow, b)

a Fig. 4.56a,b. Cytoarchitectural focal cortical dysplasia. a Coronal STIR image; b Axial FLAIR image. There is blurring of the gray-white matter junction in the left frontal region (arrow, a). Notice that cortical thickness is normal. Heterotopic neurons deepen into the white matter without reaching the ventricular wall, causing signal hyperintensity on the FLAIR image (arrow, b). Findings are similar to those of focal transmantle dysplasia

b

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4.3.7 Malformations of Cortical Development, not Otherwise Classified 4.3.7.1 Zellweger Syndrome

Zellweger syndrome (ZS), or cerebro-hepato-renal syndrome, is a lethal disorder affecting one in every 50,000 live newborns [285]. ZS is a peroxisomal disorder characterized by a host of biochemical abnormalities, basically involving marked plasma elevations of very long chain fatty acids, pipecolic acid, and bile acid intermediates [286]. Presentation is typically neonatal. Affected newborns are profoundly hypotonic and areflexic, have seizures, show a characteristic craniofacial appearance including turribrachycephaly, and display multiorgan abnormalities including cortical dysgenesis, white matter hypomyelination, hepatomegaly, polycystic kidneys, and calcific stippling of patellae, hips, and other epiphyses [286]. Life span is short, usually in the range of a few months [285]. Brain MRI displays a characteristic association of cortical dysgenesis and severely diminished myelination [285, 287]. The entirety of the cerebral cortex is abnormal. However, the pattern of cortical involvement varies regionally and among patients, with a mixture of polymicrogyria, pachygyria, and gyral pattern simplification [287]. Because affected patients are newborns or small infants, the degree of myelination is best assessed by evaluating the internal capsules. In ZS, there is lack of physiologic low T2 signal intensity, and diminished or complete absence of high T1 signal intensity, in the posterior portions of the posterior limbs of the internal capsules [287]. Zellweger syndrome is described in greater detail in Chap. 13. 4.3.7.2 Mitochondrial Disorders

Diffuse polymicrogyria has been rarely described in patients with pyruvate dehydrogenase complex deficiency [7, 288]. 4.3.7.3 Sublobar Dysplasia

This recently described abnormality [289] is characterized by localized dysplasia of a portion of one cerebral hemisphere, separated from the remainder of the hemisphere by one or more deep cortical infoldings. Presentation is with generalized seizures that

may progress to become partial complex; the neurologic examination is otherwise normal. The affected cortex is thickened, with shallow sulci and an abnormal sulcal pattern. Separation from polymicrogyria is based on the use of thin-slice volumetric imaging sequences. Associated abnormalities prominently include callosal dysgenesis [289].

4.4 Malformations of the Posterior Cranial Fossa 4.4.1 Embryology Knowledge of the main embryological steps leading to the formation of the cerebellum is required in order to understand its malformations. The development of the cerebellum differs from that of the supratentorial brain in many ways. Most importantly, the cerebellum forms from midline fusion of two paired rudiments, whereas the telencephalon cleaves along the midline to form the two cerebral hemispheres. Around the 28th gestational day, that is roughly by the end of primary neurulation, the anterior end of the neural tube becomes expanded to form the three primary brain vesicles, of which the rhombencephalon, or hindbrain, is the caudalmost. The cavity of the hindbrain will become the fourth ventricle. The upper portion of the rhombencephalon exhibits a marked constriction, the isthmus rhombencephali, which divides it from the mesencephalon, or midbrain. As the result of unequal growth of the primary cerebral vesicles, three flexures are formed and the embryonic brain becomes bent on itself in zigzag-like fashion. The two earliest flexures (cephalic and cervical flexure) appear shortly after the institution of the primary cerebral vesicles, and are concave ventrally so that the neural tube forms a wide, upside-down U shape [1]. The third bend (pontine flexure) appears during the middle of the second gestational month and is concave dorsally, thereby converting the shape of the cephalic extremity into a broad M. The rhombencephalon further divides into two secondary vesicles: an upper, called the metencephalon, and a lower, the myelencephalon. The pons develops from a thickening in the floor and lateral walls of the metencephalon. The floor and lateral walls of the myelencephalon are thickened to form the medulla oblongata, which is continuous inferiorly with the spinal cord. The cerebellum, once thought to derive

Brain Malformations

solely from the hindbrain, has in fact a dual origin from the alar plates of the caudal third of the mesencephalon (basically forming the vermis) and the alar plates of the metencephalon (basically forming the cerebellar hemispheres) [290–292]. Anterolateral migration of cells from the alar plates of the metencephalon forms the pontine nuclei. The isthmus plays a crucial role in the control of early patterning of the prospective midbrain and anterior hindbrain (“isthmic organizer”). The isthmic organizer lies at the interface of the expression of two homeotic genes, OTX2 and GBX2. Additionally, signaling molecules encoded by FGF8 and WNT1 are expressed within the isthmic organizer, and are necessary to maintain expression of EN1, EN2, and Pax 2 [293]. Moreover, the transcription factor Lmx 1b maintains isthmic WNT1 expression. Perturbations of genes involved in early cerebellar patterning have been shown to produce a wide spectrum of abnormal phenotypes, ranging from agenesis of the entire midbrain-cerebellar region to minimal abnormalities of cerebellar foliation [293]. Because of the appearance of the pontine flexure, the cranial and caudal extremities of the fourth ventricle are progressively approximated dorsally and the roof is folded inward toward the cavity of the fourth ventricle, while the alar (dorsal) laminae are splayed laterally as a consequence of the bending of the pons, and eventually lie dorsolateral to the basal laminae. Therefore, the roof plate (corresponding to the roof of the developing fourth ventricle) remains thin and is markedly expanded transversally; as seen dorsally, the roof of the fourth ventricle assumes a somewhat lozenge-shaped appearance, with the margins angling obliquely toward the midline both cephalically and caudally starting from their widest separation. Mesenchyme insinuating itself into the fold at level of the fourth ventricular roof forms the plica choroidalis, that is the precursor of the choroid plexus. This plica starts in the extremity of each lateral recess, passes mesially, and then extends caudally to the extremity of the fourth ventricle [294]. The roof of the fourth ventricle is divided by the plica choroidalis into two areas: one cranial, called the anterior membranous area (AMA), and one caudal, the posterior membranous area (PMA) (Fig. 4.57). Owing to neuroblastic proliferation, reflecting production of the neurons of the cerebellar nuclei, Purkinje cells, and radial glia, the alar laminae along the lateral margins of the AMA become thickened to form two lateral plates, called rhombic lips. This process begins at approximately 28–44 days [295], and causes the rhombic lips to enlarge and to approach each other. As the rhombic lips grow, the AMA

regresses. Eventually, the rhombic lips fuse in the midline, producing a thick lamina which constitutes the rudiment of the cerebellum, the outer surface of which is originally smooth and convex [296]. At this stage, the AMA has been completely incorporated into the developing choroid plexus. Growth and backward extension of the cerebellum pushes the choroid plexus inferiorly, while the PMA greatly diminishes in relative size as compared to the overgrowing cerebellum. Subsequently, a marked caudal protrusion of the fourth ventricle appears, causing the PMA to expand as the finger of a glove [294]. This transient protrusion has been called Blake’s pouch (Fig. 4.57). The Blake’s pouch consists of the ventricular ependyma surrounded by a condensation of the mesenchymal tissues [294]; it is a closed cavity, that is, it initially does not communicate with the surrounding subarachnoid space of the cisterna magna, whose canalization from the original leptomeningeal meshwork presumably commences at about 44 days of gestation [297]. The choroid plexus extends in the roof of the pouch a short distance caudad of the extremity of the vermis and along its under surface. The network between the vermis and the pouch progressively becomes condensed, whereas the other portions about the evagination become rarified [294]; thus, permeabilization of Blake’s pouch institutes the foramen of Magendie. The precise time of opening of the foramen of Magendie is not established [295]; however, persistence of the Blake’s pouch has been demonstrated into the fourth gestational month [298]. The foramina of Luschka also probably appear late into the fourth month of gestation [295]. During the first two gestational months the cerebellum lies within the rhombencephalic vesicle. Beginning in the third gestational month, intense neuroblastic proliferation causes it to enlarge extraventricularly. The fissures of the cerebellum appear first in the vermis and floccular region, and traces of them are found during the third month, whereas the fissures on the cerebellar hemispheres do not appear until the fifth month [296]. The groove produced by the bending over of the rhombic lip is known as the floccular fissure; when the two lateral walls fuse, the right and left floccular fissures join in the midline and their central part becomes the postnodular fissure. Because it is the first cerebellar portion to become recognizable as a separate portion, the flocculonodular lobule is also designated archicerebellum. The formation of the vermis antedates that of the hemispheres by 30–60 days [295] and is complete by the 15th gestational week; therefore, the vermis (with the exception of the nodulus) is also referred to as paleocerebellum, whereas the hemispheres (with the exception of the

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Isthmus rhombencephali AMA Choroid plexus PMA a

Blake’s pouch

Cerebellar rudiment

Foramen of Magendie

PMA b

c

Isthmus rhombencephali

d

Cerebellar hemisphere

Rhombic lips AMA Cloroid fold

Vermis PMA (Blake’s pouch)

PMA e

g

Foramen of Magendie

f

Fig. 4.57a–g. Schematic depiction of normal fourth ventricular development. a–d Sagittal views; e–g. Posterior views. Abbreviations: 4 v, fourth ventricle; AMA, anterior membranous area; PMA, posterior membranous area. a and e The initially flat roof, lozengeshaped of the developing fourth ventricle is divided by the choroid fold (the precursor of the choroid plexus) into two areas: a cranial area, called AMA, and a caudal area, called PMA. b and f: Cellular proliferation occurs at the edges of the AMA, forming the rhombic lips. These, together with the isthmus rhombencephali, contribute to the development of the cerebellar rudiment. As the rhombic lips grow, the size of the interposed AMA decreases. Eventually, the AMA completely disappears, its remnants being incorporated into the choroid fold. Notice that, as the AMA is regressing, the PMA is persisting. c, d, and g: The PMA expands as a finger of a glove, forming an ependyma-lined protrusion that is continuous with the fourth ventricle and is caudal to the choroids plexus. This structure is called Blake’s pouch. It occupies a space comprised between the vermis superiorly, and the developing occipital squama inferiorly and posteriorly. Permeabilization of the Blake’s pouch institutes the foramen of Magendie, and allows for cerebrospinal egression from the fourth ventricle into the developing subarachnoid spaces of the cisterna magna

flocculi) constitute the neocerebellum [17]. The best marked of the early fissures are the primitive fissure between the developing culmen and declive, and the secondary fissure between the future pyramid and uvula. Anatomically, the portion of cerebellum that lies anterior to the primary fissure is called anterior lobe, whereas the posterior lobe lies between the primary and flocculonodular fissure. Therefore, there is only a limited correspondence between the phylogenetic and anatomic subdivisions of the cerebellum. The cerebellar cortex consists of three layers: an external gray molecular layer; an intermediate, incomplete stratum of Purkinje cells; and an internal granular layer. Cells of the intermediate Purkinje layer and of the deep cerebellar nuclei arise from the germinal matrix in the fourth ventricular wall from 11–13 weeks and migrate radially. Neurons that will form the molecular and inner granular layer arise

from the lateral portion of the rhombic lips and, by 11–13 weeks, migrate tangentially over the surface of the cerebellum to form a transient external granular layer. Proliferation of external granular cells produces daughter cells that migrate inward to form the basket cells of the molecular layer and the internal granular layer. The external granular layer eventually disappears by the end of the first postnatal year [295].

4.4.2 Classification of Malformations No fully satisfactory classification of cerebellar malformations has been devised so far, in spite of many attempts. Most authors have tried to classify cerebellar malformations on the basis of their embryogenesis from the rhombencephalon [17, 295, 299]. Sidman and

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Rakic [300] considered that the key to morphogenesis of the cerebellum lies in understanding the differential growth rates of the cerebellar primordium. Therefore, embryology-based classification schemes mainly discriminate between paleocerebellar malformations, which have defects of the vermis as their key feature, and neocerebellar malformations, which are characterized by predominantly hemispheric abnormality. The major drawback of a purely embryological approach is that our knowledge of human neuroembryogenesis is far from complete, and rests basically on animal experimentation; moreover, it may be impossible to exactly determine the timing of a given malformation [301]. Recently, Patel and Barkovich [5] proposed an alternative, imaging-based classification scheme (Table 4.8). This approach categorizes cerebellar malformations into hypoplasias (defined as a small or incompletely formed, but otherwise normalappearing cerebellum) and dysplasias (defined as a disorganized pattern with abnormal folial pattern or presence of heterotopic gray matter nodules). Hypoplasias and dysplasias are further classified into generalized (involving both cerebellar hemispheres and Table 4.8. Classification scheme for cerebellar malformations (Patel and Barkovich) [5] I. Cerebellar hypoplasia A. Focal hypoplasia 1. Isolated vermis 2. One hemisphere hypoplasia B. Generalized hypoplasia 1. With enlarged fourth ventricle (“cyst”), Dandy-Walker continuum 2. Normal fourth ventricle (no “cyst”) a. With normal pons b. With small pons 3. Normal foliation a. Pontocerebellar hypoplasias of Barth, types I and II b. Cerebellar hypoplasias, not otherwise specified II. Cerebellar dysplasia A. Focal dysplasia 1. Isolated vermian dysplasia a. Molar tooth malformations (associated with brain stem dysplasia) b. Rhombencephalosynapsis 2. Isolated hemispheric dysplasia a. Focal cerebellar cortical dysplasias/heterotopia b. Lhermitte-Duclos-Cowden syndrome B. Generalized dysplasia 1. Congenital muscular dystrophies 2. Cytomegalovirus 3. Lissencephaly with RELN mutation 4. Lissencephaly with agenesis of corpus callosum and cerebellar dysplasia 5. Associated with diffuse cerebral polymicrogyria 6. Diffusely abnormal foliation

the vermis) and focal (localized to either a single hemisphere or the vermis). The pros and cons of this new classification scheme still require time to be fully evaluated. Based on our experience, we have decided to basically retain a morphological approach that distinguishes posterior fossa abnormalities into two broad categories: (i) cystic malformations, characterized by the presence of a substantial CSF collection resulting from active expansion of CSF spaces, and (ii) noncystic malformations, in which either there is no CSF collection or expansion of CSF spaces is passive, i.e., it results from defective cerebellar development (Table 4.9). Moreover, these malformations can also be classified into focal (i.e., with isolated vermian or hemispheric involvement), diffuse (involving both the vermin and hemispheres), and combined (with involvement of the cerebellum and brainstem).

Table 4.9. Classification scheme for posterior fossa malformations (Tortori-Donati) A) Cystic malformations Malformations of the fourth ventricular roof 1. Anomalies of the anterior membranous area (Dandy-Walker continuum) a. Dandy-Walker malformation b. Dandy-Walker variant 2. Anomalies of the posterior membranous area (Blake continuum) a. Persistent Blake’s pouch b. Mega cisterna magna Malformations of the arachnoid Arachnoid cysts B) Noncystic malformations 1. Paleocerebellar (vermian) hypoplasia a. Rhombencephaloschisis/molar tooth malformations b. Rhombencephalosynapsis c. Tectocerebellar dysraphia 2. Neocerebellar (hemispheric-vermian) hypoplasia a. Cerebellar agenesis (total and subtotal) b. Pontocerebellar hypoplasia c. Unilateral hemispheric aplasia/hypoplasia 3. Cerebellar cortical malformations a. cortical dysplasias b. granular layer aplasia c. cortical hyperplasias (Lhermitte-Duclos, macrocerebellum) 4. Isolated brainstem hypoplasia/dysplasia

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4.4.3 Cystic Malformations Cystic malformations of the posterior cranial fossa are characterized by the presence of substantial retrocerebellar and/or infracerebellar CSF collections that result from “active” (i.e., not ex-vacuo) expansion of CSF spaces. Thereby, they are distinguished from noncystic malformations, in which CSF collections are either absent or result from ex-vacuo dilatation of CSF spaces. One should be aware of the fact that the nature of posterior fossa “cysts” may be extremely variable. Some “cysts” are in fact related to massive dilatation of the fourth ventricle, others to persistence of embryonic structures such as the Blake’s pouch, others to malformative dilatation of subarachnoid spaces, others to true arachnoid loculations. Because histological verification of the nature of these CSF collections is usually not obtained, classifications, including ours (Table 4.9), may be subject to criticism. However, an important point is that some of these abnormalities are amenable to CSF shunting, which may radically improve the outcome. Therefore, an effort is required to establish diagnostic criteria that may help in treatment decision-making. In the past, CT cisternograms were performed to assess communication between these CSF collections and the subarachnoid spaces, thereby allowing differentiation of noncommunicating arachnoid cysts from other entities. In the MRI era, CT cisternography is no longer performed. MR studies of CSF flow have not been conclusively proved to be helpful in the differential diagnosis of these malformations. Therefore, the mainstay of the diagnosis rests in the assessment of a number of indirect signs, i.e., the morphology of the “cyst,” fourth ventricle, and subarachnoid spaces; the morphology of the vermis and cerebellar hemispheres (normal, hypoplastic, or compressed); the size of the posterior cranial fossa; the position of the torcular; and the presence of hydrocephalus. Two issues appear to be particularly relevant, i.e., differentiation of the Dandy-Walker continuum from global cerebellar hypoplasias, and nature identification of infraretrocerebellar CSF collections. The following discussion is an attempt to establish a number of standpoints concerning the differential diagnosis of the various malformative conditions. 4.4.3.1 Dandy-Walker Malformation Background

The term ”Dandy-Walker malformation” (DWM) was suggested in 1954 by Benda [302] to describe a

malformation consisting of a cystic enlargement of the fourth ventricle associated with agenesis or, more frequently, hypoplasia of the vermis. This malformation had originally been described by Dandy and Blackfan in 1914 [303], and subsequently studied in deeper detail by Taggart and Walker in 1942 [304]. The characteristic triad of the full-blown DWM is: (i) complete or partial agenesis of the vermis; (ii) cystic dilatation of the fourth ventricle; and (iii) enlarged posterior fossa with upward displacement of transverse sinuses, tentorium, and torcular. Hydrocephalus, albeit common [80% of cases], is not an essential criterion [9, 17]. Subsequent observations of cases with partial agenesis and rotation of the vermis and cystic enlargement of the fourth ventricle, but no substantial enlargement of the posterior fossa, led to the introduction of the term “Dandy-Walker variant” (DWV) [305]. Unification of DWM and DWV into a spectrum of variability of rhombencephalic roof development (“The Dandy-Walker continuum”) was proposed by Barkovich et al. in 1989 [306]. However, further investigations from the same group subsequently questioned whether DWV is a mild form of DWM or, rather, represents a generalized form of cerebellar hypoplasia [5]. Pathogenesis

Although pathogenetic explanations initially focused on nonpatency of the fourth ventricular foramina [303, 304], it subsequently became clear that these foramina are patent in the majority of cases [17]. Moreover, formation of the vermis is known to occur several weeks earlier than permeabilization of the foramina of Magendie and Luschka. The pathogenesis of the malformation is presently believed to be related to a developmental arrest in the hindbrain. Failure to incorporate the AMA into the choroid plexus leads to persistence of the AMA between the caudal edge of the developing vermis and the cranial edge of the developing choroid plexus. CSF pulsations cause the AMA to balloon out into a cyst that displaces the hypoplastic vermis superiorly, so that the hypoplastic vermis appears to be “rotated” in a counter-clockwise fashion. The PMA can persist unopened or become patent, accounting for the reportedly variable patency of the foramen of Magendie and association with hydrocephalus. Global enlargement of the posterior fossa may result from arrested development of the tentorium, straight sinus, and torcular, with failure of migration of the straight sinus from the vertex to the lambda, possibly as a consequence of the abnormal distention of the fourth ventricle. A genetic predisposition probably plays a role in the pathogenesis,

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although the involved genes remain undetermined [5]. Clinical Findings

DWM causes 2%–4% of hydrocephalus in children. Incidence is one in 25–35,000 live births. Hydrocephalus often is not evident at birth, but generally appears by 3 months of age [295]. Stigmata of hydrocephalus are usually represented by an enlarged head, bulging fontanelle, and developmental delay. Cerebellar findings are uncommon. Because growth of the cerebellum by apposition of cells from the external granular layer continues well into the first postnatal year, CSF shunting is required in newborns to reduce CSF pressure into the posterior fossa and favor this physiological process. In our experience, placement of the shunt catheter into the dilated fourth ventricle has been particularly effective in favoring re-expansion and further growth of the cerebellar hemispheres, which typically occurs by 6–12 months of surgery. This has been the preferred modality of treatment in patients with a patent cerebral aqueduct in our experience as well as in many other centers [299, 307, 308], and has resulted in better neurodevelopmental outcomes. Aqueductal stenosis is present in approximately 20% of cases, and affected children require additional ventriculoperitoneal shunting. Subsequent development of affected children may be variable. While some are severely retarded, as many as 47% have normal intellect with little or no motor deficit. Cognitive outcome is basically related to the presence of other brain or systemic abnormalities; patients with isolated DWM have a significantly better prognosis than those with associated CNS or systemic malformations [309]. Associated Conditions

In most instances, DWM is an isolated malformation with a low recurrence rate in siblings. However, DWM is known to occur in many conditions, including the Walker-Warburg syndrome, Coffin-Siris syndrome, Meckel-Gruber syndrome, Fraser cryptophthalmos, Aicardi syndrome [295], and hydrolethalus syndrome [310], other than in chromosomal abnormalities such as trisomy 9, 13, and 18 [295]. DWM also is a component of the Ritscher-Schinzel cranio-cerebellocardiac [3C] syndrome (Table 4.10) [311] as well as of several phakomatoses, such as neurocutaneous melanosis [312–314]. Association of posterior fossa malformations, including DWM, with facial capillary hemangiomas and arterial, cardiac, and ophthalmologic abnormalities is designated PHACE syndrome [315, 316]; this is thought to represent a vascular

Table 4.10. Ritscher-Schinzel cranio-cerebello-cardiac (3C) syndrome Inheritance

Autosomal recessive

CNS manifestations

Dandy-Walker malformation or variant

Craniofacial manifestations

Low-set ears Hypertelorism Down-slanting palpebral fissures Depressed nasal bridge Prominent occiput Cleft palate Micrognathia Ocular coloboma

Cardiac manifestations

Septal defects Valvular defects Cono-truncal abnormalities

phakomatosis (see Chap. 17). Familial MDW has also been described to occur in association with neurometabolic disorders, including congenital disorders of glycosylation (CDG) [317] and a supratentorial leukodystrophic pattern [318]. Imaging Findings

Since both DWM and DWV are radiological diagnoses, the goal of imaging is to separate a dilated fourth ventricle from extraventricular cysts, distinguish among a variety of cerebellar vermian dysgenesis syndromes, and assess degree and type of hydrocephalus. This effort requires evaluation of a number of elements, as follows (Figs. 4.58, 4.59). Osteodural coatings. The skull is enlarged, resulting in a dolichocephalic conformation in the most severe cases. The widened posterior cranial fossa results in thinning and prominence (“scalloping”) of the occipital squama and petrous ridges. The straight sinus and tentorium are elevated, and the torcular is located above the lambda (”torcular-lambdoid inversion”). The falx cerebelli typically is absent [299]. Hydrocephalus causes diastasis of cranial sutures. Brain. The hallmark of DWM is vermian hypoplasia with verticalization (i.e., counter-clockwise rotation of the vermis); as a consequence, the vermis lies behind the quadrigeminal plate (Figs. 4.58, 4.59). Foliation of the vermis is rudimentary [319], and the vermis itself is thoroughly absent in a minority of cases. While some cases of DWM show a hypoplastic vermis, in others the vermis may be better defined as dysplastic (i.e., showing abnormal foliation) [5]. The cerebellar hemispheres are winged outward against the petrous ridges due to massive dilatation

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IV Ventricle

b

sas a

IV Ventricle

c

d

Fig. 4.58a–d. Dandy-Walker malformation. a Schematic drawing, sagittal projection; b Sagittal T2-weighted image; c Schematic drawing, axial projection; d Axial T2-weighted image. The posterior fossa is enlarged and filled with a huge CSF cavity, corresponding to an enlarged fourth ventricle (a,b) Subarachnoid spaces (sas, a, c)are compressed between the ependyma-lined cyst and the occipital bone. The sagittal image shows hypoplastic vermis with verticalization (i.e., counter-clockwise rotation of the vermis) (arrowhead, b) and elevated tentorial insertion. Hydrocephalus is associated, with a patent cerebral aqueduct. Axial image shows two “hypoplastic” cerebellar hemispheres (arrowheads, d) that are winged outwards against the petrous ridges. The cerebellar falx is normal (arrow, d)

a

b

Fig. 4.59a,b. Dandy-Walker malformation in a neonate. a Sagittal T1-weighted image; b Axial T1-weighted image. The posterior fossa is enlarged and the occipital squama is scalloped. The cerebellar vermis is hypoplastic and rotated counter-clockwise (arrowhead, a), with marked elevation of the tentorium (arrows, A). The cerebellar hemispheres are hypoplastic as well (arrowheads, b). Notice associated agenesis of the corpus callosum and hypoplasia of the brainstem (a)

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a

b

Fig. 4.60a–c. Dandy-Walker malformation: postshunting evolution. a Axial CT scan; b Axial T1-weighted image. c Sagittal T1weighted image. CT scan obtained 1 day after cystoperitoneal shunt surgery shows catheter in the fourth ventricle (a); notice hydrocephalic dilatation of the temporal horns supratentorially (asterisks, a). After one year, MRI (b) shows total re-expansion of both cerebellar hemispheres and resolution of hydrocephalus. Notice, however, that rotation of the vermis persists after shunt surgery (arrowheads, c)

c

of the fourth ventricle. Placement of a shunt catheter into the dilated fourth ventricle permits expansion and growth of the cerebellar hemispheres, indicating that compression, rather than hypoplasia, basically accounts for their appearance; however, rotation of the vermis is not affected by CSF shunting (Fig. 4.60). The brainstem generally is thin, mainly due to hypoplasia of the pons. The midbrain may display a butterfly configuration in axial views, possibly related to absent decussation of the superior cerebellar peduncles. In a minority of cases, the brainstem has a normal conformation. Fourth ventricle. The hugely dilated posterior fossa “cyst” is, in fact, represented by a markedly dilated fourth ventricle. This has been confirmed in histo-

logical studies of the cyst wall, showing an internal ependymal layer coated by a stretched neuroglial layer (representing the would-be inferior vermis) and, externally, by the leptomeninges [17]. The fourth ventricle may extend upward through a congenital dehiscence of the tentorium, thereby occupying a space between the occipital lobes. Inferiorly, the cyst may bulge into the foramen magnum. Laterally, the extension of the fourth ventricle is limited by the reflection of the pia mater over the posterior surface of the cerebellar hemispheres; this sort of “lateral hinge point” is a useful differential sign from other posterior fossa cystic malformations in the axial plane, especially lateral arachnoid cysts. The choroid plexus lies at the level of the medullary insertion of the cyst. The foramen of Magendie is usually (but not necessarily) not patent, unlike the foramina of Luschka, which may be

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patent uni- or bilaterally. This is a traditional finding at pneumoencephalography [320] and may account for the variable incidence of hydrocephalus. 4.4.3.2 Dandy-Walker Variant

DVW is characterized by the same pathological and neuroradiological features of DWM, with the sole exception being the size of the fourth ventricle, which is not sufficiently large to produce enlargement of the posterior fossa. However, counter-clockwise rotation of the vermis is consistently present, indicating an original abnormality of the AMA (Fig. 4.61). Vermian rotation is a key diagnostic feature [299], allowing one to differentiate DWM from other cystic malformations, especially a mega cisterna magna. The vermis is usually also hypoplastic. Although the inferior portion of the vermis appears to be absent,

Verm

is

it may be difficult to determine which vermian folia are actually absent [5]. Hydrocephalus is an unusual feature of DWV, and is generally caused by associated malformations, such as aqueductal stenosis. Questions have arisen as to whether the denomination of DWV must be retained or should instead be abandoned in favor of a more general definition of cerebellar hypoplasia. Indeed, it can be difficult to establish when a posterior fossa is sufficiently large for an attribution to full-blown DWM to be applied in individual cases [5]. As a matter of fact, the full-blown DWM and DWV actually represent two aspects of a continuous spectrum of variability. We still believe that rotation of the vermis is the key feature that allows one to differentiate DWVs from other forms of cerebellar hypoplasia. Accordingly, we have applied this concept also to cases in which the degree of inferior vermian hypoplasia was macroscopically minor (Fig. 4.62).

Fig. 4.61a–c. Dandy-Walker variant. a Schematic drawing; b Sagittal T1-weighted image; c Axial T1-weighted image. The cerebellar vermis is hypoplastic and rotated counter-clockwise (arrowhead, b). However, different to the full-blown Dandy-Walker malformation, posterior fossa size is normal. Most of the posterior fossa is filled with a huge CSF cavity, corresponding to a dilated fourth ventricle (b,c). Both cerebellar hemispheres are hypoplastic (c). In this case, hydrocephalus is secondary to aqueductal stenosis (arrow, b)

IV Ventricle

a

b

c

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a

b Fig. 4.62a,b. Minor form of Dandy-Walker variant. a Sagittal T1-weighted image; b Axial T2-weighted image. Both the cerebellar hemispheres and the vermis are grossly well-formed. However, the vermis is rotated counter-clockwise and probably slightly hypoplastic at level of its inferior portions, with absence of well-defined fissuration (open arrows, a). The fourth ventricle freely communicates with the CSF spaces. The size of the posterior fossa is essentially normal, with mild elevation of the tentorium (thin arrows, a)

4.4.3.3 Persistent Blake’s Pouch Background

As was previously described, the Blake’s pouch is a marked caudal protrusion of the fourth ventricle that results from finger-like expansion of the PMA (Fig. 4.63) [294]. The Blake’s pouch is a normal, albeit transient, embryological structure, that initially does not communicate with the surrounding subarachnoid space. Subsequent permeabilization of the pouch institutes the foramen of Magendie. The timing of such permeabilization has not been conclusively established [296], although persistence of the Blake’s pouch has been demonstrated into the fourth gestational month [298, 321]. Failure of permeabilization with postnatal persistence of the Blake’s pouch has been suggested as an explanation for the occurrence of infra- and retrocerebellar CSF collections associated with normal cerebellum and tetraventricular hydrocephalus [322, 323]. These conditions are characterized by absence of communication between the fourth ventricle and the subarachnoid spaces in the midline, and therefore do not fit the definitions of DWM, mega cisterna magna, or arachnoid cyst. In fact, the normal appearance of the cerebellum rules out both DWM, in which the vermis is hypoplastic and rotated, and arachnoid cysts, in which the cerebellum is compressed by mass

effect. Moreover, hydrocephalus is not found in cases of mega cisterna magna because the enlarged cisterna magna freely communicates with surrounding subarachnoid spaces. Finally, resolution of hydrocephalus and cyst size decrease occur with both ventriculoperitoneal and cystoperitoneal shunting, suggesting the “cyst” likely represents a fourth ventricular outpouching that does not communicate with the surrounding subarachnoid spaces [323]. Clinical Findings

Clinically, persistence of the Blake’s pouch becomes symptomatic early in life (usually in the neonatal period) with macrocrania and hydrocephalus. However, in some cases the normal function of the foramina of Luschka may help to maintain CSF flow between intraventricular and subarachnoid spaces, thereby establishing a precarious equilibrium characterized by a compensatory ventriculomegaly; in such cases, the abnormality may become manifest in older children or even in adults [324]. Imaging Findings

Radiologically, persistence of the Blake’s pouch can produce two subsets of findings [323]. In the first category (Fig. 4.64), the cyst is purely infravermian, the fourth ventricle is markedly enlarged, and posterior fossa size is normal. In the second category (Figs. 4.65,

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4v

4v

Choroid plexus

Blake’s pouch a

Cisterna magna

Blake’s pouch

Developing occipital bone b

Fig. 4.63a,b. The Blake’s pouch. a Normal fetal development: the Blake’s pouch is a finger-like caudal expansion of the fourth ventricle (4 v) that protrudes into the developing cisterna magna. b 130-day-old human fetus: ballooning of the Blake’s pouch, which retains its continuity with the fourth ventricle but is clearly not permeabilized with respect to the surrounding subarachnoid space. Notice the choroid plexus is interposed between the vermis and the pouch, indicating that the pouch develops as an expansion of the posterior membranous area. The vermis itself is normal. (Modified from [295])

a

b Fig. 4.64a,b. Persistent Blake’s pouch: purely infracerebellar (i.e., category 1). a Sagittal T2-weighted image; b Coronal T2-weighted image. There is tetraventricular hydrocephalus. The cerebellar vermis is normally formed and not rotated. Posterior fossa size is normal. The fourth ventricle is markedly enlarged, and communicates with an infravermian cystic formation that effaces the cisterna magna. Such collection represents persistence of the Blake‘s pouch (BP, a). Compare this case with Fig. 4.63b

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Vermis 4v Blake’s pouch

b

a

c

d Fig. 4.65a–d. Persistent Blake’s pouch: infra-retrocerebellar (i.e., category 2), before and after shunting. a Schematic drawing; b Sagittal T2-weighted image and c Axial T2-weighted image at presentation; d Sagittal T2-weighted image 6 months after shunting. There is tetraventricular hydrocephalus. The vermis is well-formed and not rotated. Posterior fossa size is mildly increased. The fourth ventricle is enlarged and communicates with a cystic formation extending into the infra- and retrocerebellar space (BP) whose postero-superior wall is recognizable (arrowhead, b). The retrovermian CSF collection above the pouch is consistent with entrapped subarachnoid cisternal spaces (asterisk, b). Following shunting of the right lateral ventricle (arrowhead, d), there is marked reduction in size of both the ventricular system and the Blake’s pouch

4.66), extension of the pouch to the retrocerebellar space probably interferes with meningeal development causing elevation of the tentorium, splitting of the falx cerebelli, scalloping of the occipital squama, and increased posterior fossa size. In the latter group, the fourth ventricle is less markedly enlarged, and the brainstem can be displaced anteriorly against the clivus (Fig. 4.66). In both categories, the cerebellum is normal, as confirmed by postshunting MRI studies; particularly, absence of cerebellar hypoplasia is crucial in order to categorize the anomaly as a persistent Blake’s pouch, as vermian hypoplasia would reflect an abnormality of the AMA, rather than of the PMA. Associated brain abnormalities are consistently

absent; this could reflect a relatively late timing for this abnormality. Persistence of the Blake’s pouch in otherwise normal fourth gestational month fetuses [298] could support this theory. Recognition of this entity and differentiation from other cystic abnormalities of the posterior fossa is relevant for treatment decisions. While the preferred treatment modality for either DWM with patent cerebral aqueduct or arachnoid cysts is cystoperitoneal shunt surgery, ventriculoperitoneal derivation is a safe and effective procedure in patients with a persistent Blake’s pouch (Fig. 4.65). Incorporation of persistent Blake’s pouch within the Dandy-Walker continuum is justified by the common histological

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a

b Fig. 4.66a,b. Persistent Blake‘s pouch: infra-retrocerebellar (i.e., category 2), extreme form. a Sagittal T2-weighted image; b Axial T1-weighted image. There is very severe tetraventricular hydrocephalus. The size of the cerebellum is reduced because of increased pressure exerted by the persistent Blake’s pouch (BP, a, b), that fills almost the whole posterior fossa. The postero-superior wall of the pouch is recognizable (arrow, a). The vermis is normally formed and not rotated. The brainstem is pushed against the quadrilateral plate with deformation of the anterior aspect of the pons (a)

nature of the cavity, representing an ependyma-lined expansion of the fourth ventricle, just as the “cyst” found in Dandy-Walker malformations and variants [321, 322]. 4.4.3.4 Mega Cisterna Magna

The cisterna magna is a CSF-filled space at the base of the brain, located below the cerebellum and behind the medulla. The embryological origin of the cisterna magna is debated. According to one theory (C. Raybaud, personal communication), it originates from permeabilization of the Blake’s pouch, with establishment of a permeable foramen of Magendie that allows egress of CSF from the fourth ventricle. As such, the anatomy of the cisterna magna reflects that of the embryologic Blake’s pouch. The posterior extent of the cisterna magna is limited by an arachnoid membrane that bridges the inferior surface of the cerebellar hemispheres, thereby separating the cisterna magna from the superior vermian cistern. The cisterna magna communicates superiorly with the fourth ventricle through the foramen of Magendie, and inferiorly with the perimedullary subarachnoid spaces. Its size has been the subject of debate in the past. Gonsette et al. [325], who first introduced the term “mega cisterna magna” to describe an enlarge-

ment of the cisterna magna that was often detected by means of ventriculography, considered a normal cisterna magna to be 15 mm long, 5 mm high, and 20 mm wide on average. The term mega cisterna magna (MCM) refers to a cystic posterior fossa malformation characterized by an intact vermis, an enlarged cisterna magna, and absence of hydrocephalus (Fig. 4.67) [295, 299, 319, 322]. As such, the appearance is similar to that previously described of persistent Blake’s pouch, except for the consistent absence of hydrocephalus. Owing to the common embryological mechanism, MCM could be viewed as a “variant” of the persistent Blake’s pouch, in which eventual permeabilization of an enlarged pouch permits CSF communication, without generating obstructive hydrocephalus. Consequently, the two malformations could be viewed as a spectrum of variability of a single disorder, that we propose to name “Blake continuum”. Similarly to the persistent Blake’s pouch, the extent of the abnormal CSF collection is variable; while it may be purely infravermian in some cases, in others it extends far beyond the normal borders of the cisterna magna laterally, posteriorly, and superiorly, sometimes reaching the quadrigeminal plate cistern (Fig. 4.67) [295]. The collection may extend superiorly into a focal dehiscence of the falcotentorial junction, which is usually associated with fenestration of

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MCM

a

b

c

e

d Fig. 4.67a–e. Mega cisterna magna. Two different cases, both referred for MRI due to unrelated complaints. a Schematic drawing. There is free communication between the mega cisterna magna (MCM), the fourth ventricle, and the spinal subarachnoid spaces. Case #1. b Sagittal T1-weighted image; c Axial T2-weighted image. The subarachnoid spaces of the posterior fossa are enlarged (MCM, b, c), with scalloping of the occipital squama (arrowheads, b). Notice there is no hydrocephalus. Both the cerebellar hemispheres and the vermis are normally formed. Posteriorly, the mega cisterna magna insinuates itself into a small fenestration of the tentorial insertion (arrow, b). Splitting of the falx cerebelli, a typical finding in mega cisterna magna, is also visible (arrows, c). Case #2. d Sagittal T1-weighted image; e Axial T2-weighted image. The subarachnoid spaces of the posterior fossa are enlarged (MCM, d, e), with scalloping of the occipital squama (arrowheads, d). Posteriorly, the mega cisterna magna insinuates itself into a large fenestration of the tentorial insertion (arrow, d). The right cerebellar hemisphere appears to be reduced in size compared to the left one (e), and the vermis also shows morphological changes. It is difficult to determine whether such findings are due to hypoplasia, CSF pressure, or both. However, notice that neither signs of hydrocephalus nor compression on the ventricular structures are present

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the straight sinus [295]. The falx cerebelli is seen in approximately two thirds of cases, and is frequently bi- or tripartitioned. Developmental abnormalities of the tentorium and falx cerebelli significantly indicate interference with normal meningeal development. The posterior fossa is often enlarged due to scalloping of the occipital squama, and the torcular is displaced cranially in 12.5% of cases [322]. The cerebellum and brainstem are typically normal. The presence of intact vermis and cerebellar hemispheres strongly favors a diagnosis of MCM versus an arachnoid cyst, which typically compresses the surrounding brain. However, slight compression of the inferior or posterior vermian folia may sometimes be seen when the size of the CSF collection is large. An important concept that must be stressed is that patients with MCM do not complain of neurological signs of involvement of the posterior cranial fossa. Mental retardation, which has often been advocated as a presenting sign of MCM, is actually seen in patients with associated supratentorial conditions, such as corpus callosum dysgenesis. In itself, MCM is an asymptomatic condition that is usually discovered incidentally [299, 322, 325]. However, it is a very common abnormality, representing over 50% of all cystic posterior fossa malformations [295]. Moreover, hydrocephalus is not found in patients with MCM, because the enlarged cisterna magna freely communicates with the surrounding CSF spaces and does not obstruct CSF circulation. Important consequences of these concepts

are that (i) the presence of hydrocephalus rules out MCM and should direct the diagnosis towards a persistent Blake’s pouch; and (ii) shunt surgery has no indications and should be avoided, even in case of large CSF collections. Finally, extreme caution should be employed in newborns before labeling a posterior fossa CSF collection as MCM. We have observed an apparent neonatal MCM that developed, in a few months, into a retrocerebellar cyst that caused significant cerebellar compression and supratentorial hydrocephalus (Fig. 4.68). One should remember that arachnoid cysts may take time before generating significant compression over surrounding nervous tissues; moreover, slowly expanding arachnoid cysts may initially cause scalloping of the plastic neonatal skull, before progressive ossification forces them to expand at the expense of the surrounding brain, thereby becoming clinically manifest. 4.4.3.5 Arachnoid Cysts

Arachnoid cysts are CSF-filled cysts that do not communicate with the surrounding subarachnoid space (Fig. 4.69) and ventricular system, and usually are not associated with brain maldevelopment. Posterior fossa arachnoid cysts may be located below or posterior to the vermis in a midsagittal location (Fig. 4.70), lateral to the cerebellar hemispheres, cranial to the vermis in the tentorial hiatus, anterior

a

b Fig. 4.68a,b. Mega cisterna magna versus arachnoid cyst in a neonate. a Sagittal T2-weighted image at age 28 days; b Sagittal T2weighted image at age 7 months. Initial MR imaging is consistent with a mega cisterna magna. However, follow-up MRI clearly shows compression of the posterior aspect of the vermis (arrows, b), indicating an arachnoid cyst; also notice enlargement of the ventricular system

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cyst

a

b

Fig. 4.69a,b. Arachnoid cyst. a Schematic drawing; b Axial CT cisternography. Intrathecal iodized contrast medium administration shows posterior fossa CSF collection (cyst, b) is excluded from the surrounding subarachnoid spaces, that are filled by the contrast medium

Fig. 4.70a–c. Arachnoid cyst. a Sagittal T1-weighted image; b Axial T2-weighted image; c Coronal T1-weighted image. A large posterior fossa CSF cystic collection (ac, a–c) compresses and elevates the vermis (arrows, a) and compresses both the cerebellar hemispheres (b, c). The fourth ventricle is deformed and compressed (arrowhead, a). Supratentorial hydrocephalus is clearly seen

a

b

c

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to the brainstem (Fig. 4.71), or anterolaterally in the cerebellopontine angle cistern (Fig. 4.72). While they can be found incidentally on imaging, patients with posterior fossa arachnoid cysts are more likely to be symptomatic than those harboring cysts in other locations. Although controversy surrounds the treatment of arachnoid cysts, cystoperitoneal shunting is used for decompression of symptomatic cysts at our institution. Pathologically, arachnoid cysts are classified by the histologic composition of the cyst wall, which is either arachnoid connective or glioependymal tissue. Retrocerebellar cysts may be either arachnoid or glioependymal, whereas supratentorial ones are more often purely arachnoid in composition. However, histological classification has little relevance in terms of prognosis. Cyst walls result from splitting of the arachnoid membrane, with an inner and outer leaflet surrounding the cyst cavity. Expansion of noncommunicating cysts may occur either from a ball-valve mechanism or because of fluid secretion by the cyst wall or, more likely, along an osmotic gradient. On CT, arachnoid cysts are isodense with CSF on CT. On MRI images, arachnoid cysts appear as welldefined nonenhancing intracranial masses that are isointense to CSF in all sequences, although slight signal increase may be caused by proteinaceous fluid content. Differential diagnosis include (epi)dermoid cysts and other cystic malformations, such as MCM and persistent Blake’s pouch. It is important to underline that a retrocerebellar CSF collection can be conclusively labeled as an arachnoid cyst only with CT cisternography (Fig. 4.69). In fact, “cysts” that fill with

contrast immediately are regarded as diverticula of the subarachnoid space, whereas only those showing delayed contrast accumulation or no filling can be regarded as true arachnoid cysts. However, CT cisternography is no longer performed in the MRI era. Therefore, diagnosis must rely on indirect signs, such as the condition of the surrounding brain and the presence of hydrocephalus [300, 320, 322]. A large MCM occasionally may be confused with an arachnoid cyst. However, while an arachnoid cyst may demonstrate mass effect with displacement of the cerebellum and may cause supratentorial hydrocephalus, MCM demonstrates no mass effect, and the cerebellum and vermis are intact. Differentiation from a persistent Blake’s pouch is immediate when one considers that arachnoid cysts are not associated with an enlarged fourth ventricle. Arachnoid cysts must be differentiated from (epi)dermoid cysts. Both masses may have similar characteristics on T1-weighted and T2-weighted images, and neither show enhancement with gadolinium. On FLAIR images, arachnoid cysts give low signal because of their CSF content, whereas signal is higher in epidermoid cysts. Diffusion-weighted MRI enables performance of such differentiation easily; arachnoid cysts are hypointense in diffusionweighted images, whereas epidermoids are hyperintense because of slow water diffusion [8]. Differential diagnosis from other CSF collections is crucial for optimal treatment decisions. Although most arachnoid cysts are an incidental finding and patients are asymptomatic, arachnoid cysts may show progressive enlargement. Therefore, follow-up MR imaging is essential in order to identify candidates

b

a

Fig. 4.71a,b. Premedullary arachnoid cyst. a Sagittal T2-weighted image; b Axial T2-weighted image. Small arachnoid cyst at the cranio-cervical junction (ac, a, b) whose walls are recognizable (arrowheads, a, b). The cyst deforms and compresses the cervico-medullary junction

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a

b

c

d Fig. 4.72a–d. Antero-lateral arachnoid cysts of two different cases. Case #1: a Axial T2-weighted image; b Axial FLAIR image. Small arachnoid cyst of the right cerebellopontine angle (ac, a, b) is isointense with CSF on both T2-weighted (a) and FLAIR (b) images. There is no significant compression of the surrounding nervous tissue, although the posterior wall of the petrous bone is scalloped (arrowheads, a). Case #2: c Coronal T2-weighted image; d Axial FLAIR image. This larger arachnoid cyst causes significant compression of the homolateral cerebellar hemisphere

for surgery that, unlike other conditions such as a persistent Blake’s pouch, must involve cystoperitoneal derivation also in patients with a supratentorial hydrocephalus.

4.4.4 Noncystic Malformations This heterogeneous category comprises very diverse entities, whose common background is basically represented by the absence of indications for CSF derivation surgery. In short, these malformations are characterized by either the absence of CSF collections or the presence of CSF collections that result from passive (i.e., ex-vacuo) enlargement of CSF spaces as a consequence of defective development of cerebellar portions.

From a neuroradiological standpoint, these ab normalities can be conveniently classified into: (i) paleocerebellar hypoplasias, in which defective development basically involves the vermis; (ii) neocerebellar hypoplasias, in which there usually is a combination of vermian and hemispheric hypoplasia or, more rarely, isolated hemispheric hypoplasia; and (iii) cortical dysplasias, in which the abnormality rests primarily into an anomalous development of the cerebellar cortex, either with or without global abnormality of cerebellar size. It is, however, apparent that this classification scheme, as well as others, probably oversimplifies a much more complex reality and gathers into somewhat loosely defined categories entities that are probably significantly different from one another from both a pathological and a clinical perspective.

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4.4.4.1 Paleocerebellar Hypoplasia

Cerebellar hypoplasia is a broad category that includes very diverse entities. Semantically, hypoplasia indicates underdevelopment of a tissue or of an organ usually due to a decrease in the number of cells. Usually, the surface of a hypoplastic cerebellum is grossly smooth and the volume is reduced; however, the relative size of the fissures and folia is preserved. Conversely, the term dysplasia indicates abnormal, disorganized development, such as presence of abnormal folial pattern and gray matter heterotopia [5]. As such, dysplasia can affect a hypoplastic cerebellum. Moreover, atrophy implies that the organ reaches normal size and maturity, but shows a progressive volume loss and shrinkage due to an acquired insult or from a genetic disease not expressed during fetal development; therefore, atrophy can affect a hypoplastic or dysplastic cerebellum. It is beyond the scope of the present paper to discuss inherent differences between cerebellar hypoplasias and dysplasias, which remain the subject of debate among authors and a major obstacle to a fully acceptable classification scheme for cerebellar malformations. The general heading of hypoplasia has been used here to indicate cases with primitively small, underdeveloped cerebella as opposed to secondary atrophic changes. Paleocerebellar hypoplasia is defined as defective development of the vermis with basically normal formation of the hemispheres and absence of substantial posterior fossa cysts. Entities involving paleocerebellar hypoplasia basically include rhombencephaloschisis, rhombencephalosynapsis, and tectocerebellar dysraphia.

not exclusively found in JS, but can be present in several other apparently distinct syndromes belonging to the group of cerebello-oculo-renal syndromes, all of which are also characterized by cerebellar vermian hypoplasia and similar clinical features to those of JS. These entities include Arima, Senior-Löken, and COACH syndrome [328, 329] (Table 4.11). Little is known about the genetic background of JS. Because JS is clinically heterogeneous, it has been suggested that there may also be genetic heterogeneity [330]. Although members of the Engrailed, Wnt, Hox, and Pax gene families have been found to regulate pattern formation and segmentation in the developing brainstem, none of them has been demonstrated to play a causal role [331], and some, such as EN1, EN2, FGF8, and BAHRL1, have positively been excluded [330]. Table 4.11. Joubert-related cerebello-oculo-renal syndromes [329] Arima syndrome (1) Vermian hypoplasia (2) Congenital retinopathy (3) Cystic dysplastic kidneys (4) Autosomal recessive inheritance Senior-Löken syndromes (1) Vermian hypoplasia (2) Retinopathy (3) Juvenile-onset nephronophthisis COACH syndrome (1) Vermian hypoplasia (2) Colobomas (3) Nephronophthisis (4) Hepatic fibrosis

Pathology Rombencephaloschisis Joubert Syndrome Background

Joubert syndrome (JS) [326] is an autosomal recessive syndrome characterized by hyperpneic/apneic spells, hypotonia, ataxia, abnormal ocular movements, and psychomotor delay that is found in association with a characteristic posterior fossa abnormality, involving vermian hypoplasia and abnormal pontomesencephalic junction, which results in the “molar tooth sign” on neuroradiologic examination [327]. Although there has been a strong tendency in the literature to call JS all malformations with this neuroradiologic appearance [5], it has become increasingly clear that JS is an integrated clinical-neuroradiological diagnosis [299]. In itself, the molar tooth sign is

Only very little documentation of the neuropathologic changes in JS exists [292, 332]. Available data indicate there is malformation of multiple brainstem structures, including lack of decussation of the superior cerebellar peduncles, central pontine tracts, and corticospinal tracts. There also is marked dysplasia of caudal medullary nuclei and tracts, including the inferior olivary nuclei, solitary nuclei and tracts, and the nucleus and spinal tracts of the trigeminal nerve, associated with reduction of the nuclei of the basis pontis and reticular formation. Additionally, there is vermian hypoplasia or aplasia, with abnormal foliation, poor demarcation of cortex and white matter associated with fragmentation of the dentate nuclei [292], and separation of the two cerebellar hemispheres. Therefore, probably the term “rhombencephaloschisis” could be proposed as the best descriptor of

Brain Malformations

the complex pathological abnormality of the posterior fossa that is found in these patients (R. Canapicchi, personal communication). Clinical Picture

The classical clinical findings of JS include hypotonia, ataxia, psychomotor retardation, abnormal breathing, and nystagmus [326]. These findings can be present in variable proportions in individual cases. Absence or underdevelopment of the vermis impairs control of balance and coordination, basically resulting in truncal ataxia and decreased muscle tone that can be marked in the neonatal period and in infancy. On their own, ataxia and hypotonia are of limited diagnostic value, as they can be present in a wide range of congenital and acquired disease of the cerebellum or brainstem [333]. Vermian hypo-dysplasia probably also interferes with normal cognition, resulting in psychomotor retardation. This can be the only clinical sign in patients with the molar tooth sign, and is usually severe. No positive correlation has been found between the severity of neuropsychologic dysfunction and the composite score of posterior fossa abnormalities, although there is a correlation between increasing age and worsening psychomotor delay [334]. Caudal brainstem dysplasia, particularly abnormalities of the solitary fascicles and nuclei gracili that control afferent respiratory impulses, probably account for the abnormal breathing pattern, characterized by hyperpneic spells, in which affected infants pant, and sudden cessation of breathing that typically occurs during sleep [292, 295]. Breathing abnormalities, once believed to be characteristic [326], are in fact present in fewer than 75% of patients [333]. Their onset is typically in the neonatal period, and they tend to improve as the child grows [299, 333]. Nystagmus can be associated with oculomotor apraxia and abnormal supranuclear eye movement control, and probably results from abnormal development of the pontine nuclei, reticular formation, and vermian lobules [292]. Ocular and oculomotor disturbances are present in greater than 70% of children with JS [333]. Seizures are a less typical manifestation of the syndrome, and have not received a conclusive neuropathologic correlation. Young infants with JS often have a characteristic facial appearance, including a large head with prominent forehead, high rounded eyebrows, epicanthal folds, upturned nose with evident nostrils, open mouth with tongue protrusion, and low-set, tilted

ears [333]. The facial phenotype tends to become less severe as the child grows. Prognosis is variable, but generally poor. A number of patients have died within age 3 years in situations compatible with sudden infant death syndrome; however, it is not known whether these deaths were caused by prolonged apnea, and no satisfactory investigation has so far allowed to individuate those infants who are at increased risk for early death [333]. Survivors generally show global profound developmental delay. Breathing tends to progressively normalize as the child grows. There are a few cases of affected individuals with normal intelligence or learning abilities [335]. Imaging Findings

The neuroradiological picture is characterized by a combination of vermian and midbrain hypoplasia, resulting in the typical “molar tooth sign” [331, 336]. The molar tooth sign is seen on axial MR sections through the malformed pontomesencephalic junction (Fig. 4.73); it consists of the following triad [336]: (i) dysgenesis of the isthmic portion of the brainstem, manifest as elongation and thinning of the pontomesencephalic junction, elongation of the interpeduncular fossa, and deepening of the posterior foramen caecum; (ii) thickened superior cerebellar peduncles, which project straight back, coursing perpendicular to the brainstem; and (iii) hypoplasia of the vermis with incomplete lobulation and sulcal formation, enlargement of the fourth ventricle, and rostral shift of the fastigium [331, 336]. The molar tooth sign is seen in 85% of patients with JS, and usually represents its sole neuroradiologic manifestation [331]. Varying degrees of severity in the key abnormalities can be found, and MRI can be used to assess severity of the dysgenesis [336, 337]. The superior cerebellar peduncles are enlarged and do not decussate in the isthmus portion of the brainstem. The isthmus is therefore thin, and the interpeduncular fossa is secondarily enlarged. The vermis can be either thoroughly absent or significantly hypoplastic. In the latter case, the superior vermis usually is present, but is invariably dysplastic with abnormal foliation, whereas absence of the inferior vermis produces a midline cleft that connects the fourth ventricle to the cisterna magna, resulting in a “bat wing”, “lamp”, or “umbrella” shaped fourth ventricle in axial and coronal planes (Fig. 4.73) [299]. On sagittal planes, the fourth ventricle displays a convex roof with a high riding fastigium [336]. In the vast majority of cases, the fourth ventricle is only mildly enlarged without formation of a posterior fossa cyst or hydrocephalus, and the posterior fossa is not expanded.

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b

a

c

d Fig. 4.73a–d. Molar tooth malformation in a patient with Joubert syndrome. a and b. Axial T2-weighted images; c Coronal T2weighted image; d Sagittal T1-weighted image. The typical “molar tooth sign” results from midbrain hypoplasia with elongation and thinning of the superior cerebellar peduncles (arrowheads, a). Agenesis of the cerebellar vermis is associated, resulting in an interhemispheric cleft (arrows, b, c). As a consequence, the fourth ventricle has a lamp shape on axial (b) and an umbrella shape coronal images (c); on sagittal planes, it displays a convex shape (“ballooning”) with high-riding fastigium (d)

MRI fails to demonstrate the abnormalities of the nuclei and tracts in the caudal medulla that are believed to account for the respiratory problems exhibited by affected patients [331]; however, there usually is lack of the bulges produced over the surface of the medulla by the pyramids anteriorly and olives posteriorly. The supratentorial brain is generally normal [336]; mild to severe atrophy, corpus callosum abnormalities, delayed myelination, or lissencephaly can be seen in a minority of cases [331, 336]. A minority of patients with a greater degree of inferior vermian hypoplasia can have associated tectocerebellar dysraphia or Dandy-Walker malformation;

these patients have been classified as having “Joubert syndrome plus” [331, 336]. An occipital cephalocele is found in about one third of cases [299]. Rhombencephalosynapsis

Rhombencephalosynapsis is a rare entity characterized by vermian agenesis and fusion of the cerebellar hemispheres, middle cerebellar peduncles, dentate nuclei, and inferior colliculi along the midline, resulting in a single-lobed, hypoplastic cerebellum [299, 338]. Although usually sporadic, this condition has been observed in children born from

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consanguineous parents, indicating a likely autosomal recessive mode of inheritance [339]. Affected children primarily present with signs of cerebellar dysfunction, which represents a notable distinction among posterior fossa malformations, and delayed achievement of developmental milestones. Cognitive impairment is variable, and apparently correlates with the degree of cerebellar hypoplasia [338]. The prognosis is poor, with the majority of affected patients dying in infancy or childhood; however, a few cases have been described in young adults [293, 340]. The MRI picture closely reproduces the pathological appearance (Fig. 4.74) [338]. The single-lobed cerebellum is consistently hypoplastic, although its

size may be variable. On axial views, the cerebellum is flat-based with absence of the vallecula. There is continuation of the folia and fissures through the midline; their orientation is usually transverse, but asymmetrical hypoplasia may result in angulation of the folia and fissure across the midline [295, 338]. The fused or closely apposed dentate nuclei form a horseshoe-shaped arc across the midline [17, 295]. Vermian maldevelopment involves absence of the anterior vermis and deficiency of the posterior vermis; lack of definition of the normal vermian lobules results in a cerebellar–not vermian–configuration of the midline on sagittal views [295, 299]. However, identification of a protuberance below the fastigium of the fourth ventricle indicates the presence of the nodulus [341],

a

b

c

d Fig. 4.74a–d. Rhombencephalosynapsis. a Axial STIR image; b Coronal T2-weighted image; c Sagittal T1-weighted image. d Pathological specimens. The cerebellar white matter is completely fused across the midline at the level of the dentate nuclei (arrow, a, b), with total absence of the vermis. On sagittal images, this results in a hemispheric, not vermian, arrangement of the fissures; notice that the normal vermian folia are absent (c). The vallecula is absent (arrowheads, b). The fourth ventricle has a key-hole appearance on axial planes (a). Additionally, the fornix is fused on the midline (arrowheads, c). Pathology (d) shows fusion of the severely hypoplastic hemispheres without vermis, resulting in a single dentate nucleus with a characteristic horseshoe profile. (a–c, courtesy of Prof. U. Salvolini, Ancona, Italy; d. Reproduced from [17], with permission from Springer Verlag, Heidelberg)

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suggesting that development of the archicerebellum is not affected. Rhombencephalosynapsis is commonly believed to be a rare, isolated malformation. However, the widespread use of MRI has evidenced a higher incidence than was commonly believed, and a common association with other CNS abnormalities including abnormal gyration, fused thalami and fornices, absence of the septum pellucidum, hypoplastic temporal lobes, optic chiasm and anterior commissure, and corpus callosum dysgenesis [17, 295, 338, 341, 342]. Hydrocephalus may result from concurrent aqueductal stenosis [341]. A single case was reported in which rhombencephalosynapsis, holoprosencephaly, and absence of the ventricular system were present [343]. Systemic abnormalities are uncommon; minor hand malformations have been reported [339, 344]. Embryologically, rhombencephalosynapsis is believed to represent underexpression of a dorsalizing organizer gene [3] affecting the “isthmic organizer” at the mesencephalic-metencephalic border [293]. A candidate molecule has been identified in the Dreher Lmx 1a gene mutant mouse. This mouse harbors an autosomal recessive mutation of the LIM homeobox gene and shows agenesis of the vermis with fused cerebellar hemispheres, closely resembling human rhombencephalosynapsis. The gene affected in the dreher mutant is responsible for correct patterning of the dorsal-most cell types of the neural tube, that is, the neural crest and the roof plate, in the hindbrain region [345]; in the absence of a normally functioning gene, the roof plate fails to develop, resulting in defective dorsalization of the neural tube [346]. Associated heterotopia is found both in the cerebral and cerebellar cortex, probably due to disrupted glial limiting membranes resulting in abnormal guidance of neuronal migration [347]. This mechanism could account for the occurrence of both forebrain and hindbrain abnormalities in rhombencephalosynapsis [342]. Tectocerebellar Dysraphia

Tectocerebellar dysraphia is an uncommon abnormality consisting of occipital cephalocele, agenesis of the cerebellar vermis, and deformity of the tectum (Figs. 4.75, 4.76) [17]. Extreme traction of the brainstem towards the site of the cephalocele results in marked tectal beaking, resembling the analogous deformity seen in Chiari II malformation, and in marked dorsal angulation of the brainstem. As a result of this deformity and the absence of the vermis, the cerebellar hemispheres

rotate ventrally and may come to lie ventral and lateral to the brainstem, a condition that has been termed “inverse cerebellum” [17, 295]. Agenesis of the vermis can be difficult to demonstrate due to the extreme distortion and traction of nervous structures in the posterior fossa; the CSF-filled cleft separating the two cerebellar hemispheres can be more easily visualized on coronal planes (Fig. 4.75). The cephalocele typically contains cerebellar cortex [17]; frequently, a lipoma is located in close vicinity to the calvarial defect (Fig. 4.76). Hydrocephalus is common and likely results from aqueductal deformation and stenosis. Less consistent components are aplasia of mammillary bodies, fusion of thalami, anomalies of cerebral gyral patterns, bifid atlas or bifid occipital squama, elevation of torcular, and cervical hydromyelia [17]. Differentiation from simple traction deformities secondary to cerebellar tissue dislocation into an occipital cephalocele is based on the greater severity of the deformities, their complexity, and the severe hypoplasia or aplasia of the vermis [295, 348]. Clinically, affected newborns present with an occipital cephalocele, and are usually microcephalic [295]. Hydrocephalus requires treatment with shunt surgery. Despite medical efforts, most children die before age 10 years. Embryologically, tectocerebellar dysraphia is believed to result from an insult occurring during early embryogenesis, resulting in a cephalocele that causes extreme traction of the brainstem towards the calvarial defect. As a consequence, the tectum and cranial nerves are markedly elongated, while the cerebellum tilts lateral and ventral to the brainstem. Vermian agenesis is thought to result from the anatomical deformation preventing the cerebellar hemispheres to fuse in the midline to form the vermis [295]. Because of this, tectocerebellar dysraphia is believed to be more pertinent to cephaloceles than to other forms of vermian hypoplasias [5]. Morphologically, tectocerebellar dysraphia bears some resemblance to Dandy-Walker malformation, basically in that there is hypoplasia of the cerebellar vermis, high position of the transverse sinuses, and large posterior fossa size; tectal beaking and kinking of the brainstem are similar to those seen in the Chiari II and, more typically, Chiari III malformation. Kinking of the brainstem and vermian agenesis also figure prominently among the pathological features of Walker-Warburg syndrome. Despite these apparent similarities, the theory that tectocerebellar dysraphia is a tandem malformation linking the Chiari II and Dandy-Walker malformation [348] has not been proven.

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a

b

c

d Fig. 4.75a–d. Tectocerebellar dysraphia in a child with prior surgery for occipital cephalocele. a Sagittal T1-weighted image; b Axial T1-weighted image; c Coronal T1-weighted image. d Pathological specimen. There is extreme deformation of the midbrain, that is attracted posteriorly resulting in marked angulation of the ponto-mesencephalic junction (black arrows, a). There also is extreme deformation of the tectum, resulting in marked tectal beaking (arrowheads, a,b) that points to the site of cephalocele surgery (white arrow, a). Associated agenesis of the vermis, resulting in an interhemispheric cleft (black arrows, c), is well recognizable. There is hydrocephalus. The subarachnoid spaces ventral to the brainstem are markedly enlarged (asterisk, a). In a different case, pathology confirms midbrain deformation and marked tectal beaking (arrowheads, d). (d Reproduced from [17], with permission from Springer Verlag, Heidelberg)

4.4.4.2 Neocerebellar Aplasia and Hypoplasia

Contrary to the well-defined syndromes of vermian hypoplasia, there still is unsatisfactory nosologic definition of neocerebellar aplasia and hypoplasia [17]. Aplasias include primary nonformation of the neocerebellum and lesions that result from damage to the cerebellar anlage early during embryogenesis,

whereas in the hypoplasia the entire cerebellum, or part of it, is smaller than normal, but the individual folia are grossly or microscopically normal in appearance [295]. While cerebellar agenesis is usually isolated, cerebellar hypoplasias may be associated with supratentorial abnormalities.

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a

b Fig. 4.76a,b. Tectocerebellar dysraphia. a Sagittal T1-weighted image; b Axial T1-weighted image. Complex malformation characterized by a large occipital lipoma (asterisks, a, b) and by nervous tissue (whose origin is not easily recognizable) anterior to it (arrow, a). The posterior fossa is mostly filled with a large CSF collection. The vermis is absent, whereas the cerebellar hemispheres are hypoplastic (H, b) and seem to be attached to the lipoma; an additional small lipoma is visible anterior to the left cerebellar hemisphere (arrow, b). The tectum of the midbrain is splayed, elongated, and elevated (arrowhead, a). The midbrain is hypoplastic and attracted posteriorly, resulting in an angulation of the ponto-mesencephalic junction. The subarachnoid spaces anterior to the brainstem are markedly enlarged. (Case courtesy of Dr. B. Bernardi, Detroit, United States)

Cerebellar Agenesis

Cerebellar agenesis (synonym: neocerebellar aplasia) is an exceedingly rare abnormality involving absence of the vermis and cerebellar hemispheres. The posterior fossa is of normal or slightly reduced size and basically contains the brainstem, which lacks the normal prominence of the pons, and a CSF collection which passively fills the space normally occupied by the cerebellum (Fig. 4.77). In some instances, pea-like masses of disorganized white matter or slightly larger amounts of cerebellar tissue can be observed [349]. In these cases, the term subtotal agenesis is probably more suitable. The cerebellar remnants generally occupy the antero-superior regions in the would-be location of the quadrangular lobule, in a typically asymmetric fashion [349, 350]. The ventral pons is underdeveloped. Rarely, the size of the posterior fossa may actually be increased, probably as a result of CSF pulsation (Fig. 4.77). Supratentorial abnormalities that have been observed in association with cerebellar agenesis include hydrocephalus, agenesis of corpus callosum, and arhinencephaly [17]. The clinical picture can be surprisingly mild, and involve slight intellectual handicap or developmental delay and rather mild cerebellar motor signs [349, 350]. The paucity of clinical signs has been explained

in terms of plasticity of the fetal brain, which could permit “cerebellization” of a part of the cerebrum [349]. While the neuroradiologic diagnosis of complete cerebellar agenesis is straightforward, differentiation of subtotal cerebellar agenesis from pontocerebellar hypoplasia basically rests on both clinical grounds and the appearance of the cerebellar remnants, which typically is asymmetric in the former and symmetric in the latter [349]. The embryological origin of cerebellar agenesis is still controversial. According to traditional theories, it derives from destruction of normally developed tissue, i.e., a congenital form of cerebellar atrophy [17, 295]. This theory basically rests on the speculation that, because the posterior fossa forms, prior development of the hindbrain must have occurred [295]. However, the concept of basicranial induction of the neuroectoderm is still incompletely understood; actually, the cranial base and calvarium are fully capable of forming even when the brain fails to develop [9]. More recent theories invoke an intrinsic arrest of cerebellar development at an early stage, i.e., a severe form of hypoplasia. Mutation of homeobox genes at the level of the isthmic organizer could lead to underexpression of the dorsalizing gradient [3], similar to what probably occurs in rhombencephalosynapsis.

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a

b

c

d Fig. 4.77a–d. Cerebellar aplasia: Two different cases. Case #1: a Sagittal T1-weighted image; b Coronal T1-weighted image. The size of the posterior fossa is reduced. Cerebellar structures are completely absent, except for a rudimental structure located in the upper portion of the fossa (arrows, b). The pons is markedly hypoplastic (a).Case #2: c Sagittal T1-weighted image; d Axial T1-weighted image. The posterior fossa is markedly enlarged. Cerebellar structures are completely absent. The only recognizable structures are a thinned quadrigeminal plate, the superior medullary velum (arrows, c, d), and rudimentary middle cerebellar peduncles (MP, d). The brainstem is hypoplastic, mainly due to pontine hypoplasia. Notice that there is no hydrocephalus, and that the CSF cavity filling the posterior fossa does not displace the brainstem against the clivus, ruling out an arachnoid cyst

Pontocerebellar Hypoplasia Background

Pontocerebellar hypoplasia (PCH) (synonym: pontoneocerebellar hypoplasia) is a rare entity among posterior fossa abnormalities. The basic anatomic

abnormality involves marked size reduction of the pons, cerebellar hemispheres, and vermis. The question whether this condition results from primary hypoplasia or secondary destruction remains poorly settled, as is the case with cerebellar agenesis (see above); however, the term “hypoplasia” is preferable, at least from an imaging perspective.

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Clinical Syndromes

PCH represents a heterogeneous disorder with similar neuroradiologic features. Clinical and pathological features may differ significantly among patients with similar MRI pictures. PCH can be isolated or associated with supratentorial abnormalities (Table 4.12). PCH Type 1 of Barth (PCH-1)

PCH Type 1 of Barth is an autosomal recessive disorder characterized by neonatal onset, congenital contractures, ventilatory insufficiency, and early death [351, 352]. The pathological hallmark of PCH-1 is spinal anterior horn involvement with similarities to spinal muscular atrophy [352].

Table 4.12. Causes of cerebellar hypoplasia (modified from [357]) Viral

Cytomegalovirus

Chromosomal

Trisomy 18

Familial cerebellar Autosomal recessive hypoplasia X-linked PEHO (infantile cerebello-optic atrophy) Cerebral calcifications and cerebellar hypoplasia Biochemically defined causes

Carbohydrate deficient glycoprotein (CDG) syndromes Mitochondrial respiratory chain defects Glutaric aciduria type I

Part of a complex malformation

Lissencephaly with cerebellar hypoplasia (LCH) Congenital muscular dystrophies (WalkerWarburg, Fukuyama, muscle-eye-brain syndromes) Marden-Walker syndrome Oto-palato-digital syndrome Oral-facial-digital syndrome

PCH Type 2 of Barth (PCH-2)

PCH Type 2 of Barth is an autosomal recessive disorder, so far described only in European children. The disease features progressive microcephaly, severe lack of mental and motor development, and characteristic dyskinesia/dystonia that usually starts in infancy [351, 352]. There is no anterior horn involvement. Carbohydrate-Deficient Glycoprotein (CDG) Syndromes

CDG are a newly discovered group of inherited disorders, also called congenital disorders of glycosylation. These result from abnormal synthesis of sugar groups that are parts of glycoproteins. Most affected patients have a special physiognomy, neurological problems that include psychomotor retardation, ataxia, hypotonia, little or no head control, failure to thrive, lethargy and unresponsiveness, and liver and/or intestinal problems. PCH has been described in autopsy reports [353]. Increased serum sialotransferrin biologically marks these syndromes, thereby allowing for verification of suspected diagnoses. Mitochondrial Respiratory Chain Defects

de Koning et al. [354] described a lethal case of PCH showing clinical features similar to those of PCH-1 but without spinal anterior horn involvement, in which there was elevated lactate concentration in plasma and urine; biochemical analysis demonstrated multiple deficiencies of respiratory chain enzymes in skin fibroblast. MRI demonstrated diffuse PCH associated with abnormal signal intensity in the supratentorial white matter. Lissencephaly with Cerebellar Hypoplasia (LCH)

Although classical lissencephaly involves primarily the cerebral cortex, malformations in this spectrum can be associated with significant cerebellar

Toxic causes

i.e., phenytoin

Pontocerebellar hypoplasia (of Barth)

PCH type I PCH type II

underdevelopment, and have recently been referred to as lissencephaly with cerebellar hypoplasia (LCH) [134] (see above). Mutations in the LIS1, DCX, and RELN genes have been found to cause some LCHs, but additional classes of genes remain undetermined. The clinical spectrum involves small head circumference and cortical malformation, ranging from agyria to simplification of the gyral pattern, and from near normal cortical thickness to marked thickening of the cortical gray matter [134]. One of the LCH subtypes also displays corpus callosum agenesis [134]. Cerebellar manifestations range from midline hypoplasia to diffuse volume reduction and disturbed foliation; therefore, some cases may be better defined as having cerebellar dysplasia. Cases associated with RELN mutation display particular severity of cerebellar and hippocampal involvement [134]. Extreme cerebellar hypoplasia has been noted to occur in microlissencephalic patients [133]. Congenital Muscular Dystrophies (CMDs)

CMDs associated with structural brain abnormalities include Walker-Warburg, Fukuyama, and muscleeye-brain diseases (see above). These entities most likely represent different degree of severity along a malformation spectrum. Supratentorial abnormalities are basically represented by the cobblestone cortex, which is thought to result from failure to block neuronal migration at the pial barrier [355]. Poste-

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rior fossa abnormalities include PCH, Dandy-Walker malformations, cerebellar cortical dysgenesis, and a characteristic posterior kink of the brainstem that is exclusively seen in the Walker-Warburg syndrome (Fig. 4.40). Neuroradiology

Hypoplasia of the vermis and cerebellar hemispheres involves marked reduction in size with a reduced number of folia (Fig. 4.78), as opposed to cerebellar atrophy, in which there is a normal number of thin folia [356], and to partial agenesis, in which there is a reduced number of folia but the present folia are normal [357]. However, such distinction may not be straightforward on imaging. On midsagittal sections, the vermis is small, but retains a relatively normal shape, with a larger posterior lobe and a smaller anterior lobe separated by a shallow primary fissure. The vermis is not rotated, and the shape of the fourth ventricle is normal, establishing a crucial differen-

tial diagnostic sign with Dandy-Walker variants [299, 319]. The cerebellar hemispheres are symmetrically small, flattened, and located close to the tentorium [356, 357]. The pons is small, with a decreased or absent bulge of its anterior surface on sagittal images [356]. Owing to the reduction in size of the cerebellum, the subarachnoid spaces are passively enlarged [357]. Thereby, there is no “cyst” in the posterior cranial fossa, allowing differentiation from MCM in which, additionally, there is a normal pons. The overall posterior fossa size is normal or slightly small, with normal or mildly verticalized tentorium. In PCH-1 and PCH-2, the abnormality is restricted to the posterior fossa with a substantial lack of supratentorial anomalies. However, all patients with PCH must be scrutinized for associated supratentorial abnormalities, basically involving lissencephalic cortices, in order to identify different etiologies. One must also remember that PCH-1 and PCH-2 are integrated clinical-neuroradiological diagnoses. Recognition of these entities is important in view of the

b a

Fig. 4.78a–c. Pontocerebellar hypoplasia. a Sagittal T2weighted image; b Coronal T2-weighted image; c Axial T2weighted image. The size of both the cerebellar hemispheres and of the vermis is diffusely reduced. Notice there is a reduced number of folia, as opposed to cerebellar atrophy, in which there is a normal number of thin folia, and to partial agenesis, in which there is a reduced number of folia but the present folia are normal. On midsagittal sections (a), the vermis is small, but retains a relatively normal shape. The vermis is not rotated, unlike in Dandy-Walker variants. The subarachnoid spaces and the fourth ventricle are dilated exvacuo. The pons is also hypoplastic

c

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possible autosomal recessive transmission, requiring genetic counseling [358]. Unilateral Hemispheric Aplasia/Hypoplasia

Unilateral cerebellar hypoplasia is probably more common than bilateral hypoplasia [295], whereas unilateral aplasia is exceptional [358]. Although it is usually a sporadic anomaly, it has been described in association with ipsilateral cutaneous organoid nevus [359], Aicardi syndrome [360], and facial hemangioma; the latter association is a part of the

PHACE syndrome spectrum [315, 316]. There often is associated inferior vermian hypoplasia, resulting in a cleft that connects the fourth ventricle with the subarachnoid spaces (Fig. 4.79). The ipsilateral cerebellar peduncles also show reduced size. The homolateral dentate nucleus and contralateral inferior olivary and pontine nuclei are hypoplastic. Contralateral underdevelopment of the brainstem is found in case of unilateral aplasia [361]. The pathogenesis is unknown and may not be uniform, with some cases possibly resulting from prenatal destructive lesions [361].

a

c

b

d Fig. 4.79a–d. Cerebellar hypo-aplasia. Two different cases. Case #1: a Sagittal T1-weighted image; b Coronal T2-weighted image. Diffuse form of cerebellar hypoplasia involving both the inferior vermis and the left cerebellar hemisphere (b). Notice that interpretation of the sagittal image may be tricky. The cleft that appears to connect the fourth ventricle with the cisterna magna (arrowhead, a) is due to hypoplasia of the inferior vermis; below that, the right cerebellar hemisphere fills the gap on the midline (CH, b). Coronal planes clear the view, showing that the inferior vermis is absent (arrows, b) and the left cerebellar hemisphere is hypoplastic. Case #2: c Axial T1-weighted image; d Coronal T1-weighted image. Partial aplasia of the right cerebellar hemisphere: the right cerebellar hemisphere is partially absent with secondary enlargement of the subarachnoid spaces. Notice that the CSF cavity does not exert mass effect; in fact, the inferior portion of the fourth ventricle is attracted to the right (arrow, c). This rules out an arachnoid cyst (compare with Fig. 4.72)

Brain Malformations

Cerebellar Cortical Malformations

Until recently, abnormalities of cerebellar foliation and fissuration were believed to be microscopic and basically detectable by histology, with a notable exception being Lhermitte-Duclos disease. However, the widespread use of high-field MR equipment has provided evidence that the incidence of cerebellar cortical malformations is higher than was previously thought. Although minor cerebellar dysplasias are commonly found on histological examination within the cerebellar white matter or vermian nodulus of otherwise normal newborns [17], larger dysplasias are obviously pathologic. They are found either as isolated entities or, more commonly, in patients with congenital muscular dystrophies, intrauterine infection, or other supra- and infratentorial malformations. Cerebellar cortical malformations have also been observed in the vicinity of posterior fossa tumors [199, 362], raising the suspicion of a possible pathogenetic association. Classification of cerebellar cortical malformations from a neuroimaging perspective is problematic. This depends basically on the fact that correlation with pathologic data is usually lacking. Three broad categories can be identified for classification purposes, i.e., (i) cortical dysplasia, corresponding to the pathological categories of heterotopia, caused by disturbed migration of neuroblasts from the rhombic lip, and dysplasia, resulting from disturbances of cortical layering and gyrus formation [17]; (ii) granule layer aplasia, which results in congenital cerebellar atrophy; and (iii) hyperplasias, a still controversial category including very diverse entities such as the LhermitteDuclos disease and macrocerebellum. Still today, there is an enduring debate as to whether Lhermitte-Duclos disease is a neoplastic, malformative, or hamartomatous condition [363]. Because the Lhermitte-Duclos disease has been found to be consistently associated with Cowden syndrome, a genetic disease characterized by multiple hamartomas and malignancies, the two conditions are presently considered to represent a single phakomatosis [364, 365]. The brain MRI manifestations of this entity are described in Chap. 17. Unilateral hemispheric enlargement can be found in hemimegalencephaly as well as in several conditions associated with somatic hemihypertrophy, including Beckwith, Klippel-Trenaunay-Weber, and RussellSilver syndromes. Finally, cases of isolated cerebellar hemihypertrophy have rarely been reported [366].

Cerebellar Cortical Dysplasia

Background

This category comprises anomalies resulting morphologically in abnormal cerebellar foliation and fissuration. Pathologically, heterotopia form abnormal clusters of gray matter in the cerebellar white matter, whose size is often microscopic: therefore, they may remain undetected on MRI [362]. True cortical dysplasia corresponds to areas of smooth, thick cortex showing interlacing nests of granular and molecular layers with irregularly arranged Purkinje cells [17]. Often, the two types of malformation are associated. Although the term cerebellar polymicrogyria is often used [362], its appropriateness has been questioned, basically from a semantic perspective [367]. In one histologically proven case, there was deep folding of the cerebellar surface, with fusion of sulci in the upper parts and entrapment of the deep sulcal portions [368], consistent with a pathological definition of polymicrogyria. Embryologically, cerebellar cortical dysplasias are believed to occur from a pathologic process involving genetically or environmentally disturbed migration of Purkinje and granule cells, improper function of cellular and interstitial signaling that guide developing cells and axons, or both [5]. An important role in the foliation and lamination of the cerebellar cortex is also played by the leptomeninges; selective destruction of the leptomeninges has been shown to result in defective foliation, granule cell ectopia, and reduction in cerebellar size [17]. Cerebellar cortical dysplasias can be isolated, but more often they are associated with other malformations, such as vermian abnormalities, corpus callosum dysgenesis, and cerebral cortical malformations [362]; as a consequence, correlation with neurologic focal symptoms or developmental/cognitive deficits is often problematic [362]. They have also been described in chromosomal abnormalities, congenital muscular dystrophies, intrauterine infection, phakomatoses (i.e., PHACE syndrome) [316], and as a result of exposure to gamma radiation and ethanol [368]. We also observed a case of isolated rostral vermian dysplasia in a child with Cohen syndrome, whose main radiologic feature is a megalic corpus callosum. When present, supratentorial abnormalities typically dominate the clinical picture [366]. Isolated dysplasias may be incidental findings, or can be found in patients with developmental delay or cognitive disorders. A clear-cut clinical-radiological correlation is difficult to establish. However, patients with isolated vermian dysplasia are more likely to be asymptomatic than those with diffuse involvement of the hemispheres.

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Neuroradiology

Classification of cerebellar cortical dysplasia into subtypes from a neuroradiological standpoint has been attempted by Demaerel [366] (Table 4.13). Basically, type 1 dysplasias involve the vermis and type 2 dysplasias involve the cerebellar hemispheres. Although lack of histological verification and the presence of overlapping features are substantial drawbacks, this classification offers a rationale to approach these malformations from a radiological perspective. The MRI appearance of cerebellar cortical dysplasias is variable. Basically, MRI shows abnormal foliation and fissuration. MRI signs [362] can be reconducted to three main categories, as follows. It is noteworthy that the three groups of abnormality may coexist in individual patients. Abnormal foliation/fissuration: these are the most common MR abnormalities in patients with cerebellar cortical dysplasia. MRI signs include defective, large, or vertical fissures; blurred gray-white matter interface; abnormal arborization of the white matter; and heterotopia within the cerebellar white matter (Fig. 4.80). Localized fissural malorientation, with individual folia running vertically rather than horizontally, may involve the rostral vermis [369] or one cerebellar hemisphere [370]. This probably represents a mild form of cerebellar dysplasia in patients without elicitable cerebellar neurological deficit. Cortical thickening: It often coexists with abnormally oriented folia and fissures, and results in an irregularly smooth, bumpy cerebellar surface (Fig. 4.80). This pattern may selectively involve certain areas or diffusely surround a poorly digitated white matter in both hemispheres. Diffuse cortical thickening is frequent in case of cerebellar involvement from intra-

uterine cytomegalovirus or toxoplasma infection, and may be associated with subcortical calcification. However, we have seen a case of diffuse cortical thickening involving both cerebellar hemispheres, which were also markedly hypoplastic. Subcortical cysts: A characteristic, albeit rare, MRI finding is the presence of multiple, variably sized subcortical cyst-like inclusions (Figs. 4.42, 4.43). These are isointense with CSF in all MRI sequences, and likely represent subarachnoid spaces engulfed by the fusion of disorganized folia at the boundary between normal and polymicrogyric cortices [238]. They preferentially involve the posterior portions of the cerebellar hemispheres and are associated with absence of normal folia and fissures. Subcortical cysts have been reported in congenital muscular dystrophies of the Fukuyama [238] and muscle-eye-brain type [241]; in the latter, hypoplasia of the pons is consistently associated. Recently, they have also been identified in patients without clinical or laboratory evidence of muscular dystrophy [371]. Granular Layer Aplasia

Granular layer aplasia (also called primary degeneration of the granular layer) is a rare autosomal recessive disorder that has not yet been linked to a specific etiology [17]. The original damage is destruction or depletion of precursor cells in the external granule layer, a transient germinal layer located over the surface of the fetal and neonatal cerebellum from which the granule, basket, and stellate cells of the granular layer develop as a result of inward migration. As a consequence of such destruction, the granular layer fails to develop. This is different from secondary destruction of an already developed granular layer, although such differentiation may be difficult to establish even on histological examination [17].

Table 4.13. Classification of cortical dysplasia according to Demaerel [367] Type

Radiological features

1a

– Malorientation of the fissures in the anterior lobe of the vermis Cerebellar hemispheric extension of the vermian abnormalities is uncommon

1b

– Malorientation of the fissures in the anterior lobe of the vermis – Irregular foliation of the anterior lobe and part of the posterior lobe of the vermis Cerebellar hemispheric extension of the vermian abnormalities is common; associated cerebral abnormalities may occasionally be seen

2

Cerebellar hemispheric abnormalities consisting of one or more of the following: – Cortical dysgenesis (bumpy gray/white matter junction) with or without small included cysts – Cortical hypertrophy – Aberrant orientation of the folia Type 1b changes in the vermis can be seen in more than 60% of the patients; associated cerebral abnormalities can be seen in more than 50% of the patients

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a

b

c

d Fig. 4.80a–d. Cerebellar cortical dysplasia: two different cases. Case #1: a Sagittal STIR image; b Axial T2-weighted image. Diffuse abnormality of foliation of both cerebellar hemispheres and the inferior vermis (arrow, a). Case #2: c Sagittal T1-weighted image; d Coronal T2-weighted image. Diffuse cerebellar dysplasia involving both the cerebellar hemispheres, whose cortex shows a bumpy, thickened appearance similar to cerebral polymicrogyria (d). An islet of heterotopia is recognizable deep within the right cerebellar white matter (arrow, d). Foliation of the vermis is absent (c). The cerebellum is globally hypoplastic

Affected children exhibit characteristic clinical features, represented by hypotonia, strabismus, delayed motor development, nonprogressive ataxia, delayed language development with dysarthria, and mental retardation [372]. Symptoms are present from early childhood and remain stationary [17]. MRI detects diffuse cerebellar atrophy [372], characterized by a small cerebellum with shrunken folia and large fissures (Fig. 4.81). As such, atrophy is clearly distinguishable from cerebellar hypoplasia, in which the fissures are of normal size compared with the folia [5]. The brainstem and cerebrum are normal. Because cerebellar atrophy can be the end result of progressive

metabolic injury of different etiologies and, in several instances, its cause remains undetermined, granular layer hypoplasia can be reasonably suspected only if cerebellar atrophy is detected in a newborn. Macrocerebellum

This uncommon condition was reported by Bodensteiner in 1997 [373], and is characterized by abnormally large cerebellum with preservation of the overall shape. Cerebellar volume exceeds normal by at least 2 standard deviations. Clinically, affected patients show hypotonia, delayed motor and cogni-

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b Fig. 4.81a,b. Granular layer aplasia. a Sagittal T2-weighted image; b Coronal T2-weighted image. Shrunken appearance of the cerebellar vermis (a) and hemispheres (b). Marked reduction in cerebellar size, dilatation of the subarachnoid spaces, and defective myelination all contribute to the globally high signal intensity of the cerebellum on T2-weighted images (b). The brainstem is normal

a

b Fig. 4.82a,b. Macrocerebellum. a Sagittal T1-weighted image; b Coronal T2-weighted image. Marked increase in size of the whole cerebellum, without evidence of focal cortical dysplasia. Notice that the size of the posterior cranial fossa is normal. The fourth ventricle is small

a

tive development, and oculomotor apraxia. On MRI [374], the cerebellum is disproportionately large but appears to have normal imaging features in terms of tissue characteristics (Fig. 4.82). There is consistent association with delayed myelination of the supratentorial white matter. The etiology is unknown, but it could be related to the cerebellum responding to the elaboration of growth factors intended to augment the slow development of cerebral structures [374].

4.4.4.3 Isolated Brainstem Hypoplasia/Dysplasia

Pathological categorization of brainstem abnormalities includes dysplasias of the inferior olivary nuclei, anomalies of crossing of the corticospinal tracts, aplasia of the corticospinal tracts, hypertrophy of the corticospinal tracts, aplasia of the dorsal spinal tracts, and congenital facio- and ophthalmoplegia (Moebius syndrome) [17]. Our experience has been that iso-

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lated brainstem abnormalities are encountered only exceptionally. What follows is a brief account of this limited experience. Brainstem Hypoplasia in Horizontal Gaze Palsy with Scoliosis

Horizontal gaze palsy with scoliosis is a rare autosomal recessive disorder characterized by congenital absence of conjugate horizontal eye movement with progressive scoliosis developing in childhood or adolescence. Affected patients compensate for their deficit by turning their heads in the desired direction, thereby obtaining regular binocular vision. Horizontal gaze palsy has been related to dysfunction of abducens nuclei and medial longitudinal fasciculus

(MLF), whereas scoliosis is thought to be caused by lower brainstem nuclear abnormalities. On MRI, the prominence normally produced by the abducens nuclei on the fourth ventricular floor is absent; the medulla is also hypoplastic and shows a butterfly configuration. In a case we observed, MRI also revealed a hypoplastic pons whose posterior two thirds were split into two halves by a midsagittal cleft extending ventrally from the fourth ventricular floor (Fig. 4.83) [374]. Embryologically, the pons is developed from the ventrolateral wall of the metencephalon approximately between gestational weeks 5 and 8. During this period, the developing fourth ventricle shows a ventral furrow that deeply indents the posterior aspect of the metencephalon. Failed development of

Fig. 4.83a–c. Brainstem hypoplasia in horizontal gaze palsy with scoliosis. a Sagittal T1-weighted image; b, c. Axial T2-weighted image. Patient is a 13-year-old girl with congenital horizontal gaze palsy and progressive idiopathic scoliosis. On sagittal planes, hypoplasia of the brainstem is evident; plus, there is a depression of the fourth ventricular floor (arrowhead, a). On axial planes at level of the medulla, the pyramids (P, b) are not prominent with respect to the inferior olives (IO, b), and the floor of the fourth ventricle is tent-shaped (arrows, b). At level of the pons, the normal prominence of the abducens nuclei is absent (arrows, c); additionally, the posterior two thirds of the pons are split into two halves by a midsagittal cleft extending ventrally from the fourth ventricular floor (“split pons sign”) (arrowhead, c)

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medial pontine structures including the abducens nuclei and MLF could result into persistence of an abnormally deep ventral fourth ventricular furrow. A butterfly configuration of the medulla is further evidence of maldevelopment of dorsomedial brainstem structures [374]. Segmental Brainstem Agenesis

Congenital absence of a segment of the brainstem has been reported exceptionally, and has involved the inferior pons with pontomedullary disconnection [375] or the upper pons and mesencephalon [376]. Because severe cerebellar hypoplasia was consistently associated, these cases cannot be regarded as isolated brainstem malformations; however, the pathologic and neuroimaging picture is dominated by segmental brainstem aplasia. Affected patients had severely impaired neurological conditions with prominent central respiratory disturbances, and died in early infancy. A pathogenetic role for a mutation or deletion in the EN2 gene has been speculated to exist [376]. Perhaps more frequently, one may encounter isolated hypoplasia of portions of the brainstem. In a case we observed, unilateral pontomesencephalic hypoplasia was found in a patient with congenital third cranial nerve palsy (Fig. 4.84). Hypertrophy of the Corticospinal Tracts

Unilateral hypertrophy of the corticospinal tract is usually associated with a prior destructive lesion

in the contralateral cerebral hemisphere [17, 377]. The volume of the pyramid is increased and causes it to bulge with posterior dislocation of the inferior olivary nucleus. The bulging medullary pyramid is well depicted on axial MRI sections (Fig. 4.85). The main differential concern is an intrinsic glioma. Although benign hypertrophy should theoretically yield isointense signal with normal brain, abnormal myelination has been reported to occur within the hypertrophied tract [378], and could possibly cause T2 prolongation. Absence of contrast enhancement is not sufficient to rule out low-grade tumors. Therefore, we believe close follow-up of apparent pyramidal hypertrophy with MRI is mandatory.

4.5 Chiari Malformations 4.5.1 Chiari I Malformation Background

The Chiari I malformation is a congenital hindbrain abnormality characterized by downward displacement of elongated, peg-like cerebellar tonsils through the foramen magnum into the upper cervical spinal canal (Fig. 4.86), sometimes associated with descent and distortion of the bulbo-medullary junction and often complicated by hydrosyringomyelia (HSM) and

a

b Fig. 4.84a,b. Ponto-mesencephalic hypoplasia in a 2-month-old infant with congenital left third nerve palsy. a, b. Axial T2-weighted images. The left anterolateral portion of the pons (arrow, a) and the homolateral cerebral peduncle (arrow, b) are hypoplastic

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a

b Fig. 4.85a,b. Brainstem hyperplasia. a Axial T1-weighted image; b Axial T2-weighted image. The right half of the medulla oblongata is hypertrophic (arrow, a, b). This finding has been stable for 5 years, without evidence of MR signal modifications

hydrocephalus. Associated anomalies include osseous abnormalities at the craniovertebral junction and basilar invagination. Although this abnormality was initially described in autopsy observations, the extensive use of MRI has made clear that a condition of caudal tonsillar ectopia is much more common than was previously believed, and that such condition is often associated with a broad spectrum of clinical and neuroradiological features. However, the increase of reported cases has emphasized the need for greater understanding of the pathogenesis and clinical manifestations of this abnormality [379]; often, the questions raised by the various published articles have been more numerous than the answers given. From a terminological perspective, it should be stressed that the term “Arnold-Chiari malformation type I” is often misused to refer to caudal tonsillar displacement [380]. In fact, “Arnold-Chiari malformation” is an abandoned synonym of the Chiari II malformation, that is, malformation of the posterior cranial fossa with caudal vermian displacement associated with myelomeningocele. Pathogenesis

Contrary to what the term might suggest, this anomaly is inherently different from Chiari II or III malformations, except for the name of the Austrian pathologist H. Chiari, who first described these entities in 1891 [381]. In fact, unlike Chiari II or III malformations, the Chiari I malformation is not related with neural tube closure defects. It is believed that the anomaly may be primarily related to a disorder of

the paraxial mesoderm and, particularly, to hypoplasia of the occipital bone due to underdevelopment of the occipital somites, with reduced volume and overcrowding of the posterior cranial fossa, which contains the normally developed hindbrain [382]. The possible association with other skeletal developmental abnormalities, such as basilar invagination, further reduces the size of the posterior fossa, thereby increasing overcrowding and downward herniation of nervous structures. Although the vast majority of cases appear to occur sporadically, recent reports of increased incidence in monozygotic twins or triplets [383, 384] suggest a possible underlying genetic disorder in some cases; however, the possible risk of inheritance has not been determined yet. As was previously stated, there is a significant incidence of HSM and hydrocephalus in patients with Chiari I malformation. Hydrocephalus is found in 6%–25% of cases (Fig. 4.87) [381, 385], whereas the incidence of HSM is variable according to the various series, ranging from 37% to 75% [381, 385–387]. CSF cavities may extend over variable distances along the spinal cord (see Chap. 38). They involve more often the cervical spinal cord, but may also be holocord. They involve the medulla (i.e., syringobulbia) in a minority of patients. Significantly, hydrocephalus tends to be more common in patients who also have HSM [381]. This is due to the fact that both hydrocephalus and HSM result from impaired CSF flow at the foramen magnum due to abnormal pulsatile motion of the cerebellar tonsils, producing a selective obstruction of CSF flow from the cranial cavity to the

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a

b

c

d Fig. 4.86a–d. Chiari I malformation. a Sagittal T1-weighted image; b Sagittal T2-weighted image; c Coronal T1-weighted image; d Axial T1-weighted image. The posterior fossa is small. The peg-like cerebellar tonsils (T, a, b) herniate into the foramen magnum (arrows, a, b). Tonsillar ectopia is greater to the right (arrows, c). Note that the vermis (V, a, b) is located intracranially, and is raised by the underlying tonsils. Axial image shows crowding of the foramen magnum due to the presence of the tonsils (T, d) behind the medulla oblongata. In this case, crowding of the posterior fossa causes abnormal CSF circulation leading to hydrocephalus

Fig. 4.87. Chiari I malformation in a craniosynostotic patient, associated with hydrocephalus. Sagittal T1-weighted images. Severe ectopia of the cerebellar tonsils (T). Notice the vermis is in its normal position (V). There is associated hydrocephalus

Brain Malformations

spine during systole [388]. It has been proposed that ball-valve obstruction at the foramen magnum produces increased systolic CSF waves in the spinal compartment, thereby promoting bulk flow of CSF into the spinal cord through dilated perivascular spaces, resulting in HSM [381, 389]. Thickening, hyalinization, and calcification of the arachnoid and dura mater, possibly resulting from chronic friction of the cerebellar tonsils against bone, may further constrict the herniated hindbrain at the foramen magnum, thereby contributing to clinical symptoms and the development of HSM and hydrocephalus [390]. Rupture of these dural bands could account for the cases of spontaneous regression of a Chiari I malformation that have been, albeit rarely, reported in the literature [391, 392]. The issue of the so-called “acquired” Chiari I malformation also must be addressed. It is known that caudal herniation of the hindbrain, indistinguishable from the Chiari I deformity, may occur secondary to CSF hypotension, either iatrogenic (i.e., after the establishment of ventricular and subarachnoid shunts or multiple lumbar taps) [393–396] or spontaneous [397], as well as to raised intracranial pressure (i.e., due to intracranial tumors) [398, 399] or venous hypertension (i.e., arteriovenous malformations). Typically, there is complete reversal of tonsillar descent after surgical treatment of the predisposing condition, as is documented by follow-up MRIs [400]. We believe that these “acquired” conditions should be clearly distinguished from the congenital Chiari I deformity, and that the term “acquired Chiari I malformation” is a misnomer that should be abandoned in favor of the more correct “acquired tonsillar herniation.” Clinical Findings

Although the Chiari I malformation has been referred to as “adult-type Chiari malformation” because a significant proportion of affected patients present in adulthood, it is in fact a congenital abnormality that can be, and in fact often is, discovered in childhood. The advent of MRI has played an unique role in the increased recognition of this abnormality, which often is discovered incidentally; in fact, a significant proportion of children [14%–56% of cases] [386, 387, 401] is neurologically normal at presentation, and the diagnosis is made when an MRI is performed for another reason. Moreover, a significant degree of tonsillar ectopia (i.e., up to 12 mm) may be found in completely asymptomatic children [402]. Therefore, the clinical significance and appropriate management of these patients often remains uncertain

[402]. The presentation of Chiari I malformation is often characterized by vague and ambiguous symptoms. Many patients are misdiagnosed with conditions such as multiple sclerosis, fibromyalgia, chronic fatigue syndrome, or psychiatric disorders. Affected patients frequently experience symptoms months to years prior to diagnosis, and some may present after flexion injuries to the neck from chiropractic cervical manipulation [403, 404]. Initial symptomatology often is related to hindbrain compression and includes headache, neck pain, numbness, weakness, incoordination, nystagmus, and ataxia, among other symptoms [381, 386, 387, 402]. There is a general consensus in that the degree of tonsillar descent grossly correlates with the presence of signs and symptoms [402, 405]; however, cranial and brain measurements alone have not been found to correlate significantly with the prognosis and the incidence of complications [406]. When HSM is present, a host of additional symptoms that relate to spinal cord involvement become prominent and generally overshadow other clinical manifestations. Scoliosis is found in 28% of cases [387]. Signs of raised intracranial pressure may develop in cases of associated hydrocephalus. Imaging Findings

Measurement of the degree of downward displacement of the cerebellar tonsils is critical in order to diagnose a Chiari I malformation. The extent of this ectopia is measured on a midsagittal MR image from the tips of the cerebellar tonsils to a line drawn from the basion to the opisthion (Fig. 4.88) [383, 386, 407]. There has been a significant amount of controversy concerning the exact degree of tonsillar ectopia that should be regarded as abnormal. It is generally accepted that displacement of the cerebellar tonsils by less than 3 mm is normal. Aboulezz et al. [407] considered herniation of at least one cerebellar tonsil 5 mm or more below the foramen magnum to be pathologic, and between 3 and 5 mm to be borderline. Elster et al. [386] considered 3 mm herniations to be definitely pathologic if accompanied by other features such as syrinx, cervicomedullary kinking, or elongated fourth ventricle. Milhorat et al. [381] used 5 mm as a cut-off; however, 9% of their patients exhibited tonsillar herniation of less than 5 mm despite having symptoms that were considered to be typical of Chiari I malformation. Other authors have correlated the degree of tonsillar descent to patient age [408]; in general, the cerebellar tonsils ascend with increasing age. In the first decade of life, 6 mm is pathologic. In the second decade, this decreases to 5 mm. Further decreases occur in the following

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a

b Fig. 4.88a,b. Measurement of tonsillar ectopia on MRI. a Sagittal T1-weighted image in a normal child; b Sagittal T1-weighted image in a child with Chiari I malformation. A line is drawn to connect the basion (B) to the opisthion (0) on sagittal images. The extent of tonsillar ectopia is measured drawing a perpendicular line from the tip of the tonsils to the B–O line. Notice that in the normal individual (a), the tip of the tonsils is above the B–O line. Instead, this Chiari I individual (b) has marked tonsillar descent (9.3 mm below the B–O line). In our experience, we have used 3 mm below the B–O line as a cut-off

decades. In our clinical experience, in which all patients with a neuroradiological diagnosis of Chiari I malformation have received a thorough neurological and neurosurgical assessment, we have used 3 mm as a cut-off for normal individuals in the pediatric age group, and considered ectopia greater than 5 mm to be definitely pathological. Mild (i.e., 3–5 mm) ectopia was considered significant in presence of: (i) neurological signs or symptoms that can be related to hindbrain compression; (ii) peg-like deformation of the tonsils; (iii) a syrinx. Therefore, we believe that all individuals with 3–5 mm displaced tonsils should be carefully assessed neurologically. Asymmetric tonsillar herniation is common; unilateral tonsillar ectopia is considered significant when it exceeds 5 mm than the contralateral side [386]. Coronal MR images are especially useful to assess asymmetric tonsillar herniation (Fig. 4.86). Overcrowding of the posterior cranial fossa produces a number of additional features, including: (i) effacement of the CSF spaces in the posterior fossa, and especially of the vallecula and cisterna magna, which represents a useful clue on axial CT and MRI images; (ii) compression of the fourth ventricle; (iii) compression of the anterior aspect of the medulla by a retroflexed odontoid process; and (iv) downward displacement of the medulla in a significant amount of

cases, with the ponto-medullary junction approaching the basion. In a minority of cases, a true posterior cervicomedullary kinking, similar to that seen in Chiari II malformations, may be seen in association to tonsillar descent. These latter cases have been referred to as the “bulbar” or “myelencephalic” variant of the Chiari I malformation (Fig. 4.89) [385, 409]. This variant probably results from a smaller posterior fossa as compared to classical Chiari I malformation, with increased degree of neural overcrowding and downward displacement of the medulla. It is noteworthy that associated skeletal anomalies, such as platybasia and basilar invagination, also are relatively more common in patients with the bulbar variant than in classical Chiari I’s (P. Tortori-Donati and A. Rossi, unpublished observations). Clinically, patients with the bulbar Chiari I variant are less likely to be asymptomatic than patients with the classical Chiari I malformation. Because HSM is a significant contributor to the clinical picture and to the eventual outcome, it is critical that all patients with a diagnosis of Chiari I malformation undergo MR imaging of the spinal cord. The reverse is also true, in that all patients with an apparently isolated HSM should be investigated for a possible Chiari I malformation.

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b Fig. 4.89a,b. Chiari I malformation, myelencephalic type. a Sagittal T1-weighted image; b Coronal T1-weighted image. Cerebellar tonsils are ectopic bilaterally (T, a, b). The vermis is in its normal position (V, a). Note elongation of the medulla oblongata (arrowheads, a) and cervicomedullary kinking (arrow, a)

a

Alterations in craniospinal brain and cord motion were discovered before the advent of MRI. In a myelographic study conducted in Chiari I patients [410], crowding of the neural structures with abnormal, abrupt downward systolic displacement of the brainstem and cerebellar tonsils resulted in a plugging effect with narrowing of the CSF pathways at the foramen magnum, whereas diastolic recoil of the nervous structures disimpacted the foramen magnum. Flow-sensitive phase-contrast MRI studies have been used to demonstrate noninvasively anomalies in CSF flow at the foramen magnum both in normal individuals and Chiari I patients, and to assess the benefits of decompressive surgery [388, 411–413]. In normal subjects, arrival of the systolic arterial pulse increases the cerebral blood volume, thereby displacing a corresponding amount of CSF from the basilar cisterns to the cervical subarachnoid space; then, cerebral venous outflow and recoil of the spinal dura mater produce an opposite, caudocranial diastolic CSF wave. Analyses of CSF flow in Chiari I patients have yielded controversial results, mainly due to the different techniques that were used by the various investigators. Some authors [388, 411] demonstrated selective obstruction of systolic CSF flow from the cranial cavity to the spine with normal upward diastolic CSF flow in Chiari I patients, whereas others [413] detected increased systolic caudal and diastolic cranial motion of the spinal cord, with unchanged

systolic and impaired diastolic CSF flow. Motion-sensitive MRI techniques detect restoration of normal flow dynamics after successful decompressive surgery [411]. Although of interest in the understanding of the pathogenesis of this condition, MRI flow studies have not yet been successfully incorporated into treatment decision-making. However, they could be helpful in demonstrating disturbances of CSF velocity and flow at the foramen magnum in patients with mild tonsillar ectopia, thereby facilitating the diagnosis in cases where conventional MRI findings are doubtful. As was previously stated, skeletal abnormalities, such as platybasia, basilar invagination, atlantooccipital assimilation, craniosynostosis, and fused cervical vertebrae, are a frequent finding [24% of cases] [386]. Associated brain malformations are much less common. In a series of 147 patients, Elster et al. [386] found only single cases in whom associated callosal lipoma, septo-optic dysplasia, and aqueductal stenosis were identified. A Chiari I malformation is found in 20% of patients with idiopathic growth hormone deficiency, in association with the typical picture of small anterior pituitary, absent stalk, and ectopic posterior pituitary [414], indicating a possible common embryologic derangement [414, 415]. An association with midline germ cell tumors of the suprasellar and pineal regions has also been described [416].

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4.5.2 Chiari II Malformation Background

The Chiari II malformation is a congenital abnormality of the hindbrain characterized by a smaller than normal posterior cranial fossa with downward displacement of the vermis, brainstem, and fourth ventricle into the foramen magnum and cervical spinal canal. A host of other abnormalities of the skull, brain, spine, and spinal cord may be associated, thereby generating a complex and polymorphous picture. There has been much confusion and disagreement in the literature concerning the definition of this malformation [417]. Among the numerous, often misleading denominations that were proposed in the past, the term “Arnold-Chiari malformation” gained much popularity, and is still today used by many as a synonym of “Chiari II malformation.” In our day-today practice, we have favored the latter denomination for the sake of a uniform classification following the original paper by Chiari [381]. The Chiari II malformation is found in all patients with open spinal dysraphisms (i.e., myelomeningoceles and myeloceles) [385, 409, 418]. This association is consistently present [418], and has been explained pathogenetically by McLone and Knepper on the basis of defective primary neurulation [419]. Consequently, the Chiari II malformation and open spinal dysraphisms are not merely “associated”; rather, they should be regarded as two aspects of a single disease entity [385, 409, 418]. Because the severity of the hindbrain malformation may be extremely variable, a number of patients may have a nearly normal-sized posterior fossa with minimal, or even absent caudal hindbrain displacement. Indeed, subtle, minimal Chiari II features will be present in all individuals with open spinal dysraphisms, and should therefore be actively sought [385, 409, 418]. Although all patients with open spinal dysraphisms harbor a Chiari II malformation, the reverse is not true. Indeed, although greater than 90% of patients with Chiari II malformation have open spinal defects, a minority of cases are discovered in patients with closed spinal dysraphisms. However, these involve exclusively the exceedingly rare myelocystoceles [418] (see Chap. 39). Pathogenesis

The pathogenesis of the Chiari II malformation has attracted the interest of numerous investigators, who conceived a large number of theories to explain its

kaleidoscopic manifestations [385]. Description of all these theories is beyond the scope of this presentation. At present, the “unified theory” proposed in 1989 by McLone and Knepper [419] is widely accepted as the most satisfactory explanation of the diverse manifestations of the Chiari II malformation and open spinal dysraphism. According to this theory, the medial walls of the primitive central canal of the neural tube (“neurocele”) normally appose and occlude the neurocele transiently during primary neurulation. In experimental mice, failure to occlude the neurocele is caused by the same defect involving failure of neurulation with formation of a myelomeningocele, i.e., defective biosynthesis of cell surface glycoproteins. Because the neurocele is patent, CSF flows downwards and leaks freely through the spinal defect into the amniotic cavity. This results in chronic CSF hypotension with collapse of the developing ventricular system. Consequently, the rhombencephalic vesicle (developing fourth ventricle) fails to expand, which causes lack of induction of the perineural mesenchyme of the posterior cranial fossa. Both the cerebellum and brainstem eventually are forced to develop within a smaller than normal posterior fossa. Consequently, the pontine flexure does not develop, and the cerebellum, medulla, and cervicomedullary junction herniate caudally through the foramen magnum. Moreover, the cerebellum also is displaced cephalically through the tentorial incisura. CSF hypotension in the supratentorial brain may impair neuronal migration, callosal development, and formation of the skull, producing various associated malformations of the nervous tissue and osteomeningeal coating. Clinical Features

The most common early symptom of this condition is respiratory stridor, often occurring within 1 or 2 weeks of birth. Stridor usually disappears spontaneously within a few days, or at most 3 months. On occasion, it may be associated with signs of hindbrain dysfunction, such as difficult swallowing, intermittent apnea, aspiration, cessation of breathing, and arm weakness. There appears to be no significant statistical correlation between the degree of caudal displacement of the brainstem and the clinical status [420]. Indeed, symptoms such as breathing and swallowing difficulties are probably related to the disorganization of brainstem nuclei rather than to mechanical distortion [421]. Hydrocephalus presents with signs of raised intracranial pressure, that include bradycardia, opisthotonus, hypertonic upper limbs, hyperreflexia, headache, and seizures. Because hindbrain

Brain Malformations

dysfunction is a leading cause of death, some patients are eligible for surgical decompression, a procedure that involves removing the posterior arch of the upper spine overlying the malformation. Because of the significant risks associated with this procedure, including profuse intraoperative bleeding, infection, and CSF fistula, the indications must be carefully evaluated. Brainstem evoked potentials are a powerful tool in the clinical assessment of these patients and may be helpful to better identify candidates for surgery. Imaging Findings

The Chiari II malformation is characterized by a host of pathological features that generate a complex picture on neuroradiological investigations. Although caudal hindbrain displacement is the principal abnormality, there is a wide array of anomalies that involve the supratentorial compartment, the skull and meninges, and the spine and spinal cord. As with other brain malformations, MRI is the single best neuroimaging modality. However, CT still plays a role in the depiction of bony abnormalities, other than in the follow-up of patients undergoing CSF shunting procedures. Skull and Cervical Spine

As was previously detailed, the principal osseous abnormality is represented by a smaller than normal posterior cranial fossa, resulting from abnormal development of the occipital somites due to insufficient expansion of the rhombencephalic vesicle. Other osteomeningeal abnormalities include lacunar skull, or “lückenschädel,” scalloping of the petrous bones, clivus, and odontoid process, and widening of the foramen magnum and upper cervical canal. These abnormalities represented a mainstay of the radiological diagnosis before the advent of CT and MRI. Lacunar skull, or craniolacunia, is a classic Xray sign of the Chiari II malformation. It is found in 55%–85% of cases [385], and is represented by patchy, irregular thinning of the calvarium, producing multiple defects that involve both the inner and outer tables. In the most severe cases, a thin fibrous layer is the only coverage to the underlying brain. This transient honeycomb appearance of the skull is already present during the 7th gestational month, and is clearly detected in the neonatal period; subsequently, the lacunae tend to diminish in size and progressively disappear after the 6th month of life. Because they result from deranged ossification of the membranous bone, they are unrelated to a condition of raised intracranial pressure [422], and their shape bears no resemblance to that of the underlying convolutions.

Scalloping of the bones encircling the posterior fossa is well depicted by CT. Concavity of the posterior wall of the petrous ridges is caused by the relentless pressure exerted by the cerebellum. Inconsistent in neonates, it may become prominent in older children and shorten the internal auditory canals. The foramen magnum is enlarged in approximately three fourths of cases. The posterior margin of the odontoid process is frequently scalloped, and the upper portion of the cervical canal is widened. A paradoxical widening of the subarachnoid spaces anterior to the cord may result from a combination of mesodermal dysplasia and abnormal CSF pulsation caudal to the plugged foramen magnum [385]. The occipital squama is flat, and may be tilted posteriorly. The posterior arch of the atlas is often incompletely developed; in such case, the intervening gap is bridged by a thick fibroelastic band that constricts the underlying nervous structures. Meningeal abnormalities mainly involve the tentorium, great cerebral falx, and falx cerebelli. The tentorium is verticalized and attaches to the occipital squama close to the foramen magnum, thereby contributing to reduce the overall size of the posterior fossa. The resulting low position of the torcular and transverse sinuses is a major risk factor for bleeding during decompression surgery, and must be carefully assessed by MR angiography. The great cerebral falx is consistently hypoplastic and fenestrated, resulting in multiple interdigitations of the cerebral hemispheres along the midline. The falx cerebelli is also consistently absent [423]. Posterior Cranial Fossa

Because the posterior fossa is smaller than normal, there is a lack of vital space for the nervous structures of the hindbrain, that are necessarily squeezed out of the posterior fossa during their growth. This process results in the pathological hallmark of the Chiari II malformation, i.e., a caudal displacement of the inferior vermis, medulla, cervicomedullary junction, and fourth ventricle into the foramen magnum and upper cervical canal, forming a cascade of herniations that is particularly well depicted on sagittal MR images (Fig. 4.90). As a result, there is crowding of the foramen magnum with chronic constriction exerted by bony and fibrous structures on the herniating brain. This may result in mechanically induced ischemia of the inferior vermis and cervicomedullary junction, revealed by increased signal on T2-weighted MR images (Fig. 4.91). Chronic mechanical compression may eventually result in a “vanishing cerebellum” [424], a condition that must be differentiated from

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b

a

Fig. 4.90a–c. Chiari II malformation in a newborn before shunting. a Sagittal T1-weighted image; b Axial T2-weighted image; c Coronal T2-weighted image. The membranous posterior fossa is small (black arrowheads, b, c). Midsagittal image shows caudal ectopia of the vermis, the so-called cerebellar peg (open white arrow, a); the fourth ventricle is reduced to a thin fissure (black arrowhead, a). On axial planes, the cerebellum has a hearts shape and tends to engulf the brainstem (thin arrows, b). Additional features include tectal beaking (white arrowhead, a), thickening of the interthalamic mass (thin white arrow, a), and dilatation of the suprapineal recess of the third ventricle (asterisk, a). Stenogyria is seen in the occipital region (open black arrows, b). Severe hydrocephalus is present (a, c)

c

Fig. 4.91a,b. Chiari II malformation in a newborn. a Sagittal T2-weighted image; b Axial T2-weighted image. Sagittal image shows similar features to those described in the previous case (compare with Fig. 4.90). Abnormal hyperintensity of the cerebellar peg is related to ischemic phenomena due to mechanic compression (arrow, a). The fourth ventricle is thin and flattened, and tectal beaking is more evident than in the previous case. Axial image shows another typical feature of Chiari II malformation, i.e., interdigitation of the mesial surface of the hemispheres due to focal fenestration of the falx, secondary to mesodermal dysplasia (arrows, a)

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primary cerebellar hypoplasia associated with Chiari II (see below, Chiari IV malformation). Caudal vermian herniation. The herniating vermian lobules are usually represented by the nodulus, uvula, and pyramid. They extend caudally, stretching posterior to the medulla and spinal cord for a variable length, forming the so-called cerebellar peg. In most instances, the peg reaches the C2–3 level. Rarely, it extends further caudally to the lower cervical or upper thoracic vertebrae. Exceptional cases of spinal cerebellar ectopia have been described in patients with Chiari II malformation [425], and also as isolated cases [426]. It is important to recognize that the herniating midline cerebellar structure is represented by the vermis. This marks an important difference from the Chiari type I malformation, in which the cerebellar tonsils, and not the vermis, herniate into the foramen magnum. In Chiari II malformation, the cerebellar tonsils are located lateral to the medulla and may abut, but usually do not cross, the foramen magnum. Brainstem herniation. Downward displacement of the brainstem results in a low position of the pons and pontomedullary junction, which approaches the foramen magnum. The pons is also reduced in its anteroposterior diameter. The medulla herniates caudally through the foramen magnum, and so does the bulbomedullary junction. Also the cervical spinal cord tends to be displaced caudally, but the extent of such displacement is limited by the dentate ligaments, which attach to the lateral surface of the spinal cord and hold it in place [427]. As a consequence, the medulla buckles posterior to the spinal cord, forming the cervico-medullary kink. The pivot of the kink is represented by the inferior portion of the gracile and cuneate tubercles. The cervico-medullary kink

a

b

is located anterior to the cerebellar peg, and reaches further caudally than the peg in the vast majority of cases. Fourth ventricle. The fourth ventricle is usually elongated and stretched vertically, and often its inferior portion herniates, together with the choroid plexus, into the foramen magnum. Sometimes, a localized dilatation is found at its bottom end. The size of the fourth ventricle varies depending on the severity of the malformation, from slit-like or completely effaced in severe forms to normal or near-normal in minimal forms. However, one should note that an isolated fourth ventricle may look deceivingly normal in Chiari II patients. Indeed, such condition should suggest the search for shunt malfunction or other causes of fourth ventricular entrapment. Classification of the hindbrain deformity. The cervicomedullary deformities were categorized by Emery and MacKenzie in 1973, and further revised by Wolpert et al. in 1988 [420] (Fig. 4.92). In the type 1 deformity, the fourth ventricle and medulla do not descend through the foramen magnum, and the only deformity is a cerebellar peg through the foramen magnum. In type 2, the fourth ventricle descends vertically through the foramen magnum in front of the cerebellar peg. In type 3, the medulla is buckled below the spinal cord, forming the cervicomedullary kink behind the cord itself. This type is further categorized depending on whether the fourth ventricle is collapsed (3a) or dilated (3b). Lateral and cranial cerebellar herniation. The cerebellum is not only squeezed inferiorly but also extends laterally, thereby effacing the cerebellopontine angle cisterns. In some cases, the brainstem is completely

c

d

Fig. 4.92a–d. Chiari II malformation: classification of hindbrain deformity. Type 1 (a): The fourth ventricle and medulla do not descend through the foramen magnum, with the only deformity being an inferior vermian peg through the foramen magnum. Type 2 (b): The fourth ventricle descends vertically through the foramen magnum in front of the vermian peg; cervico-medullary kinking may be present. Type 3a (c): Cervico-medullary kinking is associated with a collapsed fourth ventricle. Type 3b (d): Cervico-medullary kinking is associated with a dilated fourth ventricle

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engulfed by the cerebellum, and a stripe of cerebellar tissue is visible in front of the brainstem on sagittal MR images (Fig. 4.93). Axial images will show the basilar trunk to be completely engulfed between the brainstem posteriorly and the cerebellum anterolaterally. As it wraps around the brainstem, the cerebellum stretches and displaces the cisternal segment of various cranial nerves, and especially the 7th–8th cranial nerve complex, which may result in hypoacusia and vestibular dysfunction. Often, the superior vermis is also displaced cranially through a widened tentorial incisura, resulting in the so-called towering cerebellum in coronal MR images [385]. Such feature is seen more often in children with long-standing ventriculoperitoneal shunts (Fig. 4.94). In fact, supratentorial ventricular dilatation usually prevents significant superior cerebellar herniation. After CSF diversion, the herniating vermis displaces laterally the temporal and occipital lobes, thereby enlarging both the interhemispheric fissure and supravermian carrefour [385]. As it squeezes through the tentorial hiatus, the vermis is distorted, and the orientation of the sulci may become abnormally sagittal. Supratentorial Abnormalities

In addition to their hindbrain deformity, patients with Chiari II malformation typically display various abnormalities of the supratentorial brain.

Tectal beak. The most consistent of these is represented by an abnormality of the quadrigeminal plate, best detected on sagittal images, which results from fusion and hypoplasia of the superior quadrigeminal tubercles and stretching and distortion of the inferior quadrigeminal tubercles. As a result, the quadrigeminal plate stretches posteroinferiorly, forming an elongation designated the tectal beak (Figs. 4.90, 4.94) [427]. The size of the beak is variable depending on the severity of the malformation. In case of extreme crowding, the beak lodges between the two cerebellar hemispheres, whereas only a thickening of the inferior quadrigeminal tubercles will be visible in minor cases [385]. Stenogyria. The gyral pattern is often abnormal, displaying multiple small gyri with normal-thickness, histologically normal cortex. This feature, designated stenogyria (Fig. 4.94) [428], is most prominent over the medial surface of the posterior parietal and occipital lobes, and is therefore best detected on sagittal MR images. Care should be taken not to mistake this abnormal gyral pattern with cortical malformations, such as polymicrogyria. Indeed, malformations of the cerebral cortex have been an exceptional finding in our experience, and have been mainly represented by isolated subependymal heterotopic nodules.

b

a Fig. 4.93a,b. Chiari II malformation before shunting. a Sagittal T1-weighted image; b Axial T2-weighted image. Sagittal image shows isointense tissue located anteriorly to the brainstem (H, a). As shown on axial images, this tissue is the anterior portion of one cerebellar hemisphere that engulfs the brainstem (arrows, b). Midsagittal image also shows the so-called “accessory lobe” above the vermis (asterisk, a), corresponding to the medial portion of the occipital lobes. All these features are related to crowding and stretching of nervous structures

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b Fig. 4.94a,b. Chiari II malformation after ventriculoperitoneal shunting. a Coronal T1-weighted image. b Sagittal T1-weighted image. The cerebellum tends to extend rostrally through an enlarged tentorial hiatus and is located between the mesial surface of the two hemispheres (“towering cerebellum”) (arrows, a). Sagittal image shows dysgenesis of the corpus callosum (arrowheads, b), diffuse parieto-occipital stenogyria (asterisks, b), and marked tectal beaking (arrow, b). The caudal portion of the fourth ventricle is dilated (D, b) and trapped between the cerebellar peg and the caudalized medulla

Accessory lobe. The apposed medial surfaces of the temporal lobes often penetrate between the vermis and the straight sinus to create an apparently independent cerebral lobe, designated the accessory lobe [385], which is often visible on midsagittal scans (Fig. 4.93).

the third ventricle (Figs. 4.90, 4.93). The latter feature often persists after CSF shunting (Fig. 4.94), and is found in the vast majority of Chiari II patients. Dilatation of the lateral ventricles is often asymmetrical and prevails posteriorly.

Callosal dysgenesis. The corpus callosum is often abnormal, either because of true dysgenesis or secondary to mechanical distortion and hydrocephalus. Callosal distortion is often remarkable after CSF shunting and can result in bizarre configurations (Fig. 4.94), such as a brace shape [385].

As was previously mentioned, there is a spectrum of variable severity in the neuroimaging manifestations of Chiari II malformations, so that individual cases may look significantly different from one another. The principal determining factor is the size of the posterior fossa, which in turn is determined by the degree of expansion of the rhombencephalic vesicle during early gestation. In less severe cases, the size of the posterior fossa may look normal, no cerebellar herniation is present, and the fourth ventricle has a normal shape. In such condition, superficial observation could dismiss the picture as normal. Indeed, subtle Chiari II signs are invariably present; these typically include thickening of the inferior quadrigeminal tubercles, dilated suprapineal recess, presence of an accessory lobe, and low position of the pontomedullary junction (Fig. 4.95) [385].

Hydrocephalus. Supratentorial hydrocephalus is a consistent finding in neonates with Chiari II malformation. It can be present at birth (Fig. 4.90), but usually develops within 72 hours of myelomeningocele surgery. Therefore, CSF diversion is required in all these patients. Shunt malfunctions, cord tethering, trapped fourth ventricle, and hydrosyringomyelia are frequent causes of relapsing ventricular dilatation. Because these children often undergo CT scanning for evaluating ventricular size, care should be employed to limit X-ray exposure to the minimum. Apart from hydrocephalus, the shape of the third and lateral ventricles often is abnormal. Sagittal MR images typically show verticalization of the lamina terminalis and dilatation of the suprapineal recess of

Minimal Features

Spinal Cord

The typical coexistence with open spinal dysraphisms has been described earlier. These malformations are described in Chap. 39. In operated patients, hydro-

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a Fig. 4.95. Chiari II malformation: minimal form in a child with prior myelomeningocele surgery. Sagittal T1-weighted image. At first glance, no malformative features seem to be present. Posterior fossa size is grossly normal, and the cerebellum is completely located intracranially with no vermian herniation. The fourth ventricle is perhaps slightly larger than normal. However, closer inspection reveals a number of subtle Chiari II features, including dilatation of the suprapineal recess of the third ventricle (asterisk), hypertrophy of the inferior colliculi (thin arrow), and accessory lobe (open arrow). Moreover, there is dysgenesis of the corpus callosum (arrowheads)

syringomyelia often develops as a combined result of cord tethering and impacted foramen magnum. Elongation of these cavities may vary from localized to holocord. Scoliosis often develops as a result of cord tethering and may be aggravated by hydrosyringomyelia. Spinal cord imaging of treated myelomeningoceles often is very difficult due to the extreme spinal deformity, and may require 3D imaging with curvilinear reconstructions.

4.5.3 Chiari III Malformation The original paper by Chiari [381] included the description of a case of cervical spina bifida combined with multiple hindbrain anomalies. Since then, the definition of the Chiari III malformation has been expanded to include patients with herniation of the hindbrain in a low occipital and/or high cervical cephalocele in combination with pathological and imaging features of Chiari II malformation (Fig. 4.96) [20]. This condition has a high early mortality rate, and causes severe neurological deficits in survivors [20, 409].

b Fig. 4.96a,b. Chiari III malformation. a Sagittal T1-weighted image; b Sagittal T2-weighted image. There is an inferior occipital meningoencephalocele, containing both CSF (M, b) and cerebellar tissue (arrow, a, b). The latter is slightly T2 hyperintense, possibly due to either dysplastic or ischemic changes. There is concurrent dysgenesis of the corpus callosum (arrowheads, a), hypertrophy of the quadrigeminal plate (T, b), and hypoplasia of the pons (P, b)

The relative paucity of reported cases, with the largest series so far being that of Castillo et al. [20], which comprises 9 cases, still leaves some uncertainty as to the distinction from isolated occipital or occipitocervical cephaloceles and cervical myelocystoceles or meningoceles. In our opinion, the following conditions must be met in order to classify a posterior cephalocele under the Chiari III heading:

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Location: the cephalocele consistently involves the occipital bone below the inion, with possible extension into the high cervical (C1–3) spine; purely cervical cephaloceles are exceptional [429], and as such, they must contain cerebellar tissue in order to match the Chiari III definition. Contents: the cephalocele must contain at least a part of the cerebellum, but may also contain the occipital lobe(s) and the medulla and pons. If not herniated, the

brainstem is usually at least distorted and stretched posteriorly. The fourth and lateral ventricles and basilar cisterns may also herniate into the cephalocele, and may be disproportionately dilated compared to the intracranial CSF spaces. Associated Chiari II features: the posterior fossa is disproportionately small, with at least one of the following associated elements: caudal displacement of the brainstem; tectal beak; lateral overgrowth of

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b Fig. 4.97a–d. Chiari IV malformation in two different patients, both with prior history of myelomeningocele repair. Case #1: a Sagittal T1-weighted image; b Axial T2-weighted image. There is moderate cerebellar hypoplasia without crowding of the posterior fossa. The brainstem is caudalized (M, midbrain; P, pons), with the whole midbrain lying below an axial plane drawn perpendicularly to the dorsum sellae. Case #2: a Sagittal T1-weighted image; b Axial T2weighted image. There is marked cerebellar hypoplasia, with only a rudiment of the cerebellum visible (C) lateral and posterior to the midbrain (M). The pons (P) is markedly hypoplastic. Also in this case there is no significant crowding of the posterior fossa, although the latter is very small. The brainstem is significantly displaced caudally, as in the previous case

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the cerebellum into the cerebellopontine angle cisterns; enlarged interthalamic mass; dilated suprapineal third ventricular recess; and corpus callosum dysgenesis. Hydrocephalus may caused by associated aqueductal stenosis. As such, the Chiari III malformation may be viewed as a severe variant of occipital or occipitocervical cephalocele, in which the large extent of the extracranial herniation prevents adequate distension of the primitive rhombencephalic vesicle with subsequent development of a small posterior fossa. As with other cephaloceles, the herniated nervous tissues are believed to be nonfunctioning. Indeed, pathological examinations of resected specimens show areas of pressure necrosis, heterotopias, gliosis, meningeal inflammation, and fibrosis [20]. One should also be aware of the fact that venous drainage pathways are often aberrant, and major venous structures are often contained within the herniated sac. Therefore, MR angiography is a very useful tool to demonstrate venous anatomy prior to surgery, in order to avoid potentially life-threatening complications.

4.5.4 Chiari IV Malformation In his 1896 paper, Chiari described a fourth type of hindbrain anomaly, corresponding to severe cerebellar hypoplasia [430]. However, the term “Chiari IV malformation” was discarded by subsequent investigators. In 1996, Tortori-Donati [385] reintroduced the term to designate the association of severe cerebellar hypoplasia with Chiari II signs in patients with myelomeningocele (Fig. 4.97). Such association appears to represent a well-defined, albeit small, patient subgroup within the Chiari II malformation complex. Pathological and imaging findings of this condition include absent or severely hypoplastic cerebellum, small brainstem, and large posterior fossa CSF spaces, as opposed to caudal cerebellar displacement and collapsed posterior fossa CSF spaces seen in typical Chiari II patients [385]. These features make it questionable whether the embryogenetic theory of the Chiari II malformation can be used to explain also the occurrence of a Chiari IV malformation. One should be aware of the fact that extreme crowding of nervous structures into a small posterior fossa may result in pressure necrosis of the cerebellum, a condition that has been termed the “vanishing cerebellum” [424]. It is difficult to determine whether this clastic theory is fully tenable. Indeed, the cerebellar peg may deteriorate from long-standing compression at the foramen magnum; however,

it often is difficult to conclusively determine whether patients born with a small cerebellum have primary hypoplasia of congenital atrophy. We tend to favor a condition of primary cerebellar hypoplasia because of the rudimentary shape of the cerebellar remnant with little appreciation of intervening sulci.

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I “malformations” – an acquired disorder? J Neurosurg 1981; 55:604–609. 394. Sathi S, Stieg PE. “Acquired” Chiari I malformation after multiple lumbar punctures: case report. Neurosurgery 1993; 32:306–309. 395. Chumas PD, Armstrong DC, Drake JM, Kulkarni AV, Hoffman HJ, Humphreys RP, Rutka JT, Hendrick EB. Tonsillar herniation: the rule rather than the exception after lumboperitoneal shunting in the pediatric population. J Neurosurg 1993; 78:568–573 396. Lazareff JA, Kelly J, Saito M. Herniation of cerebellar tonsils following supratentorial shunt placement. Childs Nerv Syst 1998; 14:394–397. 397. Atkinson JL, Weinshenker BG, Miller GM, Piepgras DG, Mokri B. Acquired Chiari I malformation secondary to spontaneous spinal cerebrospinal fluid leakage and chronic intracranial hypotension syndrome in seven cases. J Neurosurg 1998; 88:237–242. 398. Lee M, Rezai AR, Wisoff JH. Acquired Chiari-I malformation and hydromyelia secondary to a giant craniopharyngioma. Pediatr Neurosurg 1995; 22:251–254. 399. Sheehan JM, Jane JA Sr. Resolution of tonsillar herniation and syringomyelia after supratentorial tumor resection: case report and review of the literature. Neurosurgery 2000; 47:233–235. 400. Payner TD, Prenger E, Berger TS, Crone KR. Acquired Chiari malformations: incidence, diagnosis, and management. Neurosurgery 1994; 34:429–434. 401. Meadows J, Kraut M, Guarnieri M, Haroun RI, Carson BS. Asymptomatic Chiari Type I malformations identified on magnetic resonance imaging. J Neurosurg 2000; 92:920– 926. 402. Wu YW, Chin CT, Chan KM, Barkovich AJ, Ferriero DM. Pediatric Chiari I malformations. Do clinical and radiologic features correlate? Neurology 1999; 53:1271–1276. 403. Bunc G, Vorsic M. Presentation of a previously asymptomatic Chiari I malformation by a flexion injury to the neck. J Neurotrauma 2001; 18:645–648. 404. Leong WK, Kermode AG. Acute deterioration in Chiari type 1 malformation after chiropractic cervical manipulation. J Neurol Neurosurg Psychiatry 2001; 70:816–817. 405. Ball WS Jr, Crone KR. Chiari I malformation: from Dr Chiari to MR imaging. Radiology 1995; 195:602–604. 406. Christophe C, Dan B. magnetic resonance imaging cranial and cerebral dimensions: is there a relationship with Chiari I malformation? A preliminary report in children. Europ J Paediatr Neurol 1999; 3:15–24. 407. Aboulezz AO, Sartor K, Geyer CA, Gado MH. Position of cerebellar tonsils in the normal population and in patients with Chiari malformation: a quantitative approach with MR imaging. J Comput Assist Tomogr 1985; 9:1033–1036. 408. Mikulis DJ, Diaz O, Egglin TK, Sanchez R. Variance of the position of the cerebellar tonsils with age: preliminary report. Radiology 1992; 183:725–728. 409. Cama A, Tortori-Donati P, Piatelli GL, Fondelli MP, Andreussi L. Chiari complex in children: neuroradiological diagnosis, neurosurgical treatment and proposal of a new classification (312 cases). Eur J Pediatr Surg 1995; 5:35–38. 410. Du Boulay GH, Shah S, Currie JC, logue V. The macheanism of hydromyelia in Chiari type I malformation. Br J Radiol 1974; 47:579–587. 411. Bhadelia RA, Bogdan AR, Wolpert SM, Lev S, Appignani BA, Heilman CB. Cerebrospinal fluid flow waveforms: analysis in patients with Chiari I malformation by means of gated

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Magnetic Resonance Imaging of the Brain in Preterm Infants

5

Magnetic Resonance Imaging of the Brain in Preterm Infants Luca A. Ramenghi, Fabio Mosca, Serena Counsell, and Mary A. Rutherford

CONTENTS 5.1 Normal Appearances of the Developing Brain 199 5.1.1 Introduction 199 5.1.2 Practical Issues 199 5.1.2.1 Magnet Systems 199 5.1.2.2 Coils 199 5.1.2.3 Transport 200 5.1.2.4 Monitoring Equipment 200 5.1.2.5 Immobilization 200 5.1.2.6 Temperature Maintenance 200 5.1.2.7 Sedation 200 5.1.2.8 Monitoring 200 5.1.2.9 Safety Issues 200 5.1.2.10 Pulse Sequences and Scanning Parameters 201 5.1.3 Normal Appearances of the Developing Brain 201 5.1.3.1 Cortical Folding 201 5.1.3.2 Ventricular System and Extracerebral Space 203 5.1.3.3 Germinal Matrix 204 5.1.3.4 White Matter and Myelination 204 5.1.3.5 Myelination 206 5.1.3.6 Basal Ganglia and Thalami 207 5.1.3.7 Preterm Brain at Term 208 5.1.4 Summary 209 5.2 5.2.1 5.2.2 5.2.2.1 5.2.2.2 5.2.2.3 5.2.2.4 5.2.3 5.2.3.1 5.2.3.2 5.2.3.3 5.2.3.4 5.2.3.5 5.2.3.6 5.2.4 5.2.5 5.2.6 5.2.7 5.2.8 5.2.9 5.2.10 5.3

Pathology of the Preterm Baby 210 The Brain of Preterm Babies 210 Periventricular Leukomalacia (PVL) 210 Introduction 210 Pathogenesis 210 Neuroimaging of PVL 211 Assessment of Prognosis 217 Germinal Matrix Hemorrhage-Intraventricular Hemorrhage (GMH-IVH) 217 Introduction 217 Pathogenesis 217 Timing of GMH-IVH 219 Complications of GMH-IVH 219 Neuroimaging of GMH-IVH 221 Assessment of Prognosis 222 Choroid Plexus Hemorrhage 222 Cerebellar Hemorrhage 223 Congenital Periventricular White Matter Cavitations 223 Infections 226 Multicystic Encephalomalacia and Asphyxia 226 Venous Thrombosis 226 Infarctions 230 Concluding Remarks and Application of Quantitative MRI 230 References

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5.1 Normal Appearances of the Developing Brain 5.1.1 Introduction Magnetic resonance imaging (MRI) allows the developing brain to be studied in superb detail either in the fetus or in the infant born preterm. Serial imaging provides valuable insights into both normal maturation and the response of the developing brain to a variety of insults.

5.1.2 Practical Issues 5.1.2.1 Magnet Systems

The integration of an MR scanner into a neonatal intensive care unit (NICU) provides a unique opportunity to image preterm infants and infants in the acute phase of an insult, without compromising their intensive care [1, 2]. Images of normal babies in the first part of this chapter have been obtained on a 1 Tesla (Oxford Magnet Technology/Picker International) neonatal MRI system situated in the neonatal unit at the Hammersmith Hospital in London (UK). Preterm babies with brain lesions shown in the second part of the Chapter have been studied with a 1.5 Tesla Philips MR unit situated at the Leeds General Infirmary in Leeds (UK), and with a 1.5 Tesla (Horizon LX, EchoSpeed/General Electrics) situated at the “Istituti Clinici di Perfezionamento,” Buzzi Hospital, Milan (Italy). 5.1.2.2 Coils

A specially designed transmit/receive quadrature birdcage coil (32 cm × 23 cm) was used for all examinations performed at the Hammersmith Hospital. This coil allows infants to be studied up to a maxi-

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mum weight of about 5 kg. A receive-only quadrature coil commonly used for the adult head and knee was utilized at Leeds and Milan hospitals. 5.1.2.3 Transport

We have used a specially designed nonmagnetic transport trolley to minimize handling of the neonate while being able to continue life monitoring, and ventilation where required, during the move from incubator to the imaging system [1–3]. 5.1.2.4 Monitoring Equipment

As monitoring equipment must be MR compatible, all noncompatible monitoring used in the NICU is switched prior to entering the scanning room. Oxygen lines are attached to the piped supply prior to entry into the scanning room. Infusion pumps are attached to a wall-mounted rail within the scanning room but beyond the 5 Gauss line. Ventilated infants are imaged using an MR compatible ventilator (babyPAC neonatal, pneuPac limited, UK) or using a conventional ventilator sited in an RF cupboard or secured outside the 5 Gauss line. 5.1.2.5 Immobilization

Effective immobilization of the neonate is vital in order to obtain high quality MR images. Immobilization may be achieved with a vacuum-pack or Olympic bag, containing small polystyrene balls. The air is evacuated from these bags with suction to ensure a close fit around the baby’s head. Ventilated neonates need to be imaged supine to accommodate the endoor nasotracheal tube and ventilator tubing. Neonates who are not ventilated were imaged on their side whenever possible. 5.1.2.6 Temperature Maintenance

In order to maintain the infant’s temperature, they are swaddled in blankets and the temperature of the scanning room is set at 27° C, the same as the temperature on the neonatal unit. Additional heating for extremely preterm neonates can be provided with bubble wrap, woolen hats, and “gel bags,” which retain their heat once warmed in a microwave oven. The temperature of the babies imaged at Leeds and Milan was maintained with similar protections,

although the scanning room temperature was set at 21°–23° C. 5.1.2.7 Sedation

Sedation with oral chloral hydrate (20–30mg/kg) is occasionally necessary, but the majority of preterm infants can be successfully imaged during natural sleep following a feed or while sedated for ventilation [4, 5]. 5.1.2.8 Monitoring

Oxygen saturation, heart rate, temperature and, where required, mean arterial blood pressure are monitored throughout the examination. We use a Hewlett Packard Merlin life support system situated in a radiofrequency-shielded cupboard within the scanning room. Oxygen saturation is measured by pulse oximetry (Nellcor oxiband or oxisensor D20 transducer with a Nellcor pulse oximeter, Nellcor Incorporated, Pleasanton, CA, USA), and heart rate is measured using chest ECG leads. ECG leads and electrodes must be MR compatible; we use Blue sensor (Medicotest, Olstykke, Denmark) ECG electrodes and ECG leads with current limiting resistors (NDM Division, American Hospital Supply Corporation, Ohio, USA). Radiofrequency fields can cause currents in conduction loops which may cause burns. Therefore, care must be taken to ensure that ECG leads do not form conductive loops and skin contact is kept to a minimum. The electrodes should be placed close together, but not touching, to minimize ECG interference by the magnetic field. ECG leads should be plaited in order to minimize loops across which potential differences may occur. Temperature may be measured by placing an MR-compatible temperature probe in the axilla. An experienced pediatrician remains in the scanning room, observing the monitors and the infant during scanning. 5.1.2.9 Safety Issues

The number of people in the scanning room is kept to a minimum. However, two neonatologists and a radiographer are essential to prepare a ventilated neonate. A metal check form, including specific neonatal items such as Serle arterial lines with terminal electrodes, electronic name tags, and metal poppers on clothes, is completed by the pediatrician or nurse

Magnetic Resonance Imaging of the Brain in Preterm Infants

caring for the baby and checked by the radiographer before transporting the baby to the magnet. Acoustic noise exposure is reduced by several measures incorporated into the design of the system, including lagging and gradient cable immobilization. The Olympic bag used to immobilize the infant’s head reduces the infant’s exposure to acoustic noise levels still further. In addition, individual ear plugs are made using dental putty and molded into the external ear. These are then covered with neonatal ear muffs (Natus Minimuffs, Natus Medical, Inc., San Carlos, CA, USA). 5.1.2.10 Pulse Sequences and Scanning Parameters

The neonatal brain has a higher water content (92%–95%) than the adult brain (82%–85%), and so T1 and T2 values are greater. These values decrease with increasing gestation [6, 7], and adult values are reached in early childhood [8]. This means that echo times (TE), repetition times (TR), and inversion times (TI) have to be increased. We have found the T2weighted FSE to be the optimal sequence for demonstrating myelination in the premature brain. The IRFSE sequence provides excellent gray/white matter contrast, and is also useful for assessing myelination [9]. The sequence parameters used in London are as follows: for the T1-weighted conventional spin-echo sequences, the parameters are 600/20/2 (TR/TE/excitations); a 4-mm section thickness, with nine sections obtained; and a 192 × 192 matrix. For the T2-weighted fast spin-echo (FSE) sequences, the parameters are 3500/208/2, 4; a 4-mm section thickness, with nine sections obtained; an echo train length of 16; interecho spacing of 16; and a 256 × 256 matrix. For the inversion recovery (IR) FSE sequences, the parameters are 3500/32/4; an inversion time of 950; a section thickness of 5 mm, with six sections obtained; an echo train length of 16; interecho spacing of 16; and a 256 × 256 matrix. The sequence parameters used in Leeds and Milan are as follows: for the T1-weighted spin-echo images 800/13 (TR/TE); 180-mm field of view (FOV); 4-mm section thickness with a 0.4 mm gap; and a scan time of 3 min 50 sec. The parameters for T2-weighted fast spin-echo images were 6000/200; echo train length of 13; FOV of 180 mm; section thickness of 3 mm with no gap; and a scan time of 5 min. We have been unable to use diffusion-weighted sequences on the MR system used in London, but we did use diffusion-weighted images in preterm infants imaged at Leeds [10] and Milan, similarly to those obtained in other small studies [11, 12].

5.1.3 Normal Appearances of the Developing Brain The images showed in this part of the Chapter were obtained from a cohort of over 200 preterm infants born at a gestation of less than 30 weeks at the Hammersmith Hospital. The gestational age (GA) for the infants was calculated from the date of the last menstrual period and confirmed with data from early antenatal ultrasound scans. 5.1.3.1 Cortical Folding

The most obvious change in the preterm brain between 24 weeks and term is the increase in cortical folding [13]. Cortical development occurs from approximately 8 weeks, initially with replication of neurons and glial cells in the germinal matrix. The cortical layers are formed by neuronal and glial cell migration from the germinal matrix. A layer adjacent to the ventricle, called the subventricular layer, is probably mainly responsible for later glial cell proliferation and migration [14]. In the cerebral hemispheres the layers form from the inside out, so that layer 6, which lies medially, is laid down first. The mature cortex consists of six layers. Neuronal migration to the cerebral cortex is completed by 20–24 weeks of gestation in the human brain. Between 29 weeks’ gestation and term cortical gray matter volume increases from approximately 60 ml to approximately 160 ml [12]. The subsequent increase in cortical gray matter volume is secondary to glial cell migration, neuronal differentiation, and organizational changes. During early gestation, the brain is smooth or “lissencephalic” in appearance, but as growth proceeds the typical convoluted pattern develops allowing a considerable increase in the surface area of the brain. Primary sulci begin as a shallow groove with widely separated side walls and straight ends (Figs. 5.1, 5.2). The groove then becomes deeper, and the side walls become progressively steeper, approximating and eventually meeting each other. These secondary sulci may show V-shaped or bifid ends. With continued maturation, the gyri and sulci become complex and side branches develop as seen in the adult brain. Each of the gyri and matching sulci are named according to their site within the brain. Postnatal MRI can be performed as early as 23 weeks’ gestation, and at this stage a rim of cortex is demonstrated as high signal intensity on T1-weighted images and low signal intensity on T2-weighted images when compared to the underlying white matter. There may be some variation in cortical maturity in infants born at the same gestation (Fig. 5.2).

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Fig. 5.1a–c. Normal appearances at 25 weeks’ gestation. a–c Axial T2-weighted images. The brain is smooth with only minimal cortical folding. Rudimentary sulci are demonstrated: calcarine fissure (thick arrow, a); sylvian fissure (thick arrow, b); and central sulcus (thick arrow, c). Notice the optic radiation (thin arrow, a) and the prominent posterior horns of the lateral ventricles. The low signal intensity corpus callosum can also be clearly seen

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Fig. 5.2a–g. Cortical folding from 25 weeks’ gestation to term equivalent age. a–g Axial T2-weighted images at the level of the centrum semiovale. a 25 weeks’ gestation; b 25 weeks’ gestation, showing some rudimentary central sulcation in this infant; c 26 weeks’ gestation; d 30 weeks’ gestation; e 32 weeks’ gestation; f 34 weeks’ gestation; and g term equivalent age

Magnetic Resonance Imaging of the Brain in Preterm Infants

Visual assessment of MR images is sufficient for identifying major abnormalities or discrepancies in maturation. Visual analysis of images of termequivalent preterm infants is not sufficient to detect a milder delay or abnormality in cortical folding. There are several visual scores that have been used [2, 15], but computer quantification techniques are necessary to identify more subtle changes in folding [16]. In order to study cortical development in more detail we have developed a computerized method for quantifying cortical folding (Fig. 5.3) [17]. We use T2-weighted fast spin echo images, as these give optimum contrast between the cortex and underlying white matter. The process involves drawing a cortical contour as a template for each slice of the brain. The program then measures the length and curvature of this cortical contour. A curvature code is produced. The cortical density is obtained and the product of this and the curvature code gives a cortical convolution index. Using this program we have shown an exponential increase in the whole cortical convolution index (measuring all slices through the brain but excluding the cerebellum) from 24 weeks until term. At term, equivalent age preterm infants show less cortical folding than infants born at term (Fig. 5.2) [17]. While this effect seems to relate to the degree of prematurity, the presence of chronic lung disease and exposure to steroids are also important factors [18, 19]. A reduction in cortical gray matter volume in preterms at term equivalent age and in relationship

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to steroid treatment for chronic lung disease has also been demonstrated [12, 20]. The differences in cortical development compared with those infants born at term may be associated with the increase in neurocognitive and neurobehavioral disorders seen in expreterm children [21–23]. 5.1.3.2 Ventricular System and Extracerebral Space

Very preterm infants 5 mm) is a useful marker, as all these babies have cerebral palsy compared to those with smaller cysts. Location is another predictor, with posterior lesions having the worse prognosis. In addition, a symmetrical appearance also seems to influence the outcome, as parieto-occipital cavitations were related to cerebral palsy in all cases compared to only 60% of those having asymmetrical lesions [43]. Visual Impairment

Cerebral visual impairment is regarded as visual impairment due to a disturbance in the posterior pathways of the optic radiation and/or the primary visual cortex. Major contributions have been derived from studies by Cioni et al. [79] and Lanzi et al. [80], who discovered that almost half the babies with severe PVL had reduced visual field and abnormal ocular motility, whereby highlighting the importance of impairments in the optic radiation more than in the visual cortex. Cognitive Outcome

A major contribution in the understanding of the development of cognitive problems comes from Marin-Padilla [81, 82], who first described in autopsy studies the events that follow white matter damage of PVL. The overlying cortical layer tends to remain intact thanks to a different blood supply but is functionally deprived of incoming inputs (corticopetal fibers), and is also unable to make connections due to corticofugal fibers destruction. In other words, there is a functional isolation of this cortex, with a potential functional short-circuitry of corticofugal fibers as they try to repair by reattaching in the proximity of the cortex. This short-circuitry should correlate not only with cognitive impairments, but also with the development of epileptic foci.

In addition, Inder’s studies, using a quantitative three dimensional volume MRI technique, have shown reduction of cortical gray matter of those preterm babies with prior white matter lesions [78].

5.2.3 Germinal Matrix Hemorrhage-Intraventricular Hemorrhage (GMH-IVH) 5.2.3.1 Introduction

Intracerebral hemorrhage is more common in the neonatal period than at any other time of life. A progressive reduction in the number of different kinds of intracranial hemorrhages has been associated with a relative increase in cases of GMH-IVH, especially in premature babies [40]. GMH-IVH is now the most frequent and important cause of intracranial hemorrhage in neonates, mainly due to the fact that neonatal intensive medicine has changed life expectations of those premature babies who are most at risk of developing GMH-IVH [83]. A progressive reduction in the number of babies developing severe intraventricular hemorrhage has been noticed over the last few years in neonatal intensive care medicine, while the number of preterm babies showing ischemic lesions has remained pretty constant. 5.2.3.2 Pathogenesis

Schwartz [84] and Rydberg [85] were the first to recognize that intraventricular hemorrhage in preterm infants derives from the large terminal vein in the subependymal germinal matrix. The germinal matrix (Fig. 5.5) is a transient structure that, during fetal life, is present in all the subependymal areas and is the site of vigorous neuroblast mitotic activity until the 18th–20th week of life. After this time, despite the persistence of glioblastic mitotic activity, the relative size of the germinal matrix progressively decreases (Fig. 5.6) from a width of 2.5 mm at 23–24 weeks to 1.4 mm at 32 weeks, and it tends to disappear in a caudo-cranial direction, first around the posterior horns and finally, sometimes near term of gestation, around the anterior horns of the lateral ventricles. In general, germinal matrix tissue is most abundant in the caudate nucleus immediately adjacent to the lateral ventricles, where it is still prominent at 28–32 weeks of gestation, although matrix can also be seen around the frontal horns until the term of gestation [44, 86]. The site of GMH depends on the

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maturity of the infant. Leech and Kohnen [87] found that 90% of subependymal hemorrhage occurs over the head of the caudate nucleus, adjacent to the foramen of Monro, and only 5% over the body of the caudate nucleus or in the occipital germinal matrix (Fig. 5.23). The facts that the germinal matrix surrounding the frontal horns does not originate bleeding and that the preferential site of GMH is the lateral portion of the caudate nucleus have highlighted the potential role of anatomical predisposing factors. Many authors have linked the location of hemorrhage to the course of the veins that drain this region of the brain, particularly the terminal vein (with

a

major blood flow changing direction sharply at that junction in a peculiar U-turn), in line with the view that GMH is essentially of venous origin, a hypothesis which unifies the consensus of most researchers [88–90]. Other authors believe that there is multifocality of GMH, although the bleeding in the caudothalamic zone accounts for most intraventricular extensions of hemorrhage (Figs. 5.24, 5.25). This multifocality of GMH appears to be in contrast with the above-mentioned hypothesis of local anatomical predisposition [83]. In accordance with both theories, to reinforce the idea of the venous origin of GMH there is evidence of blood tunneling along the perivenous space of the germinal matrix veins, leading to compression of patent veins and secondary rupture of smaller connecting tributaries [90]. This, in turn, is likely to cause venous stasis, increased venous pressure, and reduced perfusion pressure in the area where the terminal vein is the terminus of medullary, choroidal, and thalamostriate veins and empties into the internal cerebral vein [90]. This sequence of events associated to venous stasis may be more frequent in subjects with thrombophilia, a genetic predisposition to develop thrombosis more often in the venous rather than arterial vessels. Accordingly, we have found a clear trend to develop GMH-IVH in thrombophilic babies with factor II (antithrombin) abnormality [91]; Petaja et al. found the same trend in subjects with factor V Leiden abnormality [92].

b Fig. 5.23a,b. Germinal matrix hemorrhage in two different infants. a Axial T2-weighted image in a 28-week-old baby shows germinal matrix hemorrhage at the right caudo-thalamic notch (white arrow). Notice minimal dependent blood level in the left occipital horn (black arrow). b Axial T2-weighted image in a 26-week-old baby shows more atypical germinal matrix hemorrhage along the posterior horn of the lateral ventricle (white arrow)

Fig. 5.24. Mild intraventricular hemorrhage caused by germinal matrix bleed in a preterm baby born at 28 weeks of gestation. Axial T2-weighted image. There is dependent, hypointense blood in the posterior horns (black arrows) with the germinal matrix as the bleeding source (white arrows)

Magnetic Resonance Imaging of the Brain in Preterm Infants

a

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From a clinical perspective, respiratory distress syndrome is the most consistently recognized predisposing risk factor to GMH-IVH in premature infants; in particular, hypercapnia, pneumothorax , and the fluctuating pattern of systemic blood pressure are the most significant factors. All these conditions may be major causes of increased cerebral venous pressure in the premature infant [93]. 5.2.3.3 Timing of GMH-IVH

Leech and Kohnen, in a large autopsy series, indicated that the risk of finding hemorrhage at autopsy increases steadily in the first day of life, but stabilizes thereafter [87]. The introduction of real-time ultrasound allows frequent scanning of high-risk infants to accurately time the onset of GMH-IVH. Ultrasound studies suggest that 90% of GMH-IVH occur in the first week of life, with the majority occurring within the first 3 days of life [93]. 5.2.3.4 Complications of GMH-IVH Parenchymal Hemorrhage/Venous Infarction

Approximately 15% of babies with GMH-IVH also present with unilateral parenchymal hemorrhage, better known as venous infarction. The region involved can be quite large, just dorsal and lateral to the external angle of the lateral ventricle, usually saving the cortical mantle; however, location and size can vary [83]. Less often, the lesion develops in more

Fig. 5.25a,b. Severe intraventricular hemorrhage in a preterm baby born at 26 weeks of gestation. a Axial T2weighted image obtained at 2 days of life; b Axial T2-weighted image obtained 4 weeks later (30 weeks corrected gestational age). A large intraventricular clot is visible in the left ventricle (a). Its size is significantly reduced 4 weeks later (b). Progression of maturation phenomena of the brain can be noted, especially with regards to cortical infolding; a thick periventricular band in the white matter (phenomena of cell migration) visible at presentation (a) can not be detected 4 weeks later (b)

posterior parts of the brain, in the temporal lobe or around the atrium (Fig. 5.26). In these cases, the inferior ventricular or lateral atrial veins are involved. It is still possible to have bilateral venous infarction, but this condition is extremely rare and well differentiated from PVL. At the beginning, the lesion appears as a triangular density often not touching the ventricle. Later, the lesion grows and extends to the ventricle, merging the area of increased density due to matrix hemorrhage [43]. Sometimes there is no progression to this stage, and the lesion remains as a triangular density. The hyperdensity area tends to decrease in size during the second week, and the actual infarcted area can result smaller than expected. Cystic degeneration is the most common evolution of severe cases, with a smooth-walled cavity in the parenchyma communicating with the ventricle (unlike in PVL) [43]. In the past, parenchymal hemorrhage was considered an extension of a very severe GMH-IVH. Presently it is thought to derive from venous infarction. The debate on the pathogenesis is still open, but the hypothesized mechanisms include the obstruction of the terminal vein with reduction in perfusion of the white matter drained by this vein. It has also been suggested that parenchymal ischemia and hypoperfusion, caused by vasoactive compounds generated by the GMH-IVH, can aggravate in the parenchyma the effects of vein obstruction [83]. This mechanism may take into account those venous infarctions occurring during less severe forms of GMH-IVH. Timing of this lesion is uncertain, although it seems to follow the initial intraventricular bleed from a few hours up to a few days [83].

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Fig. 5.26a,b. Evolving venous infarct unusually located in the posterior horn of the left lateral ventricle in a 27-week-old baby with intraventricular hemorrhage at 10 days of life. a Posterior coronal ultrasound scan shows large venous infarct just lateral to the left atrium. b Axial T2-weighted image shows the posterior venous infarct in addition to intraventricular blood (arrows) and ventricular dilatation

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Hydrocephalus

Progressive ventricular dilatation is not an uncommon sequela to GMH-IVH (Fig. 5.26). Multiple small clots may obstruct the ventricular system or the channels of reabsorption in the acute stage; they may also cause chronic arachnoiditis of the basal cisterns, involving the deposition of extracellular matrix proteins and obstruction of the foramina of the fourth ventricles or the subarachnoid space over the cerebral hemisphere [94]. The incidence of progressive ventricular dilatation is closely related to the severity of the initial hemorrhage, and can be acute (within days) or chronic (within weeks). The acute form is due to impairment of CSF absorption, whereas the chronic form is likely to originate from obliterative arachnoiditis [83]. Volpe stated that the severity of the initial IVH is the most critical determinant of not only the likelihood of progressive ventricular dilatation, but also the temporal evolution and the course [83]. It is difficult to disagree with this view. In fact, our experience, as well as published data from other authors, have shown that the majority of infants who develop hydrocephalus tend to have rapidly progressive ventricular enlargement initially or slightly later, especially if they have experienced very severe GMH-IVH. Most uncommon is a slow progressive ventricular dilatation, usually seen between 10 and 14 days after the GMH-IVH with a very high likelihood of spontaneous resolution. The odds of progressive ventricular enlargement in the weeks after hemorrhage increases by 5% in grade II, and 40%–80% in more severe forms [43, 83, 93]. It is also necessary to monitor those infants in whom dilatation has become static for a 4–6-week

period, since a maximum of 5% may develop progressive dilatation at a later stage [83, 93]. Ultrasound is the most appropriate imaging modality for the initial assessment of ventricular size [43]. The slightly rounded shape of the frontal horns can represent the initial appearance of dilatation, whereas balloon-shaped frontal horns are a sign of severe dilatation. Latero-lateral and diagonal measurements of the diameter are a well-established modality to monitor ventricular dilatation. Absence of widening of the frontal horns may be falsely reassuring, as neonates tend towards overdilatation of the occipital horns (“colpocephaly”). Many units have their own guidelines for measuring the frontal horns, but very often not for the posterior horns [43]. MRI can be useful, as detailed imaging is often required prior to shunting surgery and also after surgery to verify the functioning of the shunt, provided the proven MRI compatibility of the intraventricular device. Pseudocysts

Cavitation within the germinal matrix is called germinolysis and typically occurs at the caudo-thalamic notch, resulting in a “pseudocyst” due to the lack of a proper epithelium [95, 96]. During the postnatal period, pseudocysts occur mainly following small to moderate GMH-IVH, although a mechanism based on “pure infarction” of the germinal matrix has been hypothesized. Accordingly, we have sometimes detected pseudocysts at the caudo-thalamic notch a few weeks after birth in “normal” preterm babies, with no obvious reason for this. Pseudocysts can also be present at birth. In these cases, many different prenatal conditions, such as

Magnetic Resonance Imaging of the Brain in Preterm Infants

TORCH group infections, have to be excluded. Less often, prenatal asphyxia, feto-fetal transfusion, metabolic diseases, intrauterine growth retardation, and karyotype anomalies should be investigated [44]. Prenatal pseudocysts are thought to arise incidentally when the developing germinal matrix outgrows its blood supply [83, 93]. Pseudocysts can also be located around the frontal horns of the lateral ventricles. In this case, they are always prenatal and do not seem to correlate with GMH (see below, congenital periventricular cavitations) [97–99]. Although the germinal matrix may persist around the frontal horns even in late gestation, we have never observed hemorrhage in this area with MRI studies.

The evolution of intraventricular clots is quite predictable. They become isodense from the center outwards, showing central lysis; few fragments are often detectable in the cavity at a later stage [43]. CT

CT is very accurate for the diagnosis of any form of hemorrhage (Fig. 5.27), and may detect small areas of parenchymal hemorrhage in the acute phase in the periphery of the brain, which are not easily visualized on ultrasound examination. Nevertheless, it is less frequently used for obvious reasons and especially to avoid ionizing radiation exposure, thanks to the improved availability of MRI scans for infants.

5.2.3.5 Neuroimaging of GMH-IVH Ultrasound

The accuracy of ultrasound diagnosis was reported to approach 90% in old studies comparing ultrasound with CT [100]. Ultrasound has become the primary modality to identify all degrees of GMH-IVH, although the validity of ultrasonographic diagnosis is difficult to investigate. An increased sensitivity of ultrasound in diagnosing GMH-IVH was noticed, with an increase in the diameter of the germinal and intraventricular hemorrhage in a small number of studies where ultrasound was compared to postmortem findings. The sensitivity of ultrasound appeared more linearly related to size when more scans were performed, reaching a value of 100% for hemorrhages larger than 1 cm [43]. The abnormality marker used to diagnose GMH remains the detection of a globular area of intense, increased echogenicity, although a suspicion of hemorrhage can be proposed when irregular luminal plexus borders appear together with densities in the occipital horns. Sometimes, this precedes the typical rounded thickening of the plexus near the foramen of Monro. The abnormality should be demonstrated in two planes, although the first suspicion is often made during coronal scanning. Larger hemorrhages may rupture into the lateral ventricle, and can appear as an echogenic clot within the ventricle provided that there has been fibrin deposition [43]. After a few days, the ependyma becomes denser, probably due to reactive chemical inflammation in response to intraventricular blood, a process that may last for a few weeks. This finding, even in the absence of obvious clots, may be sufficient to diagnose prior IVH.

Fig. 5.27. Massive intraventricular hemorrhage in a 31-weekold preterm baby imaged at 2 days postnatal life. Axial CT scan shows huge intraventricular hemorrhage. The lateral ventricles are dilated. (Case courtesy P. Tortori-Donati, Genoa, Italy)

MRI

This technique provides excellent visualization of the germinal matrix, showing high signal on T1-weighted images and low signal on T2-weighted images, especially up to the 30th week of gestation (Figs. 5.5, 5.6). After this time, T2-weighted images remain the best sequence to follow physiological germinal matrix involution (see first section). GMH has similar characteristics to normal germinal matrix, but is detectable due to its irregular shape and asymmetry (Fig. 5.23). Very preterm babies may show small lesions, consistent with subependymal

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hemorrhage, in different areas than the classical sites (caudo-thalamic notch), more often in the posterior horns (Fig. 5.23). These hemorrhages seem to not be visible on ultrasound [101]. IVH, more often identified in the posterior horns of the lateral ventricle, is an obvious diagnosis with MRI (Figs. 5.24, 5.25), making this technique the most accurate for GMH-IVH investigation, although MRI scanning is not practical for sick, unstable neonates during the first days of life. MRI has improved the detection of venous infarction associated to GMH-IVH (Fig. 5.26), although caution is needed as subependymal hemorrhages may appear to have white matter involvement due to partial volume effects. Nevertheless, Keeney et al. demonstrated that MRI performed between 29 and 44 weeks postconceptual age was superior to both ultrasound and CT in assessing the extent of any parenchymal injury associated with GMH-IVH [102]. MRI shows signal changes following any form of intracranial hemorrhage, including IVH, according to the timing of hemorrhage. The typical hyperintense hemorrhagic signal on T1-weighted images usually appears in the so-called subacute phase, usually between 4 days and 2 weeks after the initial bleed (Fig. 5.28), whereas the long lasting hemosiderin deposition seems to be visible only after 3–4 weeks [93]. 5.2.3.6 Assessment of Prognosis

Determination of neurological prognosis is very complex, as babies with GMH-IVH are usually the most

a

premature, and many confounding variables may play a role. Death can also be considered an outcome, and it seems that the more severe the degree of hemorrhage, the higher the mortality rate, especially when the size of the intraparenchymal involvement (venous infarct) is included [83]. In the absence of ventricular dilatation and parenchymal lesion, the outcome does not differ from infants born of the same degree of prematurity but without evidence of GMH-IVH [83]. The study by Fletcher et al. [103] well highlights the outcome of posthemorrhagic ventricular dilatation: preterm babies with shunted hydrocephalus performed significantly poorer in motor performance and visual-spatial tests, but not language tests, confirming that hydrocephalus seems to adversely affect nonverbal cognitive skills. With an equally severe ventricular dilatation, the presence of a venous infarct plays an important role. Major handicaps range from 60% to 100% in infants with this complication, depending on the extension and the location of the lesion (fronto-parietal lesions are less severe than posterior ones), especially in babies with a birth weight less than 1 kg [43, 83].

5.2.4 Choroid Plexus Hemorrhage Choroid plexus hemorrhage is very commonly represented in studies based on autopsy with varying percentages. Larroche reported minor bleeding into the choroid plexus associated with IVH in 25% of cases, whereas in full-term babies choroid plexus hemorrhage is the most frequent form of intraventricular

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Fig. 5.28a,b. Late appearance of evolved venous infarct at 4 weeks of age in a baby born at 26 weeks of gestation who suffered an intraventricular hemorrhage. a Sagittal ultrasound scan; b sagittal T1-weighted image. The area of involved parenchyma is equally visible with ultrasound (arrow, a) and MRI (arrow, b). Studies performed at Leeds General Infirmary, Leeds, UK

Magnetic Resonance Imaging of the Brain in Preterm Infants

bleed [93, 94, 104]. In the most recent autopsy studies performed on preterm infants with IVH, the choroid plexus was only rarely the only source of intraventricular blood, whereas the germinal matrix was the principal source [105, 106]. The in vivo diagnosis is very complex and intricate. Ultrasound diagnosis should be based on sequential scans showing cavitation in the hematoma adjacent to the choroid plexus. A simple intraventricular clot adjacent to the choroid plexus is not sufficient to diagnose a primitive choroid plexus hemorrhage [43]. In our experience, the MRI diagnosis of choroid plexus hemorrhage was found to be quite difficult. We have imaged a number of scans of premature babies in their first days of life, and we could only very rarely ascertain the choroid plexus origin of the intraventricular bleed (Fig. 5.29). In minor intraventricular bleeding of premature babies, a hemorrhagic germinal matrix was almost always detectable (Fig. 5.23).

Fig. 5.29. Choroid plexus hemorrhage in a preterm baby born at 33 weeks’ gestation. Axial T2-weighted image. Bleeding originates from left choroids plexus (white arrow). The intraventricular phase of the choroid plexus hemorrhage is very mild and easily missed (black arrows)

5.2.5 Cerebellar Hemorrhage Cerebellar hemorrhage seems to be quite frequent on postmortem examinations performed in very low birth weight infants. It has been associated with traumatic birth and supratentorial hemorrhage; it was related to tightly bound ventilatory masks used in the past [107–111]. Data based on MRI studies

show that 8% of preterm infants less than 32 weeks GA suffer from cerebellar hemorrhage, although the incidence is increasing with decreasing GA. Ultrasound studies performed via the posterior fontanel, more sensitive than the conventional anterior fontanel, show a lower incidence (about 3%). Cerebellar lesions may account for significant cognitive impairment, but their role as isolated findings remains to be assessed [112].

5.2.6 Congenital Periventricular White Matter Cavitations Preterm newborn babies infrequently present small cavitations around the frontal horns of the lateral ventricles. This abnormality can be easily misdiagnosed for congenital leukomalacia, but it should be referred to as congenital germinolysis. It generally carries a good prognosis, especially when it represents an isolated finding [95–99]. On ultrasound, these cavitations are visible on coronal and parasagittal lateral scans. They are echofree areas that not rarely are subdivided into two or three smaller (pseudo)cysts separated by very thin septa. On coronal scans, they often appear to be isolated from the ventricles in more frontal sections, while they are adjacent to the frontal horns in slightly posterior cuts. They can be differentiated without difficulty from PVL lesions, which are located at the superior and external angle of the frontal horns of the lateral ventricle [93, 95]. On MRI, their diagnosis is quite obvious in axial and coronal sections; perhaps diagnosis is easier on T2-weighted images (Fig. 5.30). The frequent presence of multiple septa, indicating their germinolytic nature, is often visible together with remnants of germinal matrix tissue (Fig. 5.30). In more rare cases, these pseudocysts are detectable also in the temporal horns; in such locations, consideration should be given to congenital rubella (Fig. 5.31) and cytomegalovirus, although we have observed these abnormalities also in the absence of obvious congenital infections (Fig. 5.32). In general, we believe these pseudocysts have a very good prognosis when they are isolated findings. Caution is needed when in association with other findings, as they can derive from congenital infections or even chromosomal abnormalities.

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L. A. Ramenghi, F. Mosca, S. Counsell, and M. A. Rutherford Fig. 5.30a–c. Congenital periventricular cavitations in two different patients. a Axial T1-weighted image obtained at 3 days life in a preterm baby born at 32 weeks of gestation. Cysts are visible in the frontal periventricular white matter (white arrows). These cysts do not represent congenital periventricular leukomalacia and are presumably germinolytic. The baby at 4 years of age remained asymptomatic. b, c Axial T2-weighted images in a baby born at 31 weeks of gestation. Usual appearance of congenital frontal “benign” cysts. Residual germinal matrix tissue (open arrow, b) is often represented around the cavitation, suggesting their germinolytic nature. The cysts are often multiple and divided by septa (thin arrows, b, c). The child was asymptomatic at 2 years corrected age

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Fig. 5.31a,b. Infection-related periventricular cavitations in a baby born at 30 weeks with congenital rubella. a Parasagittal ultrasound scan; b coronal T2-weighted image. Periventricular cyst (arrow) is visible in right temporal lobe on ultrasounds (arrow, a). MR shows periventricular cysts in both temporal lobes (arrows, b)

Magnetic Resonance Imaging of the Brain in Preterm Infants

Fig. 5.32. Periventricular cysts in a preterm baby born at 30 weeks of gestation. Coronal T2-weighted image. Two cysts (arrows) are visible around the frontal and temporal horns. These cysts are likely to derive from germinolysis; no congenital infection was found despite repeated investigations. Neurological follow-up of this baby was normal at 3 years of age

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Fig. 5.33a,b. Klebsiella infection in a preterm baby born at 32 weeks’ gestation. a, b Axial T1-weighted images at 3 weeks of age. There are congenital frontal cysts (arrows) and unusual areas of increased signal with linear appearance in the periventricular and subcortical white matter. The baby was investigated for congenital infection; at day 14 he presented with sepsis and a positive blood culture for Klebsiella. The baby was normal at 2-year follow-up

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Fig. 5.34a,b. Congenital cytomegalovirus infection in a baby born at 33 weeks from an HIV-positive mother. The baby had cytomegalovirus isolated from saliva and urine. a Coronal ultrasound scan; b coronal T1-weighted image. Ultrasounds show hyperechogenicities (arrows, a) of the thalamo-striate arteries, known as “mineralizing vasculopathy.” Similar findings are not visible on MRI (arrow, b); however, MRI shows multiple cortical lesions and some punctuate lesions in the white matter, showing increased signal

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5.2.7 Infections

5.2.9 Venous Thrombosis

There is no specific infectious agent affecting premature babies more often than term babies (Fig. 5.33). The most common agents causing congenital infections in term babies can also affect the developing brain of preterm babies, with special regard to cytomegalovirus (Fig. 5.34), which produces different lesion patterns depending on the GA at which infection occurs [114] (see Chapter 12). The importance of this concept can be generalized to other infections, and be considered more important than the nature of the infectious agent [114].

The frequency of this condition is not well known in full term neonates, and even less in preterm babies. The clinical symptoms in neonates are less obvious than in adults, and neuroimaging confirmation can not always be straightforward, especially during the very acute phase. The pathognomonic “empty delta sign” on CT is a “triangle” of decreased density due to the contrast-enhanced blood flowing around the clot. On MRI, the thrombus can appear hyperintense on T1-weighted images. These appearances are typical of the subacute phase, and from this timing, the diagnosis is difficult even with MRI. Phase contrast MR venography is a very helpful modality in this field. Venous thrombosis usually affects term babies, although we have observed quite a few mildly premature babies showing underlying venous thrombosis that appeared in the form of late and unexpected GMH-IVH, severe subcortical and periventricular leukomalacia, posterior fossa hemorrhage, and simple ultrasound “edema” with enlarging diameter of the venous vessels (Figs. 5.36–5.38) [115]. Dural sinus thrombosis may be secondary to trauma, increased hematocrit, sepsis, dehydration, cardiac failure, and, more often, inherited thrombophilia [62].

5.2.8 Multicystic Encephalomalacia and Asphyxia Diffuse ischemic damage to the brain late in gestation may result in multicystic encephalomalacia, although a greater number of premature babies can suffer such a severe insult (Fig. 5.35). Injury to the basal ganglia and thalami may present in the same way as asphyxia affects the brain of newborn babies at term, although the specific regions within the basal nuclei can be different and the cortical highlighting less intense. In premature babies, the most common target of hypoxia is thought to be the white matter.

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Fig. 5.35a–c. Early MRI findings in asphyxia. 29-week-old twin newborn surviving after resuscitation in the delivery room, imaged at 4 days. The baby was born with very low hemoglobin level (5 g/dl) and subsequently died. a Axial T1-weighted image; b axial T2-weighted image; c axial diffusion-weighted image (DWI). Diffuse signal abnormalities are seen both on T1- and T2-weighted images (a, b), suggesting a very severe global ischemic insult. On DWI, multiple areas of restricted diffusion are visible (arrowheads, c), although the left occipital lobe already shows very decreased signal (arrow, c) corresponding to decreased ADC values compatible with cell death. In this preterm baby the brain seemed to respond to the global ischemic insult as does the brain of babies born at term of gestation

Magnetic Resonance Imaging of the Brain in Preterm Infants

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Fig. 5.36a–f. Venous thrombosis in a preterm baby born at 33 weeks’ gestational age. a coronal ultrasound scan at 16 days of life; b–f MRI at 16 days; b axial T2-weighted image; c sagittal T1-weighted image; d axial diffusion-weighted image; e axial gradient-echo T2*-weighted image f, axial T2-weighted image. Coronal ultrasounds scan shows intraventricular hemorrhage (white arrows, a) that was unexpectedly discovered during earlier routine ultrasound scans performed on days 2, 7, and 12. MRI confirmed intraventricular bleeding (white arrow, b); bilateral abnormality in the periventricular areas was also suspected (arrowheads, b). Moreover, diffuse thrombosis affecting the superior sagittal sinus (open arrows, c), torcular (T), the straight sinus (arrowheads, c), and the vein of Galen and deep venous system (thin arrows, c) was identified. DWI showed linear appearance of abnormally restricted signal in the deep frontal lobes (arrows, d). Gradient-echo imaging highlights blood breakdown products with a linear pattern (arrowheads, e), corresponding to the anomalies detected with DWI. Blood is also present in the ventricular lumen (arrows, e). The abnormalities observed in the frontal white matter (arrows, f) are highly suspected for thrombosis of the medullary veins. This imaging pattern follows the anatomy of the medullary veins and confirms the original suspicion of thrombosis of small venous vessels. No anticoagulant therapy was administered due to the presence of intraventricular hemorrhage. Studies performed at Leeds General Infirmary, Leeds, UK

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c

Fig. 5.37a–c. Venous thrombosis in a baby born at 34 weeks’ gestational age, with sudden onset of seizures at day 4 postnatal life. a Coronal ultrasound scan; b axial T1-weighted images; c sagittal T1-weighted image. Ultrasounds show increased echogenicity in the periventricular areas suggestive of a hypoxic insult similar to the acute phase of periventricular leukomalacia, associated with intraventricular bleeding (open arrows, a). MRI confirms the periventricular abnormality, showing as increased signal, and the intraventricular blood (b). However, MRI also shows unexpected diffuse venous thrombosis affecting the major sinuses and the internal venous system (c). It is very likely that venous thrombosis caused both the intraventricular bleeding and the parenchymal lesion (compare with Fig. 5.36)

Fig. 5.38a–f. Venous thrombosis in a baby born at 35 weeks’ gestational age, presenting at birth with mild asphyxia and requiring ventilation for three days. a, b Coronal ultrasound scan at 6 h of life; c coronal ultrasound scan after 24 h; d axial T1-weighted image; and e coronal MR venogram at 7 days; f coronal MR venogram after 3 weeks. On initial ultrasound scan there is diffuse hyperechogenicity and unusually enlarged dural sinuses (arrows, a, b). Ultrasounds after 24 h (c) fail to identify the abnormal echogenicity and the enlarged venous vessels. At 7 days, thrombus is visible in the right transverse sinus (arrow, d); MR venogram clearly shows an obstructed right transverse-sigmoid sinus (e). It is intriguing to associate the early ultrasound signs (enlarged veins suggesting obstruction and diffuse parenchymal hyperechogenicity suggesting generalized edema) with obstruction due to venous thrombosis, that probably partially resolved somehow, as shown 24 h later by ultrasounds. MR venogram after 3 weeks of treatment with low molecular weight heparin (e) shows signs of recanalization of the previously thrombosed sinus, although a difference of caliber with the unaffected side is noticeable



Magnetic Resonance Imaging of the Brain in Preterm Infants

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e

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b

c

Fig. 5.39a–c. Neonatal infarction in a preterm baby born at 34 weeks’ gestational age, suffering from cardiac failure due to severe supraventricular tachycardic crisis. a Axial T1-weighted image; b axial T2-weighted image; and c axial T1-weighted image obtained at 4 weeks’ postnatal life. Both T1-weighted (a) and T2-weighted images (b) show outcome of large stroke in the territory of the left middle cerebral artery. Notice reduced size of homolateral cerebral peduncle (arrow, c) due to axonal degeneration; such finding is surprisingly precocious compared to the timing of a similar event in adult patients suffering from stroke

5.2.10 Infarctions Neonatal stroke is usually reported in full-term babies, whereas data on preterm babies are lacking. Infarction can be seen as an area of increased signal intensity on T2-weighted images. The largest reported series of preterm babies shows no essential differences in the appearance of neonatal stroke when compared to full-term babies [64]; we have had a similar experience. Outcome-defining criteria are comparable to those used for full-term infants, with special attention to the involvement of the PLIC (Fig. 5.39).

5.3 Concluding Remarks and Application of Quantitative MRI MRI is an ideal and safe technique for imaging the developing brain, with the extensive maturation that occurs from 23–40 weeks’ gestation. MRI well depicts known pathologies seen on ultrasound, and also those very subtle anomalies not always corresponding to a well-defined clinical outcome. The neuropathological correlates for neurodevelopmental impairments, especially for the cognitive deficits of very preterm babies, are not well defined. Quantitative MR studies have identified some abnormalities, such as increased ADC values in the central white matter and lower relative anisotropy as compared with infants born at term [73]. Preterm infants at term have a 6% decrease in whole

brain volume compared to infants born at term; they also have an 11.8% decrease in cortical gray matter volume, a 15.6% decrease in right hippocampal volume, a 12.1% decrease in left hippocampal volume, and a 42.0% increase in the size of the lateral ventricles. Therefore, individuals who were born very preterm continue to show noticeable decrements in brain volumes and striking increases in lateral ventricular volume into adolescence. The functional significance of these abnormalities deserves further investigation. Other selective areas of the brain, such as basal ganglia, corpus callosum, and cerebellum have showed reduced volumes compared to term born controls [116–119]. This differentiation is far from explaining clinical correlates, as previous studies on adolescent with brain lesions did not correlate with intellective performances. The main area for further research remains the investigation of ex utero brain development of the preterm brain, including aspects of neonatal intensive care on the developing brain.

Acknowledgements We would like to thank all the staff in the Robert Steiner MR Unit and within the Department of Paediatrics and the Hammersmith and Queen Charlottes Hospitals in London. We are also grateful to the radiological staff of Leeds General Infirmary in Leeds and to the pediatric neuroradiology team (Drs Fabio Triulzi, Andrea Righini, Cecilia Parazzini, and Elena Bianchini) of Milan ICP Hospitals. We are also grateful to the Medical Research Council for their continued support.

Magnetic Resonance Imaging of the Brain in Preterm Infants

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Neonatal Hypoxic-Ischemic Encephalopathy

6

Neonatal Hypoxic-Ischemic Encephalopathy Fabio Triulzi, Cristina Baldoli, and Andrea Righini

6.1 Introduction

CONTENTS 6.1

Introduction 235

6.2

Neuropathology and Pathogenesis 235

6.2.1 6.2.2

Selective Neuronal Necrosis 236 Parasagittal Cerebral Injury 237

6.3

Neuroradiology

6.3.1 6.3.2 6.3.3 6.3.3.1

Ultrasounds 237 Computerized Tomography 237 Magnetic Resonance Imaging 237 MR Techniques in the Evaluation of HIE 237 Magnet 237 Coils 238 Conventional Sequences 239 Advanced Imaging Techniques 240

237

6.4

Conventional MRI Features in HIE

6.4.1 6.4.2 6.4.3

Selective Neuronal Necrosis 241 Multicystic Encephalomalacia 245 Parasagittal Lesions 245

6.5

Advanced MRI Features of HIE 248

6.5.1 6.5.2

Diffusion Imaging 248 MR Spectroscopy 259

6.6

Ischemic Infarction in the Newborn 254

6.6.1

MRI Features References

254

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Hypoxic-ischemic encephalopathy (HIE) is the major recognized perinatal cause of neurological morbidity both in premature and full-term newborns [1]. During the perinatal period, hypoxemia and/or ischemia usually occur as a result of asphyxia; brain biochemical changes associated with hypoxemia, ischemia, and asphyxia are extremely complex and, other than to duration and severity of the event, are strictly related to the state of brain development and maturation. Different from adults, in whom diffuse and prolonged anoxic-ischemic injury causes diffuse brain injury that predominantly involves the gray matter, neonatal HIE is generally more selective, both in premature and full term infants. The selectiveness of brain damage caused by HIE in newborns follows the rapid changes in biochemical, cellular, and anatomical constitutes of the neonatal nervous system. Relative energy requirements in various portion of the brain are related to the state of brain maturity at the time of the injury, as is well documented in vivo by PET studies [2]. To a large extent, it is possible to state that in case of mild to moderate brain injury the premature brain shows greater vulnerability in white matter, whereas full term infants more typically exhibit gray matter damage. In case of prolonged and profound HIE, gray matter involvement occurs also in the premature newborn, whereas full-term newborns exhibit a diffuse gray matter injury leading to multicystic encephalomalacia.

6.2 Neuropathology and Pathogenesis In order to understand the complexity of neuroradiologic features of HIE, a schematic review of neuropathology and pathogenetic mechanisms of brain injury is proposed. According to Volpe [1], two major varieties of injuries can be observed in full-term new-

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born HIE, i.e., a) selective neuronal necrosis, and b) parasagittal cerebral injury.

6.2.1 Selective Neuronal Necrosis Selective neuronal necrosis (SNN) is the most common variety of injury in neonatal HIE. According to the different type of insult, four basic regional patterns of SSN have been identified: a) Diffuse pattern: severe and prolonged insult in both term and premature infants; b) Cerebral cortex–deep nuclear pattern: moderately to severe, relatively prolonged insult, primarily in term infants; c) Deep nuclear–brainstem pattern: severe, abrupt insult, primarily in term infants; d) Pontosubicular pattern: undefined temporal pattern, primarily in preterm infants Obviously, the pattern refers to the areas of predominant neuronal injury, and a considerable overlap is common. a) Diffuse pattern. In case of very severe and prolonged insult, a diffuse neuronal injury occurs in both premature and term infants. Neurons of the cerebral cortex are extremely vulnerable; the most vulnerable cortical region is the hippocampus, followed by the perirolandic and calcarine cortex. In very severe insults, a diffuse involvement of the cortex occurs and neurons in the deeper cortical layers (particularly those located in the depth of the sulci) are significantly affected. Thalamic neurons can be consistently affected, as well as hypothalamic neurons and those of the lateral geniculate bodies. Neurons of the putamen are somewhat more likely to be affected in the term infant, whereas neurons of the globus pallidus are predominantly affected in the preterm infant. The combination of putaminal-thalamic neuronal injury is one of the typical features of HIE, particularly in term infants. Neurons of the brainstem can be involved as well, and their involvement can frequently be observed in combination with basal ganglia-thalamic involvement. Finally, also cerebellar neurons seem to be extremely vulnerable to hypoxic-ischemic insults; Purkinje cells are the most vulnerable cerebellar neurons in the term infant, as opposed to internal granule cell neurons in the premature infant. b) Cerebral cortex–deep nuclear pattern. This is probably the most typical magnetic resonance imaging (MRI) pattern, and refers to an involvement

of some characteristic cortical areas (typically the perirolandic area) together with the putamen and thalamus. It could be secondary to a moderate or moderate-severe insult that evolves in a gradual manner. c) Deep nuclear–brainstem pattern. In approximately 15%–20% of infants with HIE, involvement of deep nuclear structures (basal ganglia, thalamus, and brainstem tegmentum) is the predominant lesion; however, until the advent of MRI, detection of this kind of injury in the first weeks or months of life was not frequent. This is probably due to the fact that at least part of these lesions may evolve into the so-called status marmoratus, a condition that cannot be neuropathologically detected before age 9–10 months. d) Pontosubicular pattern. In this type of SNN, neurons of the basis pons and the subiculum of hippocampus are primarily involved. The lesion is characteristic of premature infants, and is strongly associated with periventricular leukomalacia. Pathogenesis of SNN

Different factors may explain the typical selective vulnerability to asphyxia demonstrated by some neuronal groups in the neonatal brain. In recent years, there has been increasing evidence regarding the importance of regional metabolic factors and of the regional distribution of glutamate receptors. As demonstrated in vivo by PET studies [2], the neonatal gray matter exhibits strong regional differences in FDG consumption; as a general rule, areas with higher myelinogenesis and/or synaptogenesis, i.e., areas already having activated functions, show higher metabolic rate and energy utilization. These metabolic conditions may consequently render these neurons particularly vulnerable to severe, abrupt ischemic insults. On the other hand, the regional distribution of glutamate receptors, particularly of the NMDA type, now appears to be the single most important determinant of the distribution of selective neuronal injury [1]. The topography of glutamate synapses parallels that of hypoxic-ischemic neuronal death in vivo, and the particular vulnerability of certain neuronal groups in the perinatal period correlates with a transient, maturation-dependent density of glutamate receptors. Finally, factors related to the severity and temporal characteristics of the insult appear to be of particular importance in determining SNN. As previously reported, in the different patterns of SNN the severity and the duration of the injury can greatly modify the regional distribution of neonatal brain lesions.

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6.2.2 Parasagittal Cerebral Injury The term parasagittal cerebral injury (PCI) refers to lesions involving both the cerebral cortex and subcortical white matter, with a bilateral, parasagittal distribution at the level of the superomedial aspect of the cerebral convexity. Albeit usually roughly symmetrical, PCI can be more evident in one hemisphere; the parieto-occipital aspect of the hemispheres is usually more severely affected that the anterior part. PCI is characterized by cortical necrosis, usually without hemorrhagic component. Atrophic gyri or ulegyria are the chronic neuropathological features. PCI almost invariably affects full-term infants suffering from perinatal asphyxia. Pathogenesis of PCI

The pathogenesis of PCI primarily relates to cerebral perfusion imbalance. It can be considered the dominant ischemic lesion of the full-term infant [1]. The areas of necrosis involve the border zones between the end fields of the major cerebral arteries, particularly at the level of the parieto-occipital aspect at the border zone of the three major cerebral arteries. Border zones are the brain regions most susceptible to falls in cerebral perfusion pressure. To a large extent, it can be stated that diminished cerebral blood flow secondary to systemic hypotension is the major pathogenetic factor in neonatal PCI.

6.3 Neuroradiology 6.3.1 Ultrasounds Cranial ultrasounds still have a considerable value in the evaluation of term infants with HIE. The most typical findings in the acute phase are represented by poor differentiation between gray and white matter with effacement of the sulci, as well as diffuse increased parenchymal echogenicity. These features can be related primarily to diffuse cerebral edema. In the acute phase, hyperechogenic basal ganglia predict poor outcome [3] (Fig. 6.1); on the other hand, as many as 50% of ultrasound scans in neonates with HIE are normal [4]. At present, ultrasound examinations can be considered as a first step technique for each suspected HIE, allowing prompt evaluation of neonates with poor prognosis. How-

ever, an MRI study should follow if a clinical history of HIE is present.

6.3.2 Computerized Tomography Computerized tomography (CT) provides considerable diagnostic information in neonates with HIE. However, the value of CT is greater several weeks after injury. During the acute phase, CT scan demonstrates diffuse brain hypodensity with loss of cortical gray-white matter differentiation. The presence of low attenuation in the thalami on postnatal days 2–4 is predictive of poor outcome [5]. In the subacute phase (4–7 days), especially in presence of hemorrhagic necrosis, the affected cortical and deep gray matter may exhibit diffuse hyperdensity, whereas the white matter is still diffusely hypodense (Fig. 6.2). Although both acute thalamic hypodensity and subacute hyperdensity are reliable prognostic predictors, a negative CT does not have valuable prognostic significance. Therefore, the role of CT in the acute phase of HIE is presently of limited importance, as opposed to MRI studies.

6.3.3 Magnetic Resonance Imaging In recent years, MRI has become the technique of choice in evaluating the greater part of neonatal CNS diseases. MRI is the only imaging technique that can discriminate myelinated from neonatal unmyelinated white matter. It offers the highest sensitivity in detecting acute anoxic injury of neonatal brain. With proper coils and sequences, it can exquisitely depict neonatal brain anatomy and locate pathology, offering a robust and reliable tool in the prognostic assessment of neonatal CNS diseases [6]. Recent MR developments, such as the use of diffusion techniques or the increasing reliability of MR spectroscopy, have further improved the MRI capability to investigate the neonatal brain. 6.3.3.1 MR Techniques in the Evaluation of HIE a) Magnet

To obtain reasonably high signal-to-noise ratio, a high field magnet (1.5 T) should be preferred. Such a magnet has a number of advantages in the evaluation of the newborn brain. First, it allows more flex-

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Fig. 6.1a–d. HIE in a full-term newborn: ultrasound evaluation. a Normal full-term newborn, coronal section passing through basal ganglia. b–d Full-term newborn with severe HIE. b Two days after the insult. Bilateral mildly hyperechogenic thalami (arrows). c One week after the insult. Perisylvian region is also bilaterally hyperechogenic. The lateral ventricles are slightly enlarged. d Three weeks after the insult. Diffuse hyperechogenicity involves both basal ganglia and perisylvian cortex. The subarachnoid spaces and lateral ventricles are enlarged

ible use of imaging basic parameters, such as a sufficiently thin section or a reasonably small field of view. Second, it provides a more reliable use of techniques such as echo planar imaging and spectroscopy. For modern imaging applications such as diffusion tensor imaging (DTI), a powerful gradient system should be considered with a strength greater than 30 mT/m and a slew rate greater than 100 T/m/s. The era of ultra-high field magnet (3T and greater) is still in its first days concerning neonatal applications. However, it seems to be the most promising step for using more technical demanding techniques, such as high resolution spectroscopy or high resolution DTI.

b) Coils

The small brain of a neonate is undoubtedly better evaluated by a dedicated coil. The typical transverse coverage of a standard head coil is 25–30 cm, whereas to optimize the signal-to-noise ratio for a neonatal brain a transverse coverage of 15–20 cm should be required. Even though a dedicated neonatal head coil is usually not offered by the majority of manufacturers, a variety of quadrature extremity coils are well suitable for the neonatal head. These type of coils should be used instead of standard head coils in the routine examination of the neonatal brain. For evalu-

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Fig. 6.2. Severe HIE, acute-subacute pattern (6 days after injury). Axial CT images. The affected cortical and deep gray matter (arrows) exhibit diffuse hyperdensity, whereas the white matter is still diffusely hypodense

ating brain by means of SENSE-like techniques, a new generation of coils has been designed. The SENSE head coil has a relatively small diameter and seems easily suitable for neonatal imaging.

tocol should first of all provide good quality T1- and T2-weighted images with a maximum field of view of 16–18 cm and a slice thickness of 3–4 mm. Only as a second step should other sequences be considered.

c) Conventional Sequences

T1-weighted sequences. A conventional spin-echo sequence with TR shorter than 600 ms and TE shorter than 15 ms is still the sequence of first choice in evaluating neonates with HIE. Inversion recovery sequences offer an extremely high contrast between gray and white matter and between myelinated and unmyelinated white matter. With fast inversion recovery techniques this result is now obtained in few minutes. However, in our experience conventional spin-echo T1-weighted images have exhibited greater contrast than fast inversion recovery sequences in the evaluation of hyperintense lesions secondary to

For conventional MR imaging of neonatal HIE, the basic information that still remains necessary is represented by T1- and T2-weighted images. In our experience, proton-density and FLAIR images have not been mandatory. T1- and T2-weighted images reliably depict the typical MRI features of anoxic-ischemic damage. This should be considered when a pulse sequence protocol is tailored for the neonatal brain, particularly in newborns that undergo MR examination without sedation. A neonatal MR imaging pro-

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anoxic-ischemic insult, both in premature and fullterm newborns. T2-weighted sequences. To achieve good contrast resolution between gray and unmyelinated white matter, conventional spin-echo (CSE) sequence parameters should be different from those used for adult brain imaging [7]. This is particularly true for T2-weighted images, where a TR of at least 3,000 ms and a TE of at least 120 ms should be selected to obtain sufficiently high contrast between gray and unmyelinated white matter. The major disadvantage of CSE T2-weighted sequence with a TR of 3 sec is the long acquisition time. For this reason, the use of fast spin-echo (FSE) T2-weighted sequences is progressively growing. The shorter acquisition time of FSE T2-weighted sequences is more suitable for a neonatal study without sedation. Moreover, the accuracy of both techniques appears to be similar [8]. However, the progressive loss of T2 paramagnetic effects with the increase of echo train length must be considered, particularly in case of HIE with suspected hemorrhagic components.

neurologic/cognitive outcome have not been fully determined [9]. Due to a progressive decrease of signal-to-noise ratio, longer b values are presently not used in neonatal diffusion imaging. Values between 600 and 700 are usually reported. MR spectroscopy. Recently, proton magnetic resonance spectroscopy (1H-MRS) has allowed one to study normal metabolite concentrations in the human brain at different developmental stages, providing a better understanding of the pathophysiological mechanisms in the neonatal brain [10]. Single voxel techniques are now reliable and faster; thus, 1H-MRS has become an important tool in the evaluation of neonatal brain, particularly regarding metabolic and anoxic injuries. It was recently demonstrated that 1H-MRS is even more accurate than DWI in the acute detection of perinatal asphyxia [11].

d) Advanced Imaging Techniques

6.4 Conventional MRI Features in HIE

Diffusion-weighted imaging (DWI). Diffusion imaging has rapidly proved to be an exciting technique, thanks to the availability of very strong and rapidly acting gradients. New generation high-field MR units routinely offer DWI sequences along the three orthogonal planes, with a b value of usually 1,000, together with the mean of the three images (the so-called trace), in order to limit the difference in signal intensity related to white matter anisotropy. To obtain reliable information from DWI, the calculation of the apparent diffusion coefficient (ADC) is necessary. Parametric images of calculated ADC can easily differentiate truly modified diffusion values from artifact due to T2 contamination (i.e., T2 shine-through). More recent developments in diffusion techniques have made it possible to obtain both longer b values (up to 10,000) and a greater number of axes to apply diffusion gradients. The latter capability permits calculation of not only the ADC but also the dominant diffusion vector for each voxel and the relative anisotropy (RA) values for different tissues (diffusion tensor imaging: DTI). Both ADC and RA rapidly change with gray and white matter maturation and development, and can be variably affected by different neonatal injuries, first of all by ischemic-anoxic injury. Thus, DTI seems to have a dramatic potential in the investigation of both neonatal brain maturation and injuries. However, one should keep in mind that correlations between abnormalities on DTI and

Neuroradiological counterparts of neuropathologic lesions are still not completely elucidated. Barkovich [12] subdivided MRI findings in the term infant with HIE according to the severity of hypotension. In case of mild to moderate hypotension, typical MRI features are mainly characterized by parasagittal lesions involving vascular boundary zones, whereas profound hypotension involves primarily the lateral thalami, posterior putamina, hippocampi, and corticospinal tracts including the perirolandic gyri, but mainly sparing the remaining cortex. Independently from the severity of the hypoxiahypotension and according to recent insights on the neuropathology and pathogenesis of HIE, it seems that parasagittal lesions occurring in the vascular boundary zones are primarily, if not exclusively, related to hypotension. Instead, lesions of the basal ganglia, perirolandic area, and hippocampi are primarily related to impairment of energy substrates that selectively damages areas with higher metabolic requirements or with higher regional distribution of glutamate receptors, particularly of the NMDA type. However, it seems evident that some overlap between these two conditions is possible. To a large extent, the reason why individual infants with ischemia may primarily develop either PCI or the various patterns of SNN is not entirely clear. However, the severity and the temporal characteristics of the insult are likely to be very important factors [1].

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6.4.1 Selective Neuronal Necrosis In our personal experience, the most frequent type of injury on MRI in term newborns consists of selective involvement of areas with higher energy requirements, i.e., the lateral thalami, posterior lentiform nuclei, hippocampi, and perirolandic cortex. A. Thalami and lentiform nuclei. The thalami are involved most frequently in their ventro-lateral portions, whereas involvement of lentiform nuclei basically occurs in the posterior portion of the putamina. In the acute phase, when diffuse brain edema predominates (Fig. 6.3), the thalami and lentiform

nuclei can be relatively hypointense to isointense with respect to normal thalami and lentiform nuclei on T1weighted images and hyperintense on T2-weighted images. They progressively become hyperintense on T1-weighted images after 3–7 days from the insult, and eventually hypointense on T2-weighted images a little later (6–10 days) (Fig. 6.4) [13]. In the very acute phase, it can be difficult to detect signal abnormalities on both T1- and T2-weighted images. However, it was reported that CSE T2-weighted sequences with TR 3,000 ms and TE 60 ms may confidently show isointensity of the deep gray matter nuclei with the white matter, instead of the normal hypointensity [14]. Some difficulties can arise in differentiating pathological T1 hyperintensities from normal myelination in milder forms of HIE. As pointed out by Ruth-

Fig. 6.3a,b. Severe HIE, early acute pattern (first day) on conventional MRI. a Axial T2-weighted image; b axial T1-weighted image. There is diffuse, slight T2 hyperintensity and T1 iso-hypointensity at the level of thalami and lentiform nuclei

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Fig. 6.4a–f. Different degrees of putaminal-thalamic neuronal injury during the acute-subacute phase (1 week). a, c, e Axial T1weighted images; b, d, f axial T2-weighted images. a, b Only the posterior part of the putamen seems to be involved; c, d more typical putaminal-thalamic variant; e, f more diffuse involvement of deep structures is evident. Note that, at this time, lesions are hypointense on T2-weighted images

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erford [15], a complete loss or change in the normal signal intensity of the posterior limb of internal capsule (PLIC) may be seen following perinatal asphyxia. The posterior part of PLIC is normally myelinated in full-term newborns, whereas the signal from myelin may be diminished in case of anoxic insult. Conversely, the thalami and lentiform nuclei adjacent to PLIC show a clear-cut increase in signal intensity (Fig. 6.5). According to Rutherford et al.[16], absence of a normal PLIC in asphyxiated infants has a high positive predictive value (100% of abnormal neurodevelopmental outcome). Different hypotheses can account for the characteristic T1 shortening of the lateral thalami and

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posterior putamina that becomes appreciable after 3–5 days. Among these, cellular reaction of glial cells and macrophages containing lipid droplets [17] and micromineralization of necrotic cells occurring in neurons or swollen axons near perinatal lesions [18] could be significant factors. Other locations. In order of frequency, other locations of brain involvement in full-term newborns with HIE include the perirolandic and primary auditory cortex and optic radiation (Fig. 6.6), the hippocampal formation and limbic cortex (Fig. 6.7), and the dorsal mesencephalic structures (Fig. 6.7). The evolution of the MRI signal intensity pattern in these locations is

Fig. 6.5a,b. Putaminal-thalamic neuronal injury. a Axial T1-weighted image, normal control; b axial T1-weighted image, newborn with HIE: a on normal images, the most hyperintense structure is the posterior limb of the internal capsule; b in putaminal-thalamic neuronal injury, the most hyperintense structures are the posterior part of lentiform nuclei and the medial aspects of the thalami

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Fig. 6.6a–c. Moderate HIE one week from injury. a–c Axial T1-weighted images. Abnormal T1 hyperintensity is present at the level of primary auditory cortex (thin arrows, a, b) and motor cortex (arrow, c), as well as in the optic radiations (thick arrows, a, b)

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similar to that described for thalamic and putaminal lesions. Of note, milder HIE can show only small bilateral putaminal or lateral thalamic lesions (Fig. 6.4), whereas more severe HIE shows involvement of both deep and superficial gray matter. Moreover, as reported by Barkovich [12], thalamic and lenticular lesions, as well as mesencephalic lesions, can also be detected in premature newborns with documented severe HIE, most frequently in association with typical periventricular white matter injuries (Fig. 6.8).

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The evolution of selective lesions is characterized by progressive atrophy of the basal ganglia and thalami, with possible transitory cavitation and persistent T2 hyperintensity in the damaged rolandic cortex (Figs. 6.9–11). The timing of disappearance of T1 hyperintensities is still not completely understood. However, it is a matter of fact that, after a couple of months from the anoxic insult, they are no longer detectable, except for particularly severe cases (see below), in which they tend to coalesce and progressively correspond to calcifications detectable on CT.

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Fig. 6.7a–c. Severe HIE, 1 week from injury. a–c Axial T1-weighted images. The limbic system is involved at the level of the hippocampus (arrows, a, b) and cingulate gyrus (arrows, c). The dorsal mesencephalon and superior vermis also show abnormal hyperintense signal (a)

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Fig. 6.8a, b. HIE in a 35 gestational weeks premature newborn, 2 weeks after the insult. a, b Axial T1-weighted images. There is diffuse hyperintensity of thalami and lentiform nuclei, as well as thin periventricular hyperintensities (arrows), more typical of premature injury

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Fig. 6.9a–c. Same case of Fig. 6.7a–c Axial T1-weighted images, 1 month after injury. The involvement of the limbic system is confirmed by significant bilateral hippocampal atrophy (a). Cavitations ensue at the level of thalami and lentiform nuclei (b), whereas diffuse involvement of rolandic areas and superior frontal gyri is also evident (c)

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Fig. 6.10a–d. Moderate HIE. a, c Axial T1-weighted images and b, d axial T2weighted images at 1 week after insult (a, b) and at three years of age (c, d). Follow-up study shows hypotrophic thalami, appearing hyperintense on T2-weighted image and slightly hypointense on T1-weighted images. Slight T2 hyperintensity is also visible at the level of the posterior part of lentiform nuclei

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Fig. 6.11a–c. Moderate to severe HIE, end stage (1 year follow-up). a, b Axial T2weighted images; c axial CT image. Thalamic hypotrophy is evident on both MRI and CT. The postero-lateral aspects of thalami are hyperintense on T2-weighted images and slightly hyperdense on CT. The rolandic cortex (b) is thin, and the subcortical white matter is hyperintense on T2-weighted images

Similar to premature infants with periventricular leukomalacia, midsagittal MR images will often show thinning of the corpus callosum, most commonly involving the middle or posterior body, resulting from degeneration of transcallosal fibers.

6.4.2 Multicystic Encephalomalacia When the anoxic insult is particularly severe and prolonged, a diffuse damage of the brain ensues.

Brain swelling with diffuse T1 hypointensity and T2 hyperintensity can be detected in the first 2– 3 days, followed by marked T1 hyperintensity and T2 hypointensity involving the basal ganglia and thalami. The lesions rapidly evolve in cavitation, with the final aspect of multicystic encephalomalacia (Figs. 6.12, 13). Calcifications can be detected on CT within the first 3–4 weeks after the anoxic insult (Fig. 6.13). The only preserved regions in multicystic encephalomalacia are the medulla oblongata and cerebellum.

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Fig. 6.12a–d. Severe and prolonged HIE. a, b Axial T1-weighted images at 1 week; c axial and d coronal T1-weighted images at 3 weeks after the insult. Initial study shows diffuse gray matter hyperintensities (a, b). Follow-up study (c, d) shows diffuse cavitations and brain atrophy (multicystic encephalomalacia)

6.4.3 Parasagittal Lesions In our experience, isolated parasagittal lesions are far less common that deep ones. They are usually associated with milder forms of HIE, and typically involve the parasagittal cortico-subcortical frontoparietal, and sometimes occipital, regions. During the acute phase, the affected cortex shows increased

T2 signal intensity and decreased T1 signal intensity, related to the presence of edema. Cortical T1 hyperintensities can be found after 4–7 days from the insult (Fig. 6.14). As the lesion evolves, cortical shrinkage with marked cortical thinning becomes evident. This pattern forms a typical mushroom-shaped aspect of the affected gyri, called ulegyria by neuropathologists (Fig. 6.15) [18].

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Fig. 6.13a–f. Severe and prolonged HIE. a Axial T1-weighted and b axial T2-weighted images 1 week after the insult. c Axial T1weighted image, d axial T2-weighted image, and e, f axial CT images 1 month after the insult (e, f). The MR study in the subacute phase (a, b) shows marked gray matter hyperintensity on T1- weighted images and hypointensity on T2-weighted images. One month follow-up study shows striking diffuse cavitations and brain atrophy, with basal ganglia calcifications on CT

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Fig. 6.14a, b. Parasagittal lesions 1 week after the insult. a Coronal T1-weighted image; b axial proton density-weighted image. Bilateral parasagittal cortical hyperintensities are evident on both T1- and PD-weighted images (arrows)

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Fig. 6.15a–c. Parasagittal lesions. a Axial CT during subacute phase (10 days after injury); b, c axial T1-weighted images during chronic phase (9 months after injury). The lesions are particularly severe, and ulegyric cortex is detectable on follow-up MR study. The rolandic strip and basal ganglia seem almost partly preserved

6.5 Advanced MRI Features of HIE 6.5.1 Diffusion Imaging Preliminary reports suggest that DWI may be useful in the early detection of perinatal brain ischemia, even though some limitations can occur in the very early phases of injury. Robertson et al. [19] reported 12 patients with diffuse perinatal ischemia, in whom line-scan DWI was performed between 13 hours and 8 days from perinatal asphyxia. Line-scan DWI mainly showed deep gray matter and perirolandic white matter lesions earlier than conventional MR imaging, even though it may underestimate the eventual extent of injury. Delayed neuronal and oligodendroglial cell death due to apoptosis in areas with lower metabolic demand is one of the most intriguing factors that can explain DWI underestimation of final injury extent [20]. Barkovich et al. [11] reported 7 patients with HIE studied with DWI within 24 hours of injury. In that study, diffusion images showed small abnormalities in the lateral thalami or internal capsules in all seven patients, whereas T1-weighted images were normal in all; T2-weighted images were normal in three patients and showed T2 prolongation in the basal ganglia or white matter in the other four. Comparison with clinical course in all seven patients and with

follow-up MR studies in four showed that diffusion images underestimated the extent of brain injury. Very recently, McKinstry et al. [21] prospectively evaluated DTI in ten newborns with HIE during the first week of life; they confirmed that MR diffusion images obtained on the first day after injury do not necessarily show the full extent of ultimate injury in newborn infants. According to these recent studies, the current role of DWI techniques in the evaluation of acute HIE can be summarized as follows: a) Images obtained during the first 24 hours after injury can demonstrate focal abnormalities not recognized by conventional acquisition techniques; however, they do not necessarily show the full extent of ultimate injury in newborn infants (Figs. 6.16–20); b) Images obtained between the second and fourth days of life (when conventional images can still be negative or poorly informative) reliably indicate the extent of injury (Fig. 6.21); c) By 7–10 days, DWI is progressively less sensitive to perinatal brain injury, due to the transient pseudonormalization of diffusion images. During this period, conventional images can be more sensitive than diffusion (Fig. 6.22); d) Overall, even though diffusion imaging can readily demonstrate whether brain lesions followed perinatal asphyxia, it may not be suitable as a gold standard for detection of brain injury during the first day after injury in newborn infants.

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Fig. 6.16a–e. Moderate to severe HIE, first day study. a Axial T1-weighted image; b axial post-Gd T1-weighted image; c axial T2weighted image; d, e diffusion-weighted images (diffusion gradient through the slices). Conventional pre- and postcontrast images show diffuse brain edema without evidence of focal lesions. Diffusion-weighted images show abnormal hyperintense signal involving both thalami (arrows, d, e), as well as the white matter of the left cerebral hemisphere

6.5.2 MR Spectroscopy Markedly elevated lactate levels in infants suffering from severe perinatal asphyxia were first reported about 10 years ago [22]. In that paper, 1H-MRS data demonstrated regional differences in lactate elevation, with greater increase in Lac/NAA ratio in the basal ganglia than in the occipitoparietal cerebrum. This approximately corresponded to signal abnormalities that were observed with early DWI after term hypoxia-ischemia. However, differently from DWI, MR spectroscopy performed in the first 24 hours after birth is sensitive to the presence of hypoxic-ischemic brain injury, and seems to be suitable as a gold stan-

dard for detection of brain injury during the first day after injury in newborn infants [11]. Moreover, as recently reported both by Zarifi et al. in a study on 26 full-term infants with HIE [23] and by Cappellini et al. [24], higher lactate-choline ratios in basal ganglia and thalami of infants with perinatal asphyxia are predictive of worse clinical outcomes. Absolute ADC values in the same brain regions did not indicate a statistically significant relationship with clinical outcome. Therefore, cerebral lactate levels seem to be more useful than DWI techniques in identifying infants who would benefit from early therapeutic intervention.

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Fig. 6.17a–h. Severe HIE, same case of Fig. 6.3 a, b axial T2-weighted images; c, d axial T1-weighted images; e, f diffusion-weighted images (trace); g, h ADC images (trace). Conventional T1- and T2-weighted images show diffuse edema. Both the basal ganglia and rolandic cortex are roughly isointense with white matter on both sequences (arrows, b, d). Both diffusion weighted and ADC sequences demonstrate abnormal diffusion within superficial and deep gray matter, although signal abnormalities are more striking at the level of the rolandic cortex (arrows, f, h)

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Fig. 6.18a–d. Diffusion-weighted and ADC images: comparison between a neonate with severe HIE (a, c) (same case of Fig. 6.17) and a normal newborn (b, d). Notice severe signal abnormality of perirolandic gray matter in the patient with HIE (a, c)

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Fig. 6.19a–d. Same patient of Fig. 6.17, 1-month follow-up. Sagittal T1weighted images on first day (a, b) and after 1 month (c, d). Comparison between first day exam (a, b) and 1month follow-up (c, d) demonstrates good prediction value of first day diffusion studies (see Fig. 6.17). The gray matter is diffusely involved, with eventual multicystic encephalomalacia. However, chronic evolution of gray matter injury displays some differences between gray matter areas that are more frequently involved in HIE (i.e., rolandic cortex, putamen, thalamus, etc.) and the remaining cortex. While the latter shows typical cystic or malacic pattern, the former still exhibits clear-cut T1 hyperintense signal (arrows, c, d), probably due to the different histological composition of more “mature” gray matter: more myelin, more synapses, more dendrites, etc.

Fig. 6.20a–c. Moderate HIE. a Axial T1weighted image and b diffusion-weighted images on day 1; c axial T1-weighted image after 1 week. Acute-stage diffusion-weighted image clearly shows the involvement of thalami (arrow, b) and optic radiation, whereas auditory cortex and putaminal injuries are not seen. However, both putaminal and thalamic involvement is evident on conventional imaging after 1 week

b

Fig. 6.21a,b. Mild HIE. a, b Diffusion-weighted images after 3 days. Small lesions in limbic system at the level of the hippocampal formation (arrows, a) and isthmus of cingulated gyrus (arrows, b) were only shown by diffusion images. The lesions were confirmed in follow-up study

a

b

c

d

Fig. 6.22a–d. Moderate HIE with parasagittal lesions, study at 10 days. a Axial T1weighted image; b axial T2-weighted image; c diffusion-weighted image; d ADC image. Conventional sequences better show the real extent of injury. Diffusion-weighted and ADC images show only part of the lesions (arrows, c, d)

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6.6 Ischemic Infarction in the Newborn Typical neonatal focal infarction ensues within 2– 3 days from birth, and presents more commonly with seizures [1]. The greater part of neonatal infarctions are idiopathic. Among the recognizable forms, coagulopathies are the most common cause. However, it is a fact that during the first 2–3 days of life the newborn baby is at greater risk for focal cerebral infarction. Therefore, a correlation with the complex hemodynamic changes occurring during the first minutes and hours of extrauterine life must be considered. During the first 2 days, cranial ultrasounds are poorly sensitive in the detection of focal cerebral infarction. When visible, infarction appears as an area of slight hyperechogenicity, ill-defined and difficult to evaluate in its peripheral cortical extension due to the limited field of view of ultrasonography.

a

6.6.1 MRI Features MRI is the technique of choice in evaluating neonatal focal cerebral infarctions. DWI is the best modality to identify infarction in the acute phase [19]. DWI shows striking increase in signal intensity in the acute phase of the infarction, similarly to that demonstrated in the adult age group. A clear-cut decrease of ADC values (Fig. 6.23) can as well be easily detected in calculated images. Both DWI and ADC images can define more precisely than conventional imaging the extension of the focal infarction, even in the hyperacute phase. The signal intensity on DWI usually normalizes after 6–10 days. On both T1- and T2-weighted images, acute infarction appears as a “missed” cortical segment (Fig. 6.23). The edematous cortex shows increase of T2 signal intensity and decrease of T1 signal intensity, thus approaching the signal intensity of the unmyelinated white matter; this results in the “disappeared cortex” sign. Large infarcts, especially when they involve the basal ganglia, are frequently hemorrhagic, and paramagnetic aspects of degradation products of hemoglobin can be detectable after few days (Fig. 6.24).

b

c Fig. 6.23a–c. Acute arterial infarction, first day exam. a Axial T1-weighted image; b axial T2-weighted image; c ADC image. On both T1- and T2-weighted images acute infarction appears as a “missed” cortical segment (arrows, a, b) due to gray matter edema. In cortical infarction, the ADC technique (c) is usually more reliable in defining the final extent of injury, even in the first day of injury

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b

References 1. Volpe JJ. Neurology of the Newborn, 4th edn. Philadelphia: Saunders, 2001. 2. Chugani HT, Phelps ME, Mazziotta JC. Positron emission tomography study of human brain functional development. Ann Neurol 1987; 22:487–497. 3. Connolly B, Kelehan P, O’Brien N, Gorman W, Murphy JF, King M, Donoghue V. The echogenic thalamus in hypoxic ischaemic encephalopathy. Pediatr Radiol 1994; 24:268– 271. 4. Stark JE, Seibert JJ. Cerebral artery Doppler ultrasonography for prediction of outcome after perinatal asphyxia. J Ultrasound Med 1994; 13:595–600. 5. Roland EH, Poskitt K, Rodriguez E, Lupton BA, Hill A. Perinatal hypoxic-ischemic thalamic injury: clinical features and neuroimaging. Ann Neurol 1998; 44:161–166. 6. Triulzi F, Baldoli C, Parazzini C. Neonatal MR imaging. Magn Reson Imaging Clin N Am 2001; 9:57–82. 7. Nowell MA, Hackney DB, Zimmerman RA, Bilaniuk LT, Grossman RI, Goldberg HI. Immature brain: spin-echo pulse sequence parameteres for high-contrast MR imaging. Radiology 1987; 162:272–273 8. Engelbrecht V, Malms J, Kahn T, Grunewald S, Modder U. Fast spin-echo MR imaging of the pediatric brain. Pediatr Radiol 1996; 26:259–264. 9. Neil J, Miller J, Mukherjee P, Huppi PS. Diffusion tensor imaging in normal and injured developing human brain – a technical review. NMR Biomed 2002; 15:543–552. 10. Huppi P. Advances in postnatal neuroimaging: relevance to pathogenesis and treatment of brain injury. Clin Perinatol 2002; 29:827–856. 11. Barkovich AJ, Westmark KD, Bedi HS, Partridge JC, Ferriero DM, Vigneron DB. Proton spectroscopy and diffusion imaging on the first day of life after perinatal asphyxia: preliminary report. AJNR Am J Neuroradiol 2001; 22:1786– 1794. 12. Barkovich AJ. Pediatric Neuroimaging, 3rd edn. Philadelphia: Lippincott Williams & Wilkins, 2000. 13. Barkovich AJ, Westmark K, Partridge C, Sola A, Ferriero DM. Perinatal asphyxia: MR findings in the first 10 days. AJNR Am J Neuroradiol 1995; 16:427–438. 14. Barkovich AJ, Hajnal BL, Vigneron D, Sola A, Partridge JC,

Fig. 6.24a,b. Subacute arterial infarction, 1week exam. a Axial T1-weighted image; b axial T2-weighted image. The deeper part of the lesion shows some T1 hyperintensity and T2 hypointensity, probably due to degradation products of hemoglobin

Allen F, Ferriero DM. Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring system. AJNR Am J Neuroradiol 1998; 19:143–149. 15. Rutherford MA. MRI of the Neonatal Brain. London: WB Saunders, 2002. 16. Rutherford MA, Pennock JM, Counsell SJ, Mercuri E, Cowan FM, Dubowitz LM, Edwards AD. Abnormal magnetic resonance signal in the internal capsule predicts poor developmental outcome in infants with hypoxic-ischemic encephalopathy. Pediatrics 1998; 102:323–328. 17. Schouman-Claeys E, Henry-Feugeas MC, Roset F, Larroche JC, Hassine D, Sadik JC, Frija G, Gabilan JC. Periventricular leukomalacia: correlation between MR imaging and autopsy findings during the first 2 months of life. Radiology 1993; 189:59–64. 18. Friede RL. Developmental Neuropathology, 2nd edn. Berlin: Springer, 1989:534–545. 19. Robertson RL, Ben-Sira L, Barnes PD, Mulkern RV, Robson CD, Maier SE, Rivkin MJ, du Plessis A. MR line-scan diffusion-weighted imaging of term neonates with perinatal brain ischemia. AJNR Am J Neuroradiol 1999; 20:1658– 1670. 20. Pulera MR, Adams LM, Liu H, Santos DG, Nishimura RN, Yang F, Cole GM, Wasterlain CG. Apoptosis in a neonatal rat model of hypoxia-ischemia. Stroke 1998; 29:2622–2630 21. McKinstry RC, Miller JH, Snyder AZ et al. A prospective, longitudinal diffusion tensor imaging study of brain injury in newborns. Neurology 2002;59:824–33 22. Groenendaal F, Veenhoven RH, van der Grond J, Jansen GH, Witkamp TD, de Vries LS. Cerebral lactate and N-acetylaspartate/choline ratios in asphyxiated full-term neonates demonstrated in vivo using proton magnetic resonance spectroscopy. Pediatr Res 1994; 35:148–151. 23. Zarifi MK, Astrakas LG, Poussaint TY, Plessis Ad A, Zurakowski D, Tzika AA. Prediction of adverse outcome with cerebral lactate level and apparent diffusion coefficient in infants with perinatal asphyxia. Radiology 2002; 225:859– 870. 24. Cappellini M, Rapisardi G, Cioni ML, Fonda C. Acute hypoxic encephalopathy in the full-term newborn: correlation between Magnetic Resonance Spectroscopy and neurological evaluation at short and long term. Radiol Med 2002; 104:332–340.

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7

Cerebrovascular Disease in Infants and Children Robert A. Zimmerman and Larissa T. Bilaniuk

CONTENTS 7.1

Introduction 257

7.2 7.2.1 7.2.2 7.2.3 7.2.4 7.2.5 7.2.6 7.2.7 7.2.7.1 7.2.7.2 7.2.7.3 7.2.7.4 7.2.8 7.2.9 7.2.10

Imaging Approach to Cerebrovascular Disease 257 Conventional Ultrasound 258 Transcranial Doppler Ultrasound 258 Computed Tomography 258 Computed Tomographic Angiography 259 Magnetic Resonance Imaging 259 Magnetic Resonance Arteriography and Venography 260 Magnetic Resonance Diffusion-Weighted Imaging 260 Trace 261 CSF and Fluid Spaces 261 Gray Matter 261 White Matter 261 Magnetic Resonance Perfusion 262 Magnetic Resonance Spectroscopy 262 Conventional Angiography 262

7.3 7.3.1 7.3.2 7.3.2.1 7.3.2.2 7.3.2.3 7.3.3 7.3.4 7.3.4.1 7.3.4.2 7.3.4.3 7.3.4.4 7.3.5 7.3.5.1 7.3.5.2 7.3.5.3 7.3.5.4 7.3.5.5 7.3.6 7.3.7 7.3.8 7.3.9 7.3.10

Childhood Cerebrovascular Disease 262 Sickle Cell Disease 263 Vasculitis 265 Infectious 265 Takayasu’s Arteritis 266 Other Vasculitides 266 Heart Disease 266 Hypercoagulable States with Thrombosis 268 Protein C and S Deficiency 268 Antiphospholipid Antibodies 268 Homocystinuria 268 Chemotherapeutic Agents 269 Primary and Secondary Vascular Wall Disease 269 Ehlers-Danlos Syndrome 269 Neurofibromatosis Type I (NF1) 269 Fibromuscular Dysplasia 270 Moyamoya Syndrome 270 Radiation Vasculopathy 270 Congenital Vascular Hypoplasia 271 Vascular Trauma 273 Migraine Headaches 275 Metabolic Diseases 275 Hypoxia 275

7.4 7.4.1 7.4.2 7.4.3 7.4.4 7.4.5

Nontraumatic Intracerebral Hemorrhage 277 Cerebral Aneurysms 277 Hemorrhagic Infarction 279 Coagulopathies 279 Hypertension 279 Sinovenous Occlusion 280

7.5

Conclusions 282 References

283

7.1 Introduction The nature of cerebrovascular disease affecting the pediatric patient is different from that in the adult. Atherosclerotic sources of thrombotic occlusion and thrombotic or plaque emboli are not usually an issue in infants and children. The nature of cerebrovascular injury in infants and children is dependent on the age at which the insult occurs and the mechanism of the insult. Insults in the premature infant, which consist of periventricular leukomalacia (PVL) and germinal matrix hemorrhages (GMH) (see Chapter 5), are quite different and distinct from injuries in term infants, who sustain deep gray matter infarctions, parasagittal watershed infarctions and middle cerebral artery infarctions (see Chapter 6). The term infant injuries are somewhat, but not that different from those that occur in children beyond infancy. Complicating the large number of different etiologies for the primary cerebrovascular pediatric diseases that result in injuries, such as infarctions and bleeds, there are the secondary cerebrovascular disease processes that have arisen due to various recent therapeutic methods and innovations in dealing with neoplastic diseases. For example, leukemia and brain neoplasms require chemotherapy and radiation therapy and at times also bone marrow transplantation. The spectrum of pediatric cerebrovascular disease includes thrombotic infarction secondary to chemotherapy, radiation-induced vasculopathy, and infarctions and aggressive infections related to aspergillosis in immunosuppressed patients (see Chapter 11).

7.2 Imaging Approach to Cerebrovascular Disease The imaging evaluation of the patient with cerebrovascular disease will depend on the age of the patient (fetus, infant, child, adolescent), the acuteness and stability of the illness, the availability of

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imaging modality, and the knowledge and skill of the people ordering and performing the examinations. The options include conventional ultrasound (US), computed tomography (CT), computed tomographic angiography (CTA), magnetic resonance imaging (MRI), magnetic resonance angiography divided into magnetic resonance arteriography (MRA) and magnetic resonance venography (MRV), magnetic resonance spectroscopy (MRS), magnetic resonance diffusion weighted imaging (DWI), magnetic resonance perfusion imaging (PI), and conventional cerebral arteriography.

7.2.1 Conventional Ultrasound US is limited to the neonatal and infant age group because of the need for an acoustic window, i.e., the anterior fontanelle. Once the fontanelle closes, the window is gone. The advantages of US are its portability to the crib-side of sick infants, its lack of need for sedation, and its relatively quick study time. Ventricular enlargement or compression, the presence of central brain bleeds, the shift of the midline structures, and the presence of gross areas of brain edema are findings that can be demonstrated with US. The disadvantages are that large areas of the brain are usually not visualized and therefore not examined, such as portions of the frontal lobes and the posterior parietal and occipital lobes. The posterior fossa is rarely studied successfully unless additional acoustic windows are utilized. The differentiation of hemorrhage within the white matter from ischemic infarction is not accurate, and the recognition of small areas of PVL or even large symmetric areas of PVL is not necessarily easy. The use of US in infants is operator dependent and, therefore, it is the skill of the technician or doctor who performs the examination that either maximizes or minimizes the information obtainable.

7.2.2 Transcranial Doppler Ultrasound Transcranial Doppler (TCD) ultrasound is also a technique that requires very skilled acquisition of data. TCD is used to measure the velocity of flow in cm/s in the major vessels at the circle of Willis. Knowledge of the vascular anatomy is critical if reproducible results are to be obtained. With good data, TCD can be used to demonstrate both reduced and increased velocity of flow in the internal carotid and middle cerebral

arteries, which reflects change in caliber of a vessel, i.e., stenosis.

7.2.3 Computed Tomography CT is the initial imaging test in most children and adolescents presenting with acute stroke symptoms, whether it is due to ischemic infarction or to a hemorrhagic bleed within the brain. Unless an arteriovenous malformation (AVM), infection, or a tumor is suspected, most CT is done without contrast enhancement. Single slice helical or spiral scanning takes only minutes to perform a brain study. Multiple slice CT (4 slice) takes on the order of a minute or less. These rapid scan times have decreased the need for sedation in emergency patients. Strokes are shown as hypodensity of the involved area of the brain with mass effect depending on the size and age of the infarction. Mass effect in larger ischemic infarcts is seen by 24 h post ictus, progresses for several days, and then resolves. Hypodensity in the mature myelinated brain of the older child and adolescent begins as a blurring of gray/white matter definition [1], followed by clear-cut lower density at the site of infarction. Loss of density can be seen as early as 6 h after ictus [2]. The presence of a thrombus or calcific embolus in the middle cerebral or basilar arteries may be seen as hyperdensity (Fig. 7.1) [3]; however, while frequent in adults, in our own experience it has been uncommon in children. Moreover, a slightly dense basilar artery is usually normal in children as long as its density is similar to that of the internal carotid arteries. Contrast enhancement occurs at the site of infarction, once the blood brain barrier (BBB) becomes open with the ingrowth of new vessels. Generally, some enhancement can be seen as early as 3–5 days post ictus and it can last for 3–5 weeks. Reabsorption of infarcted tissue produces encephalomalacia. In the basal ganglia, thalamus, and brainstem, chronic cystic changes are referred to as lacunar infarctions. Atrophy in the form of ventricular dilatation and sulcal prominence accompanies the chronic stages of larger cerebral infarctions. Demonstration of acute hemorrhage is a particularly important aspect of CT. The globin molecule of hemoglobin is dense, absorbing more of the x-ray beam than the adjacent brain. Hounsfield units (HU) for clots are in the 50–100 range, denser than brain, less dense than calcification [4]. Localization of the site of blood, parenchymal, ventricular, subarachnoid (SAH), subdural, or epidural, is relatively accurate with CT.

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Fig. 7.1. Thrombosis of the left middle cerebral artery. Unenhanced axial CT. A thrombosed hyperdense (arrow) left middle cerebral artery is seen. Subsequent MRI (not shown) demonstrated a large left middle cerebral artery infarction

SAH is best seen on CT, with fluid attenuated inversion recovery (FLAIR) MR sequence as a second option (Fig. 7.2) [4]. Blood within the brain takes approximately 3 h to undergo clot retraction, during which time serum exudes and the hematoma becomes more dense [5]. The extruded serum may be helpful in outlining the hematoma. Surrounding vasogenic edema within the adjacent brain is also not uncommon, a manifestation of adjacent cerebral injury secondary to the process producing the bleeding and the bleeding itself. With time, the globin molecule breaks down and the density of the clot is lost [6]. For example, it takes about 24 days for a 2.5 cm clot to become isodense to the brain, and still later to become hypodense [6]. Ultimately, all but a slit-like collection of hemosiderin will remain, along with adjacent changes due to the damage caused by the bleed and/or the process that produced the bleeding (i.e., AVM, aneurysm, etc.).

a

b Fig. 7.2a,b. Subarachnoid hemorrhage in a 16-month-old female. a Unenhanced axial CT; b axial FLAIR image. CT scan (a) shows hyperdense blood outlining the midbrain, part of the chiasmatic cistern, and the left cerebellar sulci. There is early hydrocephalus with dilatation of the temporal horns. MRI at the level of the odontoid through the upper cervical spinal canal shows the cervical spinal cord to be bathed in subarachnoid blood which is bright. A fluid level (arrow, b) is present superiorly

7.2.4 Computed Tomographic Angiography CTA is the rapid acquisition of data utilizing spiral or helical CT during the bolus injection of iodinated contrast material, and then 3D reconstruction of the data set. The main application of this technique has been to study adults with aneurysms, although there is no reason why this should not be used in children as well. The main limitation in children has been related to the size and rapidity of the bolus contrast material injection when venous access is limited.

7.2.5 Magnetic Resonance Imaging In older infants and children, once myelination of the brain is complete, standard T1- and T2-weighted pulse sequences can demonstrate acute, subacute, and chronic infarcts, blood products, and vascular flow voids in a manner sufficient to diagnose many of the routine vascular diseases (Fig. 7.3). FLAIR imaging

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a

b

c

Fig. 7.3a–c. Watershed (partially hemorrhagic) infarctions in parasagittal distribution in a congenital heart disease patient. a Axial T2 weighted image (6000/99); b axial FLAIR image; c axial DWI. Bilateral parasagittal watershed high signal intensity abnormalities consistent with infarcts are seen (a). Within the areas of high signal intensity are lower signal intensity zones of deoxyhemoglobin. FLAIR image (b) shows the bilateral parasagittal watershed infarcts between the anterior and middle cerebral arteries anteriorly, and between the posterior cerebral and middle cerebral arteries posteriorly. DWI (c) shows restricted motion of water with high signal intensity bilaterally at sites of infarction.

demonstrates water within tissue to a much greater degree and more exquisitely than T2 turbo spin-echo imaging. With FLAIR, the water within the ventricles and sulci is black, but the water within the infarct generates a very bright signal intensity (Fig. 7.3) [7]. Gadolinium enhancement with T1-weighted images is used to demonstrate BBB disturbances in subacute infarction. Enhancement may be seen 3 days after infarction and can last for a variable period of time, from many weeks to months. Hemorrhage can be detected and its evolution characterized by MRI. T1-weighted images show oxyhemoglobin as isointense, deoxyhemoglobin as slightly hypointense, methemoglobin as bright, and hemosiderin as dark signal intensity. T2-weighted images show oxyhemoglobin as bright, deoxyhemoglobin as dark, intracellular methemoglobin as dark, extracellular methemoglobin as bright, and hemosiderin as dark. Gradient-echo T2*-weighted imaging is a valuable adjunct to routine MRI sequences. It demonstrates with great sensitivity blood products within cerebral tissue by a loss of signal (blackness) at the affected sites. The black foci of no signal are produced by dephasing of the protons that occur secondary to the paramagnetic effects of iron in the components and by-products of blood.

7.2.6 Magnetic Resonance Arteriography and Venography Today, MRA is performed to demonstrate both arteries and veins and to help characterize the nature of blood vessel abnormalities [8]. This can be done with 3D time-of-flight (TOF), 2D TOF, 3D phase contrast (PC), and 2D PC MRA. When there is hemorrhage present at the site of vessels investigated, PC MRA is utilized to avoid incorporation of the high signal intensity of the methemoglobin of the hematoma into the image of vascular flow. 3D TOF and 2D TOF are used for arteries and veins, respectively. A saturation pulse is applied at the top of the head when venous flow needs to be removed from the image, whereas a saturation pulse is applied at the bottom of the image of the brain when arteries need to be removed, such as when an MRV is performed.

7.2.7 Magnetic Resonance Diffusion-Weighted Imaging Random motion of water molecules arises predominantly from diffusion, but also the flow of blood from the capillary bed contributes to this effect. Although these effects can be separated, the techniques for doing this are difficult, so that usually the combined effect is measured and is called the apparent diffu-

Cerebrovascular Disease in Infants and Children

sion coefficient (ADC) [9]. Although the principle of the technique has been known for many years, DWI became available only a few years ago, because very strong rapidly acting gradients are required for in vivo studies, and these have only recently become available on whole-body MRI scanners. The apparent diffusion can be measured in any desired direction (x-, y-, or zaxis) by acquiring images in the presence of very large field gradients applied in that direction. Acquisition of a series of images with different gradients allows the ADC to be accurately quantitated. The effect of the motion of water molecules decreases the signal intensity from that expected as a result of the usual contrast mechanisms (T1, T2, T2*); regions of tissue with higher ADC will be less intense on the images. 7.2.7.1 Trace

The “trace” is the average of the ADC in three perpendicular directions. This value is relatively easy to measure, and like anisotropy, is indicative of the physiological state of the tissue [10]. In normal adult brain, the ADC values fall broadly into three different ranges that are characteristic of the three categories of material in the brain. 7.2.7.2 CSF and Fluid Spaces

The ADC values are those expected from unrestricted diffusion. The trace ADC values of CSF are about 3.0 × 103 mm2/s, and are the same in all directions (anisotropy) [11]. 7.2.7.3 Gray Matter

Tissue restricts the diffusion of water, so that the trace ADC values for gray matter are lower than that for CSF, lying in the range of 0.8–1.2 × 103 mm2/s. However, the restriction is the same in all directions, so there is no anisotropy [11]. 7.2.7.4 White Matter

The axon sheath acts as a significant barrier to the diffusion in a direction perpendicular to the fiber axis, and thus the ADC of white matter in the brain is isotropic, variable with the direction of measurement of the diffusion. The trace value is somewhat less than that of gray matter, and falls in the range 0.4–0.6 × 10 -3 mm2/s [11].

Following birth, the ADC changes in a fashion commensurate with the expected postnatal myelination [12]. The ADC of white matter decreases and becomes more anisotropic during the first 6 months. While there are many factors that affect the ADC, it is possible to explain the main features of the changes that occur in edema in terms of the redistribution of water between two compartments. In the intracellular compartment, the diffusion of water is highly restricted so that the ADC is low, whereas [13] in the extracellular compartment, the diffusion of water is less than that in free water (or CSF), but nonetheless, is significantly higher than in the intracellular compartment. The measured ADC is essentially an average of these two values, weighted according to the relative volumes of water in the two compartments. The observed changes in the different type of edema are: (1) cytotoxic edema: the movement of extracellular water into the cell increases the fraction of water in the compartment with the lower ADC, so that ADC value falls; (2) vasogenic and interstitial edema: here the water is predominantly extracellular, so that the component with the larger ADC dominates and the ADC is larger than normal [14]. Brain edema following ischemia has been the focus of many studies using DWI. Within the first hour, when acute cytotoxic edema develops, the ADC decreases, so that the lesion appears brighter on DWI. Changes are visible on DWI before any change can be appreciated on conventional CT or T1- and T2-weighted images. With time, as the vasogenic edema develops, the lesion will darken on DWI because the ADC increases. The regions of abnormal brain indicated on DWI and on the T2-weighted images are similar, but not identical: the region in which the diffusion is changed is, in general, greater than the region in which the T2 is altered [15]. DWI has revolutionized our ability to see abnormalities in tissue due to change in the restriction of movement of water molecules, such as acute infarctions (Fig. 7.3) The ability to process these images rapidly to determine accurately numerical values, in the form of apparent diffusion coefficients, may have meaning as to how severe the changes are. Can diffusion imaging differentiate infarction from ischemia? To answer this question, more studies and research are needed. As DWI finds wider application to the evaluation of the pediatric patient presenting with acute neurological picture, it is anticipated that the incidence and promptness with which cerebrovascular disease is diagnosed in this population will increase.

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7.2.8 Magnetic Resonance Perfusion

7.2.10 Conventional Angiography

There are two techniques for looking at vascular perfusion in the brain. These are the tracer techniques, one involving bolus gadolinium injection with T1weighted imaging [16] and the other the EPI star technique, without gadolinium injection, in which the incoming blood is altered by an RF pulse placed over the carotid artery in the neck and then imaged in the brain [17]. Quantification of blood flow by either technique is difficult, but relative perfusion can be seen. Bolus techniques measurement of time-to-peak enhancement and production of maps of the relative cerebral blood volumes throughout the brain have proven useful.

Conventional arteriography remains the gold standard for the demonstration of vasculitis, collateral blood flow, emboli within vessels, feeding vessels of an AVM, and the anatomy of an aneurysm [8]. The process requires experience and skill in that vascular access is not as easy in children and infants as in adolescents and adults, and vascular spasm of the catheterized vessel is more common. The catheters utilized are smaller in younger patients, and the volumes of contrast that can be used are affected (restricted) by body weight. Much of the former need for arteriography in the pre-MRI era has been circumvented by the development of MRI with MRA, MRV, and DWI.

7.2.9 Magnetic Resonance Spectroscopy

7.3 Childhood Cerebrovascular Disease

Acute infarction in the brain alters the measurable levels of cerebral metabolites seen with MRS. N-acetylaspartate (NAA) decreases as neurons are destroyed, while lactate, a by-product of anaerobic metabolism not normally seen, becomes elevated (Fig. 7.4) [18]. With complete tissue necrosis, MRS shows complete absence of cerebral metabolites.

Estimates of the incidence of stroke in children in the United States and Canada, both ischemic and hemorrhagic, has been given as 2.5 per 100,000/year versus an incidence of 100–300 per 100,000/year in adults [19]. This series [19] had the hemorrhagic strokes

Fig. 7.4. Proton spectroscopy of acute infarction. A single voxel spectrum was acquired from cortex and some white matter in predominantly the right posterior temporal/occipital region. T2weighted MRI showed bilateral watershed infarctions. Proton spectroscopy was performed with a TE of 10 ms and a TR of 1,600 ms. The study shows decreased N-acetyl aspartate (NAA) and markedly elevated lactate. The lactate appears at 1.3 ppm as a doublet, while NAA is at 2 ppm

Infarction

Lac

Cr

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ml

3.5

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Cerebrovascular Disease in Infants and Children

at 1.89/100,000/year, at a higher rate than the ischemic strokes, which were 0.63/100,000/year. With the advent of MRI, the incidence of both will have increased significantly, but with the further advent of DWI, the incidence of ischemic stroke will have clearly exceeded that of hemorrhagic by a major factor. There is a need for current MRI and MR diffusion-based statistics to reveal the real incidence of stroke in children, which appears to be much higher than previous estimates. A later study of pediatric stroke from 1995, performed in Canada, gave the incidence of ischemic and sinovenous stroke as 1.2/100,000/year. In the Canadian study, infants less than 1 year of age represented 38.5% of strokes, between 1 and 5 years 24%, while from 5–18 years 37.6%. Large vessel arterial disease was present in 42.7%, small vessel arterial disease in 36.5%, and sinovenous disease in 20.8%. The etiology of the stroke was cardiac disease in 20.8%, infection or inflammation in 16.7%, coagulopathy in 7.3%, large vessel dissection in 6.3%, and metabolic disease in 3.1%. The etiology was not determined in 19.8% in this series, whereas in older series the etiology was undetermined in approximately one third [20]. Younger children are more often affected by complications of congenital heart disease, producing either hypoperfusion watershed infarction or embolic stroke within a vascular territory [21]. The older child and adolescent fall victim to traumatic vascular injury, such as dissections of the carotid and middle cerebral artery, leading to thrombosis or thromboembolism [22, 23].

7.3.1 Sickle Cell Disease Within both the pediatric and adult stroke population there are patients with sickle cell disease. These patients have both small vessel hypoperfusion disease causing lesions within the white matter of the centrum semiovale, and stenoses and/or occlusions of the more proximal major vessels, leading to infarctions within vascular territories [21]. Systematic evaluation of sickle cell stroke data has given us some insight into the incidence of stroke in this population [22, 23]. The incidence of clinically apparent infarctions in children with sickle cell disease is 21/416 (Fig. 7.5) [24]. These infarcts are all due to large vessel stenoses or occlusions, and involve the cortex ± white matter and/or the basal ganglia. In a cohort of sickle cell children followed from age 6 for 8 years, an incidence of silent infarctions of 17% was found at the start of the study,

and an incidence of 22% at the end of the study [25]. These patients were clinically asymptomatic, but when tested neuropsychologically were found to have lower scores than controls on arithmetic, vocabulary, visual motor speed, and coordination evaluation [26]. The patients with clinical infarctions performed significantly worse on most neuropsychological tests [26]. In follow-up MR studies of the cohort, patients with prior infarction had a 12.1% incidence of a new or worse infarction, while patients with an initial normal MRI had only a 1.9% risk of subsequent infarction [25]. Altogether, the sickle cell stroke population is thought to constitute 6% of United States children with the acute onset of hemiplegia. The annual risk of initial stroke in sickle cell disease is estimated to be 0.7%/year. Subsequent infarction, after the first stroke, occurs in 50%–75% of untreated patients (not transfused), with 80% having a second infarction within 36 months. A second trial regarding sickle cell disease and infarction is also of interest. This study deals with TCD evaluations, and is called the STOP 1 Trial. A TCD velocity of > 200 cm/s in the distal internal carotid or middle cerebral artery was classified as elevated. Of 1,934 sickle cell children evaluated, 9.4% were at or above this level. The patients also had MRIs, and of the patients with elevated TCDs 36.9% had silent infarcts (Fig. 7.5) [27]. The patients with elevated TCDs were randomized into two groups. The first received standard treatment, and the second were put on chronic transfusion therapy. In the first group there were 13 clinical infarctions and 1 bleed in 71 patients (19.7%), versus only 1 infarction in 56 (1.8%) in the other group. As a result, the study was closed after only 16 months [27].

7.3.2 Vasculitis 7.3.2.1 Infectious

Bacterial infection of the wall of both arteries and veins can occur with meningitis, resulting in stenoses or thrombosis of the vessel, which leads to infarction. The incidence of infarctions in meningitis in the preMRI literature varies from a low 4.7% in hemophilus type B meningitis to a high 27% [28, 29] in a variety of other organisms. Based on our own experience, MRI with diffusion detects small infarctions of perforators that otherwise would not be found by any other method and thus missed, indicating that the true incidence of infarction is underestimated in the

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Fig. 7.5a–f. Sickle cell disease (different patients).a Axial FLAIR image; b, c, e axial DWI; d axial T2WI (6000/99); f 3D TOF MRA. MRI (a) shows deep white matter, right-sided hyperintensity consistent with infarction. In the same patient, DWI shows restricted motion of water in the deep white f matter sites of infarction as well as two small cortical areas, one in the right parietal and one in the left frontal (arrows, b). In a symptomatic 7-year-old female, DWI (c) shows acute infarction on the right in both the middle and posterior cerebral artery vascular territories. In a different patient (a 2-year-old male, found to have abnormal TCD on the left, in distal internal carotid and middle cerebral artery), MRI done the next day shows a slight increased signal (arrows, d) in the head of the caudate and anterior putamen. In the same patient, DWI shows restricted diffusion in the head of the caudate and anterior putamen (arrow, e). In this case, 3D TOF MRA shows that the distal internal carotid artery on the left is markedly narrowed, as is the proximal middle cerebral artery (arrow, f). The proximal anterior cerebral artery A1 segment is not seen on the left

Cerebrovascular Disease in Infants and Children

literature. Most of our patients are studied because of seizures, new onset of weakness, decreased mental status, or prolonged fevers. Most of the patients with infarction complicating meningitis are infants in the first 2 years of life, and the organisms tend to be the more virulent ones, such as streptococcus. If MRA demonstrates large vessel vasculitis, in our experience the outcome is very poor (Fig. 7.6). Fortunately, the infarctions occur more often in the territories of the perforators and tend to involve the frontal white matter, with outcomes that are not poor. Syphilis was once one of the more frequent causes of cerebral vascular disease in adults but not children, as it occurs as a vasculitis in the tertiary stage [30, 31]. Congenital syphilis remains a possible cause of infarction in children, especially when it has not been recog-

nized clinically. Some viral infections are also able to produce a vasculitis, leading to infarction [20]. Herpes simplex virus type I and II are the best known, but varicella may be a more frequent cause [32, 33]. HIV infection has a recognized vascular infection component, occurring late in the disease and involving large vessels in one of two ways: either as a inflammatory fibrosis of the wall producing narrowing that leads to infarction, or as an inflammatory disruption of the internal elastic membrane with resultant aneurysmal dilatation of the involved vessels (Fig. 7.6) [34]. Among fungal infections, aspergillosis and mucormycosis are the recognized causes of large and small vessel disease where vessel wall invasion and thrombosis lead to infarction. Aspergillosis is found in the setting of the immunosuppressed patient (i.e., bone marrow trans-

Fig. 7.6a–d. Infectious vasculitis (different patients). a MRA; b. axial ADC map; c, d. Contrast-enhanced axial CT scan. In a 1-year-old female with streptococcal meningitis and vasculitis, MRA shows that the proximal right middle cerebral artery is markedly narrowed (arrow, a). The left middle cerebral artery is occluded. In this case, ADC map derived from diffusion images shows infarction of a large portion of the left hemisphere, seen as hypointensity (arrows, b). There is also involvement of both thalami and of the right internal capsule region. In a different hemophiliac patient (c) in whom HIV vasculitis has caused aneurysmal dilatation of the middle and anterior cerebral arteries, enhanced CT demonstrates aneurysmal dilatation of some of the vessels involving the circle of Willis. In a different patient (d), HIV infection has produced vascular stenosis and infarction, and enhanced CT shows contrast enhancing infarcts in the left basal ganglionic region. In addition, there is atrophy of the brain manifested as dilated sulci and ventricles

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plant, chemotherapy) [35], and mucormycosis in the setting of diabetes and ketoacidosis [36]. The infectious causes of vasculitis are only a small component of the overall list of etiologies (Table 7.1) [20]. However, they are among the more treatable causes if diagnosed early and treated effectively. In case of other types of vasculitis, often there is a more wide ranging spectrum of involvement of other organ systems, and this complicates management. In many of these, CNS imaging is used to identify the presence of cerebral involvement when the underlying disease is known. In some cases, findings on brain MRI stimulate a search for the underlying disorder. Table 7.1. Cerebral Vasculitis Infections Necrotizing Collagen vascular Systemic diseases Giant cell arteritides Hypersensitivity Primary CNS Miscellaneous

from hypertension with renal artery or aortic stenosis, in a lesser number of patients [38]. Vascular imaging, whether by MRA or, better yet, by conventional arteriography (the gold standard for diagnosis of vascular stenosis), delineates the distribution of vascular involvement. MRI is utilized to demonstrate cerebral ischemic strokes. 7.3.2.3 Other Vasculitides

In most patients with vasculitis, MRI will be the most successful test for showing infarction, whether acute, subacute, or chronic. However, recognizing the involvement of the artery by vasculitis is frequently beyond the current capability of MRA. Severe forms may be obvious on MRA, but most will require conventional arteriography in order to be detected. Some may not be seen even on these studies, and only be identified by biopsy of the vascular wall or on the basis of laboratory studies.

7.3.3 Heart Disease 7.3.2.2 Takayasu’s Arteritis

This disease affects the aorta and its branches, primarily in young females. Involvement of the subclavian artery is present in 85% of patients [37], of the carotid arteries in 50% [37], and of the vertebral arteries in 20% [37]. Cerebrovascular disease is due either to ischemic stroke from vascular stenosis, in 5%–10% of patients (Fig. 7.7), or to intracerebral hemorrhage

Infarction in the brain of pediatric patients with heart disease has a multitude of possible causes (Table 7.2). Among all etiologies of ischemic stroke in young patients past the neonatal period, between one fifth to one third are presumed cardiac in origin, often embolic. Congenital heart disease is the most common cardiac disorder that causes stroke. Patent foramen ovale and atrial septal defect, relatively mild forms of congenital heart disease, have both been

Fig. 7.7. Takayasu’s disease involving multiple vessels in a 18-year-old female with prior ischemic infarction in basal ganglia on the left. 3D TOF MRA, coronal projection. MRA shows involvement of anterior and middle cerebral artery (arrows), as well as the distal internal carotid artery on the left

Cerebrovascular Disease in Infants and Children Table 7.2. Cardiac causes of infarction Congenital heart disease Valvular heart disease Cardiac arrhythmias Other cardiac Myocarditis Left ventricular aneurysm Cardiac tumor Cardiac surgery Kawasaki disease

correlated with an increased risk of embolic stroke (Fig. 7.8) [39, 40]. In children with more severe congenital heart disease, such as hypoplastic left heart syndrome (HLHS), ischemic brain lesions have been found in utero, at delivery, and in the immediate postnatal period when the ductus arteriosus closes. In one series reported, 18 of 40 HLHS patients had hypoxic-ischemic or hemorrhagic lesions [41]. PVL, ischemic infarction, and

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brainstem necrosis were the major hypoxic-ischemic lesions. A significant relationship has been found between cardiac surgery and brain damage [41], especially when cardiopulmonary bypass with hypothermic total circulatory arrest is used. Our study (Tavani et al., unpublished data) found 5 of 24 (20.8 %) patients to have such abnormalities prior to surgery, and 15 of 24 (62.5 %) of patients to have such findings following surgery. PVL (Fig. 7.8) and some of the ischemic strokes seen in this patient population are not embolic, but represent a hypoxic-hypoperfusion watershed injury. In pediatric patients with cardiomyopathy, congestive heart failure or other end-stage cardiac disease, especially when complicated by pulmonary problems, episodes of bradycardia, hypotension, or hypoxia, lead to watershed infarction in the parasagittal distribution between anterior and middle and posterior and middle cerebral arteries. Acutely, these are best demonstrated by DWI (Fig. 7.3).

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Fig. 7.8a–c. Congenital heart disease in different patients. a Axial CT scan; b axial DWI; c sagittal T1-weighted image (600/14). In a 17-year-old male with congenital heart disease and acute onset of right hemiparesis, CT scan shows a vague hypodensity involving the cortex in the left hemisphere in the precentral gyrus (arrow, a). In the same patient, DWI done the same day shows restricted motion of water as high signal intensity in the perirolandic region. The infarction was thought to be embolic based on clinical findings with echo. In a different term patient, several days old, who underwent cardiac repair for congenital heart disease, MRI (c) shows abnormal increased signal intensity in the periventricular white matter

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7.3.4 Hypercoagulable States with Thrombosis There are a large number of etiologies of hypercoagulable states, both primary and secondary (Table 7.3), many quite rare (i.e., homocystinuria) and some thought previously to be rare (i.e., protein C deficiency), but more recently recognized with increasing frequency as a cause of stroke in pediatric patients. Imaging findings in most of the ischemic infarcts due to hypercoagulability do not reveal the underlying disorder, and are thus nonspecific. However, their presence necessitates that hypercoagulable states be excluded as part of the clinical diagnostic workup of pediatric stroke when more obvious etiologies (i.e., presence of a dissection) are not present.

Primary Protein C deficiency Protein S deficiency Antithrombin III deficiency Fibrinogen disorders Anticardiolipin antibodies Lupus anticoagulant Secondary Polycythemia vera Essential thrombocythemia Homocystinuria Hyperviscosity Sickle cell disease Chemotherapeutic agents

lipids shared by platelets, coagulation factors, and endothelial cells, producing thrombosis in young patients [45, 46]. Imaging findings are nonspecific ischemic infarctions.

7.3.4.1 Protein C and S Deficiency

Protein C and S are vitamin-dependent plasma proteins; C, an anticoagulant, and S, a cofactor for C. Protein C is formed in the liver. Acquired and inherited forms of deficiency occur resulting in stroke, typically an ischemic infarct due to spontaneous thrombosis of the proximal vessel. Imaging findings are nonspecific (Fig. 7.9). Recognition of this etiology of infarction in young patients is increasing in frequency [42–44]. 7.3.4.2 Antiphospholipid Antibodies

IgG and IgM antibodies, including lupus anticoagulant and anticardiolipin antibodies, target phospho-

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Table 7.3. Hypercoagulable diseases

7.3.4.3 Homocystinuria

Homocystinuria is an autosomal recessive genetic defect in which methionine metabolism is affected. Skeletal and cutaneous abnormalities, dislocated lens, and light skin with 50% incidence of mental retardation and a 15% incidence of seizures are found clinically [47]. Spontaneous thrombosis of both arteries and veins occurs, resulting in infarctions, which, by themselves, are nonspecific [48]. Vascular catheterization for arteriography should be avoided when the diagnosis is known or suspected. The physical appear-

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Fig. 7.9a,b. Hypercoagulable infarction. a Axial FLAIR image; b 3D TOF MRA. MRI (a) shows an acute infarction as increased signal intensity within the right basal ganglia and thalamus. There is mass effect on the body and frontal horn of the lateral ventricle. In the same patient, MRA shows focal area of narrowing (arrow, b) in the horizontal portion of the right middle cerebral artery

Cerebrovascular Disease in Infants and Children

ance of the patient with the history of stroke should lead to the appropriate clinical laboratory workup.

7.3.5.1 Ehlers-Danlos Syndrome

7.3.4.4 Chemotherapeutic Agents

This is a genetic disease of collagen formation with multiple subtypes based on inheritance and clinical manifestation, in which the skin is excessively elastic, the joints hyperextensible, and the vascular bed potentially abnormal. Type IV, which represents less than 20% of Ehlers-Danlos cases, arises from a defect on chromosome 2 [50], and is the variety associated with cerebrovascular complications [51]. Impairment in the synthesis of type III collagen, the major form of vascular collagen, results in vascular weakening with aneurysmal dilatation of internal carotid and vertebral arteries. There is also an increased incidence of intracranial aneurysms. Spontaneous development of carotid cavernous fistulae has also been reported. Catheterization for conventional arteriography is not without risk, as dissections are possible.

L-asparaginase has been implicated in producing a hypercoagulable state by suppressing liver production of clotting factors after several weeks of therapy [49]. Decreased levels of plasminogen, antithrombin, fibrinogen, and factors IX and XII are noted [49]. Both arterial and veno-sinus occlusions as well as intracerebral hemorrhage occur (see Chapter 11 for details).

7.3.5 Primary and Secondary Vascular Wall Disease Both primary and secondary diseases occur that affect the walls of the major feeding arteries in the neck, skull base, or proximal intracranial circulation. In general, the infarctions that result are more often ischemic than hemorrhagic, whether due to luminal narrowing or emboli that are formed and launched from the sites of involvement. The infarctions are nonspecific as to etiology in most, but not all cases as, for example, vertebral dissection pattern of infarction. The location of the infarction indicates the need for evaluation of the vascular circulation supplying the involved distributions, usually by conventional arteriography, although MRI and MRA have proven to be very successful at demonstrating vascular dissections.

7.3.5.2 Neurofibromatosis Type I (NF1)

NF1, a genetic disease localized to chromosome 17 (see Chapter 16), can produce cerebrovascular disease through two mechanisms: (1) involvement of renal arteries can result in hypertension which can lead to intracerebral hemorrhage [52], and (2) involvement of cerebral vessels can produce stenosis and moyamoyalike picture [53] (Fig. 7.10), or infarction in the distal distribution of the vessel.

Fig. 7.10. Neurofibromatosis type I with moyamoya in a 14-year-old male. Coronal 3D TOF MRA. There is marked narrowing of the distal left internal carotid artery (arrow), irregularity and narrowing of the distal right internal carotid artery, and enlargement of the basilar artery with extensive collaterals supplying the anterior circulation

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7.3.5.3 Fibromuscular Dysplasia

Fibromuscular dysplasia (FMD) is a nonatherosclerotic angiopathy of young women and occasionally boys [54] that is inherited as an autosomal dominant in some. Most patients are asymptomatic and never identified. Transient ischemic attacks and ischemic infarcts arise from emboli and/or dissection at the site of involvement. Identification of FMD depends on conventional angiography as MRA is unreliable. The “string of beads” appearance of the vessel, a series of constrictions and dilatations (Fig. 7.11), is due to both hyperplasia and thinning of the media of the vessel.

Fig. 7.11. Fibromuscular dysplasia. Common carotid arteriogram. The distal internal carotid artery is shown in its cervical and intrapetrosal portions to be irregularly beaded (arrows). This patient also had renal artery involvement

degree in the Japanese population, where it was first described [56]. Clinical symptoms vary, from none to headaches, transient ischemic attacks, and hemiplegia. CT is poor at identifying the disease other than in showing an acute infarction or hemorrhage (from rupture of a collateral). On CT, contrast enhancement of numerous collaterals at the base of the brain may mimic subarachnoid infiltrative process. MRI and MRA are the noninvasive diagnostic procedures that are most successful in demonstrating the disease. Attenuation of the flow void of the distal internal carotid artery, decrease in size of the flow void of the middle cerebral arteries, and the presence of abnormally numerous small collateral blood vessel flow voids within the basal ganglia, hypothalamus, and thalamus are the T2 findings plus or minus new or old infarcts [57] (Figs. 7.12, 13). MRA shows the internal carotid artery stenosis or occlusion and the myriad of small collateral blood vessels [57]. This condition is an example where the postgadolinium-enhanced 3D TOF MRA, in addition to the pregadolinium MRA, is useful. Gadolinium is also useful in demonstrating subacute infarctions by the disturbance in their blood brain barrier (BBB) producing contrast enhancement of the infarction (Figs. 7.12, 13). Conventional arteriography is the ultimate gold standard in the evaluation of patients suspected to have moyamoya syndrome. Much of the collateral blood supply arises from the distal posterior circulation (basilar artery, posterior communicating arteries, posterior cerebral arteries), necessitating a vertebral artery injection in addition to study of both internal carotid arteries (Fig. 7.12). In general, MRI and MRA are diagnostic (Figs. 7.12, 13), and conventional arteriography is reserved for presurgical evaluation prior to vascular anastomosis. Surgery is done by using the vasculature of the scalp placed via a burr hole, to help develop additional collateral circulation (encephaloduroarteriosynangiosis) [58]. Preoperative arteriography should include both external carotid arteries.

7.3.5.4 Moyamoya Syndrome

7.3.5.5 Radiation Vasculopathy

Moyamoya (in Japanese meaning puff of smoke) describes the arteriographic finding of collateral blood vessels and their angiographic blush, which is due to stenosis and/or occlusions of the distal internal carotid arteries [55]. Many diseases can produce this picture, i.e., NF1, sickle cell disease, and radiation vasculopathy; however, the disease is most often idiopathic and, while worldwide, is found to a greater

One of the effects of irradiation, as used in therapy of pediatric brain tumors, is damage to the endothelium of blood vessels. This occurs not only in the vascular bed of the tumor, but also can occur in the normal vasculature of the cerebrum. Opening up of the BBB can begin in the weeks to months following completion of radiation therapy, and is seen on MRI as the development of new vasogenic edema along with contrast enhancement postgadolinium injection. Often

Cerebrovascular Disease in Infants and Children

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Fig. 7.12a–c. Moyamoya disease (different patients). a Axial T2WI (6000/99); b Gdenhanced axial T1-weighted image; c Conventional arteriogram. In a 4 year old female with known moyamoya, MRI (a) shows multiple areas of prior infarction on the right, seen as areas of high signal intensity. There are numerous small hypointense collateral flow voids in both the basal ganglia and in the region of the splenium of the corpus callosum. The arrows (a) point to only a few of the many. In a different patient aged 9 years with moyamoya disease and recent acute onset of symptoms, postcontrast MRI shows contrast enhancing infarcts in the right hemisphere within the caudate head and lenticular nucleus (arrows, b). In another case (a 7-year old-male with known moyamoya), conventional arteriogram with common carotid artery injection on the left shows occlusion of the origin of the middle cerebral artery from the internal carotid (arrow, c). The distal middle cerebral artery is reconstituted from extensive collateral moyamoya vessels

small vessels are affected and there may or may not be a permanent residual injury. In children who are longterm survivors of brain tumor, i.e., hypothalamic and chiasmatic gliomas and medulloblastomas, large and small vessel injury may be seen [59]. Stenosis of the distal internal carotid arteries (Fig. 7.14) with development of collaterals can produce a moyamoya-like picture. Infarctions within the affected vascular territory, with or without moyamoya pattern of collaterals, are the primary concern. Clinically, these can present as transient ischemic attacks, but their progression to frank infarction occurs at an unpredictable rate. MRI and MRA remain the best ways to evaluate postradiotherapy patients noninvasively. Radiation vasculopathy can also present as small areas of hemorrhage (see Chapter 11). Initially, this was thought to be radiation-induced formation of telangiectasia or small cavernomas, which bled. Subsequently, this has been called into question and the

hemorrhages may be manifestations of small vessel injury [60]. These small bleeds are best demonstrated by MRI and are seen as foci of signal intensity changes which depend on the chemical state of the blood products (Fig. 7.14). Gradient-echo T2*-weighted images are the most sensitive for all types of blood products, especially those that are minute.

7.3.6 Congenital Vascular Hypoplasia Developmental hypoplasia or absence of a vessel at the circle of Willis is not an uncommon finding on conventional arteriography, MRA, or at autopsy (50%) [61]. Most often this variation is not of clinical significance, until an acquired occlusion of a major vessel occurs in which the absence of a vessel does not permit the establishment of adequate collateral

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Fig. 7.13a–d. Moyamoya disease in a 10-month-old girl with Fanconi syndrome. a Axial T2-weighted image; b Coronal T2-weighted image; c Gd-enhanced axial T1-weighted image; d 3D TOF MRA, coronal projection. T2-weighted images (a, b) show diffuse reduction of the vessels of the circle of Willis and an excess amount of tiny flow voids in the basal cisterns, consistent with collateral circulation (rete mirabilis). An infarction with blood-brain-barrier damage is also visible in the right rolandic region (c). MRA shows stenosis of the carotid siphons (with a mouse-tail appearance) (arrows, d), diffuse stenosis of the vessels of the circle of Willis, and the rete mirabilis in the region of the perforating arteries. (Courtesy Dr. P. Tortori-Donati, Genoa, Italy)

circulation in order to prevent the development of an infarction. Under these circumstances, the variations in the circle of Willis take on a much greater significance. Hypoplasia or absence of major brachiocephalic vessels supplying the brain is much less common than at the circle of Willis. True agenesis of the carotid arteries is associated with absence of the carotid canals in the skull base [62]. Carotid agenesis or hypoplasia have also been found in association with congenital facial hemangiomas [63] and in the setting of PHACE syndrome, a vascular phakomatosis [64] (see Chap-

ters 17 and 35), and other orbital region developmental anomalies, such as microphthalmos. In a young adult or child, a hypoplastic internal carotid artery is a setup for potential infarction with any hypotension, arrhythmia, or other insult. MRA and conventional arteriography are the most specific diagnostic methods, although MRI, by demonstrating the size of the arterial flow void, may be the first test that leads to recognition of the problem. Vertebral arteries are commonly of different sizes, the left more often larger than the right. Marked discrepancies in size do occur with the hypoplastic

Cerebrovascular Disease in Infants and Children

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Fig. 7.14a,b. Radiation vasculopathy (different patients). a. Conventional left common carotid arteriogram; b axial FLAIR image. In a teenage female who presents with transient ischemic attack, postradiation therapy for hypothalamic astrocytoma, conventional arteriogram shows marked narrowing of the distal internal carotid artery (arrow, a). In a different teenage male, long-term survivor of posterior fossa ependymoma treated with surgery, chemotherapy and irradiation, MRI shows a hypointense rim of hemosiderin outlining a cavernoma in the left thalamus (arrow, b). There are extensive high signal intensity radiation changes at the site of the boost portal in the parietal lobes

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vertebral artery ending in only the posterior inferior cerebellar artery. This is a setup for potential problems. Transient occlusion of the vertebral artery is thought to be possible with marked rotation of the head and cervical spine. Forced rotation, as with chiropractic manipulation, has been found to result in occlusions and dissections of the vertebral artery, leading to infarction in the cerebellum. The lack of effective collateral sources of blood supply in the case of hypoplasia of the vertebral artery may predispose these patients to such events, whether the turning has been forced, occurs accidentally (i.e., car accident), or is self induced.

7.3.7 Vascular Trauma The effect of both penetrating and blunt vascular trauma, if exsanguination does not result, is on the distal vascular bed supplied by the involved vessel, leading to ischemia and infarction. When the brachiocephalic, carotid, or vertebral vessels are damaged, cerebral infarction is not rare. With regard to

brain injury, vascular trauma is not limited to the chest and neck region, as injury to the internal carotid artery can occur within the skull base, at the intracavernous or supraclinoid segment, or at its bifurcation. Penetrating injuries can occur anywhere intracranially. Blunt injury can produce intimal tear, spasm, thrombosis, intramural dissection, dissection aneurysm, pseudoaneurysm, and complete transection [65]. Intimal tear is a site for thrombus formation, which can be a source of emboli to distal sites within the brain. The intimal tear also permits blood access to the wall of the carotid artery, producing an intramural dissecting hematoma. The subintimal blood folds the intima in an irregular fashion, producing the “classic” arteriographic picture (Fig. 7.15) seen in the carotid, middle cerebral, and vertebral arteries with dissections. Conventional arteriography is the gold standard, while MRA and MRI (T1-weighted images with fat suppression to look for intramural clot) are often diagnostic. Distal emboli produce infarction. In the vertebral circulation, involvement is most often of the thalami, cerebellum, occipital lobes, and occasionally the brain stem (Fig. 7.15). The history of

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d Fig. 7.15a–d. Vascular trauma (different patients). a Internal carotid arteriogram; b left vertebral arteriogram; c axial T2-weighted image (3000/120); d selective internal carotid arteriogram. In a teenage male with blunt trauma and internal carotid artery dissection, marked narrowing and irregularity of the internal carotid artery in the neck is seen (arrows, a). In a child with vertebral artery dissection, left vertebral arteriogram with reflux into the right vertebral artery shows irregular narrowing on the right (arrow, b). In a different patient (a 4-year-old male with vertebral artery dissection from trauma), MRI shows multiple areas of high signal intensity infarctions involving the left cerebellum, cerebellar peduncle, and brainstem (arrows, c). In another young child with pseudoaneurysm secondary to puncture wound of carotid artery, selective internal carotid arteriogram shows pseudoaneurysm (arrow, d) arising from the anterior wall of the carotid in the neck

blunt trauma may not be obvious, therefore requiring careful questioning about the mode of trauma, such as shooting a rifle, football practice, jumping on a trampoline, or a visit to the chiropractor. In carotid dissections, the new onset of a Horner’s syndrome is an important sign as it points to disruption of the sympathetic fibers in the carotid wall and indicates a need for imaging evaluation. Pseudoaneurysms develop as a result of disruption of the vascular wall with formation of a periarterial

hematoma contained by fascia. Once the clotted hematoma cavitates, the hole communicates with the arterial lumen. The risk to the cerebrum is from emboli formed within the pseudoaneurysm. MRI, MRA, and conventional arteriography demonstrate pseudoaneurysms in the neck and intracranially (Fig. 7.15). Penetrating injuries in adults are due to missiles (bullets) and stab wounds (knives), but in children are more often related to intraoral trauma, when the child falls on a stick or a pencil held in the mouth.

Cerebrovascular Disease in Infants and Children

The object is forced either superiorly through the skull base toward the anterior cerebral arteries, the frontal lobes (transcribriform), or, more commonly, posteriorly into the carotid artery in the neck, where a dissection or pseudoaneurysm occurs, a source of intracranial emboli and infarction.

7.3.8 Migraine Headaches Complicated migraine have the occurrence of transient neurological deficit or altered mentation in association with the headache. Permanent neurological deficits may occur, but are uncommon in children (1 in 132) [66]. The exact incidence of stroke from vasospasm is unknown both in the adult and pediatric population. MRI FLAIR imaging is used to identify lesions in the white matter which are consistent with past episodes of ischemia. These appear as scattered bright areas. In addition, we have now seen a number of teenagers with and without neurological deficits, but with watershed infarctions (Fig. 7.16), both acute and chronic, in which the history has been migraine headache. We have also seen several adolescents with acute thalamic infarctions identified on DWI during the course of their acute complicated migraine attack. In all of these patients it is necessary to exclude an underlying source for infarction, such as protein S deficiency.

7.3.9 Metabolic Diseases Mitochondrial dysfunctions are one of the genetic causes of stroke in children (Table 7.4). These include mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) [67]; myoclonic epilepsy with ragged red-fibers (MERRF); MERFF/ MELAS overlap syndrome; and Kearns-Sayre syndrome. Mitochondrial encephalopathies are suspected when lactic acidosis (diagnosed by serum, CSF analysis, or MRS) occurs in association with seizures, recurrent strokes, and respiratory failure. DNA classification of these disorders is now possible in many instances [68]. The proposed mechanism of stroke is regional failure to produce sufficient energy Table 7.4. Genetic causes of stroke Hereditary connective tissue disorders Ehlers-Danlos syndrome (type IV) Marfan syndrome Homocystinuria Menkes syndrome Organic acidemias Methylmalonic Propionic Glutaric type III Mitochondrial MELAS MERRF Kearns-Sayre syndrome Leigh disease Neurocutaneous syndromes Neurofibromatosis type I Hereditary dyslipoproteinemia Tangier disease Progeria

to maintain cell function. Sites of normal high energy metabolism appear to be at greatest risk when attacks occur. MRI, DWI, and MRS provide the imaging information for diagnostic workup (Fig. 7.17). MRA is useful to exclude other vascular diseases that might mimic mitochondrial disease, such as basilar artery stenosis.

7.3.10 Hypoxia

Fig. 7.16. Migraine in a 17-year-old male with visual problems and headaches. Axial FLAIR image. There is abnormal increased signal in the left parietal watershed, consistent with infarction

Hypoxic injury to the brain does occur in older infants, children, and adolescents, but does not represent the same magnitude of problem as it does in the preterm and term infant. Often, the hypoxic injury is a complication of another disease process, such as trauma, when the patient has been thrown from the car and

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Fig. 7.17. Mitochondrial disease in a 4-year old-male with known mitochondrial disease presenting with acute language problems. Axial DWI. There is restricted motion of water as high signal intensity in posterior left temporal lobe, left thalamus, and left frontal cortex

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the medullary respiratory center has failed, or in case of child abuse with whiplash impact injury when the same occurs. In these situations, both the primary brain injury and the secondary hypoxia contribute to the ultimate outcome. Resuscitated cardiorespiratory arrests, seizures with poor airway, and near drowning are among other potential etiologies of more specific hypoxic injury. In older infants, the central gray matter and frontal, temporal, and occipital cortex are involved, often with relative sparing of the rolandic cortex and white matter. Such findings are seen in near sudden infant death syndrome (SIDS), transiently during imaging before death. Such a picture, while compatible with SIDS, is also consistent with suffocation as a part of child abuse. In the older child and adolescent, when near drowning occurs, the high metabolic rate areas of the brain, such as the lenticular nuclei, are first to be affected. MRI including DWI is the procedure of choice in demonstrating the acute imaging findings as high signal intensity (Fig. 7.18). CT is often much less revealing.

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Cerebrovascular Disease in Infants and Children

7.4 Nontraumatic Intracerebral Hemorrhage Cerebrovascular disease presenting as hemorrhage (subarachnoid, intraparenchymal, and/or intraventricular), is relatively frequent even when premature neonates with germinal matrix are excluded. The etiology of the bleeds (Table 7.5) is varied, but vascular malformations and bleeding diathesis are most common. Most often, patients suffering from intracranial hemorrhage have sudden onset of symptoms and require emergency care and rapid and precise evaluation by imaging. Emergency noncontrast CT is the initial step in identifying the presence of blood, its location and size, the degree of mass effect, and any accompanying hydrocephalus (Fig. 7.19). The workup of the etiology of the hemorrhage generally requires MRI, MRA, perhaps MRV (i.e., to diagnose sinus thrombosis), and conventional arteriography as the definitive gold standard in treatment planning of AVMs and aneurysms. Arteriovenous malformations and occult vascular malformations are described in Chapters 8 and 9, respectively. Table 7.5. Etiologies of nontraumatic intracerebral hemorrhage Vascular malformation Aneurysm Hypertension Bleeding diathesis Drug Brain tumor Sinovenous occlusive disease

7.4.1 Cerebral Aneurysms Aneurysms of cerebral blood vessels are uncommon in children, despite the concept that these are usually congenital in origin, indicating that only the weakness in the vessel’s wall is congenital, but not the aneurysm. When an intracerebral hematoma (ICH) is found in an infant or child, without history of trauma, an AVM is usually the first consideration as the eti-

ology. However, aneurysms do occur, although the total number in pediatrics is only 5% of the total number of aneurysms in the general population [69]. Pediatric aneurysms are of interest because there is a distinct male dominance, a greater incidence of large and giant aneurysms, and a lower incidence of multiple aneurysm than in the adult population [70, 71]. Twenty-four to fifty-four percent of pediatric aneurysms are located in the distal internal carotid artery circulation, while more than 15% are in the posterior circulation and 4% are found on the posterior communicating artery [71]. The types of aneurysms in pediatrics are as follows: saccular 50%–70%, giant 20%–40%, mycotic (due to infectious process) 5%– 15%, traumatic 5%–15%, and multiple 2% [71]. The relatively high incidence of traumatic and mycotic aneurysms means that attention has to be paid to the possibility of peripherally located aneurysms which, in addition to trauma and infection, include other etiologies such as tumor emboli (atrial myxoma, rhabdomyoma) and arteritis [72]. Aneurysms also occur with AVMs, moyamoya syndrome, and sickle cell vascular disease [72]. Symptoms related to pediatric aneurysms are due to mass effect of the aneurysm in up to 45% of patients over age 5 years [72]. Both seizures and signs of infarction are present in less than 10% of pediatric patients [73]. In pediatric patients there is a greater concern for conditions which predispose to aneurysm formation. These include aortic coarctation, polycystic kidney disease, fibromuscular dysplasia, Marfan’s Syndrome and Ehlers-Danlos syndrome type IV [72]. CT is most often the initial diagnostic study performed in evaluation of patients suspected to have an aneurysm. The imaging findings are either SAH, SAH and ICH, or a hyperdense mass, the aneurysm itself (Fig. 7.19). MRI and MRA are the next step, although if the clinical situation dictates, conventional arteriography before surgery and/or interventional treatment may be indicated (Fig. 7.19). On T2-and sometimes on T1-weighted images, MRI shows the hypointense flow void of the lumen of the nonclotted aneurysm (Fig. 7.19). Blood products, due to rupture, may be found adherent to the aneurysm, a good sign of which aneurysm has bled when more than one is present.

Fig. 7.18a–e. Hypoxic brain injury in two different patients. a axial FLAIR image; b ADC map; c, d axial FLAIR images; e coronal T2-weighted image. In a near-drowning child, axial FLAIR image (a) shows high signal intensity abnormalities in the lenticular nuclei bilaterally and in the thalamus. In the same patient, ADC map (b) shows that the abnormalities are more extensive, involving the corpus callosum and temporal occipital cortex and subadjacent white matter. In a different patient (a 10-year-old boy with prolonged cardiac arrest) axial FLAIR images (c, d) show hyperintense signal in the posterior putamen and thalamus bilaterally (thin arrows c, d), left calcarine region (open arrow, c), and rolandic cortex bilaterally (arrowheads d). Basal ganglia abnormalities give high signal also on T2-weighted images (arrows, e)

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Fig. 7.19a–f. Cerebral aneurysms (different patients). a, b. Axial CT scan; c. selective left vertebral arteriogram; d. coronal T2-weighted image (6000/99); e, f 3D TOF MRA. In a 6-month-old male with ruptured anterior cerebral artery aneurysm presenting with acute subarachnoid hemorrhage and intracerebral hematoma, CT scan shows blood in the right frontal lobe (arrow, a) and within the subarachnoid space between two frontal lobes extending into the chiasmatic cistern and around the brainstem. There is early hydrocephalus with dilatation of the temporal horns. In a different 4-year-old male with giant basilar artery aneurysm presenting with f subarachnoid hemorrhage and hydrocephalus, CT scan shows a calcified mass (arrow, b) in the interpeduncular chiasmatic cistern region. There is increased density in the interhemispheric fissure and in the fissures of the middle cerebral arteries, consistent with subarachnoid blood. The temporal horns are markedly enlarged from hydrocephalus. In the same patient, selective left vertebral arteriogram (c) shows giant basilar artery aneurysm. In another infant with peripheral giant mycotic aneurysm and presenting with the CT scan picture of a right frontal intercerebral hematoma suspected to be child abuse, MRI shows a hypointense flow void representing the patent lumen of the aneurysm (white arrow, d). There is vasogenic edema in the surrounding brain (black arrowhead, d). Between the vasogenic edema and the patent lumen of the aneurysm there is laminated clot in the wall of the giant aneurysm. In the same patient, MRA shows the patent lumen of the aneurysm on the right (white arrow, e). In a different patient (a 12-year-old male presenting with acute severe headache), coronally reconstructed 3D TOF MRA shows a 3 mm aneurysm (arrow, f) arising from the A1 segment of the anterior cerebral artery

Cerebrovascular Disease in Infants and Children

Blood products may be found within the aneurysm when some degree of clotting has occurred (Fig. 7.19). CT is more sensitive to acute SAH than MRI, while FLAIR MRI is more sensitive to subacute SAH than CT [4]. MRI (T2 and susceptibility sequence) is equal to CT in sensitivity for acute ICH and IVH, but more sensitive than CT for subacute and chronic blood products. MRA is performed with 3D TOF sequence for the demonstration of aneurysm, unless methemoglobin is shown on T1-weighted images (Fig. 7.19). If methemoglobin is present, then 3D PC MRA is the procedure of choice in order to avoid confusion of clotted and flowing blood. Aneurysms greater than 3 mm should be visible with good segmentation and/or multiplanar reconstruction (MPR) technique (Fig. 7.19) [8]. Contrast-enhanced MRA can be used to increase the conspicuity of the lumen of the aneurysm. An advantage of MRI and MRA over conventional arteriography is the ability to demonstrate the wall of the aneurysm (thickness, clot) and the condition of the surrounding brain (i.e., infarction, mass effect, hydrocephalus). MRA can also show whether spasm of the intracranial vessels is present or not.

7.4.2 Hemorrhagic Infarction In adults, autopsy studies have found that 50%–70% of embolic strokes are hemorrhagic, compared to 2%–20% of nonembolic ones. Most hemorrhagic strokes found at autopsy were not hemorrhagic on CT within the first 48 h after ictus. The pathogenesis of hemorrhage in an embolic infarct has one of two mechanisms: (1) the embolus moves on or lyses, flow is re-established, and blood breaks through the wall of the damaged vessel; (2) there is good collateral blood flow which, by retrograde flow, reperfuses the damaged vascular bed, producing the same insult. Cardiac disease is the most common etiology of pediatric embolic disease, and congenital heart disease is the most common. Numerous other disease processes can be associated with embolism (i.e., fibromuscular dysplasia, traumatic vascular injury, cerebral aneurysms). Venous sinus occlusive disease, especially with cortical vein thrombosis, is another cause of hemorrhagic infarction. The mechanism of infarction and bleeding is different than in embolic stroke. The venous outlet becomes obstructed so that the blood coming in via the arteries is impeded, builds up pressure by increasing the local cerebral blood volume,

produces ischemia, and eventually ruptures into the surrounding damaged tissue. On CT, the high-density hemorrhagic infarction is within a vascular territory when embolic in nature, and not when due to venous occlusive disease. Transformation of a nonhemorrhagic ischemic infarction to a hemorrhagic one can be shown both by CT and MRI over a course of time. MRI shows the blood products according to their chemical state, and often shows nonhemorrhagic components as part of the infarction. Susceptibility scanning and DWI are important techniques that should be used in addition to routine T1- and T2-weighted images.

7.4.3 Coagulopathies Bleeding diathesis can be found in association with certain hematologic malignancies, such as acute leukemia, where thrombocytopenia below 20,000 platelets/mm3 is problematic [20]. Hemophilia has a reported incidence of 2.2%–14% of intracranial hemorrhage, and it is this bleeding that is the leading cause of death [74]. Anticoagulation for surgical purposes (as in operative treatment of congenital heart disease) or as therapy for a hypercoagulable or thrombotic disorder are other potential etiologies for ICH. Vitamin K deficiency in neonates results in decreased factors II, VII, IX, and X [75]. Today, 1 mg of vitamin K is given at birth; however, previously, when it was not given, intracranial hemorrhage was a risk in breast fed babies.

7.4.4 Hypertension High blood pressure in pediatric patients is relatively rare, less than 1% of children [76]. Causes include coarctation of aorta, renal disease, and endocrine diseases. Most of the hypertensive events that affect the brain in the pediatric population either result in edema or ischemia in the posterior watershed between the posterior cerebral and middle cerebral arteries. Damage to the BBB by increased pressure can lead to vasogenic edema, best seen on FLAIR MRI (Fig. 7.20) but not positive for acute infarction on DWI. However, vasospasm can also occur, resulting in infarction, which can be diagnosed very promptly when acute with DWI. Bleeds in the basal ganglia, brainstem, and cerebellum or cerebral hemispheres do occur in children (Fig. 7.20), but are less common than in adults with hypertension.

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Fig. 7.20a,b. Hypertension (different patients). a coronal FLAIR image; b gradient-echo susceptibility scan. In a 10-year-old child with acute lymphocytic leukemia and chemotherapeutically induced hypertension with disturbance in the blood brain barrier in the biparietal watershed, MRI shows hyperintensity of the cortex (arrows, a). Diffusion imaging was negative, and the changes resolved with treatment. In a different case (a 12-year-old male with severe chronic hypertension secondary to renal disease), MRI (c) shows multiple bilateral hypointense sites of prior bleeding within the basal ganglia

7.4.5 Sinovenous Occlusion Two types of venous occlusive disease present as neurologic compromise with acute onset of symptoms [77]. These are: (1) superficial dural sinus thrombosis with or without cortical vein thrombosis; and (2) deep venous thrombosis. The setting for deep venous thrombosis is the very young age of patients, often newborns or young infants, and significant dehydration. Superficial dural sinus thrombosis tends to occur in older patients (not exclusively) and to have a wide variety of etiologies, including dehydration, sepsis, and hypercoagulable states (Table 7.6). Superior sagittal sinus thrombosis may be relatively asymptomatic if only that structure is involved; however, with the frequent involvement of transverse sinuses and cortical veins, cerebral infarction, often hemorrhagic, becomes more frequent and acutely symptomatic. Superior sagittal sinus thrombosis may present with chronic symptoms, such as papilledema with pseudotumor cerebri, and given that clinical diagnosis, imaging evaluation is required. Obstruction of the deep venous system affects the thalami and basal ganglia and, at times, the periventricular white matter, and produces infarction, often hemorrhagic in part.

Table 7.6. Sinovenous thrombosis: etiologies Infections of head and neck Dehydration Chemotherapeutic agents Inflammatory disorders, i.e., bowel disease Collagen vascular disease Hypercoagulable states Flow-related, i.e., AVM Iatrogenic

Noncontrast CT is often the initial diagnostic study in the patient with sinovenous occlusion. The most specific CT finding is the presence of hyperdense clot in the sinus or deep veins (Fig. 7.21). Unfortunately, infants tend to have normally relatively large dense dural venous sinuses that can be misdiagnosed as thrombosed by the less experienced. The presence of hemorrhage and edema in the brain and/or thrombosed cortical veins make the diagnosis easier (Fig. 7.21). The delta sign is a sign of subacute superior sagittal sinus thrombosis described on contrastenhanced CT, wherein the central less dense thrombus in the sinus is outlined by denser enhancing dural coverings of the sinus. MRI and MRV are now the gold standards in diagnosis of sinovenous thrombosis [8]. Conventional

Cerebrovascular Disease in Infants and Children

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e Fig. 7.21a–i. Venous thrombosis (different patients). a–c axial CT scan; d, e sagittal T1-weighted image; f coronal 2D TOF MRV with saturation of arterial input; g, i axial T2-weighted images; h axial DWI. In a 1-month-old male with dehydration and deep venous thrombosis of the internal cerebral vein and tributary veins, the two adjacent CT slices show clot in the internal cerebral veins (arrow, a) as well as subependymal veins and choroid plexus. There is hypodensity in the left thalamus consistent with infarction. In a teenage female with cortical vein thrombosis, CT scan (c) shows a large parietal area of infarction with mass effect on the lateral ventricle and subfalcial shift of the midline structures. The infarct is both hypodense and peripherally hyperdense. The peripheral hyperdensity (arrow, c) is an area of hemorrhagic infarction. In a different patient with sagittal sinus thrombosis, MRI shows a hyperintense clot within the sagittal sinus. A slightly hyperintense clot is present in the straight sinus (arrow, d). A thrombosed cortical vein can also be seen (open arrow, d). In a 1-month-old dehydrated infant with deep venous thrombosis, MRI shows a hyperintense clot in the internal cerebral vein (arrow, e) as well as within the vein of Galen and straight sinus. The thalamus, beneath the internal cerebral vein, is swollen and decreased in signal intensity.

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Fig. 7.21a–i. (continued) ... In another case with sagittal sinus and transverse sinus thrombosis with collateral venous drainage, MRV with saturation of arterial input (f) shows segments of flow at the site of the superior sagittal sinus interrupted by gaps due to clots (arrows, f). There are multiple small collateral veins over both hemispheres. There is absence of both transverse venous sinuses. In a 9-year-old female with cortical vein thrombosis and infarction, MRI shows cortical hyperintensity in the right parietal lobe at the site of infarction. A large hypointense thrombosed cortical vein can be seen (arrow g). In the same patient, DWI (h) shows the area of restricted motion of water due to infarction to be larger than seen on the T2WI. In a one-month-old dehydrated male with medullary vein thromboses due to deep venous thrombosis, MRI (i) shows bilateral multiple white matter areas of hypointensity, indicating thrombosis within deep medullary veins

arteriography is almost never used. On MRI, absence of the flow void in the sinus is the initial finding in the hyperacute-acute thrombosis. This is best seen on T1weighted images. Over several days, the clot becomes T1 hyperintense (methemoglobin) (Fig. 7.21). 2D TOF MRV is used before methemoglobin is present, and demonstrates the thrombosis as a lack of flow-related enhancement in the affected sinus (Fig. 7.21). Once methemoglobin has formed, the procedure for MRV is 2D phase contrast, wherein the image is insensitive to the T1 hyperintensity of methemoglobin and is made up by only the moving protons. In the absence of blood movement, the sinus lacks signal from flow. Brain tissue affected by the lack of venous drainage is visualized on T2-weighted images, FLAIR, susceptibility, and DWI (Fig. 7.21). Vasogenic edema can occur from venous obstruction, and can be best seen on FLAIR. Acute infarction requires DWI, but can be seen on T2-weighted images. Hemorrhagic components, while seen on T2-weighted images (Fig. 7.21) and perhaps on T1-weighted images, are best shown by T2 susceptibility sequences.

7.5 Conclusions The imaging diagnostic workup of the pediatric patient with cerebrovascular disease depends to a large extent on the neuroradiologists and their ability to perform and interpret correctly the appropriate studies. There is now a wide array of studies with varying specificity and some pitfalls. However, it has never been easier than now to obtain the important information. CT remains the initial screening test for most acute events occurring beyond early infancy, but while it is good for SAH, ICH, and IVH, it is often less informative regarding etiology of bleeds and in the demonstration of acute ischemic infarction and hypoxia. MRI with T1, T2, FLAIR, DWI, susceptibility scanning, MRA, and MRV have revolutionized the capability of the neuroradiologist to provide diagnostic information to the clinician. Despite the imaging advances, arriving at the etiology of ischemic stroke is still mostly dependent on the history and laboratory findings. Conventional arteriography has been relegated to a limited, but important, role in providing definitive information in specific circumstances (aneurysm, AVM, vasculitis, etc.).

Cerebrovascular Disease in Infants and Children

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50. Nicholls AC, De Paepe A, Narcisi P, Dalgleish R, De Keyser F, Matton M, Pope FM. Linkage of a polymorphic marker for the type III collagen gene (COL3A1) to atypical autosomal dominant Ehlers-Danlos syndrome type IV in a large Belgian pedigree. Hum Genet 1988; 78:276–281. 51. Roach ES, Zimmerman CF. Ehlers-Danlos syndrome. In: Caplan LR, Bogouslavsky J (eds) Cerebrovascular Syndromes. London: Oxford University Press, 1995. 52. Pellock JM, Kleinman PK, McDonald BM, Wixson D. Childhood hypertensive stroke with neurofibromatosis. Neurology 1980, 30:656–659. 53. Rizzo JF, Lessell S. Cerebrovascular abnormalities in neurofibromostis type 1. Neurology 1994; 44: 1000–1002. 54. Emparanza JI, Aldamiz-Echevarria L, Perez-Yarza E, Hernandez J, Pena B, Gaztanaga R. Ischemic stroke due to fibromuscular dysplasia. Neuropediatrics 1989; 20:181– 182. 55. Suzuki J, Takaku A. Cerebrovascular “moyamoya” disease. Arch Neurol 1969; 20:288–289. 56. Kudo T. Spontaneous occlusion of the circle of Willis. Neurology 1968; 18:485–496. 57. Yamada I, Matsushima Y, Suzuki S. Moya-moya disease: diagnosis with three-dimensional time-of-flight angiography. Radiology 1992; 184:773–778. 58. Rooney CM, Kaye EM, Scott M, Klucznik RP, Rosman NP. Modified encephaloduroarteriosynangiosis as a surgical treatment of childhood moyamoya disease: Report of five cases. J Child Neurol 1991; 6:24–31. 59. Mitchell WG, Fishman LS, Miller JH, Nelson M, Zeltzer PM, Soni D, Siegel SM. Stroke as a late sequela of cranial irradiation for childhood brain tumors. J Child Neurol 1991; 6:128–133. 60. Allen JC, Miller DC, Budzilovich GN, Epstein FJ. Brain and spinal cord hemorrhage in long-term survivors of malignant pediatric brain tumors: a possible late effect of therapy. Neurology 1991; 41:148–150. 61. Menkes JH, Sarnat HB. Cerebrovascular Disorders. In: Menkes JH, Sarnat HB (eds) Child Neurology. Lippincott Williams & Wilkins, 2000:885. 62. Quint DJ, Silbergleit R, Young WC. Absence of the carotid canals at skull base. Radiology 1992; 182:477–481. 63. Pascual-Castroviejo, Viano J, Pascual-Pascual SI, Martinez V. Facial haemangioma, agenesis of the internal carotid artery and dysplasia of cerebral cortex: case report. Neuroradiology 1995; 37:692–695. 64. Rossi A, Bava GL, Biancheri R, Tortori-Donati P. Posterior fossa and arterial abnormalities in patients with facial capillary haemangioma: presumed incomplete phenotypic expression of PHACES syndrome. Neuroradiology 2001; 43:934–940. 65. Zimmerman RA. Vascular injuries of the head and neck. Neuroimaging Clin N Am 1991; 1:443–459. 66. Hockaday JM. Basilar migraine in childhood. Dev Med Child Neurol 1979; 21:455–463. 67. Kim IO, Kim JH, Kim WS, Hwang YS, Yeon KM, Han MC. Mitochondrial myopathy-encephalopathy-lactic acidosisand strokelike episodes (MELAS) syndrome: CT and MR findings in seven children. AJR Am J Roentgenol 1996; 166:641–645. 68. DiMauro S, Moraes CT, Schon EA.Mitochondrial encephalopathies: problems of classification. In: Sato T, DiMauro S (eds) Mitochondrial Encephalopathies. New York: Raven Press, 1991: 113–127. 69. Locksley HB. Report on the cooperation study of intracra-

Cerebrovascular Disease in Infants and Children nial aneurysms and subarachnoid hemorrhage. J Neurosurg 1966; 25:219–239. 70. Zimmerman RA, Atlas S, Bilaniuk LT, Hackney DB, Goldberg HI, Grossman RI. Magnetic resonance imaging of cerebral aneurysm. Acta Radiol Suppl 1986; 369:107– 109. 71. Choux M, Lena G, Genitori L. Intracranial aneurysms in children. In: Raimondi A, Choux M, Di Rocco C (eds) Cerebrovascular disease in children. Vienna: Springer, 1992:123–131. 72. Lasjaunias P. Intracranial aneurysms in children. In: Lasjaunias P (ed) Vascular Diseases in Neonates, Infants and Children: Interventional Neuroradiology Management. Berlin: Springer, 1997.

73. Sedzimir CB, Robinson J. Intracranial hemorrhage in children and adolescents. J Neurosurg 1973; 38:269–281. 74. Kerr CB. Intracranial haemorrhage in hemophilia. J Neurol Neurosurg Psychiatry 1964; 27:166–173. 75. Visudhiphan P, Bhanchet P, Lakanapichanchat C, Chiemchanya S. Intracranial hemorrhage in infants due to acquired prothrombin complex deficiency. J Neurosurg 1974; 41:14– 19. 76. DeSwiet M. The epidemiology of hypertension in children. Br Med Bull 1986; 42:172–175. 77. Barron TF, Gusnard DA, Zimmerman RA, Clancy RR. Cerebral venous thrombosis in neonates and children. Pediatr Neurol 1992; 8:112–116.

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Arteriovenous Malformations: Diagnosis and Endovascular Treatment Laecio Batista, Augustin Ozanne, Marcos Barbosa, Hortensia Alvarez, and Pierre Lasjaunias

CONTENTS 8.1 8.1.1 8.1.2

Introduction 287 Role of Imaging in the Pediatric Age Group 288 Arterial and Venous System in Children 290

8.2 8.2.1 8.2.2 8.2.3 8.2.3.1 8.2.3.2 8.2.3.3 8.2.3.4 8.2.3.5

Classification of Cerebral Vascular Malformations 290 Pial, Dural, or Choroidal Lesions 291 Timing of Genesis 292 Angioarchitecture and Morphology 292 Angioarchitecture 292 Size 294 Location 295 Multiplicity 295 Complex Cranio-Facial Vascular Lesions 295

8.3 8.3.1 8.3.2 8.3.3 8.3.4

Specificities per Type 296 Pial Lesions 296 Dural Lesions 297 Vein of Galen Aneurysmal Malformation 302 Craniofacial Metameric Lesions 309

8.4 8.4.1 8.4.2

Treatment 310 Therapeutic Objectives and Follow-Up Imaging of Embolic Agents 313 References

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8.1 Introduction Cerebral arteriovenous malformations (CAVMs) or shunts have different characteristics in children when compared with adults with respect to multifocal lesions, induced remote arteriovenous shunts [1, 2], venous thrombosis, systemic manifestations, large venous ectasias, high flow lesions, and rapid cerebral atrophy [3–5]. Conversely, high-flow angiopathic changes are seldom seen with the same frequency as in adults; flow-related arterial aneurysms are absent [6], whereas proximal occlusive arteriopathic changes are more frequent. For this reason, management protocols derived from experience in adults cannot be applied to the pediatric population. In particular, adult-based AVM grading is especially inappropriate for children, because (1) cerebral elo-

quence is difficult to assess, particularly in the first years of life; (2) most lesions are fistulas or multifocal; (3) their drainage usually involves the entire venous system; and (4) the possibility for recovery in children is different from adults. In addition, a high grade AVM that would be dangerous to operate in an adult may not necessarily be dangerous for the patient if left unoperated, or at least more dangerous than a lowgrade AVM. The decision-making process in children includes, in addition to the conventional objectives, various specific factors, such as anatomic analysis of veins and the brain myelination process. Thereafter, progressive deficits related to congested cerebral veins, poorly controlled seizures, hemorrhages with or without specific arterial or venous changes upstream and downstream the AVMs, or headaches without hydrocephalus or macrocrania can become immediate objectives for staged or partial targeted treatment. In our experience, all children that were considered completely cured at follow-up did not show recurrent arteriovenous shunting or new symptoms at later clinical or angiographic follow-up. Neurocognitive evaluation is an important followup criterion in neonates and infants, even without deficit, hemorrhage or seizure; it helps to assess treatment quality and success. Failure to obtain a normal maturation process can constitute a therapeutic failure if the optimal moment for intervention has been missed. This points to the difference between early irreversible damage and damage by persistent disorder and secondary destruction. Brain calcifications, which can be observed in both instances, indicate failure to obtain normal hemo- and hydrodynamic conditions for the maturing brain. When discussing CAVM or vascular diseases in children, one wonders whether it represents an artificial grouping. AVMs in children are primarily characterized by specific diagnostic and therapeutic challenges in which they develop. Some rare lesions are exclusively encountered in children, mainly in neonates and infants. The anatomic characteristics of neonatal and infant brain and the immaturity of its system flexibility create a specific group of symptoms and thera-

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peutic objectives. This vulnerability means that the lesion rapidly becomes lethal or creates a disabling state, whereas a similar lesion in adult would produce fewer symptoms and damage.

8.1.1 Role of Imaging in the Pediatric Age Group Children have higher risk of complications related to femoral puncture than adults, due to the small caliber of the femoral artery and its vulnerability to vasospasm. Contrast restriction exists in this group (6cc/ kg). Due to small body surface and organic immaturity of neonates and infants, in cases of secondary cardiac overload due to the CAVM, fluid volume should be cautiously monitored. In our experience, the procedure should not exceed 2 h. Thus, catheter angiography is reserved in most of the cases: (1) if endovas-

cular treatment is foreseen in the same session, and (2) in the presence of persistent unclear diagnosis by other methods, i.e., clinical, computerized tomography (CT), and magnetic resonance imaging (MRI). Numerous useful morphological and functional information, such as feeders, location, mass effect, brain damage, and veno-dural patency, can nowadays be anticipated from noninvasive examinations. Ducreux [7] demonstrated that functional MRI in proliferative angiopathy provides data for a better understanding of symptoms (Fig. 8.1). Antenatal ultrasounds and/or MRI can demonstrate vein of Galen aneurysmal malformations (VGAMs) (Fig. 8.2), dural sinus malformations (DSMs) (Fig. 8.3), or exceptionally cerebral arteriovenous malformations (CAVMs). Presence of fetal cardiac failure or encephalomalacia are suggestive of brain pathology. In other situations, the antenatal diagnosis will guide the delivery of the child in the presence of a qualified pediatric unit (Fig. 8.4).

Fig. 8.1. Functional-MRI in proliferative angiopathy (Ducreux 2002). MR perfusion imaging in a vein of Galen aneurysmal malformation with proliferative activity: nidal area (1), at the level of the centra semiovale (2), and at the level of the central sulci (3). From left to right, T2-weighted (a), TTP (b), CBV (c) and CBF (d) parametric perfusion images. The color scale shows high values in red, mean values in green, and low values in blue. Note the high CBV and CBF values in the nidal zone (white arrow). Note increased perfusion in the left corona radiata (yellow arrow), and the bilaterally increased TTP values remote from the nidus in the white matter (white arrowheads). Truncation of the images in the right posterior region is due to artifact from the shunt valve

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a

Fig. 8.2. Fetal MRI showing a vein of Galen aneurysmal malformation

b

Fig. 8.3. Fetal MRI: diagnosis of dural sinus malformation (DSM)

Fig. 8.4a–c. Antenatal diagnosis of cortical arteriovenous fistula (CAVF) in a female baby with severe neonatal cardiac failure. Two CAVFs at angiography. Embolization of both CAVFs was performed at age 17 days with immediate clinical improvement. Normal cardiac function at 2 months

c

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8.1.2 Arterial and Venous System in Children The arterial tree in neonates is likely to have an immature pericytic coverage, which suggests higher fragility and risk of rupture during vascular procedures (surgical and endovascular) in this age group. Gross anatomy does not differ from adults [8], with few exceptions: (a) the existence of a more competent and complete circle of Willis, (b) usual normal kinking of the cervical internal carotid arteries, and (c) widely patent anastomoses between the external and internal carotid arteries. Children have higher cardiac pulse than adults, and one often can see veins during arterial phase examination in TOF-sequences (2DTOF/3D-TOF), even in the absence of arteriovenous shunts. The normal postnatal maturation demands a vascular environment, especially venous, to be free of venous hypertension or congestion. The venous system in the pediatric age group presents numerous peculiarities. The hydric dural resorption system of neonates is still immature, which results in the medullary venous system being responsible for both the cerebral venous drainage and the intrinsic and extrinsic cerebral water dynamics. The granulations are not yet functional before 2 years of age; their maturation is delayed if the hemodynamics of the dural sinuses is abnormal. The maturation of the jugular bulb is simultaneous with that of the jugular foramen and also occurs after birth, allowing free flow through the sigmoid sinus towards the internal jugular vein. Simultaneously, the occipital and marginal sinuses regress [9]. At birth, the torcular drains the entire venous flow towards the posterior outlets, as the sylvian veins have not yet been “captured” by the parasellar venous plexus. This alternate pathway is usually present at 6 months. Some uneven ballooning of the transverse sinuses is observed in the roentgenograms of the fetuses from the second half of the fourth to the seventh month. After 20 weeks, the inner caliber of the transverse sinuses gradually becomes even. From birth to age 1 year, the inner diameter of the transverse sinus decreases somewhat. After age 1 year, the sinus has an adult appearance. In our experience, the inner diameters of the sigmoid sinuses remained relatively constant and small during fetal life, ranging in size from 1–2 mm. Up to the sixth fetal month, the course of the sigmoid sinuses differs from that of adults in that they follow a gentle convex curve medially in Towne’s view. After the 6th fetal month, the sigmoid sinuses follow a gentle convex curve laterally. At this stage, the course of the sinuses approaches that of adults.

The inner diameter of the jugular sinus increases by only 1 mm from the 3rd to the 7th fetal month, and is extremely small (1–2 mm on average). After birth, it rapidly increases, forming a bulb-like enlargement at 2 years of age. This is the formation of the (high) jugular bulb. During the period when the jugular sinus is small and poorly developed, the amount of stagnant venous blood drains from (mostly the convexity of) the cerebrum and cerebellum. The formation of the (high) jugular bulbs takes place after birth (clearly visible on angiograms, 2 years after birth) and is likely related to hemodynamic factors, resulting from a change from the fetal lying-down position to the postnatal erect posture [9]. In the presence of intracranial arteriovenous shunts, dysmaturation of basal sinus drainage may occur. Thus, embryonic dural sinus patterns can persist, accompanying the underlying disease as seen on venous phase magnetic resonance angiography (MRA) (Fig. 8.5). Under high sinusal pressure, hydric imbalance initially produces macrocrania, ventriculomegaly (if the cranial sutures are open), and later hydrocephalus with transependymal resorption. Tonsillar prolapse associated to severe degree of brain atrophy (melting syndrome) and pial venous congestion occur later, when sutures are already closed with occluded jugular bulbs. Hence, normal head circumference is misleading.

8.2 Classification of Cerebral Vascular Malformations Arteriovenous shunts represent an heterogeneous group of vascular lesions, traditionally classified according to morphologic criteria or technical accessibility [10–12]. Clinical experience shows that apparently identical lesions can produce different symptoms. Conversely, quite morphologically different vascular lesions can produce identical clinical manifestations. Nowadays, endovascular techniques allow distal approach to the territories and access to lesions located in the immediate vicinity of eloquent areas. Classification of vascular cerebral malformations aims to reflect their natural history with regard to degree of vascular adaptation (system response) [13] to the conditions created by the CAVM.

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a

b

c

d Fig. 8.5a–d. Neonatal cerebral drainage. a, b Schematic representation. At this age, venous drainage converges into superior and posterior sinuses. Posterior fossa drainage is via the latero-mesencephalic vein and the superior petrosal sinus to the cavernous sinus and caudally to the jugular bulb. There is no cortical venous drainage to the cavernous sinus yet (hatched). c, d Late phase of a carotid angiogram in a baby with vein of Galen aneurysmal malformation

8.2.1 Pial, Dural, or Choroidal Lesions According to the meningeal space from which arteriovenous (AV) lesions primarily develop, one can classify AV lesions into pial, dural, or choroidal (subarachnoid). Cerebral pial AVMs are located in the subpial space [15–17], and are supplied by pial cerebral arteries (Fig. 8.6). Pial AV shunts include cerebral AVM, cor-

tical AVF, proliferative angiopathy, and hemorrhagic angiopathy. Dural arteries arising from the external and internal (ICA siphon) carotid or vertebral arteries may contribute to the supply of dural lesions. In the pediatric age group, the middle meningeal artery is almost always involved, and often develops flow-related aneurysms. This group includes dural sinus malformations (DSM) and juvenile dural AV shunts.

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Choroidal plexus AV shunts occur in the choroidal fissure; the vein of Galen aneurysmal malformation (VGAM) is the embryonic entity of this group. The choroidal branches arise from the basilar tip, posterior cerebral, anterior choroidal, and anterior cerebral (pericallosal or anterior communicating) arteries.

sidering all the harmful effects of high-flow lesions on the growing and maturing brain, it is difficult to believe that most CAVMs discovered in adults were present as such at birth [16]. The word “congenital” means during the time of gestation, based on the postulate that the fetus is fully developed at birth. However, construction of a vascular tree is not a static process, but rather results from complex biological factors and events starting in the embryo and continuing in the fetus, neonate, and infant. The vascular tree is maintained, repaired, and modified according to metabolic demands, resulting with time in a renewal of the entire structure [17], which is genetically programmed and controlled. Alterations in the required program or cellular logistics will result in a different construction, and the vascular tree may eventually be abnormal. An abnormal vascular architecture may therefore be due to a construction failure (embryonic, fetal, or perinatal) or a failure in the renewal process (postnatal). Thus, CAVMs can result from a congenital event, and albeit morphologically unexpressed at birth they will become detectable later. The impact of this congenital event is primarily cellular, somehow affecting the vascular modeling and remodeling chain [18]. For this quiescent dysfunction to be revealed as a morphological abnormality, secondary “revealing” triggers or “mutations” are needed. They are not yet identified, but are likely to include mechanical, hormonal, pharmaceutical, hemodynamic, thermal, radiation, viral, infective, and metabolic factors. The different nature and timing of the revealing trigger (or triggers) could result in the variety of AVMs that are known today [16] (Table 8.1). VGAMs (Fig. 8.2), and DSMs (Fig. 8.3) are often diagnosed in utero. The VGAM defect obviously occurs during the embryonic period and becomes manifest during fetal life. The DSM defect occurs during the early fetal period and also develops at the end of this period. All other CAVMs occur and develop during the perinatal period at the earliest, but most likely after infancy and during adulthood. In our experience, only 1% of nongalenic CAVFs were diagnosed in utero over the past 20 years (Fig. 8.4).

8.2.2 Timing of Genesis

8.2.3 Angioarchitecture and Morphology

CAVMs are considered to be congenital in nature; it is implicit that a “malformation” is present at birth, even though it may be discovered much later in life. However, there is no evidence that AV shunts diagnosed in adults are present as such in children. Con-

8.2.3.1 Angioarchitecture

a

b Fig. 8.6a,b. Pial malformation is placed in the subpial space. 1, venous drainage; 2, venous pouch; 3, venous reflux; 4, dural opening; 5, cortical reflux; 6, subpial reflux; 7, medullary reflux; 8, subcortical reflux; 9, secondary pial reflux; 10, dural sinus flow

Appropriate analysis of angioarchitecture allows understanding of past events and anticipation of

Arteriovenous Malformations: Diagnosis and Endovascular Treatment

Cerebral vasculature (capillary-venous junction)

Cellullar substrate = target Window of exposure = timing (system in activity, ...)

Mutation or primary trigger (humoral, immune, infectious, trauma ...) Remaining vasculature Dormant Defect (transmissible)

Reversible focal change or irreversible dormant focal change (dna repair systems, p53, ...) (failure to repair) Mutation or revealing trigger (humoral, immune, infectious, trauma ...) Arterio venous shunt Induced stresses (shear stresses, ...) Brain “AVM” nidus

Reversible or permanent regional changes (high flow angiopathy)

future ones; it helps to identify potential causes of symptoms, recognize underlying anatomical risk factors, and guide our therapeutic attitude. For instance, epilepsy or neurological deficit are more frequent in temporal pial PAVMs with venous ectasia and cortical or veno-sinusal high pressure, especially if a long subpial course of a cortical vein is present. Assessment of both arteries and veins is an important element at this point. Nidus versus fistula. A nidus consists of a group of small AV shunts within a vascular meshwork. The term fistula describes a direct opening of one or several arteries into an enlarged draining vein (Fig. 8.7). Arterial vascular changes in cerebral AV shunts. Flowrelated aneurysms are due to shear forces established on the arterial wall due to AV shunt; these are absent in children. If distal or intranidal false aneurysms (normally in older children) can be seen in the acute stage of a hemorrhagic episode, endovascular embolization may become a priority, as early recurrence is more frequent in children than in adults. Headache is often associated with arterial stenosis and, in this population, with a raised intracranial pressure. A moyamoya type of high flow angiopathic process [1]

Normal vasculature

Table 8.1. Cerebral vasculature (capillary-venous junction)

expresses a certain degree of angiogenesis, as confirmed by the presence of transdural supply several years after establishment of the diagnosis. Such a situation should be differentiated from proliferative angiopathy. Venous angiopathy. Abnormalities of the venous system are more frequent than arterial ones. It is likely that most symptoms before the age of 3 years are venous-related. Venous pouches are often noted in children, since thrombosis and high flow are characteristic features in this age group. Paradoxically, huge pouches in children can be diagnosed with almost no mass-related symptoms, illustrating the ability of infant’s head to enlarge. However, seizures are frequently associated with spontaneous (partial) thrombosis of the pouch. Increasing size of the pouches can be observed over time on serial CT/ MRI, subsequent to the development of restriction of the downstream outlets [13]. Venous “ischemia” is a generic denomination that includes various types of symptomatic venous congestion/restriction, from focal to melting-brain syndrome. The latter is specific to infants. It consists of rapid destruction of the brain, usually involving the subcortical white matter with ventriculomegaly. This phenomenon is associated with severe neurological manifestations and no

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a a

b b Fig. 8.7a,b. a Arteriovenous fistula with enlarged draining vein. b Presence of nidus in an arteriovenous malformation

signs of increased intracranial pressure, although these are usually present before the syndrome takes place. It may be diffuse and symmetrical, or focal in pial CAVMs. These findings are never encountered in adults, illustrating the role played by subpial and medullary veins in the maintenance and development of the white matter in the pediatric age group. The melting brain syndrome can be observed in CAVMs and DSMs. In the latter, the acute onset of venous ischemia often leads to hemorrhagic venous infarction, rather than to subacute atrophic changes (Fig. 8.8).

Fig. 8.8a,b. Axial (a) and sagittal (b) T1-weighted images show focal melting brain syndrome in the posterior fossa due to the early venous ischemia produced by the cerebellar arteriovenous malformation. Note ventricular enlargement

Flow velocity: AV shunts can show very slow flow (as in DSM), mild flow (as in micro-AVMs), or very high flow (as in cases of VGAM and pial CAVF) (Fig. 8.4). 8.2.3.2 Size

The shunting zone can be variably sized, and is therefore named micro, macro, or giant. Thus, one has micro-AVM, micro-AVF, macro-AVM, and macroAVF according to angioarchitecture. Cerebral AVMs

Arteriovenous Malformations: Diagnosis and Endovascular Treatment

do not grow, although they can enlarge by angiogenesis or an angioectatic process. If an intrauterine defect occurs, the impact area, size, and severity will be related to the timing of the causative event in relation to migration and the transformation of the “stem” to “committed.” The earlier the causative event, the larger the area of impact and the higher the chances of multifocality. The later the event, the more focal the defect and the smaller the lesion. Growth of an AVM as such will not occur. A large nidus will not result from the growth of a small one, but express a defect shared by a large group of cells fired by the revealing trigger on a clone of cells carrying a dormant defect [16]. Most of so-called AVM growths are due to high flow angiopathy changes and angiogenesis in response to clot, ischemia, and operative procedures (embolization, surgery or radiotherapy), or to proliferative angiopathy. 8.2.3.3 Location

In contrast to some diseases such as moyamoya, CAVM can occur anywhere in the brain. Whereas fistula are always superficial and cortical, nidustype PAVMs can be superficial, cortico-subcortical, deep, paraventricular or mixed, supra- or infratentorial. The nidus itself does not entrap parenchymal or neural structures. On MRI sequences, CAVMs are typically cortico-ventricular and wedge-shaped. Deep diencephalic lesions can be isolated or included in a cerebro-facial metameric syndrome (CAMS). Dural sinus malformations (DSMs) and infantile types of dural AV shunt (IDAVS) occur at the level of the torcular-lateral sinus complex and will be discussed later. The adult type of dural shunts seen

in children (ADAVS) occurs in the cavernous sinus. VGAMs lie on the choroid fissure from the pineal gland area to the interventricular foramina, more or less seated on the midline. 8.2.3.4 Multiplicity

Cerebral AVMs can be single or multiple. In our experience, multifocality in children is twice that of adults (18% versus 9%). They are usually spread bilaterally or supra- and infratentorially. Mixed shunt characteristics rarely occur in multifocality (i.e., association of nidus and fistulous types). More often, one finds the same type of angioarchitecture in all sites in the same individual, i.e., multiple fistulae or multiple niduses. Such multiple CAVF are highly suggestive of hereditary hemorrhagic telangiectasia (HHT-1). 8.2.3.5 Complex Cranio-Facial Vascular Lesions

Complex cranio-facial vascular diseases are rare lesions that include two recently recognized forms of presentation, both carrying an underlying metameric linkage between the intracranial and facial vascular territories: (1) cerebrofacial arteriovenous metameric syndrome (CAMS) and (2) cerebrofacial venous metameric syndrome (CVMS). CAMS corresponds to Wyburn-Mason or Bonnet-DechaumeBlanc syndromes, whereas CVMS to Sturge-Weber syndrome (SWS) [19, 20]. According to the involved metamere (hypothalamo-nasal, prosencephaloorbito-maxillar, or rhombencephalo-mandibular), these lesions are named CAMS-1, CAMS-2, CAMS3 and CVMS-1, CVMS-2 or CVMS-3, respectively (Fig. 8.9).

Fig. 8.9. Cerebrofacial topographic correspondence in arteriovenous and venous metameric syndromes (CAMS and CVMS). (From [20], with permission)

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8.3 Specificities per Type 8.3.1 Pial Lesions Pial cerebral AV shunts include CAVM, CAVF, proliferative angiopathy, and hemorrhagic angiopathy. The common denominator is a subpial location and its postnatal diagnosis. CAVM can be cortical, deep, or subependymal (paraventricular) in location, or buried in the white matter; however, different location does not correspond to pathological diversity. Cortico-ventricular CAVMs typically show a pyramidal shape on CT and/or MRI. The lesion itself can appear as a fistula, a nidus-type, or a mixed type. The CAVF type always lies superficial on the cortical surface, supra- or infratentorially. In this situation, the dilated arterial feeders (usually one to three) more commonly originate from pial arteries away from the midline (basilar artery or circle of Willis) and drain into very dilated veins, often associated with venous pouch. CAVMs drain into the pial venous system and interfere early with the local hydrovenous function. However, in some cases the rapid passage into the subarachnoid spaces probably prevents some of these CAVF from damaging the brain, as seen normally in similar spinal cord lesions. In symptomatic patients, nidus-type CAVMs produce functional symptoms, such as seizures (resulting from venous congestion or bleeding), hemorrhage, and progressive neurological deficit including

developmental delay related to early interference between AVM drainage and cerebral venous maturation (Fig. 8.10). Single CAVF and multifocal lesions in children are highly suggestive of HHT1, also called Rendu-OslerWeber syndrome (ROW). CAVMs of the central nervous system are present in approximately 8% of HHT1 patients [21]; Willinsky [5] reported that 28% of patients with multiple CAVMs had HHT1. HHT1 is an autosomal (9q) disorder of strong penetrance and variable expression; in adults, it is characterized by multiple mucocutaneous and visceral telangiectasias, which produce recurrent hemorrhagic complications. Epistaxis is common in adults with HHT1 but rare in children [22, 23] (Fig. 8.11). The disease involves failure of the remodeling process due to an abnormal binding protein (endoglin) to TGFβ1, which compromises locally the reconstitution of the venous capillary junction [24]. Merland [25] emphasized the role played by pulmonary fistulas in the neurological symptoms. They can produce CNS manifestations as the result of emboli (septic or not). Among these, formation of brain abscesses may be a prominent manifestation of this disease, and may rarely represent its initial presentation. When CNS manifestations are seen in patients with HHT1, the search for pulmonary AVF is mandatory, and fistulous disconnection should be performed. If CAVM is associated to pulmonary AVF, the latter should be treated first. Multiple CAVM can be expressed in a sporadic form, without familial history or manifestations of HHT1. Batista [26] reported a rare association of two

a

b Fig. 8.10a,b. Cortical arteriovenous fistula in a young infant with focal, yet significant, melting brain syndrome

Arteriovenous Malformations: Diagnosis and Endovascular Treatment

to recurrent hemorrhages within the first 6 months. These lesions are also placed in the CAVM group, yet we do not consider these as a true CAVM or a proliferative angiopathy, as their clinical and angioarchitectural characteristics are specific: small scattered “nidus-like” lesions in subcortical/white matter areas. The arterial feeders are normal in size, and the area drains into normal veins. Due to the type of nidus, which is intermingled with the normal brain, embolization or surgical treatment is not indicated. These lesions respond dramatically to radiotherapy, and we observed excellent results in such cases (Fig. 8.14). Imaging Findings

Fig. 8.11. Cortical arteriovenous fistula in a child with hereditary hemorrhagic telangiectasia 1 (HHT1)

pial high-flow fistulas with nonvascular intracranial malformations (lipoma, arachnoid cysts, and cortical dysplasia) (Fig. 8.12). In neonates with CAVF, high flow interfering with normal brain homeostasis can induce, in few weeks, focal melting syndrome secondary to venous ischemia and/or hemorrhage, justifying rapid treatment. In other cases, the long subpial course of cortical vein draining the fistula may produce epileptic foci or neurocognitive delay. Proliferative angiopathy represents a type of pial AV shunt characterized by angiogenetic and angioectatic activity. Angiographic studies show discrepancy between the apparent size of the “nidus-like” network of vessels (involving one complete lobe or hemisphere, uni- or bilaterally) and the draining veins, which are often normal or slightly enlarged. Secondary proximal arterial stenosis is part of this pathology. Transdural supply in various locations demonstrates the diffuse character of the angiogenetic activity of this disease, that is often confused with PAVM and named diffuse or holo-hemispheric nidus (Fig. 8.13). Proper recognition and classification is important, as it implies anticipation of normal brain tissue intermingled with the vascular spaces on MRI images [7]. Seizures are the most common clinical symptoms at presentation, although headache and progressive deficit are also possible. Single hemorrhage is an exception; however, recurrent ones are very frequent. Hemorrhagic angiopathy. Revealed by intracerebral hemorrhage, this lesion demonstrates high tendency

MRI sequences give important information. T1weighted sequences should be obtained at least on axial and sagittal planes, and allow detailed analysis of the nidus. The brain status (edema, atrophy, mass effect, encephalomalacia, and transependymal resorption) is much better appreciated on FLAIR and T2-weighted sequences. Calcification and hemorrhage require gradient-echo images. In symptomatic intranidal partial venous thrombosis, the hypersignal in T1- and T2-weighted sequences indicates slow flow, rather than hemorrhage. Mass effect exerted by venous pouches on the surrounding brain can result from partial thrombosis and extravascular reaction. On CT scan, one has to be cautious not to misinterpret intravascular blood (into giant venous pouch) as hemorrhage (parenchymal hematoma); contrastenhanced sections will confirm the intraluminal nature of blood. CT scan can also demonstrate thin parenchymal calcifications, indicating brain insult and chronic venous ischemia. In the presence of multiple pial lesions, HHT1 should be suspected, and lung screening by CT is recommended. In multiple AVMs, correlation of MRI with clinical history and angiographic findings helps to determine which among the various lesions is the one responsible for symptoms; thereafter, proper treatment can be initiated.

8.3.2 Dural Lesions Pediatric dural arteriovenous shunts (DAVSs) are rare, with only few reports dealing with these lesions in the literature [1, 27, 28]. In contrast to adults, dural arteriovenous fistulae (DAVF) in children are likely to be congenital [29], despite reported cases in literature as part of adult series [30–32].

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Fig. 8.12a–g. Cortical arteriovenous fistula (CAVF). a Carotid injection shows an ipsilateral cortical arteriovenous fistula on the temporal cortex. b Vertebral angiogram, lateral view shows a pial arteriovenous fistula supplied by a short circumferential artery from the basilar tip and draining into an ectatic tegmental vein. c Angio-3D shows the exact fistulous point. d The “basket” created into the venous ectasia and occluding the AVF by two small coils. e Vertebral angiogram, lateral view: immediate control shows complete occlusion of the basilar fistula. f, g Angiographic control at left internal carotid artery and vertebral artery, lateral view: complete occlusion of both CAVFs

Arteriovenous Malformations: Diagnosis and Endovascular Treatment

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b Fig. 8.13a,b. Proliferative angiopathy involving the entire left frontal lobe: MRI (a) and angiographic (b) features

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Fig. 8.14a–c. Hemorrhagic angiopathy: before treatment (a), when it produced a cerebellar hematoma (b), and 1 year after stereotaxic radiotherapy (c)

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In general, authors tend to apply to children the experience gained in the adult population, ignoring the specificities of the pediatric population such as cerebral and skull maturation, dural changes, venous vasculature, and CSF pathways. In neonates, clinical features include cardiac failure (usually mild) and coagulation disorders (consumption), whereas in infants there is increased intracranial pressure (with irritability, macrocrania, neurocognitive delay, and seizures). By analyzing the clinical history and anatomical features obtained with catheter angiography, CT, and MRI, three different types of DAVS can be described in this age group: (1) dural sinus malformation (DSM); (2) infantile or juvenile type DAVS (IDAVS); and (3) adult-type DAVS (ADAVS) [28]. DSM: the AV shunts are a secondary event to the dural sinus malformation. Most often, DSM are revealed clinically in the first months of life; 20% of cases are diagnosed in utero by ultrasounds. Two types can be distinguished: 1. DSM involving the torcular and adjacent sinuses, with giant pouches and mural AV shunts (Fig. 8.15). The malformation is usually seen as a giant dural sinus lake, with partial thrombosis already apparent. The dural sinus lake communicates with the other sinuses; normal cerebral veins open into the malformed sinus. There often are restricted outlets, due to dysmaturation of one jugular bulb. The degree of lateralization (lateral, sigmoid sinus, jugular bulb) or the midline location (torcular-superior sagittal sinus) and also the magnitude of the dural lake and thrombosis are predictive factors, with a more favorable evolution for DSM away from the torcular. a

Midline-located DSM, associated with multiple slow-flow AV shunts within the sinus wall, contribute to the venous congestion of the brain, even in absence of pial venous reflux. Spontaneous thrombosis of the outlets further compromises the cerebral venous drainage, leading to venous infarction and parenchymal hemorrhage (Fig. 8.16). Postnatal growth of these lesions has been seen, with appearance of cavernomas or association with facial or calvarial venous malformations. In the presence of patent venous outlets, the clinical evolution remains subacute with macrocrania and mental retardation, but cerebral damage can be expected. Treatment must preserve the lake, preventing a radical venous approach. The aim is to preserve appropriate venous drainage to the brain and to occlude the mural AV shunts, until the cavernous capture allows the exclusion of the malformation. In some instances, progressive separation of both circulations can be achieved to avoid retrograde venous congestion. In lateralized dispositions that spare the torcular, the capability of the normal side to provide brain drainage is the most important prognostic sign. A similarly favorable evolution is seen in distal superior sagittal sinus locations away from the torcular. 2. DSM of the jugular bulb with otherwise normal sinuses produce an apparent sigmoid sinus-jugular bulb “diaphragm” and are associated with a petromastoid-sigmoid sinus high-flow AVF, usually single-holed. Such disposition is very different from the normal variations seen in the region where the sigmoid sinus is absent [33]. The malformation corresponds to a dysmaturation of the jugular bulb, with occlusion of the distal sigmoid sinus and normal postb

Fig. 8.15a,b. Partially thrombosed dural sinus malformation (DSM) involving the torcular and adjacent sinuses. Catheter angiogram (a) and schematic (b)

Arteriovenous Malformations: Diagnosis and Endovascular Treatment

a

b

Fig. 8.16a–c. Superior sagittal sinus DSM. MRI and CT performed at 7 and 8 months of age, respectively, demonstrate the superior sagittal sinus DSM and the spontaneous thrombosis (c) of the sinuses with rapid venous infarction, hemorrhage, and ventricular rupture (b)

c

natal occlusion of the marginal sinus. Although the AV shunt is usually of the high-flow type (the cerebral venous drainage is preserved), symptoms are mild in most cases. Prognosis is excellent with occlusion of the AVF, eventually with thrombosis of the sigmoid sinus distal to the superior petrosal sinus opening. Infantile DAVS: IDAVS are lesions with high flow and low pressure, with multifocal dural AV shunts. The sinuses are much larger than normal, but no lakes exist. They remain patent for a long time. Several unusual high flow angiopathic changes are noted, in particular on dural arteries with arterial aneurysms (Fig. 8.17). During evolution the venous drainage is craniofugal, usually unilateral, without any contralateral dural sinus reflux despite the high flow. The evolution includes: (1) Persistent high flow, with

patent outlets: the sinus sump effect creates remote cortical pial AVSs. The latter are usually asymptomatic, and may regress after occlusion of several dural AVSs. (2) Uni- or bilateral jugular bulb stenosis and occlusion, with increased hydrodynamic manifestations and bilateral pial vein congestion and reflux. In this case, tonsillar prolapse and even syringohydromyelia may take place [34]. Clinical onset often occurs at preadolescence, often a few years after well-tolerated, minor craniofacial traumatic or bleeding events. Cranial nerve deficits are often the initial symptom. If the first symptom is neglected, macrocrania and mental retardation develop. Progressive neurological symptoms (involving both the cerebrum and posterior fossa) occur at a later stage, usually after 10 years of age. Rerouting of the venous drainage towards the cavernous sinus may

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b Fig. 8.17a,b. Juvenile or infantile dural arteriovenous shunt with multifocal fistulas in a 12-year-old child. Typical MRI (a) and angiographic (b) features

also produce proptosis and facial vein enlargement. In cases with rerouting into cerebral pial veins, seizures, neurological deficits, mental retardation, and brain calcifications appear. Treatment by arterial embolization is always partial. Multifocality leads to recurrence, with new shunts opening near the previously embolized ones. The long term prognosis is poor with neurological deterioration in early adulthood. Treatment in these cases is usually disappointing, as the cerebral impairment is only partially reversible. Hemorrhagic events can occur at this final phase. Adult-type DAVS: Anatomically, almost all ADAVS are located at the cavernous venous plexus. Sigmoid ADAVS are very rare, and multifocality has not been described. Extra-sinusal ADAVS (duro-subdural and osteodural) have not been encountered. Clinically, ADAVS are encountered in very young children, and several cases of neonatal cavernous fistulas have been described [35–37]. Many of these lesions become spontaneously thrombosed. It is noteworthy that neonatal ones never drain in the pial veins. If treatment is contemplated, cases with ophthalmic venous drainage alone will benefit from manual compression at the medial cantus; other agents or venous approach to the parasellar region have been used. Imaging Findings

MR images confirm the type of lesion (DSM, IDAVS, or ADAVS) as well as the anatomical distribution and extent of the dural involvement. In DSM, the initial

examination is important to establish clinical prognosis, as shunts away from midline have a much better evolution than midline ones (with torcular involvement). Tonsillar prolapse can be assessed on sagittal views. Postcontrast T1-weighted images differentiate AV shunts from cystic posterior fossa malformations, such as the Dandy-Walker malformation or mega cisterna magna. In ADAVS, thickening of the cavernous sinus can be observed. Enlargement of the ophthalmic veins correlates well with conjunctival congestion. In rare cases of DSM, complex venous anomalies may exist, and MRI will demonstrate developmental venous anomalies (DVA) associated to cavernomas; the latter can produce hemorrhage which must be differentiated from hemorrhage from deep venous infarction [38].

8.3.3 Vein of Galen Aneurysmal Malformation VGAM is a nonhereditary disease with a 3:1 male predominance. The first description of a possible VGAM occurred in 1895 [39], in which a false VAGM was represented: it was in fact a cerebral AVM draining into a dilated vein of Galen. It is convenient to distinguish true and false VGAM (i.e., vein of Galen aneurysmal malformation from vein of Galen aneurysmal dilatation, VGAD) (Fig. 8.18), as they represent different diseases. Anatomically, VGAM represents an AVM of the median vein of prosencephalon, the embryonic precursor of the vein of Galen itself, as was first recognized by Charles Raybaud [39] (Fig. 8.19).

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Arteriovenous Malformations: Diagnosis and Endovascular Treatment

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Fig. 8.18a–c. Vein of Galen aneurysmal dilatation (false vein of Galen aneurysmal malformation). 10-year-old boy with untreated macrocrania. a, b vertebral and c late carotid angiograms. Note the deep venous reflux, testifying the presence of a matured vein of Galen confluent

c

Fig. 8.19. Vein of Galen aneurysmal malformation. Choroidal arterial feeders of the arteriovenous shunt. Dilatation of the vein of Galen. Venous reflux in longitudinal sinus and cortical veins. Persistence of the falcine and occipital sinuses

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The arterial disposition (persistent limbic arch) (Fig. 8.20) and persistent venous embryonic routes, such as dorsal diencephalic vein (the so-called epsilon) (Fig. 8.21) and the falcotentorial sinus (Fig. 8.22), support the embryonic nature of this AV shunt [40]. The arterial supply in VGAM usually involves all the choroidal arteries from the posterior cerebral, anterior cerebral, anterior communicating, supraclinoid carotid, and tip of the basilar arteries (Fig. 8.19); subependymal arteries from the circle of Willis can also feed the lesion. The shunt itself lies into the subarachnoid space of the choroidal fissure. The nidus of the lesion is located on the midline, and receives bilateral and often symmetrical supply. When one feeder side is more prominent, the venous pouch, due

to jet force effect, will be shifted to the opposite side. According to angioarchitecture, two forms of VGAM exist, i.e., choroidal and mural. The choroidal type corresponds to a very primitive condition, with a contribution of several choroidal arteries and an interposed network before the opening into the large venous pouch. This condition is encountered in most neonates with poor clinical scores (Fig. 8.23). The mural type is frequently encountered in infants, who tend to have a better tolerance to the disease and better clinical scores (Fig. 8.24). Intermediate forms exist, but their importance is only from a technical/management point of view. So far, we have not seen a true VGAM associated with another type of CAVM.

Fig. 8.20. Persistent limbic arch between the posterior and anterior cerebral arteries in an embolized vein of Galen aneurysmal malformation

a

b Fig. 8.21a,b. Vein of Galen aneurysmal malformation. Lateral view and 3D angiography during venous phase show the typical epsilon shape draining the internal cerebral vein

Arteriovenous Malformations: Diagnosis and Endovascular Treatment

a

b Fig. 8.22a,b. Persistent embryonic patterns of dural sinuses in presence of vein of Galen aneurysmal malformation: occipital sinus (arrow, b) and marginal sinus. Absence of straight sinus associated with presence of falcine dural channel (arrowhead, b) draining the venous pouch towards the posterior third of the superior sagittal sinus

a

b Fig. 8.23a,b. Vein of Galen aneurysmal malformation, choroidal type. Vertebral angiogram, anteroposterior (a) and lateral (b) views

The venous drainage in both forms is towards the dilated median vein of the prosencephalon; no communication exists with the deep venous system of the brain. The thalamo-striate veins (diencephalic primitive veins) join the subtemporal ones, demonstrating a typical “epsilon” shape on lateral view angiograms (Fig. 8.21). Analysis of dural sinuses shows absence of the straight sinus, with a falcine (falcotentorial) dural channel draining the venous pouch towards the pos-

terior third of the superior sagittal sinus (Fig. 8.21). Occipital and marginal embryonic sinuses persist in neonates and young infants. Clinically, congestive cardiac failure is present during the neonatal period, and is mainly encountered in choroidal forms. After VGAM is suspected by clinical examination, a pretherapeutic evaluation should be obtained, including: (1) clinical history since birth (i.e., convulsion and hemorrhage do not occur in VGAM at neonatal age, unless brain damage

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b Fig. 8.24a,b. Vein of Galen aneurysmal malformation, mural type. a,b Carotid angiograms

Infant

Necknate

has already taken place); (2) evaluation of renal and liver function; (3) transfontanellar ultrasounds for possible encephalomalacia; (4) echocardiogram to assess cardiac tolerance and associated anomalies (i.e., cardiac defects); (v) MRI to provide morphological information (the diagnosis of pial high-flow AVF in neonates would have completely different therapeutic consequences and approach) and evaluate the status of myelination; and (vi) electrocardiogram. Since the neurological prognosis is difficult in neonates, we have established a neonatal score based on nonneurological manifestations and gross neurological status (Tables 8.2, 3). A score of less than 8/21 results in a decision not to treat, as the prognosis is independent from what could be achieved on the VGAM itself, the damage being irreversible even if not yet visible on imaging. A score between 8 and 12/21 requires emergency endovascular intervention. A score greater than 12/21 leads to medical treatment until the child is aged 5 months, providing there is no failure to thrive; at 5 months, embolization is performed regardless of the symptoms. In our experience, angiography and treatment at 5 months has shown the best efficacy of embolization against the risk of cerebral maturation delay. Unnecessary earlier management does not improve the neurological status and carries a higher risk of failure and technical morbidity. Therefore, pediatric follow-up criteria include monthly evaluation of head circumference and weight, and an MRI examination at 3 months. Obviously, alteration in any of these parameters will prompt endovascular management. Decrease in head circumference indicates loss of brain substance and early suture fusion.

Child 5 years

Congestive cardiac failure Macrocrania hypercephalies

Multiorgan failure encephalomalacia

hydrodynamic disorders Dural venous thrombosis (sigmoid s., jugular bulb)

Fall off in head circumference

Dural venous tcongestion and supratentorial pial reflux bone hyperthrophybulb)

Infratentorial pial reflux and congestion

Tonsillar prolapse

Facial venosis collateral circulation epistatis

Optimal therapeutic window Hydromyelia or syringomyelia

Neurocognitive delay s/ependymal atrophy (pseudy ventriculomegaly) calcifications (chronic venous ischemia)

Conclusions neurological deficitis cerebro-meningeal haemorrhages

Epilepsy neurological deficitis

Table 8.2. Natural history of vein of Galen aneurysmal malformations

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Arteriovenous Malformations: Diagnosis and Endovascular Treatment Table 8.3. Neonatal evaluation score Hepatic function 3 No hepatomegaly. Normal function 2 Hepatomegaly. Normal function 1 Moderate or transient hepatic insufficiency 0 Coagulation disorder. Elevated enzymes. Renal function 3 Normal 2 Transitory anuria 1 Instable diuresis under treatment 0 Anuria Respiratory function 5 Normal 4 Polypnea. Bottle finished 3 Polypnea. Bottle not finished 2 Assisted ventilation. Nl saturation-FI021 cm in diameter; - associated with solid components; - associated with unusual clinical signs (precocious puberty, Parinaud syndrome, hydrocephalus)

10.3 Extra-axial Tumors 10.3.1 Choroid Plexus Tumors Choroid plexuses are composed of an ependymal layer and an underlying mesenchymal stroma with fibroblasts, vascular elements, and arachnoidal cellular nests [196]. Choroid plexus neoplasms may originate from the ependymal layer or the mesenchymal stroma [196]. Neoplastic degeneration of the epithelium may produce benign (papillomas) or malignant tumors (carcinomas); uncommon mesenchymal masses include meningiomas, hemangiomas, and lipomas [196]. 10.3.1.1 Choroid Plexus Papilloma Epidemiology and Clinical Picture

Choroid plexus papillomas (CPPs) are rare tumors of neuroectodermal origin, accounting for 0.5%–3% of intracranial tumors in children according to various reports [124, 197–201]. In the great majority of cases, these tumors are discovered within the first two years of life [38, 197, 198, 200, 202]. In 12.5%–42% of cases, as suggested by its large size, the tumor is congenital [199, 201], i.e., the mass develops during intrauterine life and becomes clinically evident within the first

two months of life [203]. As many as 42% of tumors presenting in infants within 60 days of birth are CPPs [201]. CPP is the third most common neoplasm in children younger than 2 years, after astrocytoma and MB [199]. Male predilection is widely reported [38, 124, 197, 200, 201]. In females, a high incidence of CPP is found in the Aicardi syndrome [124, 196], an X-linked dominant entity characterized by infantile spasms, callosal hypo-agenesis, and chorioretinopathy [204]. The morphology of the corpus callosum should therefore be carefully evaluated in all girls with CPP. CPPs may be located wherever a choroid plexus is found within the ventricles [197, 201]; however, in children they typically are supratentorial, and involve the lateral ventricles (80% of cases) [196, 197, 201, 205, 206]. Generally, these neoplasms originate from the epithelium of the choroid glomus. Therefore, they are located in the ventricular atria [205]. Their size may be huge (up to 7 cm in diameter) [198]. Only very rarely are they located in the third ventricle (4% of pediatric cases) [197, 199, 201], whereas the fourth ventricle (16% of pediatric cases) [197, 201] and the cerebellopontine angle cisterns are typical adult locations [38, 124, 197, 199]. In the first year of life, plasticity of the incompletely ossified skull and unmyelinated nervous tissue allows congenital neoplasms, and particularly CPPs, to attain a considerable size before becoming manifest clinically [197, 199, 200, 207, 208]. Therefore, infants generally present with macrocrania that often is asymmetric [197]; mental delay, fever, vomiting, lethargy, irritability, sensorimotor deficit, seizures, widened cranial sutures, and papilledema may follow [197, 200, 206]. Intraventricular hemorrhage due to tumor bleeding is an exceptional presentation [206]. With the exception of such cases, CSF biochemistry usually is normal [197]. Biological Behavior and Neuropathology

Macroscopically, CPP is a dark pink or gray-reddish cauliflower-like mass [38, 124, 206], in some cases more or less markedly calcified, but generally friable [197, 198]. The mass is markedly vascular [197, 201] and, when supratentorial, its blood supply is provided by the anterior, posterolateral, and posteromedial choroid arteries [205], whose tumoral branches are constantly hypertrophied, tortuous, and elongated [199]. Small hemorrhagic foci commonly are found within the central portions of the mass [124]. The involved ventricle is locally expanded, but the adjacent nervous tissue always is spared [124]. Vasogenic edema involves the adjacent nervous tissue in up to one-third of cases [209]. When located in a lateral

Brain Tumors

ventricle, the tumor originates as a pedunculated mass, generally in the inferior portion of the trigone at the level of the glomus [38, 197, 205]. The microscopic appearance is similar to that of the normal choroid plexus [197, 199], showing papillae with a single layer of columnar or cuboidal epithelium and an underlying vascularized connectival stroma [38, 197, 198, 206]. Occasionally, CPPs may show local aggressive features, such as loss of papillary architecture, invasion of surrounding nervous tissue [202], cellular anaplasia with giant nuclei, and increased mitoses [38, 206]; these are the so-called anaplastic papillomas [124], which may recur and metastasize [206] and have been considered precursors of choroid plexus carcinomas [197, 210]. Tumor cells retain the property of CSF production, which is typical of the normal choroid plexus; however, experimental studies have demonstrated that CSF production by CPP is four- to fivefold higher than normal [199, 211]. Overproductive hydrocephalus, a condition widely described both in the neuropathological [38, 198, 206] and neuroradiological literature [124, 196, 197, 199–201, 207, 212, 213], is the result of this uncontrolled CSF production. Hydrocephalus typically recedes after surgical excision of the mass [124, 199, 207]. The large size of the tumor also may obstruct the adjacent CSF pathways [197], causing entrapment of a temporal horn [199, 205] or occlusion of the foramina of Monro [199, 201].

to the normal structure of choroid plexus, generally iso-to hypointense on T1-weighted images and iso-to hyperintense to gray matter on T2-weighted images (Fig. 10.84) [196, 197, 200, 214]. Calcification and/or hemorrhage may locally modify the signal behavior of the tumor [124, 197, 200]. Enlarged feeding arteries may sometimes be identified by MRA (Fig. 10.84). Intense and homogeneous CE is due to rich vascularity (Fig. 10.84, 10.85) [124]. The main differential diagnosis issue is to recognize the benign or malignant nature of the tumor; in the former case, the neoplasm has a homogeneous appearance and is entirely located within the involved ventricle, whereas the adjacent nervous tissue is preserved. Oppositely, carcinomas show an inhomogeneous appearance and an invasive behavior; the surrounding nervous tissue is infiltrated and a variable amount of perilesional edema and mass effect is present, whereas anaplastic CPPs may not show a similar behavior. In exceedingly rare cases [210], benign forms can also seed the CSF (Fig. 10.86), making differentiation from anaplastic forms difficult. Other neoplasms that should be ruled out include ependymomas, PNETs, astrocytomas and, less commonly, meningiomas, metastases, and colloid cysts [197, 201]. 10.3.1.2 Choroid Plexus Carcinoma

Imaging Studies

Baseline CT generally demonstrates a smooth or lobulated, well-marginated mass, sometimes resembling a bunch of grapes, which is homogeneously isodense (Fig. 10.84) [206] or hyperdense to the surrounding nervous tissue [124, 196, 197, 200, 201, 214]. This behavior is consistent with the vascular nature of the tumor and with its location within CSF spaces [205]. Hemorrhagic foci may be seen within the mass [124, 196, 201]. Calcifications are not common in pediatric CPP [197, 200, 201]; however, because the physiological calcification of the choroid plexuses generally appears in the second decade of life, choroid plexus calcification in a small child is highly suspect, particularly when hydrocephalus is present [197]. Mixed density or heterogeneous enhancement suggest anaplastic degeneration [197, 200], which may be accompanied by ependymal and periventricular white-matter infiltration and perilesional edema [124]. However, a certain amount of periventricular white-matter edema may be seen in up to one-third of cases of benign CPP [209]. On MRI (Fig. 10.84, 10.85), CPP is a smooth or lobulated intraventricular mass, sometimes very similar

Epidemiology and Clinical Picture

The epidemiological features of choroid plexus carcinomas (CPCs) have not been completely assessed yet [198], but they would account for 20% [200] to 40 % [124, 199] of all choroid plexus neoplasms. The incidence is greater below age 5 years [124]; however, unlike CPPs, CPCs are not typical congenital or neonatal tumors. The prevailing location is in the trigones of the lateral ventricles [200], and the incidence is higher in males [124]. These malignant (grade IV) neoplasms usually arise de novo, although they may represent malignant degeneration of a preexisting CPP (anaplastic papilloma) [197, 210]. Clinical presentation is with headaches, signs of raised intracranial pressure, and focal neurological signs. Biological Behavior and Neuropathology

Histopathologically, CPC differs from CPP in that the adjacent nervous tissue usually is invaded [197, 213]. Macroscopically, the tumor tends to lose the papillary cytoarchitecture typical of both the normal choroid plexus and CPP [38, 198]. The mass is inhomogeneous due to necrotic, cystic, and hemorrhagic changes, but

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Fig. 10.84a–e Choroid plexus papilloma in a 3-month-old boy. a Axial CT scan. b Axial T1-weighted image. c Axial T2-weighted image. d Gdenhanced sagittal T1-weighted image. e 3D TOF MR angiography, axial MIP. CT shows an isodense mass within the right ventricular atrium (a). The lesion is isointense with gray matter on T1-weighted images (b), slightly hyperintense on T2-weighted images (c), and shows marked enhancement (d). A rounded, unenhancing portion (arrowhead, a–d) may represent trapped CSF among the grape-like tumor strands. Notice that hydrocephalus cannot be explained by CSF pathway obstruction; instead, it results from CSF overproduction by the tumor. Also notice hypertrophy of the anterior choroidal artery feeding the tumor, already visible in the baseline images (arrows, c,d) and confirmed by MRA (arrows, e)

Brain Tumors

Fig. 10.85 Choroid plexus papilloma in a 4-month-old boy. Gdenhanced sagittal T1-weighted image. Large, markedly enhancing, multilobulated mass fills the third ventricle and plugs the aqueduct (arrow). Hydrocephalus can be explained by CSF pathway obstruction in this case

retains marked vascular features [197]. Marked perilesional edema is present, and the mass effect upon the surrounding structures usually is pronounced [197, 213]. Individual cells show variable shape and size, and markedly resemble adenocarcinomatous cells [196]. Nuclei are variably sized, and mitoses are numerous [38]. Cellularity is dense and organized in a pseudostratified columnar epithelium [197]. Foci of completely disorganized growth are common [198]. Infiltration, focal necrosis, loss of demarcation between stroma and parenchyma, and proliferation of vascular structures are found [197], although the tumor may rarely be avascular [205]. The propensity to seed the CSF spaces, producing ventricular or leptomeningeal metastases, is marked [38, 196, 200]. Unlike CPPs, CPCs are infrequently associated with hydrocephalus. When present, hydrocephalus is caused by CSF pathway obstruction due to either the tumor itself or ependymal and leptomeningeal metastases [197].

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Fig. 10.86a–c Histologically benign choroid plexus papilloma with CSF seeding in a 6-year-old boy with macrocrania. a Gd-enhanced axial T1weighted image. b Gd-enhanced sagittal T1-weighted image. c Axial FLAIR image. Mass involving the choroid glomus of the left atrium (a) and showing a papillary pattern, similar to the normal choroid plexus. Tetraventricular hydrocephalus probably was initially caused by CSF overproduction, but is now worsened by obstruction of the distal portion of the aqueduct by an unenhancing metastatic nodule (black arrow, b). Neoplastic septa are recognizable at the level of the anterior third ventricle (arrowheads, b). In the posterior fossa, another intraparenchymal location involves the left cerebellar hemisphere (arrows, c). Enhancement of the interpeduncular fossa also is likely neoplastic (white arrow, b).

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Imaging Studies

On CT (Fig. 10.87), the mass is inhomogeneously isoto hyperdense to the adjacent nervous structures [197, 200, 205], which are more or less extensively invaded. CE is variable, but often is marked and heterogeneous [196, 200, 205]. The mass shows focal hypodense areas due to necrosis [215] or old hemorrhage and, in some cases, hyperdense portions due to calcifications (Fig. 10.87) or recent bleeding. MRI (Fig. 10.87) shows a heterogeneous mass, whose solid portions generally are iso-to hypointense on both T1- and T2-weighted images; central necrotic areas will appear hypointense on T1-weighted images and hyperintense on T2-weighted images [197, 214]. CE usually is marked and heterogeneous (Fig. 10.87). Surrounding edema, infiltration of adjacent nervous

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tissue and ependyma, and leptomeningeal spread are exquisitely depicted by MRI [196]. Entrapment of a horn of the involved ventricle is detected in up to 80% of cases [124]. Straightforward intraventricular CPCs usually are rather easily diagnosed based on the typical neuroradiological features. Conversely, when the mass is large and its intraventricular location is not easily detectable, other tumors enter the differential diagnosis scope. PNETs must be considered, because macroscopic features, such as hemorrhage and calcifications, are similar. Other neoplasms, such as ependymomas and GBMs, must also be included in the differential diagnosis. Owing to the common neuroepithelial nature, differentiation from ependymomas can be difficult also on microscopic examination [38].

Fig. 10.87a-d Choroid plexus carcinoma in a 10-month-old girl. a Axial CT scan. b Axial T1-weighted image. c Axial T2weighted image. d Gd-enhanced axial T1-weighted image. There is a huge mass in the left cerebral hemisphere that abridges the midline and abuts the contralateral foramen of Monro, causing dilatation of the contralateral ventricle. Notice that the shape of the lesion suggests it is located within, and markedly expands, the left lateral ventricle; also notice that only the frontal horn of the same ventricle is visible, reinforcing this opinion. The lesion is hyperdense on CT (a), isointense with gray matter both on T1-weighted (b) and T2-weighted images (c), and enhances markedly (d). There is marked perifocal edema. Calcifications (arrows, a), hemorrhage (open arrow, b), and neoformed vessels (arrowheads, b) can be recognized within the mass. Notice asymmetric macrocrania with splaying of the homolateral lambdoid suture (thick arrow, a)

Brain Tumors

10.3.2 Meningioma Epidemiology and Clinical Picture

Intracranial meningiomas are common tumors in adults; however, they are extremely rare in children, accounting for 1%–4% of all pediatric intracranial tumors [216], and fewer than 2% of all meningiomas [217]. The majority occurs in the second decade, whereas they distinctly are uncommon in children aged less than 4 years. However, a minority may be congenital. In the pediatric population, males are more frequently affected than females [216, 218, 219]. Clinically, afflicted children usually present with signs of increased intracranial pressure, focal neurological signs, and seizures [219, 220]. Hydrocephalus is common in cases of intraventricular meningiomas. Cranial nerve deficits may occur. Overall, symptoms mainly are related to tumor location. Pediatric meningiomas often occur within particular clinical settings, such as in patients with neurofibromatosis type 2 (NF2) [219, 221]. In this case, they may be multiple and associated with multiple schwannomas and ependymomas. The frequency of the association with NF2 varies from 19% to 41% according to various reports [219, 222]. Multiple meningiomas may also be found in patients without NF2, in which case the term “meningiomatosis” is applied; this is, however, rare in children (2.5% of cases) [219]. They may also occur as a complication of radiation therapy to the head [217]. However, this event is rare because of the very long latent period for the presentation of these tumors, which usually is 15 to 20 years [219], and is inversely related to the total radiation dose [217]. Biological Behavior and Neuropathology

Pathologically, pediatric meningiomas differ from those of adults in many ways, as follows:  Size Pediatric meningiomas usually are larger than adult ones: they often measure more than 5 cm in their largest dimension [222].  Structure A significant proportion of pediatric meningiomas is partially cystic [223].  Location Pediatric meningiomas tend to occur in somewhat atypical locations, such as the ventricular system, the optic chiasm, the cistern of the lamina terminalis (Fig. 10.88), the posterior fossa, or within the brain parenchyma without a dural attachment; however, “classical” locations along the convex-

ity and the falx cerebri are also possible [219, 224] (Figs. 10.89, 10.90). Infratentorial meningiomas are significantly frequent (19% of cases) [222]. Intraventricular meningiomas are observed more commonly in children (17%–24% of cases) [225, 226] than in adults (0.5%–4.5% of cases); they are thought to arise from meningothelial rests within the tela choroidea or the choroid plexus [219]. However, those located in the third ventricle are particularly rare [222, 226], and the recognition of their intraventricular location is crucial for a correct surgical approach.  Pathology It has long been believed that pediatric meningiomas are more aggressive and prone to malignant degeneration than their adult counterparts [218, 222]. However, recent evidence does not seem to support such theory. The incidence of malignant meningiomas is 2%–5%, a figure that approaches that found in adults [219, 220]. A possible reason is that meningeal sarcomas were incorrectly classified as malignant meningiomas in the past. The WHO classification comprises as many as 15 subtypes (Table 10.2); of these, the meningothelial type is the most frequent in children, followed by the fibroblastic and transitional types [224]. No significant differences occur compared to adults. Rhabdoid meningioma is a rare tumor containing patches or extensive sheets of rhabdoid cells. Most rhabdoid meningiomas have high proliferative indices, display aggressive clinical course, and correspond to WHO grade III [19]. Imaging Studies

MRI depicts an usually huge mass, sometimes separated from the adjacent brain by a rim composed of CSF and pial veins [219]. Intratumoral signal voids represent vessels or calcification. The tumor is usually isointense on T1-weighted images and shows a variable intensity on T2-weighted images (Figs. 10.88, 10.89). Enhancement generally is marked (Fig. 10.88) and better delineates the cystic components, which do not enhance (Fig. 10.89). A “dural tail sign” may be found; however, it commonly is absent in pediatric meningiomas, as is the lack of a dural attachment [219]. Surrounding edema is variable but may be marked (Fig. 10.90). CT scan easily identifies calcification (Fig. 10.90) and reactive hyperostosis in the adjacent bone. Meningiomas are isodense or slightly hyperdense to the adjacent parenchyma. We have observed a case of rhabdoid meningioma (Fig. 10.91). It was an extensively hemorrhagic mass abridging the tentorium, with a few necrotic components.

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c Fig. 10.88a–d Meningioma in a 4-year-old girl. a Sagittal T1-weighted image. b Axial CT scan. c Coronal T2-weighted image. d Gdenhanced axial T1-weighted image. Rounded mass located in the interhemispheric fissure between the genu of corpus callosum superiorly and the optic chiasm inferiorly. The anterior commissure is displaced posteriorly (arrows, a), indicating that the lesion is anterior to the third ventricle. The mass is slightly hyperdense on CT scan (b), hypointense to gray matter on T2-weighted images (c), and causes hydrocephalus by obstructing the foramina of Monro. Enhancement is marked and homogeneous (d)

Brain Tumors

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Fig. 10.89a–c Meningioma. a Sagittal T2-weighted image. b Axial T1-weighted image. c Gd-enhanced coronal T1-weighted image. Huge lesion of the right rolandic-parietal convexity, surrounded by perifocal edema (a). The lesion shows mixed signal behavior on both T1-weighted (b) and T2-weighted images (a), and enhances inhomogeneously (c). Notice that the adjacent convolutions are compressed and displaced (open arrows, a), a typical feature of extra-axial tumors

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b Fig. 10.90a,b Meningioma in an 8-year-old girl. a Axial CT scan. b Contrast-enhanced axial CT scan. The mass inserts onto the anterior part of the falx cerebri with contralateral midline displacement. Calcifications (arrows, a) and diffuse perifocal edema are seen. Enhancement is moderate (b)

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d Fig. 10.91a–d Rhabdoid meningioma in a 13-year-old girl. a Axial CT scan. b Axial T1-weighted image. c Axial T2-weighted image. d Gd-enhanced coronal T1-weighted image. CT shows a hyperdense mass (arrow, a) in close relationship with the right cerebellar hemisphere, which is markedly edematous (asterisk, a) with compression of the fourth ventricle (arrowhead, a). Some peripheral hypodense components are visible (open arrows, a). There is an incidental arachnoid cyst of the right temporal pole (AC, a). On MRI, the solid nodule is T1 isointense (arrow, b) and T2 hypointense (arrow, c) which, associated with the CT appearance, is strongly suggestive of acute hemorrhage. Peripheral necrosis (open arrows, b,c), cerebellar edema (asterisk, b,c), and fourth ventricular displacement (arrowheads, b,c) are well depicted, as is the arachnoid cyst (AC, b,c). Coronal sections clarify the location of the lesion, abridging the tentorium with extra-axial extension both caudally (arrowheads, d) and cranially (thick arrow, d). There is a very thin “dural tail” along the tentorium medially (thin arrows, d). Necrotic portions are persistently hypointense after Gd administration (asterisk, d)

10.3.3 Hemangiopericytoma

recently, whereas in the past they were considered an angioblastic variant of meningiomas [229].

Hemangiopericytoma (HP) is a rare tumor arising from vascular pericytes that predominates in adults and is found in only 10% of cases in children [227, 228]. Because of the histological origin, HP may arise wherever capillaries are found throughout the body. Intracranial HPs are rare tumors, representing less than 1% of CNS neoplasms in the general population [228]. They have gained an independent status only

Biological Behavior and Neuropathology

Although an infantile variant occurring within the first year of life and showing a more favorable outcome has been described, no significant histological differences can be demonstrated from the malignant HP that is found in older age groups [227]. In both cases, increased cellularity with pleomorphism, necrosis, hemorrhage, and frequent mitoses are

Brain Tumors

found. Therefore, distinction between the two forms is based on the clinical behavior rather than on histology [227]. Macroscopically, these huge (usually larger than 4 cm in their greatest dimension), sometimes multilobulated masses are well-demarcated, attached to the dura, and associated with profuse bleeding on resection [229]. They are aggressive lesions, with a high frequency of recurrence and extracranial metastasis. Imaging Studies

Neuroradiological examinations display a large, extra-axial mass that usually is located on the con-

vexity or parasagittally near the falx, similar to classical meningiomas (Fig. 10.92). The dural base of these tumors may be narrower than in meningiomas [229]. On CT, the lesion is slightly hyperdense, but usually lacks calcification. Contrary to meningiomas, erosion of adjacent skull is common, whereas hyperostosis is not [229]. On MRI, these well-demarcated masses show heterogeneous signal, partly due to numerous signal flow voids that represent prominent tumor vascularity (Fig. 10.92). The lesion generally is isointense on T1-weighted images and iso-to hyperintense on T2-weighted images, and shows marked CE [228].

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d Fig. 10.92a–d Hemangiopericytoma in an adolescent. a Gd-enhanced sagittal T1-weighted image. b Coronal T1-weighted image. c Axial T2-weighted image. d Gd-enhanced axial T1-weighted image. Huge mass of the right frontal convexity, extending contralaterally underneath the falx (arrows, b). Surrounding edema is not pronounced (thick arrow, c). Note the “dural tails” (arrowheads, d). The corpus callosum is deformed and compressed (a,b). Multiple intralesional flow voids reflect the hypervascular nature of the mass

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10.3.4 Meningeal Sarcoma

10.3.5 Schwannomas

Meningeal sarcomas account for 0.7%–4.3% of intracranial tumors in childhood [230, 231]. These tumors are markedly aggressive, and can invade the adjacent brain, bone, sinuses, and subcutaneous tissues (Fig. 10.93). They have a poor outcome, with only 50% of affected children surviving 1 year after surgery [231]. These lesions may arise as discrete, poorly marginated masses that show a connection to the leptomeninges, or as a diffuse meningeal sarcomatosis, similar to secondary leptomeningeal carcinomatosis [231]. Poorly defined or fringed margins on the cerebral surface are suggestive of brain invasion, and are believed to be significantly more common in meningeal sarcomas than in benign meningiomas [221]. Cystic change within the mass is another sign that, while not uncommon in benign pediatric meningiomas, should nevertheless be regarded with suspicion for malignancy [221].

Intracranial schwannomas seldom occur in children, and almost exclusively involve the 8th cranial nerve; other cranial nerves, such as the trigeminal and oculomotor nerve, are involved only exceptionally. In children and young adults, vestibular schwannomas almost exclusively are found in, and are considered to be diagnostic of, NF2; in these patients there also is a high incidence of associated meningiomas and ependymomas. In NF2, schwannomas typically are bilateral, a feature that is considered to be diagnostic of this condition. Isolated tumors (Fig. 10.94) are exceptional, and have been found in children between 7 and 16 years of age [232]. The clinical presentation of these tumors is not different from that typical of adults, i.e., progressive sensorineural hearing loss and signs of a mass in the cerebellopontine angle [232]. The size of the

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Fig. 10.93a–c Meningeal sarcoma. a Axial T1-weighted image. b Gd-enhanced axial T1-weighted image. c Gd-enhanced coronal T1-weighted image. Huge lateral mass in the posterior fossa, deforming and compressing the cerebellar structures and displacing the fourth ventricle contralaterally. The lesion is surrounded by a hypointense rim composed of dura and CSF (arrowheads, a), that indicates an extra-axial location. Note transverse sinus invasion (thick arrow, b) and extension into the subgaleal soft tissues (asterisk, c)

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Fig. 10.94a–c Isolated schwannoma in a 10-year-old girl. a Axial T1-weighted image. b Axial T2-weighted image. c Gd-enhanced axial T1-weighted image. Huge extra-axial mass originating from the right internal acoustic canal (arrows, a–c). The mass shows necrotic changes (arrowheads, a–c), and enhances markedly (c). The lesion is hypointense on T1-weighted images (a) and grossly isointense with gray matter on T2-weighted image (b). The brainstem and the fourth ventricle are deformed and compressed. There is a thin CSF rim surrounding the mass (open arrows, a,b) that reveals its extra-axial location

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mass may be variable, but children with vestibular schwannomas tend to have larger tumors than adults. Pathologically, schwannomas are solid or cystic, capsulated tumors that tend to displace, rather than infiltrate, the parent nerve. Cystic degeneration, calcification, and fatty tissue (xanthomatous variety) may be found within the tumor. A characteristic feature of pediatric schwannomas is their marked vascularity, contrary to the typical hypovascularity of their adult counterparts [232]. Therefore, there is greater risk for massive hemorrhage at surgery. Anaplastic degeneration is rare, whereas the rare malignant tumors generally are primitive and show predilection for children or young adults. In such cases, peripheral nerves are involved more frequently than nerve roots, and the tumor shows cystic degeneration and infiltrates the surrounding tissues. The differentiation from malignant or anaplastic neurofibromas may not be feasible. Vestibular nerve schwannomas typically erode the surrounding bone, resulting in an increased width of the inner acoustic meatus that may be an indirect telltale sign on CT. On MRI, schwannomas are

hypointense on T1-weighted images, hyperintense on T2-weighted images, and enhance moderately to markedly. Small tumors may be completely nested within the inner acoustic meatus or even be confined to the vestibule, whereas large tumors predominately grow in the cerebellopontine angle cisterns, displacing and compressing the brainstem; however, they will consistently extend into the inner acoustic meatus, producing a so-called “ice cream cone” appearance that excludes meningiomas or other extra-axial cerebellopontine angle lesions (Fig. 10.94) [233]. Recognition of small tumors completely nested within the inner acoustic meatus, as well as of postsurgical remnants, is obviously easier by MRI, and is greatly facilitated by contrast medium administration. The main differential diagnosis in children is intracranial capillary hemangiomas, which have a striking predilection for the inner acoustic meatus and cerebellopontine angle cistern. However, these lesions are easily excluded, because they consistently are associated with a homolateral facial hemangioma [234].

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10.3.6 Dysontogenetic Masses Epidermoid and dermoid cysts are rare, slowly growing congenital lesions, thought to arise from inclusion of epithelial elements within the neural groove at the time of neural tube closure as a result of incomplete disjunction of the neuroectoderm from the cutaneous ectoderm [88, 124, 235]. Epidermoid cysts (ECs) arise from the ectoderm-derived epidermis only, whereas dermoid cysts (DCs) also contain dermal appendages, such as hair, sebaceous, and sweat glands [124]. Dermoid Cysts

In our experience, intracranial DCs have been more common than ECs in the pediatric population [88, 124]. The most common intracranial location is midline infratentorial (i.e., adjacent to the vermis or fourth ventricle) [124, 236] (Fig. 10.95). Intracranial supratentorial locations also are possible. Other common locations include the bregmatic fontanel and the orbit, especially at level of the inner and outer orbital canthi. Clinical symptoms occur earlier than with ECs, perhaps explaining the greater frequency of DCs that are discovered during childhood as opposed to ECs. Symptoms may result from obstruction of CSF pathways, chemical meningitis related to rupture of the cyst into the ventricles or subarachnoid space, and abscess formation due to ascending infection along an associated dermal sinus [124, 237]. DCs are well-demarcated, round or oval, unilocular cystic masses, lined by stratified squamous epithelium mounted on collagenous connective tissue that, unlike ECs, contains dermal appendages, such as hair follicles, sebaceous, and sweat glands [88]. The cyst contains thick, yellowish material resulting from an admixture of sebaceous secretion and desquamated epithelium [88]. These lesions show a variable neuroimaging behavior depending on the relative proportion of the various intracystic components. On CT scan, they may be isodense with CSF (Fig. 10.95), fat (Fig. 10.96), or brain (Fig. 10.97). On MRI, the signal is highly also variable on both T1- and T2-weighted images (Fig. 10.95−10.97). T1-weighted images may show hyperintense components related to the presence of fat (Fig. 10.96), and individual lesions may be extensively bright (Fig. 10.97); however, the fact that dermoids are invariably hyperintense on T1-weighted images is a myth. Following gadolinium administration, there usually is no enhance-

ment. In some cases, portions of the cyst wall may enhance slightly. Enhancement also may involve the adjacent leptomeninges due to reactive phenomena. Abscessed dermoids show intense, ring-like enhancement (Fig. 10.98). Epidermoid Cysts

Intracranial ECs are less common than DCs in children, accounting for 0.5%–1% of all intracranial masses. Intracranial ECs usually involve the subarachnoid spaces, thus being confined to the extra-axial space; however, intra-axial locations are possible [237]. The most common location is the cerebellopontine angle, followed by the pineal region, supra- and parasellar regions, and middle cranial fossa [124]. ECs also may involve the cisterna magna, tela choroidea (usually in the temporal horn of the lateral ventricle) [237], cerebral hemispheres, and brainstem [88, 235]. Although ECs are congenital lesions, symptoms rarely occur before the third or fourth decade of life [237]. Clinical presentation depends on location. Involvement of the facial nerve and, subsequently, of the acoustic nerve with unilateral hearing loss is typical in cases of cerebellopontine angle ECs [88, 124]. Hydrocephalus may ensue in cases of suprasellar and pineal locations. Chemical meningitis secondary to leakage of tumor contents into the subarachnoid space is more common in cases of middle cranial fossa locations [124]. ECs are encapsulated lesions (the mother-of-pearl sheen capsule explains the term “pearly tumors” that sometimes is used for these cysts), filled with soft, creamy material [88]. The internal layer is composed of stratified squamous epithelium mounted on collagenous connective tissue [88]. They usually are multilocular [202]. Progressive cyst enlargement is related to epithelial desquamation with accumulation of keratin, cholesterol, and other debris within the cavity [237]. On CT scan, ECs appear as irregular, lobulated masses that are isodense with CSF and lack CE. Focal calcifications along the cyst wall have been described, but are not the rule [237]. Small ECs embedded in the subarachnoid space may remain undetected [202]. On MRI, ECs usually are isointense to CSF on both T1-weighted and T2-weighted images, and most commonly lack appreciable CE [124]. However, since signal intensity may vary significantly depending on the cyst contents, three different subtypes have been described [238]: (1) The majority of ECs (80% of cases) are T1 hypointense and T2 hyperintense due to high liquid content and low lipids and keratin; (2) about

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d Fig. 10.95a–e Dermoid in a 13-year-old boy. a Axial CT scan. b Sagittal T1-weighted image. c Sagittal T2-weighted image. d Axial FLAIR image. e Axial diffusion-weighted image. CT shows an apparent enlargement of the vallecula with questionable hypodensity with respect to isodense CSF. Notice that the margins are irregular (arrowheads, a). MRI shows a irregularly marginated lesion that compresses the inferior aspect of the vermis (thick arrow, b,c). Notice that signal intensity is slightly higher than that of CSF on both T1-weighted (b) and T2-weighted images (c). There is a bright spot on T1-weighted images along the anterior aspect of the lesion (thin arrow, b) that is consistent with a fat deposit. On FLAIR images there is clear-cut hyperintensity with respect to CSF (arrows, d). Diffusion-weighted images (e) show restricted proton diffusion within the lesion, consistent with a dysontogenetic mass. (e, Courtesy of Dr. L. Manfrè, Catania, Italy)

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d Fig. 10.96a–d Dermoid in a 7-year-old boy. a Axial CT scan. b Axial T2-weighted image. c Axial T1-weighted image. d Axial fatsaturated T1-weighted image. Hypodense lesion in the right frontotemporal region shows a more markedly hypodense component posteriorly, resembling fat (arrow, a). T2-weighted images reveal a homogeneously hyperintense mass that displaces the middle cerebral artery (arrowheads, b). T1-weighted images reveal a small, hyperintense component in the posterior portion of the mass (arrow, c), corresponding to the markedly hypodense spot on CT. This hyperintense signal is suppressed on fat-saturated sequences, confirming its adipose nature (d)

20% are T1 hyperintense and T2 isointense due to elevated triglycerides and fatty acids and absent cholesterol; and (3) a small minority are T1 hyperintense and T2 hypointense due to elevated iron content. The main differential diagnosis of EC is with arachnoid cysts. Because the vast majority of ECs is isodense with CSF on CT scan and isointense to CSF on both T1- and T2-weighted MR images, this differentiation has traditionally been regarded as difficult. On CT scan, the differentiation has traditionally been based on the typically lobulated margins of ECs, becoming more evident after intrathecal administration of iodized contrast material [124], as opposed to

the smooth external surface of arachnoid cysts [237]. MRI allows an easier differentiation between EC and arachnoid cysts if a combination of MRI techniques is employed, as follows: (1) on proton-density-weighted images, ECs are almost always slightly hyperintense to CSF, as opposed to the isointensity shown by arachnoid cysts [237]; (2) on FLAIR images, the necrotic and keratinaceous-proteinaceous content of ECs gives high signal, as opposed to the CSF-like low signal given by arachnoid cysts; (3) on DWI, arachnoid cysts show unrestricted diffusion similar to CSF, whereas ECs behave like normal brain tissue [239]; and (4) on magnetization transfer imaging, ECs show significant

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d Fig. 10.97a–d Dermoid in an 8-year-old girl. a Axial CT scan. b Axial T1-weighted image. c Axial T2-weighted image. d 3D TOF MR angiography, coronal MIP. CT shows an isodense lesion located anterolaterally to the medulla oblongata (arrows, a). The mass is spontaneously hyperintense on T1-weighted images (b) and isointense with gray matter on T2-weighted images (c). A hypointense spot within the lesion in T2-weighted images (arrowhead, c) corresponds to a stretched, encased right vertebral artery (arrowheads, d). Notice that the mass is faintly visible in the MIP image due to its short T1 (thick arrows, d)

transfer of magnetization from the solid matrix of the tumor to adjacent free water, whereas arachnoid cysts show no magnetization transfer [240]. The rare ECs showing hyperintensity on T1weighted images may be difficult to differentiate from dermoids or lipomas. However, the application of fat saturation pulses suppresses the high signal from both dermoids and lipomas, whereas the signal from ECs will remain unaffected [124]. Lipomas

In addition to those associated with dysgenesis of the corpus callosum (see Chap. 3), lipomas may essentially occur in two main sites: the quadrigeminal plate (Fig. 10.99) and the cerebellopontine angle cistern (Fig. 10.100). Although these lesions are more correctly referred to as malformations, it should be pointed out that their size may increase in parallel to the physiological increase of adipose tissue as the child grows. Therefore, lipomas located in criti-

cal areas such as the quadrigeminal plate or foramen magnum may generate symptoms due to obstructive hydrocephalus or cervicomedullary junction compression, respectively.

10.3.7 Chordoma Epidemiology and Clinical Picture

Chordomas are rare tumors, accounting for less than 1% of all intracranial tumors. They are slowly growing, locally infiltrating tumors, arising from intraosseous remnants of the notochord, a primitive cell line around which the base of the skull and the vertebral column develop [241] (Fig. 10.101). The nuclei pulposi of the intervertebral disks are the only normal notochordal elements that remain after birth. However, ectopic notochordal remnants may persist along the neural axis, and especially at its top and

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b Fig. 10.98a,b Dermoid in a 3-year-old boy. a Contrast enhanced axial CT scan. b Gd-enhanced sagittal T1-weighted image. Retrovermian dermoid (arrowhead, a,b) associated with a large abscess involving the vermis and the left cerebellar hemisphere (asterisk, a,b). There is compression of the fourth ventricle with supratentorial hydrocephalus. A dermal sinus involving the subgaleal tissues also is detected (arrow, b)

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b Fig. 10.99a,b Lipoma in a 2-year-old boy. a Axial T1-weighted image. b Sagittal T1-weighted image. Small lipoma involving the left inferior quadrigeminal tubercle (arrow, a) and superior vermian sulci (arrowheads, a,b). There is concurrent downward ectopia of the cerebellar tonsils (T, b), consistent with Chiari I malformation, causing hydrocephalus

bottom levels; chordomas arise from these ectopias. There is no known gender predilection. In children, chordomas are very unusual; only exceptionally have these tumors been described in children aged less than 5 years, and only a single congenital tumor has been reported [242].

In the general population, intracranial locations account for 35% of all chordomas, and usually involve the clivus (Fig. 10.102) in the region of the sphenooccipital synchondrosis or, more rarely, the sellar or parasellar regions; the remainder arise in the spine, mostly in the sacrococcygeal region and rarely from a

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b Fig. 10.100a,b Lipoma of the right cerebellopontine angle cistern in an 8-year-old boy. a Axial T1-weighted image. b Axial T2weighted image. There is a hyperintense lesion in the right cerebellopontine angle cistern (thick arrows, a,b). T2-weighted image clearly shows that encasement of the seventh and eighth cranial nerves (thin arrows, b). Notice chemical shift artifact (arrowheads, a,b) along the fat-brain interface

to brainstem compression; increased intracranial pressure and extension of tumor through the foramen magnum are other prominent features [241, 242]. Biological Behavior and Neuropathology

Fig. 10.101 Midsagittal section depicting the course of the notochord. (Modified from Braun IF, Nadel L. The central skull base. In: Som PL, Bergeron (eds) Head and Neck imaging, 2nd edn. St. Louis: Mosby, 1991)

vertebral body, especially in the upper cervical spine [243]. However, the sphenooccipital region is the predominant location in children [241]. Exceptionally, clival chordomas may arise as totally intradural lesions, i.e., without surgical or radiographic evidence of bone erosion [244, 245]; these intradural lesions are believed to originate from the so-called “ecchondrosis physaliphora”, intradural deposits of notochordal tissue that are found anterior to the pons in about 2% of all autopsy specimens. Children with chordomas tend to present with long tract signs and lower cranial nerve involvement due

Albeit histologically benign, chordomas typically demonstrate a potentially malignant course; they are locally invasive, destroy bone, and infiltrate the soft tissues, with a 10%–20% incidence of metastases [242]. The prevalence of atypical histological findings with corresponding aggressive behavior is greater in patients younger than 5 years, as is the incidence of metastases in the same age group [241]. Chordomas are prominently calcified and often cystic, resulting in a gelatinous semiliquid appearance on gross examination. Histologically, two distinct variants have been identified. The “typical” chordoma is composed of strands of so-called physaliphorous cells embedded in a gelatinous matrix that may be more or less represented, resulting in more compact or looser architecture. The “chondroid” chordoma has interspersed cartilaginous foci, whose amount may vary from minimal to predominately cartilaginous masses [243]. Chondroid chordomas probably represent a majority of chordomas in older children, and are reported to have a significantly better prognosis [243]. Imaging Studies

Both CT and MRI (Figs. 10.102, 10.103) should be employed in the diagnostic workup of chordomas. CT provides better demonstration of bone erosion and tumor calcification, whereas MRI is superior in delineating the full extent of the lesion [243]. The tumor

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d Fig. 10.102a–d Chondroid chordoma in a 13-year-old girl. a Sagittal T1-weighted image. b Axial T1-weighted image. c Axial CT scan. d Contrast enhanced axial CT scan. Huge mass arising from the spheno-occipital synchondrosis and bulging in the rhinopharynx anteriorly (asterisk, a,b). Posteriorly, the mass bulges into the anterior medullary cistern, causing deformation and compression of the medulla and pons (arrow, a). Scattered calcifications are recognizable in the extracranial portion of the mass (arrowheads, c). Enhancement is inhomogeneous (d)

is midline in most cases, and grows by infiltration of the surrounding bone, spheno-ethmoidal sinuses, and anterior nasopharynx (Fig. 10.102). The brainstem usually is displaced posteriorly (Fig. 10.102). MRI also is useful in demonstrating transdural transgression of tumor, a finding of surgical relevance [243]. Adjacent nervous structures may be invaded along the planum sphenoidale, the sella turcica, and the clivus. There also is significant displacement or encasement of the major vasculature, and especially of either the carotid or vertebrobasilar arteries. Systemic or CSF drop metastases

may be found in some cases, especially with transdural extension of the primary tumor [243]. On CT, clival chordomas are more or less heterogeneous masses, often containing calcified structures (Fig. 10.102) which may be ascribed to bony sequestration or calcified deposits of recent formation. Typical and chondroid chordomas have been reported to display a different behavior on MRI. Typical tumors are isointense on T1-weighted images in 75% of cases, and hypointense in the remainder [243]. The tumor is invariably hyperintense on T2-weighted

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b

a Fig. 10.103a,b Chordoma in a 13-year-old boy. a Sagittal T1-weighted image. b Contrast enhanced axial CT scan. Huge lesion arising from the basiocciput (arrow, a) and extending both anteriorly to the rhinopharynx (thick arrows, a) and posterolaterally, invading the posterior fossa and foramen magnum to extend to the suboccipital soft tissues (asterisk, a,b). Notice erosion of the odontoid process of C2 and posterior arch of C1 (b). The lesion also causes deformation and compression of the cervico-medullary junction

images, although hypointense septations may separate lobulated areas of higher signal intensity [243]. In some cases, the signal behavior may be heterogeneous due to structural anomalies and calcifications. CE is variable. Chondroid chordomas have shorter T1 and T2 relaxation times, perhaps because the gelatinous matrix is in part replaced by cartilaginous foci [243].

10.3.8 Capillary Hemangioma Capillary hemangioma (CH) is the most common tumor of infancy, occurring in up to 12% of infants of Western descent in their first year of life [246]. It usually involves the head and neck and prevails in females, with a 3:1 to 5:1 preponderance [247]. It usually is located in the skin, scalp, and orbit, where it involves the palpebrae with frequent extension to the rectus muscles [248]. Fewer than one-third of CHs are present at birth [247], whereas most appear by the first month of life [249]. They typically demonstrate rapid growth up until 6–8 months, followed by a phase of plateau between 8 and 12 months [247]. High blood flow and pressure within the mass lead to vascular dilatation and perivascular collagenization [246], which accounts for their well-known tendency

to spontaneous involution [246–248, 250], beginning by 12 months and continuing until 5–10 years of age [247]. CHs may be isolated or associated with other abnormalities within the setting of a vascular phakomatosis known as PHACES syndrome, i.e., the non-random association of: (1) extracranial CH; (2) posterior fossa malformations including the DandyWalker malformation, cerebellar hemispheric hypoplasia, and cerebellar cortical dysgenesis; (3) arterial anomalies, such as the persistent trigeminal artery and hypo-aplasia of the internal carotid, external carotid, and vertebral arteries; (4) coarctation of the aorta; (5) congenital ocular abnormalities; and (6) sternal defects [251, 252] (see Chap. 17). The intracranial compartment is a distinctly uncommon location for CHs [234]. Intracranial CHs are found exclusively in patients who also harbor cutaneous lesions; they may be nodular or diffuse, and preferentially lie homolateral to the cutaneous CH. Their natural history parallels that of their extracranial counterparts, i.e., they can either regress spontaneously along with the involution of the extracranial CH, or remain unchanged if the extracranial CH does not regress [234]. Intracranial CHs may be both extra-axial and intra-axial in location. Extra-axial CHs typically involve the inner acoustic meatus and cerebello-

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pontine angle cistern (Figs. 10.104, 10.105), and may mimic acoustic schwannomas; however, the differentiation is easy due to the coexistent extracranial CH. Other meningeal-based lesions may be found in the unco-hippocampal region (Fig. 10.105), or exceptionally appear as a diffuse leptomeningeal enhancement [234]. Intra-axial CHs almost exclusively are confined to the hypothalamus, where they appear as an enhancing thickening of infundibulum, tuber cinereum, and median eminence [234] (Fig. 10.104). On MRI, intracranial CHs are well-circumscribed lesions which are isointense on T1-weighted images and hyperintense on T2-weighted images, reflecting their content in unclotted blood [246]. Typically, CHs enhance markedly with contrast material administration both on CT and MRI, due to their highly vascular structure. MRA may depict a conglomerate of fine vessels, similar to the typical “blush” that is seen with catheter angiography [234] (Fig. 10.105). One important clinical consideration is warranted: as CHs are known to regress spontaneously or with systemic steroid and interferon therapy, surgery should be avoided unless (1) the lesion impairs primary functions (such as huge orbital or airway CH); (2) follow-up studies demonstrate lesion growth; or (3) the clinical picture deteriorates. Finally, it could be questioned whether all patients with CH of the head and neck should undergo screening MR studies of the brain with contrast material administration regardless of their neurological status in order to detect silent intracranial lesions. In fact, the prevalence of isolated extracranial CHs is very high compared to that of “syndromic” CHs. We believe that all infants with large, prevailingly unilateral, plaque-like or bulky CH of the head and neck should be screened for associated PHACES manifestations. This screening should include contrast-enhanced brain MRI, MRA of the epiaortic, cervical, and intracranial arteries, echocardiography, ophthalmologic examination, and arterial pressure measurements in both upper and lower limbs [252].

10.3.9 Extra-axial Locations of Typically Intra-axial Tumors Although rarely, typical intra-axial tumors may arise in the extra-axial spaces. This occurs particularly with posterior fossa tumors, such as medulloblastomas (Fig. 10.7), ependymomas, and pilocytic astrocytomas (Fig. 10.106). In these instances, it usually is very difficult to advance a diagnosis preoperatively due to the rarity of these lesions.

10.3.10 Metastases The vast majority of intracranial metastases are due to leptomeningeal spread of primary CNS tumors; highgrade malignancies, such as MBs, PNETs, and malignant astrocytomas, most commonly are involved. However, low-grade astrocytomas, particularly of the pilomyxoid type, can also show leptomeningeal spread at presentation [74]. The appearance of these lesions on contrast-enhanced CT and MRI may vary from discrete nodular masses to a diffuse leptomeningeal carcinomatosis that has also been defined as “neoplastic leptomeningitis”. Parenchymal metastases are exceedingly rare in the pediatric population. Brain tumors are involved only exceptionally; when two large, independent masses are detected at presentation the question of multicentricity should be raised [56]. Cerebral metastases from systemic, nonleukemic-lymphomatous tumors during childhood are rare (4.5% of cases) and carry a dismal prognosis. The primary disease is more often neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, Wilms’ tumor, or osteogenic sarcoma [253], and the brain is secondarily involved by hematogenous spread. CT and MRI findings are not specific; variably sized, often multiple enhancing masses with extensive surrounding edema usually are found. Knowledge of the primary tumor is essential for a correct diagnosis.

Fig. 10.104a–f Capillary hemangioma. a Photograph of the girl at age 11 months. b Gd-enhanced sagittal and c Gd-enhanced axial T1-weighted images at age 11 months. d Photograph of the girl at age 3 years. e Gd-enhanced sagittal and f Gd-enhanced axial T1-weighted images at age 3 years. There is a capillary hemangioma of the left upper eyelid (a). MRI shows two additional intracranial enhancing lesions at the level of the hypothalamus (arrowheads, b) and left internal acoustic meatus (arrow,c). Notice how the hypothalamic lesion recalls the normal anatomy of the hypothalamus from ventral (median eminence) to dorsal (tuber cinereum). There is incidental downward ectopia of the cerebellar tonsils (T, b,e) consistent with Chiari I malformation. Two years later and without any treatment, there is a clear-cut regression of the external hemangioma (d), paralleled by a marked reduction of both intracranial locations (arrowheads, e and arrow, f). (Permission to publish the photographs of the child was obtained from the parents.)

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Fig. 10.105a–e Capillary hemangioma. a Photograph of the girl at age 1 month. b Gd-enhanced axial T1-weighted image and c Digital angiography, anteroposterior projection at age 1 month. d Photograph of the girl at age 6 months. e Gd-enhanced axial T1-weighted image at age 6 months. This child has a large facial hemangioma that involves the right side of the face and the chin. There also is an enhancing, meningeal-based lesion of the right temporal uncus bulging into the opto-chiasmatic cistern (arrow, b). Digital angiography demonstrates typical hypervascularity of a capillary hemangioma fed by the lenticulo-striate arteries (arrows, c). Five months later and without any treatment, there is a marked regression of both the facial hemangioma and the intracranial location (arrow, e). (Reproduced from Tortori-Donati et al. (ref. 231), with permission from Springer Verlag; permission to publish the photographs of the child was obtained from the parents.)

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c d Fig. 10.106a–d Extra-axial pilocytic astrocytoma in a 3-year-old boy. a Axial T1-weighted image. b Axial T2-weighted image. c Gd-enhanced axial T1-weighted image. d Sagittal T1-weighted image. Huge, totally extra-axial mass at the level of the right pontocerebellar angle that deforms and shifts the brainstem (arrows, a–c) and tends to engulf the basilar artery. Gross cystic portions are recognizable along the medial and inferior portions of the lesion (d)

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217. Starshak RJ. Radiation-induced meningioma in children: report of two cases and review of the literature. Pediatr Radiol 1996; 26:537–541. 218. Yoon HK, Kim SS, Kim IO, Na DG, Byun HS, Shin HJ, Han BK. MRI of primary meningeal tumours in children. Neuroradiology 1999; 41:512–516. 219. Darling CF, Byrd SE, Reyes-Mugica M, Tomita T, Osborn RE, Radkowski MA, Allen ED.MR of pediatric intracranial meningioma. AJNR Am J Neuroradiol 1994; 15:435–444. 220. Drake JM, Hendrick EB, Becker LE, Chuang SH, Hoffman HJ, Humphreys RP. Intracranial meningiomas in children. Pediatr Neurosci 1985–86; 12:134–139. 221. Hope JKA, Armstrong DA, Babyn PS, Humphreys RR, Harwood-Nash DC, Chuang SH, Marks PV. Primary meningeal tumors in children: correlation of clinical and CT findings with histologic type and prognosis. AJNR Am J Neuroradiol 1992; 13;1353–1364. 222. Erdinçler P, Lena G, Sarioglu AC, Kuday C, Choux M. Intracranial meningiomas in children: review of 29 cases. Surg Neurol 1998; 49:136–141. 223. Katayama Y, Tsubokawa T, Yoshida K. Cystic meningiomas in infancy. Surg Neurol 1986; 25:43–48. 224. Sheikh BY, Siqueira E, Dayel F. Meningioma in children: a report of nine cases and review of the literature. Surg Neurol 1996; 45:328–335. 225. Kloc W, Imielin´ ski BL, Wasilewski W, Stempniewicz M, Jende P, Karwacki Z. Meningiomas of the lateral ventricles of the brain in children. Childs Nerv Syst 1998; 14:350–353. 226. Huang PP, Doyle WK, Abbott IR. Atypical meningioma of the third ventricle in a 6-year-old boy. Neurosurgery 1993; 33:312–316. 227. Herzog CE, Leeds NE, Bruner JM, Baumgartner JE. Intracranial hemangiopericytomas in children. Pediatr Neurosurg 1995; 22:274–279. 228. Cole JC, Naul LG. Intracranial infantile hemangiopericytoma. Pediatr Radiol 2000; 30:271–273. 229. Chiechi MV, Smirniotopoulos JG, Mena H. Intracranial hemangiopericytomas: MR and CT features. AJNR Am J Neuroradiol 1996; 17:1365–1371. 230. Paulus W, Slowik F, Jellinger K. Primary intracranial sarcomas: histopathological features of 19 cases. Histopathology 1991; 18:395–402. 231. Pfluger T, Weil S, Weis S, Bise K, Egger J, Hadorn HB, Hahn K. MRI of primary meningeal sarcomas in two children: differential diagnostic considerations. Neuroradiology 1997; 39:225–228. 232. Allcutt DA, Hoffman HJ, Isla A, Becker LE, Humphreys RP. Acoustic schwannomas in children. Neurosurgery 1991; 29:14–19. 233. Tortori-Donati P, Fondelli MP, Rossi A, Andreussi L. I tumori extra-assiali della fossa posteriore in età pediatrica. Rivista di Neuroradiologia 1996; 9:721–730. 234. Tortori-Donati P, Fondelli MP, Rossi A, Bava GL. Intracranial contrast-enhancing masses in infants with capillary haemangioma of the head and neck: intracranial capillary haemangioma? Neuroradiology 1999; 41:369–375. 235. Caruso G, Germano A, Caffo M, Belvedere M, La Torre D, Tomasello F. Supratentorial dorsal cistern epidermoid cyst in childhood. Pediatr Neurosurg 1998; 29:203–207. 236. Gelabert-Gonzalez M. Intracranial epidermoid and dermoid cysts. Rev Neurol 1998; 27:777–782. 237. Atlas SW. Magnetic Resonance Imaging of the Brain and Spine, 2nd edn. Philadelphia: Lippincott-Raven, 1996. 238. Gandon Y, Hamon D, Carsin M, Guegan Y, Brassier G, Guy

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pathologic correlation. Capillary hemangioma of the meninges. AJNR Am J Neuroradiol 1993; 14:529–536. 247. Lasjaunias P. Vascular Diseases in Neonates, Infants and Children. Berlin: Springer, 1997:565–591. 248. Dillon WP, Som PM, Roseneau W. Hemangioma of the nasal vault: MR and CT features. Radiology 1991; 180:761–765. 249. Burrows PE, Mulliken JB, Fellows KE, Strand RD. Childhood hemangiomas and vascular malformations: angiographic differentiation. AJR Am J Roentgenol 1983; 141:483–488. 250. Mafee MF, Schatz CJ The orbit. In: Som PM, Bergeron RT (eds) Head and Neck Imaging, 2nd edn. St Louis: Mosby Year Book, 1991:799. 251. Frieden IJ, Reese V, Cohen D. PHACE syndrome. The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol 1996; 132:307–311. 252. Rossi A, Bava GL, Biancheri R, Tortori-Donati P. Posterior fossa and arterial abnormalities in patients with facial capillary haemangioma: presumed incomplete phenotypic expression of PHACES syndrome. Neuroradiology 2001; 43: 934–940. 253. Tasdemiroglu E, Patchell RA. Cerebral metastases in childhood malignancies. Acta Neurochir (Wien) 1997; 139:182– 187.

Hemolymphoproliferative Diseases and Treatment-Related Disorders

11 Hemolymphoproliferative Diseases and Treatment-Related Disorders Paolo Tortori-Donati, Andrea Rossi, and Roberta Biancheri

Introduction

CONTENTS Introduction 11.1 11.1.1 11.1.1.1 11.1.1.2 11.1.1.3 11.1.2 11.1.2.1 11.1.2.2 11.1.2.3 11.1.3 11.1.3.1 11.1.3.2 11.1.3.3 11.1.4 11.2 11.2.1 11.2.1.1 11.2.1.2 11.2.1.3 11.2.2 11.2.2.1 11.2.2.2

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Direct CNS Involvement from Primary Disease 437 Leukemia 437 Meningeal Disease 438 Cranial Nerve Involvement 440 Chloromas and Other Leukemic Masses Lymphoma 443 Cerebral Lymphomas 443 Head and Neck Lymphomas 444 Spinal Lymphomas 445 Langerhans Cell Histiocytosis 445 Parenchymal Involvement 446 Skull Involvement 447 Spinal Involvement 447 Familial Erythrophagocytic Lymphohistiocytosis 449 CNS Disease Related to Underlying and Secondary Effects of HLD 450 Hematological and Cerebrovascular Complications 450 Hemorrhage 450 Cerebral Ischemia/Infarction 450 Dural Sinus/Venous Thrombosis 451 Infection 451 Sinusitis 451 Intracranial Infection 452

11.3 11.3.1 11.3.1.1 11.3.1.2 11.3.1.3 11.3.1.4 11.3.1.5 11.3.1.6 11.3.1.7 11.3.2 11.3.2.1 11.3.2.2 11.3.2.3 11.3.2.4 11.3.3 11.3.3.1

Treatment-related Complications 453 Radiotherapy 454 Focal Radiation Necrosis 454 Radiation Leukoencephalopathy 454 Mineralizing Microangiopathy 456 Cavernomatous Malformations 456 Neuroendocrine Pathology 457 Neuropsychological Delay 458 Second Neoplasms 459 Chemotherapy 459 Methotrexate Neurotoxicity 460 L-asparaginase Neurotoxicity 460 Cytarabine Neurotoxicity 461 Steroids 461 Bone Marrow Transplantation 461 Posterior Reversible Encephalopathy Syndrome (PRES) 462 11.3.3.2 GVHD Vasculitis 464 11.4

Conclusions 466 References

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Pediatric hemolymphoproliferative diseases (HLDs) are a constellation of disorders that prominently include leukemia, lymphoma, and histiocytoses. These conditions are invariably severe, and are burdened by elevated morbidity and mortality in the absence of proper treatment. HLDs are systemic disorders, i.e., they typically affect multiple organs and systems in the human body. While, as a whole, leukemia and lymphomas account for about 40% of all malignancies in children [1], the majority of histiocytoses are not malignant. Intensive treatment regimens have resulted in a significant increase in the number of survivors, but have also disclosed new phases of the natural history of these disorders, among which is involvement of the central nervous system (CNS). CNS disease is not consistent, but when present, it is commonly associated with worsened prognosis. Moreover, current treatment modalities, including systemic therapy (i.e., combination chemotherapy) and specific CNS prophylaxis (i.e., intrathecal chemotherapy with or without cranial irradiation), are potentially neurotoxic. Schematically, a rational approach to neuroimaging of CNS manifestations of HLD basically involves three perspectives [2]: (1) direct involvement of the CNS from primary disease, (2) other CNS disease related to underlying and secondary effects of disease, and (3) treatment-related complications.

11.1 Direct CNS Involvement from Primary Disease 11.1.1 Leukemia Leukemia is the most common neoplasm in the pediatric age group, accounting for 2.7% of new cancer diagnoses and 3.7% of cancer deaths in the United States [3]. Over 25 subtypes exist according to the

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involved stem cell line; these are further classified into acute and chronic leukemia [2, 4]. Acute lymphoblastic leukemia (ALL) is, by far, the most common of these subtypes in the pediatric age group, accounting for 78% of all pediatric leukemia and 40 new cases per million per year in children younger than 15 years [5]. Acute myeloid leukemia (AML) accounts for 16% of pediatric leukemia, whereas the remaining 6% is represented by chronic myeloid leukemia and other specified and unspecified leukemia [4]. Owing to steadfast improvements in treatment modalities, survival for leukemic children has markedly increased over the past 40 years. Although this is true for leukemia as a whole, it is especially valid for ALL. In 1960, 5-year disease-free ALL survivors were 3%, whereas they are about 80% at present [4]. CNS complications were rare in earlier years because of rapid fatality of the disease [6], whereas at present they are seen in 25%–50% of all patients with leukemia [2]. Direct involvement of the CNS is only uncommonly the initial manifestation of disease, and occurs in only 5% of patients at the onset. More often, the CNS is involved in patients with known leukemia or as a relapse after initial remission [2]. Arrival of leukemic cells to the CNS occurs either through hematogenous mechanisms or by direct spread from adjacent infiltrated bone marrow [7]. The meninges are involved much more commonly than the nervous tissues are.

a

11.1.1.1 Meningeal Disease

Meningeal infiltration can be dural, leptomeningeal, or both. Clinical presentation is similar to other forms of meningitis, with signs of raised intracranial pressure including headache, nausea and vomiting, irritability, lethargy, and papilledema [2]. Dural infiltration is rare. It can be focal or diffuse, and appears on MRI as an abnormal dural thickening that enhances strongly and homogeneously with gadolinium administration (Fig. 11.1). Leptomeningeal infiltration is much more common. As with other forms of meningeal disease (either inflammatory or neoplastic), unenhanced MRI is generally inconclusive, and contrast material injection is mandatory for identifying pathology. In most cases, subarachnoid nodules, diffuse leptomeningeal carcinomatosis (Fig. 11.2), or both, are detected on post-contrast MR images. Neoplastic sedimentation is a third, uncommon form of leptomeningeal disease characterized by accumulation of neoplastic cells at the bottom of the thecal sac due to gravity phenomena. In this case, the normal signal intensity of CSF is replaced by an abnormal intermediate signal intensity in all

b Fig. 11.1a,b Localized dural infiltration in a 13-year-old boy with acute lymphoblastic leukemia. a Gd-enhanced axial T1-weighted image. b Gd-enhanced coronal T1-weighted image. Following gadolinium administration, MRI shows a diffusely enhancing dura, with marked focal thickening over the left inferior frontal convexity (arrow, a,b). The dura is also abnormally thickened over the vertex (arrowheads, b)

MR sequences (Fig. 11.3). Typically, neoplastic sedimentations are discovered incidentally when MRI is performed to investigate the cause of repeatedly unsuccessful lumbar tap attempts. However, patients may complain from symptoms related to caudal nerve root involvement. Sensitivity of contrast-enhanced MRI to leptomeningeal infiltration is not 100%. Therefore, normal MRI findings do not exclude the diagnosis. Moreover, leptomeningeal involvement from leukemia may be undistinguishable from other conditions, such as inflammatory/infectious disease or irritation from

Hemolymphoproliferative Diseases and Treatment-Related Disorders

a

b Fig. 11.2a,b Diffuse leptomeningeal carcinomatosis in a 1-year-old boy with acute lymphoblastic leukemia and positive CSF cytology. a Gd-enhanced axial T1-weighted image. b Gd-enhanced coronal T1-weighted image. Following gadolinium administration, a diffuse leptomeningeal enhancement is evident

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Fig. 11.3a–c Neoplastic sedimentation in a 19-year-old girl with relapse of acute myeloid leukemia. MRI was performed after repeated unsuccessful attempts at lumbar tap. a Sagittal T1-weighted image. b Sagittal T2-weighted image. c Sagittal FLAIR image. MRI shows an abnormal intermediate signal intensity diffusely replacing normal CSF signal intensity into the thecal sac up to the level of the conus medullaris

hemorrhage or intrathecal chemotherapy [2]. Positive cerebrospinal fluid (CSF) cytology is ultimately necessary for diagnosis, but cytological findings can be falsely negative. Therefore, CSF analysis and MRI

are best conceived as complementary methods. Obviously, MRI in patients suspected of harboring leptomeningeal disease entails contrast-enhanced investigation of the whole neuraxis.

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11.1.1.2 Cranial Nerve Involvement

11.1.1.3 Chloromas and Other Leukemic Masses

Intracranial and intraspinal involvement other than meningeal is exceedingly rare. The most common form of parenchymal disease in leukemia is represented by cranial nerve infiltration, usually occurring during relapses of the disease. Contrast-enhanced MRI adequately depicts the thickened, enhancing cranial nerves as they course in the subarachnoid space. The 7th-8th cranial nerve pair is most commonly involved, and is easily detected on MRI after gadolinium administration (Fig. 11.4). Typically, enhancement of the facial nerve involves the inner acoustic meatus but does not reach the geniculate ganglion, which is a notable difference from facial neuritis.

Granulocytic sarcomas, or chloromas, are the single most common intracranial masses in leukemic patients, and are composed of immature granulocytes. The term chloroma indicates their typical, albeit not consistent, macroscopic greenish tint resulting from myeloperoxidase enzyme activity. Granulocytic sarcomas are more frequent in other locations such as the skin, soft tissue, and bone (Fig. 11.5), whereas they are uncommon in the CNS. They are almost exclusively found in patients with AML, and may arise within the parenchyma or have a broad meningeal attachment, in which case they are practically indistinguishable from meningiomas [2]. Granulocytic sarcomas can be solitary or multiple.

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d Fig. 11.4a–d Leukemic infiltration of the cranial nerves in two different patients. a–c Diffuse cranial nerve infiltration in a 9-monthold boy with relapse of acute myeloid leukemia and positive CSF cytology. Gd-enhanced axial T1-weighted images. Following gadolinium administration, MRI shows thickened, markedly enhancing 7th-8th cranial nerves (arrows, a), trigeminal nerves (arrows, b), and oculomotor nerves (arrows, c). d Bilateral optic nerve infiltration in a 12-year-old girl with relapse of acute lymphoblastic leukemia. Contrast-enhanced axial CT scan shows homogeneous thickening of both optic nerves (arrows)

Hemolymphoproliferative Diseases and Treatment-Related Disorders

Fig. 11.5 Chloroma of the soft tissues in a 4-year-old girl with acute myeloid leukemia. Gd-enhanced, fat-suppressed axial T1-weighted image. Following gadolinium administration, MRI shows a huge, homogeneously enhancing mass involving the soft tissues around the left mandibular ramus. The mass receded with chemotherapy

On MRI, they are iso- to hyperintense in T1-weighted images, iso- to hypointense in T2-weighted images, and show moderate to marked gadolinium enhancement (Fig. 11.6). Elevated cellularity and fast growth rate generate vascular recruitment, resulting in markedly vascular masses that may bleed profusely during surgery. However, antileukemic treatment is usually associated with complete resolution, even with large masses. Therefore, surgery is not necessary except in emergency cases, such as those causing spinal cord compression (Fig. 11.7). Leukemic mass lesions or diffuse infiltrations are uncommon outside the setting of AML. One possible manifestation is diffuse infiltration of the lacrimal gland in patients with ALL, either at presentation or, more frequently, as a relapse of disease (Fig. 11.8) [8].

a

b Fig. 11.6a,b Multiple intracranial chloromas in a 19-year-old girl with acute myeloid leukemia. a Axial T2-weighted image. b Gdenhanced axial T1-weighted image. Dural based masses along the occipital convexity (thick arrows) and in both cavernous sinuses, extending to the orbits through the superior orbital fissures (arrowheads) are evident. Note the lesions are hypointense to brain in T2-weighted images (a) and enhance moderately (b). All lesions receded with chemotherapy

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a

b

Fig. 11.7a,b Spinal chloroma in a 6-yearold boy without no prior history of leukemia who presented acutely with signs of spinal cord compression. a Sagittal T1-weighted. b Sagittal T2weighted (b) image. MRI shows a posterior epidural mass compressing the spinal cord at upper thoracic level. The mass is spontaneously hyperintense to spinal cord in T1-weighted images (a) and isointense in T2-weighted images (b) Emergency surgery was performed, revealing a solid, nonhemorrhagic tumor. Further laboratory investigations disclosed acute myeloid leukemia

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c

b

Fig. 11.8a–c Infiltration of the right lacrimal gland in a 2year-old with acute lymphoblastic leukemia. a Fat-suppressed axial T2-weighted image. b Coronal T1-weighted image. c Gdenhanced sagittal T1-weighted image. There is diffuse swelling of the right lacrimal gland, which is infiltrated with isointense tissue in both T2-weighted (open arrows, a) and T1-weighted images (open arrows, b). The globe is slightly displaced inferiorly. Following gadolinium administration, the pathological tissue enhances moderately (open arrows, c)

Hemolymphoproliferative Diseases and Treatment-Related Disorders

11.1.2 Lymphoma Lymphoma accounts for 11% of pediatric malignancies. Approximately 54% of pediatric lymphomas are non-Hodgkin lymphomas (including Burkitt’s and Burkitt-like, lymphoblastic, and large cell lymphomas), and the remainder Hodgkin disease [1, 9]. Among non-Hodgkin lymphomas, Burkitt’s, Burkittlike, and most large cell lymphomas are of B-cell lineage, whereas the remaining large cell lymphomas are T-cell lymphomas. Lymphoblastic lymphomas are histologically indistinguishable from ALL, and the distinction between the two diseases is, at best, arbitrary [9]. Unlike in adults, pediatric lymphomas are diffuse aggressive neoplasms with a propensity for widespread dissemination [9]. Involvement of the CNS by lymphoma occurs almost exclusively in the non-Hodgkin variety, and occurs in 5%–10% of patients. In the pediatric age group, lymphomas

Fig. 11.9a–d Primary cerebral lymphoma in an adolescent. a Axial T2-weighted image. b Axial FLAIR image. c Gdenhanced axial T1-weighted image. d Gd-enhanced sagittal T1-weighted image. MRI shows a lesion centered in the right trigonal region, surrounded by moderate edema. The lesion is iso- to hypointense in T2-weighted (arrow, a) and FLAIR (arrow, b) sequences, and shows marked, homogeneous enhancement (arrow, c). There is subependymal spread to the right frontal horn (arrowhead, c). Contrast enhanced sagittal T1-weighted image shows second subependymal lesion over the superior portion of the fourth ventricular floor (thick arrow, d)

involve more commonly the head and neck, rather than the cerebral, compartment. However, primary lymphoma is the most common cause of focal or multifocal mass lesions in the brains of human immunodeficiency virus (HIV)-infected children, as a consequence of Epstein-Barr virus infection [10]. Moreover, B-cell lymphomas may occur after bone marrow or organ transplantation as a result of uncontrolled proliferation of B lymphocytes in an environment of immunosuppression; Epstein-Barr virus has been implicated in the lymphoproliferative process which precedes malignant transformation [6]. 11.1.2.1 Cerebral Lymphomas

Primary cerebral lymphomas presenting either as discrete masses or infiltrations that often involve the corpus callosum, as seen in adults, are rare in

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the pediatric age group (Fig. 11.9) [11, 12]. Relative decrease of signal intensity in both T1-weighted and T2-weighted images probably reflects hypercellularity. Uncommon intracranial locations include the pituitary stalk, where affected children present with central diabetes insipidus and growth hormone deficit [13, 14]; in these cases, differentiation from other causes of pituitary thickening, such as Langerhans cell histiocytosis, germ cell tumors, and sarcoidosis, cannot be performed with neuroimaging alone. Finally, we saw an exceptional case of Hodgkin disease showing multifocal, enhancing cerebral lesions superimposed on a pattern of diffuse leukoencephalopathy (Fig. 11.10).

11.1.2.2 Head and Neck Lymphomas

In the head and neck, lymphomas involve primarily the soft tissues or bone with possible infiltration of the adjacent meninges and dural sinuses; most belong to non-Hodgkin varieties. Together with rhabdomyosarcomas, lymphomas are the most common cause for central skull masses in the pediatric age group. MRI findings of a permeative lesion of the skull base, invasion of the cavernous sinus without arterial narrowing, and infiltration along the dural surface should suggest lymphoma (Fig. 11.11) [15]. Other common sites include the jaw and the orbit [9].

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d Fig. 11.10a–d Hodgkin lymphoma in a child with positive CSF cytology. a,b Axial T2-weighted images. c,d Gd-enhanced axial T1-weighted images. MRI shows diffuse signal abnormalities involving the pons, cerebellar hemispheres, internal capsules, and periventricular white matter. Multifocal, patchy enhancement is seen with gadolinium administration

Hemolymphoproliferative Diseases and Treatment-Related Disorders

11.1.2.3 Spinal Lymphomas

Vertebral involvement from lymphoma is common and can be either primary or secondary. MRI findings include diffuse involvement of the vertebra with replacement of normal bone marrow signal intensity, posterior epidural mass formation, and cortical destruction (Fig. 11.12). These signs are useful to distinguish spinal involvement of hematopoietic malignancies from metastasis [16]. Leptomeningeal involvement by lymphoma occurs essentially as described for leukemia.

11.1.3 Langerhans Cell Histiocytosis a

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Histiocytoses are a group of disorders characterized by the proliferation and accumulation of macrophages and dendritic cells. Histiocytoses are categorized into three classes [17]: Langerhans cell histiocytosis (LCH) (class I), non-Langerhans cell histiocytosis (class II), and malignant histiocytoses (class III). LCH, formerly known as histiocytosis X, is the principal disease in the class of pediatric histiocytoses. Histologically, LCH is characterized by a proliferation of dendritic cells resembling normal Langerhans cells, i.e., histiocytic antigen-presenting cells that are normally found in the skin and represent a terminal differentiation stage of circulating monocytes. The ultrastructural hallmark of these cells is represented by the Birbeck granules, i.e., rod-shaped structures whose function is unknown. Clinical manifestations can vary from an isolated, nonprogressive bony lesion (eosinophilic granuloma) to rapidly progressive multisystem involvement (Letterer-Siwe disease); Hand-SchüllerChristian disease is the intermediate clinical form, presenting as a triad of diabetes insipidus, proptosis, and lytic bone lesions. LCH is not a neoplasm; rather, it should be considered a proliferative lesion, possibly secondary to a defect in immunoregulation [18], producing destructive effects on the tissues in which such proliferation occurs. More than half of the patients younger than 2 years with disseminated LCH die of

Fig. 11.11a–c Non-Hodgkin lymphoma of the neck in a 4-year-old boy. a Axial T2-weighted image, b and c Gd-enhanced coronal T1-weighted images. MRI shows a large laterocervical mass involving the parapharyngeal space with contralateral displacement of the airway. Following gadolinium administration, infiltration of the left cavernous sinus (thick arrow, b), dural involvement with intracranial extension (arrowheads, b,c), and invasion of the left transverse sinus (asterisk, c) are evident

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the disease, whereas unifocal LCH is usually self-limited. Age of onset varies according to the variety of LCH. Letterer-Siwe disease occurs predominantly in children younger than 2 years. Hand-Schüller-Christian disease prevails between 2 and 10 years of age. Localized eosinophilic granuloma occurs mostly frequently in those aged 5–15 years. Involvement of the CNS is seen in approximately 10%–50% of cases, and occurs almost entirely in patients with systemic disease [19]. In general, CNS involvement may be classified into those forms occurring primitively in the brain parenchyma, the meninges, or extending from neighboring bones [20].

Fig. 11.12a–c Spinal lymphoma. a Sagittal T2-weighted image. b Gd-enhanced sagittal T1-weighted image. c Gdenhanced axial T1-weighted image. Signal abnormalities involve multiple lumbar and sacral vertebrae. There also is abnormal anterior and posterior epidural tissue at the L4L5 level. Following gadolinium administration, a soft tissue mass involving the epidural space and extending through the neural foramen to the paravertebral space (arrowheads, c) is seen

found [22]. Infiltration of the nearby optic chiasm may lead to blindness [20]. The second most common location of CNS involvement by LCH is the posterior fossa. Affected patients exhibit a cerebellar-pontine syndrome with reflex or gait abnormalities followed by profound ataxia, dysarthria, dysphagia, and other cranial nerve deficits, eventually leading to fatal neurologic deterioration

11.1.3.1 Parenchymal Involvement

The most common form of CNS involvement from LCH is diabetes insipidus due to destruction of the hypothalamic-pituitary axis, occurring in 5%–50% of patients with systemic disease. Infiltration may involve the hypothalamic nuclei, pituitary stalk, or both. MRI shows thickening and marked enhancement of the median eminence, proximal infundibular stalk, or the whole pituitary stalk (Fig. 11.13), coupled with absence of the posterior pituitary bright spot, reflecting dysfunction of the hypothalamic-neurohypophyseal axis [21]. Suprasellar mass lesions can be

Fig. 11.13 Thickened pituitary stalk in a 10-month-old girl with Langerhans cell histiocytosis. Gd-enhanced sagittal T1-weighted image. There is marked thickening of the pituitary stalk, which enhances strongly (arrow)

Hemolymphoproliferative Diseases and Treatment-Related Disorders

[22]. Lesions involve the dentate nuclei regions symmetrically, with extension to the cerebellar peduncles and the pons. They present as poorly defined areas of hypodensity on CT, hypointensity in T1-weighted MR images, and hyperintensity in T2-weighted and FLAIR images, probably as a result of a gliotic and demyelinating process (Fig. 11.14) [19]. Gadolinium enhancement may sometimes be seen [22]. Similar forms of involvement may also occur in the basal ganglia [22].

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11.1.3.2 Skull Involvement

LCH produces either a solitary or multiple, sharply marginated, round or oval osteolytic lesions that may involve the bones of the calvarium, skull base, or face. Painful swelling is the most common initial sign. Proptosis from lesions of the orbital wall may also be present. When the mastoid process is involved, the findings can mimic mastoiditis. Extensive lesions of the middle ear cause destruction of the ossicles and deafness. The osteolytic lesion is usually rounded and is well depicted on conventional radiograms (Fig. 11.15). CT (Fig. 11.15) shows an osteolytic lesion that may involve the outer table alone or both the outer and inner table of the skull, accompanied by an enhancing soft tissue mass involving the pericranial soft tissue, the epidural space, or both. On MRI, the lesion has intermediate to high signal intensity in T2-weighted images and enhances strongly with gadolinium injection (Fig. 11.15). Intracranial mass lesions usually arise from neighboring bone lesions. However, meningeal-based mass lesions may arise without accompanying calvarial osteolysis [22]. Sizable masses may also originate from the choroid plexuses [22]. 11.1.3.3 Spinal Involvement

b Fig. 11.14a,b Cerebellar involvement in a 3-year-old girl with Langerhans cell histiocytosis. a Axial FLAIR image. b Coronal FLAIR image. There is bilateral symmetric hyperintensity of the dentate nucleus regions and adjacent cerebellar white matter (arrows)

The classical lesion of the spine, the vertebra plana, is a very common finding in LCH. It consists of flattening of one or more vertebral bodies, often becoming wafer-thin with close apposition of the unaffected intervertebral disks. The residual vertebra is hypointense in T1-weighted images, hyperintense in T2-weighted images (Fig. 11.16), and enhances markedly with gadolinium injection [23]. Possible extension of pathologic tissue to the ventral epidural space is common. The healing phase is often characterized by restoration of about two-thirds of vertebral height. One must caution that the appearance of vertebral LCH in the early stage of disease, i.e., before vertebral collapse occurs, is fairly aspecific and may result in a mistaken diagnosis of other vertebral tumor or infectious spondylitis. Albeit rarely, spinal LCH may present as a purely meningeal lesion (Fig. 11.17), i.e., without any bony involvement, similar to intracranial meningeal locations. The diagnosis is histological in these cases [24].

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Fig. 11.15a–e Eosinophilic granuloma of the skull, 3-year-old girl. a Conventional radiogram, laterolateral projection. b Axial CT scan. c Axial T1-weighted image. d Axial T2-weighted image. e Gd-enhanced axial T1-weighted image. Conventional radiogram (a) shows large, rounded osteolytic area in the frontal region. On CT (b) there is sharp osteolysis of both tables of the skull with beveled margins. MRI (c–e) shows soft tissue mass elevating the subcutaneous fat and abutting the dura. The lesion is iso-to hyperintense in T1-weighted images (c), hyperintense in T2-weighted images (d), and enhances markedly (e)

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Hemolymphoproliferative Diseases and Treatment-Related Disorders Fig. 11.16 Vertebra plana in a 6-year-old girl with Langerhans cell histiocytosis. Sagittal T2-weighted image shows T12 vertebral body collapse with approximation of the intact adjacent disks. The residual vertebral body is slightly hyperintense compared to unaffected vertebrae

Fig. 11.17 Intradural-extramedullary Langerhans cell histiocytosis in a 2-year-old girl. Gd-enhanced sagittal T1-weighted image shows enlarged thecal sac which is filled with an enormous amount of moderately enhancing tissue. The conus medullaris and lower thoracic cord are engulfed by the lesion. Langerhans cell histiocytosis was found on histological examination

11.1.4 Familial Erythrophagocytic Lymphohistiocytosis Hemophagocytic histiocytoses include most of the patients with class II (i.e., macrophage related) histiocytoses. These disorders may be categorized into primary and secondary. Familial erythrophagocytic histiocytosis (FEL) is the main entity in this group; albeit a primary disease, this autosomal recessive condition may be triggered by infection. Secondary hemophagocytic histiocytoses occur secondary to strong immunologic stress and activation, such as with viral disease and malignancy [25]. FEL affects small infants, with up to 70% of cases presenting within age 1 year. The disease may even present in utero. Early symptoms typically include fever and hepatosplenomegaly. In most cases, CNS involvement occurs during later stages of the disease. Irritability, bulging fontanel, stiff neck, hypotonia and hypertonia, and convulsions are the most common neurologic signs. Cranial nerve palsy, ataxia, hemiplegia/tetraplegia, blindness, and unconsciousness may also develop [25]. Pathologically, there is nonmalignant lymphohistiocytic accumulation in the

reticuloendothelial system with hemophagocytosis, mostly affecting erythrocytes. In the CNS, the meninges are initially affected, with possible spread along the perivascular spaces to the brain parenchyma [25, 26]. On MRI (Fig. 11.18) [26, 27], brain involvement in FEL consists of parenchymal atrophy involving both the cerebrum and cerebellum, diffuse abnormal signal intensity in the white matter on T2-weighted and FLAIR images, focal hyperintense lesions involving both the gray and white matter, and delayed myelination. Diffuse leukoencephalopathy is a striking finding and may be mistaken for a neurometabolic condition. Small areas of gadolinium enhancement may reflect areas of active demyelination. Calcifications at the gray-white matter junction and adjacent to areas of severe white-matter involvement are seen in the late stages of disease. MR spectroscopy shows decreased NAA/Cr and increased Cho/ Cr ratios, suggestive of neuronal depletion and gliosis [26].

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Fig. 11.18a–c Familial erythrophagocytic lymphohistiocytosis in a 7-year-old boy. a–c Axial FLAIR images. There is diffuse hyperintensity of the supratentorial white matter with involvement of the posterior limbs of the internal capsules and sparing of the arcuate fibers, corpus callosum, and anterior capsular limbs. The medullary centers of both cerebellar hemispheres are also involved (a)

11.2 CNS Disease Related to Underlying and Secondary Effects of HLD Much more commonly than from direct involvement, the CNS suffers from indirect effects of underlying HLD, basically represented by hematologic, cerebrovascular, and infectious complications. These events are the most significant contributors to both morbidity and mortality in patients with HLD.

11.2.1 Hematological and Cerebrovascular Complications Coagulation factor imbalance is very common in patients with HLD. Virtually all coagulation factors can be abnormally elevated or decreased, because of altered production, increased elimination, or drug interference [2]. As a consequence, affected children are prone to either hypercoagulable states or bleeding diathesis that often insidiously follow each other and, when unrecognized, may determine life-threatening complications. 11.2.1.1 Hemorrhage

Hemorrhage is probably the most feared event in the clinical history of these patients. Brain hemorrhage is found in as many as 15%–31% of all autopsies in

leukemics [28]. In patients with bleeding diathesis, profuse hemorrhage can occur spontaneously, or may complicate otherwise safe procedures, such as lumbar taps performed for diagnostic or therapeutic purposes (Fig. 11.19). Hemorrhage is particularly frequent and severe in acute promyelocytic leukemia, where it causes 60% of demises [28]. Hemorrhage can also be the end result of blast crises, where the white blood cell count increases to greater than 300,000/mm3 causing thrombosis of small arterioles and hemorrhagic infarction. The most devastating hemorrhagic event is disseminated intravascular coagulation (DIC), a process of diffuse, rapid activation of the clotting cascade that results in depletion of clotting factors in the blood, basically with hypofibrinogenemia and thrombocytopenia. As a result, profuse bleeding ensues from various body sites including, possibly, the CNS. Because of the emergency situation, children with DIC are usually imaged with CT. Multiple, often innumerable discrete hyperdense hemorrhagic foci are disseminated throughout the brain, with a strong predilection for the subcortical regions (Fig. 11.20). The brain is edematous with sulcal and ventricular effacement. Although survival is possible, DIC is usually a terminal condition. 11.2.1.2 Cerebral Ischemia/Infarction

Cerebrovascular ischemia may occur in patients with HLD as a complication of coagulopathy, leukocytosis,

Hemolymphoproliferative Diseases and Treatment-Related Disorders

Fig. 11.20 Disseminated intravascular coagulopathy in a child with end-stage acute lymphoblastic leukemia. Axial CT scan image. CT scan shows multiple parenchymal hemorrhages, mainly involving the subcortical regions. The brain is diffusely swollen with effacement of the right lateral ventricle and subarachnoid spaces

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Fig. 11.19a,b Spinal subdural hemorrhage in a 4-month-old boy with acute lymphoblastic leukemia and thrombocytopenia. a Sagittal T1-weighted image. b Sagittal T2-weighted image (obtained shortly after lumbar tap). There is blood accumulation in the subdural space, whose signal intensity is consistent with an acute/subacute bleed

thrombocytopenia, or secondary to a host of conditions including endocarditis, sinovenous thrombosis, tumor and septic embolism, and drugs, especially L-asparaginase [6]. However, ischemic events are much less common than hemorrhage [2]. Neuroimaging does not differ from imaging of the same condition in patients without HLD. 11.2.1.3 Dural Sinus/Venous Thrombosis

Factors contributing to sinovenous thrombosis in HLD include direct infiltration, leukostasis, hypercoagulable states, or chemotherapeutic drugs, especially L-asparaginase [2]. As with sinovenous thrombosis from other causes, the MRI appearance is dependent on clot age as a consequence of the relative concen-

trations of hemoglobin degradation by-products. MR angiography is a powerful aid in the identification of this condition. Complications of sinovenous thrombosis prominently include hemorrhagic venous infarctions.

11.2.2 Infection Control of infection is among the main goals in the management of HLD. Patients are prone to infection because of several mechanisms, i.e., (1) depletion of granulocytes due to primary disease or chemotherapy; (2) mucositis and reduced mucociliary clearance complicating chemo- and radiotherapy; and (3) depletion of physiologic flora and immunosuppression, resulting from antibiotic and steroid administration or bone marrow transplantation (BMT). Although a host of pathogens can be involved, Aspergillus accounts for as many as 30%–50% of CNS infections in BMT patients. 11.2.2.1 Sinusitis

Sinusitis is often overlooked when reporting on neuroimaging studies, but is in fact a common and

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potentially dangerous occurrence in immunocompromised children. In the vast majority of cases, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Staphylococcus aureus are the initial pathogens; administration of antibiotics, while necessary for infection control, may cause suppression of physiologic flora, leading to superimposition of Aspergillus fungal species. Aspergillosis is an aggressive infestation causing bony erosion with possible orbital and intracranial spread. Fungal sinusitis may be suspected in the presence of foci of increased CT attenuation and remarkably hypointense signal in T2-weighted images, possibly representing iron and manganese accumulation within the mycetoma [29]. 11.2.2.2 Intracranial Infection

Intracranial infection may result from direct spread from contiguous sites (especially fungal sinusitis) or from hematogenous spread, especially in the form of septic emboli complicating endocarditis. The involved pathogens include fungi, bacteria, and viruses (especially herpesviruses). Fungal Infections

Although fungal disease has been traditionally associated with dismal prognoses, new antifungal therapy have made successful treatment possible. Fungal infestation typically affects children having absolute granulocyte counts of less than 100/mm 3 for longer than two weeks [30]. Fungi, and especially Aspergillus, may cause an infectious vasculopathy, leading initially to acute infarction or hemorrhage and later extending into surrounding tissue as an infectious cerebritis or occasionally evolving into an abscess [31]. Aspergillosis appears as multiple cortical and subcortical areas of decreased CT attenuation or T2 lengthening (with or without hemorrhage) and multiple ring-enhancing lesions [32]. The intensity of contrast enhancement positively correlates with the degree of immunocompetence of the host [33]. Characteristic sites of involvement include the basal ganglia, thalami, and corpus callosum, reflecting predisposition of the perforating arteries to Aspergillus vasculopathy [31], as well as the subcortical regions. MR angiography (MRA) may display intraluminal irregularities and arterial stenosis, suggesting vasculitis [34]. Candidiasis has a different appearance on imaging studies, typically comprising numerous ring-enhancing microabscesses at the corticomedullary junction,

basal nuclei, and cerebellum [35], whereas vasculitis, hemorrhage, and thrombotic infarction are less common than with aspergillosis. Nocardiosis is also characterized by multiple ring-enhancing abscesses, possibly associated with hydrocephalus, ependymitis, and meningitis [36]. One should be aware that fungal isolation from biologic fluid cultures is a lengthy, often inconclusive procedure. Therefore, the diagnosis may remain presumptive. Empirical antifungal treatment in patients at risk is therefore recommended, even without conclusively documented disease (Fig. 11.21) [37]. Followup imaging studies in long-term survivors after successful antifungal treatment reveals complete regression of small lesions, whereas larger lesions may calcify, resulting in increased CT attenuation and T2 shortening at the lesion site. Eventually, the diagnosis is made ex iuvantibus in a significant proportion of cases. Bacterial Infections

In immunocompromised patients with HLD, bacterial infections of the CNS are less common than fungal disease. A host of pathogens may be involved, among which Listeria monocytogenes and Bacillus cereus are well known [38, 39]. Imaging features are not significantly different from those of cerebritis and abscess in general. Viral Infections

Most viral infections in HLD are caused by herpesviruses. Among these, human herpesvirus 6 (HHV-6) has recently emerged as a major cause of opportunistic viral infections in immunosuppressed patients [40]. HHV-6 is extremely widespread, with 90% of children becoming infected by age 2 years. The primary infection can be asymptomatic or mildly febrile, and include a mild skin rash called exanthema subitum [41]. Like other herpesviruses, HHV6 can persist after the primary infection. Sanctuary sites probably involve the salivary glands and brain. In immunocompromised patients, especially transplant recipients, HHV-6 can reactivate and/or reinfect, causing interstitial pneumonia, bone marrow suppression, and encephalitis [42]. On MRI, HHV-6 encephalitis resembles acute disseminated encephalitis, basically showing scattered areas of T2 prolongation in the cerebral white matter [43]. The prognosis of HHV-6 encephalitis is difficult to establish. Although adverse outcome has been reported [44, 45], we saw a case with progressive resolution of MRI abnormalities (Fig. 11.22).

Hemolymphoproliferative Diseases and Treatment-Related Disorders

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Fig. 11.21a–c Presumed cerebral mycosis, 7-year-old boy with acute lymphoblastic leukemia and prior bone marrow transplant. a Axial CT scan. b,c Gd-enhanced axial T1-weighted images with magnetization transfer. Axial CT scan shows calcified spots in the white matter adjacent to the left frontal horn and at the gray–white matter interface of the right frontal lobe anteriorly (arrows, a). Contrast-enhanced MRI shows ring enhancement of both lesions (arrows, b,c). Blood and CSF cultures were persistently negative. Antifungal therapy was administered. On follow-up MRI after two years, both lesions were markedly decreased (not shown)

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Fig. 11.22a,b Human herpesvirus 6 encephalitis in a 10-year-old boy with acute lymphoblastic leukemia. Diagnosis was made by PCR on the patient’s CSF. a and b Axial FLAIR images (a exam performed at presentation. b Exam obtained after two years). At presentation, MRI (a) shows patchy, confluent hyperintense areas in the deep white matter of both cerebral hemispheres, prevailing in the frontal lobes. Two years later, MRI (b) shows subtotal normalization of the picture

11.3 Treatment-related Complications Treatment of HLD, while beneficial in that it has dramatically increased overall survival, can result in significant toxic injury to the CNS. The goals of treatment basically include control of marrow or systemic disease and treatment or prevention of

disease in sanctuary sites, among which the CNS. Involvement of the CNS occurs in 3% of cases at presentation, but it increases to 50% of cases if prophylaxis is not instituted. Treatment options basically include irradiation, chemotherapy, and bone

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marrow transplantation. Because these modalities are also used in the treatment of other neurological conditions (i.e., brain tumors), treatment-related neurotoxicity is obviously not exclusively found in children with HLD. While current treatment modalities are undoubtedly less aggressive than in the past, they still entail significant adverse effects that may force discontinuation of therapy. The severity and reversibility of adverse effects must thus be weighed against the benefits of the treatment regimen in individual patients [2]. MRI is greatly beneficial in the identification of treatment-related complications. Early recognition of toxic injury to the brain is important to evaluate the efficacy and success of therapy and to institute early treatment of these complications, thereby increasing the chances for overall survival [6, 46].

11.3.1 Radiotherapy The role of radiotherapy (RT) in the treatment of HLD has greatly diminished in the past few years, whereas RT remains a mainstay in the adjuvant treatment of primary CNS malignancies. Regimens involving simultaneous irradiation and intravenous/intrathecal methotrexate administration, once widely used, have now been abandoned because of unacceptably high neurotoxicity. Today, RT is basically reserved for high-risk patients, i.e., children older than 10 years at presentation, with hyperleukocytosis, T-cell ALL, or lymphomatous presentation. The pathophysiology of radiation injury is still debated. Factors influencing the occurrence of RT neurotoxicity include patient age, cumulative dose of irradiation, administration modalities, and association with chemotherapy [46]. The most widely accepted explanation invokes vascular damage with small vessel injury, i.e., the so-called “tissue injury unit”, involving capillary dilatation, endothelial thickening, enlargement of endothelial nuclei, and reactive astrocytosis. Endothelial damage also results in altered fibrinolysis, with a possible role for plasminogen activator unbalance in producing spontaneous thrombosis within irradiated vessels. Other explanations include direct glioneuronal damage and an immune mechanism involving an autoimmune vasculitis [46]. RT neurotoxicity is classified into acute (occurring within 1 to 6 weeks after treatment), early-delayed (between 3 weeks and 3 months), and late-delayed (several months to years) [46]. Generally, acute and early-delayed reactions are asymptomatic and revers-

ible, whereas late-delayed toxicity is not. RT lesions may also be classified into focal, basically represented by radiation necrosis, and diffuse, such as radiation leukoencephalopathy and mineralizing microangiopathy. The main manifestations of radiation injury will be briefly discussed here. 11.3.1.1 Focal Radiation Necrosis

Focal radiation necrosis manifests as a focal, avascular mass, surrounded by vasogenic edema, occurring within the radiation port. Affected patients present with raised intracranial pressure and focal neurological signs related to location of the lesion. As many as 70% of cases occur within 2 years of RT [47]. The course is progressive, and fatal in most cases. Histologically, focal radiation necrosis corresponds to coagulation necrosis of the white matter, accompanied by fibrinoid necrosis of the vessels in the acute phase, and surrounded by neovascular proliferation in the late phase [48]. On MRI, focal radiation necrosis appears as an irregular mass that is hypointense in both short and long relaxationtime sequences, and enhances inhomogeneously due to inner necrotic changes (Fig. 11.23). Surrounding edema can be marked [48]. Differentiating radiation necrosis from recurrent tumor can be difficult with standard imaging alone. Recent studies indicate that MR spectroscopy can be helpful in performing such differentiation [49–51]. 11.3.1.2 Radiation Leukoencephalopathy

Diffuse radiation leukoencephalopathy includes a cascade of pathological events including vasogenic edema and demyelination, which can be reversible, and coagulation necrosis, which is not. Moreover, radiation injury to the blood-brain barrier may locally increase tissue concentrations of chemotherapeutic agents, thereby magnifying their toxicity [2]. This is why the association of irradiation and intravenous or intrathecal methotrexate, once widely employed, is now proscribed. On MRI, radiation leukoencephalopathy is seen as confluent areas of increased signal intensity in T2-weighted and FLAIR images. In whole-brain irradiation, signal alterations are initially periventricular (Fig. 11.24), but may progress in size and intensity over time, extending peripherally to the subcortical fibers (Fig. 11.25) [46]. However, the telencephalic commissural fibers (i.e., corpus callosum, hippocampal commissure, and anterior commissure) are typi-

Hemolymphoproliferative Diseases and Treatment-Related Disorders

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Fig. 11.23a–c Focal radiation necrosis with surrounding edema in a 6-year-old boy. a Axial FLAIR image. b Gd-enhanced axial T1-weighted image. c Axial diffusion-weighted image (b=1000). The splenium of the corpus callosum is hypointense in the FLAIR image (arrowhead, a) with surrounding hyperintensity along the fibers of the forceps major. There is strong gadolinium enhancement (arrowhead, b). The lesion is hypointense on DWI (arrowhead, c)

a Fig. 11.25 Radiation leukoencephalopathy. Axial T2-weighted image. MRI shows a diffusely swollen, hyperintense cerebral white matter with sparing of the subcortical fibers. (Courtesy of Mauricio Castillo, MD, Chapel Hill, NC, U.S.)

b Fig. 11.24a,b Radiation leukoencephalopathy in a 11-year-old boy with acute lymphoblastic leukemia. a Axial T2-weighted image. b Axial FLAIR image. MRI shows a symmetric periventricular white-matter hyperintensity. The child was asymptomatic

cally spared [46]. Most patients with radiation leukoencephalopathy are asymptomatic. However, severe cases are characterized by neurological and psychoorganic signs with progressive, sometimes rapid deterioration. Generally, there is inconsistent correlation between the clinical picture and MRI. Long-term outcome depends on the severity of white matter involvement. A decrease in white matter volume similar to that found in periventricular leukomalacia may occur as a result of diffuse radiation injury [46].

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11.3.1.3 Mineralizing Microangiopathy

Mineralizing microangiopathy is seen in 25%–30% of medium- to long-term survivors following irradiation and intrathecal administration of methotrexate. Radiation damage to small vessels may result in hyalinization and fibrinoid necrosis of small vessels with intra- and perivascular dystrophic calcification, which typically is irreversible. The basal ganglia (especially the striatum) and the gray matter–white matter interface are the most frequently involved sites. As with radiation leukoencephalopathy, there is no clear-cut correlation between the presence, degree, and location of calcification and a corresponding clinical picture, and most patients are asymptomatic. CT is superior to MRI in the identification of calcification. However, mineralizing microangiopathy may be presented as a high signal intensity in T1-weighted MR images, probably as a result of surface-relaxation effect by the calcium salt particles (Fig. 11.26) [52]. 11.3.1.4 Cavernomatous Malformations

Acquired cavernomatous malformations (CMs) are increasingly recognized as a common long-term complication after brain irradiation for malignancy [53– 55]. CM can be solitary or multiple, and are invariably localized within the radiation port. The time interval between irradiation and the detection of occult vascu-

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lar malformations ranges between 3 and 9 years [55]. Development of CM may be induced by irradiation basically in two ways. A first mechanism involves a cascade of events starting from a thrombosed vein and ending with the development of endothelial vascular spaces [55]. Specifically, radio-induced venous endothelial damage leads to venous congestion and occlusion. Teleangiectasia develops as an attempt at collateral drainage. Progressive obstruction of the venous outflow leads to venous hypertension, with resulting ischemia and microhemorrhage. Eventually, endothelization of hemorrhagic cavities and angiogenetic factor production result in formation of CM. A second, alternative mechanism could be radioinduced mutation of the long arm of chromosome 7, involving the locus responsible for familial cavernous angiomas [56]. Histologically, radio-induced CMs are similar, but not completely identical to, mature cavernous angiomas; specifically, they lack long-standing changes such as calcification and organized thrombi [55]. The neuroimaging appearance of radiation-induced CM is not different from that of cavernous angiomas, including their optimal identification with gradient-echo sequences (Fig. 11.27). However, their potential for bleeding may be more conspicuous (Fig. 11.28) [53]. Obviously, correlation of a CM to irradiation entails documentation of its absence before RT was administered. Otherwise, it may remain unclear whether irradiation simply triggered bleeding from previously unrecognized cavernous angiomas.

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Fig. 11.26a–c Mineralizing microangiopathy, 17-year-old boy. a Axial CT scan. b Axial T1-weighted image. c Axial CT scan. CT scan (a) shows fairly inconspicuous hyperdensity involving the basal ganglia bilaterally. There is an intraventricular shunt catheter. MRI (b) is paradoxically more sensitive than CT in depicting calcified spots as hyperintense areas that not only involve the basal ganglia, but also the left thalamus. However, CT scan also shows diffuse subcortical occipital calcifications (c) that were undetected by MRI (not shown)

Hemolymphoproliferative Diseases and Treatment-Related Disorders

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Fig. 11.27a,b Radiation-induced cavernomatous malformation in a 6-year-old girl. a Axial T1-weighted image. b Axial gradient-echo T2*-weighted image. MRI shows a hyperintense lesion in the white matter of the left Heschl’s gyrus (arrow, a). Gradient-echo T2*weighted image shows prominent, blooming low signal intensity (arrow, b), consistent with magnetic susceptibility effects related to hemosiderin. The imaging features of this lesion are not unlike those of other cavernous angiomas

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Fig. 11.28a–c Massively hemorrhagic radiation-induced cavernomatous malformation in a 18-year-old girl with prior acute lymphoblastic leukemia treated with brain irradiation. a Axial T1-weighted image. b Axial T2-weighted image. c Axial gradient-echo T2*-weighted image. MRI shows a huge hemorrhagic lesion in the left cerebral hemisphere, showing heterogeneous signal intensity reflecting various stages of hemoglobin degradation. There is marked mass effect with contralateral midline shift and perifocal edema. Gradient-echo image at slightly more cranial level shows additional small cavernoma contralaterally (arrowheads, c)

11.3.1.5 Neuroendocrine Pathology

Radiation injury to the hypothalamus-hypophyseal axis has only rarely been commented upon in the radiological literature. It occurs with doses greater than 1800-2000 cGy involving the sella turcica and suprasellar regions [46]. The pathogenetic mechanism

is still obscure; injury may be directed to either the vessels of the portal system or the adenohypophyseal parenchyma. Whereas low doses may lead to selective growth hormone deficit, higher doses may produce panhypopituitarism [46]; neurohypophyseal function

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is usually preserved. Remarkably, laboratory tests may reveal hormonal alterations as early as 9–12 months after treatment, whereas clinical manifestations may not become apparent before years. Therefore, laboratory surveillance is crucial in order to administer replacement treatment before definitive sequelae, such as short stature, develop. Unfortunately, there is no clear-cut correlation between MRI findings and clinical or laboratory abnormalities. MRI abnormalities include a small pituitary gland (Fig. 11.29), and failed visualization of the stalk [46]. We also saw an unusual case of a globular, spontaneously hyperintense gland in T1-weighted images in a patient without laboratory evidence of pituitary dysfunction (Fig. 11.29). 11.3.1.6 Neuropsychological Delay

Reduced intellectual quotient (IQ), learning and memory disturbances, and deficit of fine motor performances are common long-term complications of RT. Factors influencing the eventual degree of neuro-

psychological deficit include RT dose, administration modalities (i.e., panencephalic versus focal), association with chemotherapy, and patient age. In general, the younger the child at the time of therapy, the greater is the effect of neurotoxicity to normal development [46, 57]. Remarkably, leukemic children treated with chemotherapy alone seem to function considerably better in terms of late cognitive and academic effects [58]. Conventional MRI studies are not suited to predict the appearance and severity of these complications in irradiated patients [59]. Quite commonly, variable degrees of cortical atrophy with ex-vacuo enlargement of ventricles and subarachnoid space is seen in long-term survivors after RT (Fig. 11.30), but these findings do not correlate well with the degree of neuropsychological function exhibited by these patients. In one study, white matter abnormalities were associated with poor performance only in a task exploring visual motor integration in about 50% of patients, whereas intracerebral calcifications correlated with low scores in total IQ, performance IQ, and significant impairment in attention and visual motor integration tests [60].

b

a Fig. 11.29a,b Post-irradiation pituitary gland abnormalities. Two different cases. a and b Sagittal T1-weighted images (a exam performed in a 14 year-old-girl; b exam performed in a 3-year-old boy). In the first case (a), MRI shows a small anterior lobe and lack of the posterior pituitary bright spot. There was short stature but no signs of diabetes insipidus. In the second case (b), the pituitary gland is globular and bright. No hormonal abnormalities were recorded

Hemolymphoproliferative Diseases and Treatment-Related Disorders

Fig. 11.30 Cerebral atrophy at age 25 years in a long-term survivor of acute lymphoblastic leukemia treated with brain irradiation. Axial T2-weighted image. MRI shows enlarged ventricles and subarachnoid spaces

11.3.1.7 Second Neoplasms

Induction of tumor growth is a well known late complication of RT. The risk for developing second tumors in survivors of childhood malignancies is 6 to 10 times greater than the risk for developing a first cancer in the general population [61], and is significantly increased by irradiation [62]. Estimated incidence is 0.35% [62], whereas latency is in the order of 3 to 13 years of irradiation [62, 63]. Meningiomas (Fig. 11.31), glioblastomas, and astrocytomas are the most common CNS histotypes. These tumors show a pronounced tendency to aggressive biological behavior, irrespective of their histology [48]. Remarkably, MRI can reveal second tumors before they become clinically manifest [63], a fact that, combined with the often prolonged latency, poses interesting questions as to how long and how often follow-up MRI studies should be obtained after RT. As with other forms of RT injury, there is no dose-response correlation, as demonstrated by the observation that there is no significant difference in the incidence of second tumors between 2,400 cGy and 1,800 cGy recipients [62]. This raises the possibility that biological predisposition could play a role in increasing the odds of developing second tumors in some patient groups. Such predisposing conditions could be represented by chromosomal translocations, such as t(12:21), and the Li-Fraumeni syndrome, an autosomal dominant condition caused by germ-line

Fig. 11.31 Radiation-induced meningioma in a young adult who underwent irradiation for acute lymphoblastic leukemia 11 years prior to this diagnosis. Gd-enhanced coronal T1weighted image. Following gadolinium administration, MRI shows a huge extra-axial frontal mass. The falx is displaced to the left (arrowheads). The adjacent convolutions are compressed and displaced

mutations in the p53 tumor suppressor gene and characterized by the association of leukemia, CNS tumors, and sarcomas [64, 65].

11.3.2 Chemotherapy Chemotherapy is the base upon which the treatment of HLD stands. Although several chemotherapeutic agents exist, their utilization is different depending on the various conditions and stages of the disease. In HLD, the first stage of treatment is induction of remission, which is accomplished basically by means of vincristine, prednisone/dexamethasone, and L-asparaginase intravenous administration. The second basic goal of treatment is CNS prophylaxis, i.e., prevention of CNS involvement by malignancy; it basically involves intrathecal administration of methotrexate, either alone or in combination with hydrocortisone and cytarabine, the so-called triple intrathecal therapy. Subsequent treatment phases of consolidation, intensification, and maintenance basically involve months, or even years, of methotrexate administration in various doses and modalities, together with other drugs such as anthracyclines, alkylating agents, and mercaptopurine. These treatment regimens,

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while beneficial in that they have significantly lowered mortality from primary disease, bear significant consequences in terms of side effects and overall toxicity. The basic forms of chemotherapy-related neurotoxicity will be briefly exposed here. 11.3.2.1 Methotrexate Neurotoxicity

Methotrexate is the bulk of chemotherapy for HLD. It can be administered intrathecally (either by multiple lumbar taps or with the aid of intraventricular catheters, such as the Ommaya reservoir), or intravenously, either alone or in combination with other drugs. Methotrexate inhibits dehydrofolate reductase, resulting in reduced availability of tetrahydrofolate, which is essential for methylation reaction in DNA synthesis. Thereby, methotrexate is eventually expected to determine reduced replication of tumor cells, whose mitotic rate is many times higher than that of normal body cells. However, tetrahydrofolate is also required in a variety of complex biochemical reactions in the single carbon transfer pathway. As a consequence, methotrexate can inhibit the synthesis of many types of biological macromolecules, including myelin basic protein [66]. Therefore, the main toxic effect related to methotrexate is demyelination, basically resulting from inefficient myelin turnover. On MRI, methotrexate leukoencephalopathy is basically similar to RT leukoencephalopathy (Fig. 11.32), appearing as patchy, confluent areas of T2 prolongation in the supratentorial and/or

a

infratentorial white matter, involving prevailingly the deep white matter but with possible extension to the subcortical regions. T2 prolongation correlates with histopathological findings of interstitial fluid accumulation within the splitting myelin [66]. As with radiation leukoencephalopathy, methotrexate leukoencephalopathy can occur acutely (40% of cases) [66] or as a delayed reaction (60% of cases) [67]. Although hyperacute, fulminant forms of encephalomyelitis have been described [68], acute methotrexate leukoencephalopathy is usually transient and resolves after temporary or permanent withdrawal of therapy [6, 66]. Transient neurological signs develop only in a minority of those with MRI evidence of white matter damage. Focal leukoencephalopathy can involve the brain tissue surrounding malfunctioning intraventricular catheters, such as the Ommaya reservoir (Fig. 11.33) [69]. This occurs when the catheter tip becomes obstructed, thereby causing seepage of the drug around the catheter, which results in marked local increase of methotrexate concentrations. Finally, intrathecal administration of methotrexate may cause anterior lumbosacral radiculopathy, resulting in caudal nerve root enhancement on MRI [6]. 11.3.2.2 L-asparaginase Neurotoxicity

L-asparaginase is one of the drugs used to induce remission of primary disease. L-asparaginase toxicity is generally acute, presenting within one day of

b Fig. 11.32a,b Methotrexate leukoencephalopathy in an asymptomatic 1-year-old girl with acute lymphoblastic leukemia. a Axial T2-weighted image. b Axial FLAIR image. MRI shows hyperintensity prevailingly involving the periventricular white matter

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Fig. 11.33 Focal methotrexate leukoencephalopathy secondary to malfunctioning Ommaya catheter. Gd-enhanced coronal T1weighted image. Following gadolinium administration, MRI shows swollen corpus callosum with peripheral enhancement. Gadolinium enhancement also tracks along the catheter (arrowheads). (Courtesy of Mauricio Castillo, Chapel Hill, NC, U.S.)

administration [70]. L-asparaginase causes depletion of plasma proteins involved in both coagulation and fibrinolysis, resulting in either hypercoagulable states or bleeding diathesis. The vast majority of cases belong to the first category, and are represented by cortical infarcts (often multiple) (Fig. 11.34) or sinovenous thrombosis (sometimes complicated by venous infarctions). Cerebral hemorrhage is a rarer event. Finally, bilateral, symmetric non-enhancing occipital lesions, characteristic of posterior reversible encephalopathy syndrome (PRES), have been uncommonly described in the setting of L-asparaginase neurotoxicity [71]. 11.3.2.3 Cytarabine Neurotoxicity

Cytarabine is a component of the triple intrathecal therapy, used to induce remission of primary disease. Intrathecal cytarabine may result in myelopathy. Combined intrathecal drug and cranial irradiation may lead to necrotizing leukoencephalopathy. Intravenous therapy may cause a peripheral neuropathy that varies greatly in its severity. High cytarabine doses can cause dramatic side effects including seizures, cerebral dysfunction, or an acute cerebellar syndrome. In one case, MRI documented diffuse cerebral white matter abnormalities that subsequently reversed completely with normalization of neurological status [72].

Fig. 11.34 L-asparaginase neurotoxicity presenting acutely 12 hours after administration. Ten-year-old boy with acute lymphoblastic leukemia. Axial FLAIR image. MRI shows multiple hyperintense areas involving both the cortical and subcortical regions as well as the left basal ganglia, consistent with ischemic lesions. The child died a few days after this examination

11.3.2.4 Steroids

It has long been recognized [73] that long-term steroid treatment induces varying degrees of apparent cerebral atrophy, revealed by increased ventricular and sulcal size on neuroimaging studies (Fig. 11.35). There is some correlation between dosage and degree of apparent atrophy. Clinically, patients show very little, if any, clinical evidence of neurologic dysfunction. The size of CSF spaces typically returns to normal following dosage decrease or treatment discontinuation.

11.3.3 Bone Marrow Transplantation Bone marrow transplantation (BMT) has dramatically improved the chances of survival for patients harboring HLD, allowing for eradication of remaining malignant cells and suppression of the recipient’s immune system [30]. Preparation for BMT involves administration of cyclophosphamide or other cytotoxic drugs, followed by fractioned whole-body irradiation. Depending on the source of donor cells, BMT can be allogeneic or autologous. Allogeneic BMT can

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be accomplished from HLA-matched relatives, from partially HLA-matched relatives, or from unrelated HLA-matched donors. The first situation is the most favorable in terms of outcome, but is unfortunately available in only 25%–35% of cases. Autologous BMT is obtained from the patient’s own marrow; it bears less favorable perspectives in terms of prognosis, and is usually reserved for patients who either cannot obtain allogeneic BMT or in whom a first allogeneic BMT has been rejected. Early neurological sequelae after allogeneic BMT include cerebrovascular accidents, infection, and recurrence of malignancy [4]. Subacute complications basically include posterior reversible encephalopathy syndrome (PRES), a peculiar encephalopathy occurring as a complication of cyclosporin A treatment regimens. Long-term complications are associated with brain involvement from chronic graft-versus-host disease (GVHD) and with the resulting immunosuppression [4,75]. 11.3.3.1 Posterior Reversible Encephalopathy Syndrome (PRES)

One of the major concerns in patients undergoing allogeneic BMT is prevention of graft rejection and GVHD, which is aggression of immunocompetent donor T cells against host histocompatibility antigens. GVHD occurs acutely or chronically with a variety of clinical symptoms including skin rash, bowel inflammation, liver abnormalities, and lung involvement [76]. Control of GVHD is basically accomplished by administration of cyclosporin A (CsA), a potent immunosuppressant that inhibits T-cell activation and proliferation in response to alloantigens. Unfortunately, CsA is also toxic to

Fig. 11.35a,b Steroid-related cerebral pseudoatrophy. Five-year-old boy with acute lymphoblastic leukemia and a bone marrow transplant. a Axial CT image during high-dose steroid treatment show pseudo-atrophic appearance of the brain with enlarged ventricles and sulci. b Axial CT image obtained 2 months after steroid withdrawal shows normalization of ventricular and sulcal size

the CNS. CsA neurotoxicity is relatively common, occurring in 4%–29% of allogeneic BMT recipients. Toxicity occurs earlier and with increasing incidence with greater degrees of HLA mismatch, probably as a result of a greater risk for acute GVHD and vasculopathy in unrelated donor or HLA-disparate related grafts [77]. The pathogenesis of CsA neurotoxicity is related to endothelial damage with release of endothelin, prostacyclins, and thromboxane A. This “cytokine storm” results in sudden increases in systemic blood pressure, which is counterbalanced by sympathetic autoregulatory vasoconstriction. Owing to physiologically decreased sympathetic innervation, this process is less efficient in the posterior (i.e., vertebrobasilar) circulation than in the carotid arterial tree [78]. Autoregulation breakdown leads to cerebral hyperperfusion, resulting in disruption of the blood-brain barrier, fluid extravasation into the interstitium and, eventually, vasogenic edema. Remarkably, it has become increasingly clear that potentially reversible posterior encephalopathy is the end result of several pathologies involving autoregulation breakdown as their basic pathogenetic mechanism [79]. Other than CsA neurotoxicity, these include hypertensive encephalopathy, preeclampsia-eclampsia, uremic encephalopathy, hemolytic-uremic syndrome, and thrombotic thrombocytopenic purpura. This observation justifies the use of the collective term PRES [79]. Clinically, CsA neurotoxicity characteristically involves a subacute presentation of headache, seizures, decreased alertness, altered mental status, visual loss including cortical blindness, and coma, generally occurring within one month of CsA administration (range: hours to several months) [79–82].

Hemolymphoproliferative Diseases and Treatment-Related Disorders

Plasma CsA concentrations can be elevated or in the normal range (i.e., below 200 μg), indicating that the syndrome is not dose-related [81]; this could be related to long sample acquisition times or to the fact that tissue, and not plasmatic, CsA concentration is the main factor determining the onset of toxicity. Typical MRI findings of PRES (Fig. 11.36) [77, 82–85] include symmetric involvement of the posterior portions of the cerebral hemispheres with T2 and FLAIR hyperintensity and corresponding T1 hypointensity. Abnormal signal intensity is prevailingly subcortical but also involves the cortex regionally, with associated gyral swelling and sulcal effacement [77]. Contrast enhancement is usually absent, although some patients have transient enhancement of the cerebral cortex as a result of transient bloodbrain barrier disruption [86]. On diffusion-weighted images these lesions give inconspicuous low signal, whereas on apparent diffusion coefficient (ADC)

a

c

maps an increase in ADC values corresponds to areas of signal change seen on conventional MRI; such absence of restricted diffusion is consistent with vasogenic, rather than cytotoxic, edema (Fig. 11.37) [80, 86–88]. Atypical lesion distributions include the frontal lobes, basal ganglia, pons, and cerebellum (Fig. 11.38) [77, 79, 87]. Typically, there is reversibility of both clinical and imaging manifestations if CsA administration is promptly reduced or withdrawn (Fig. 11.36) [77, 81], whereas delay in the diagnosis and treatment may result in irreversible damage [86, 89]. Resolution of imaging abnormalities is faster in the subcortical white matter, whereas residual cortical abnormalities may persist longer [77]. Although CsA neurotoxic events are usually confined to fluid extravasation, more severe endothelial damage may determine red blood cell extravasation with parenchymal hemorrhage (Fig. 11.39). It has been estimated

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d

Fig. 11.36a–d Posterior reversible encephalopathy syndrome in a 7-yearold boy with acute lymphoblastic leukemia and a bone marrow transplant, presenting with seizures and visual disturbances one month after cyclosporin A administration. a Axial T1-weighted image. b Axial T2-weighted image. c,d Axial FLAIR images. At presentation (a–c), MRI show abnormal signal intensity involving the cortex and subcortical white matter in the parasagittal parietal regions bilaterally. After 2 months, axial FLAIR image (d) shows normalization of the picture

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Fig. 11.37a–c Diffusion imaging in PRES due to cyclosporin a toxicity. a Axial FLAIR image. b Axial diffusion-weighted image. c ADC map. MRI (a) shows scattered cortical-subcortical hyperintensity involving prevailingly the posterior regions. On diffusionweighted images (b), an inconspicuous signal intensity is seen. Corresponding ADC map (c) shows increased signal intensity, reflecting increased diffusion due to vasogenic edema. (Courtesy of Mauricio Castillo, Chapel Hill, NC, U.S.)

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Fig. 11.38a-c Uncommon locations of brain involvement in PRES: 14-year-old boy with aplastic anemia and a bone marrow transplantation, receiving cyclosporin. a–c Axial FLAIR images. MRI shows abnormal hyperintensities involving the pons (a) and the cortical-subcortical regions of both frontal lobes (b,c) in addition to more typical posterior involvement

that 15% of BMT patients suffer from brain hemorrhage [90]. In this case, other causes of intracranial bleeding, such as blood coagulation disorders and sinovenous thrombosis, must be ruled out. The association with typical areas of vasogenic edema involving other regions of the brain is helpful to make the diagnosis. 11.3.3.2 GVHD Vasculitis

GVHD vasculitis is a rare, acute or subacute disease process occurring with an approximate 2-year latency from allogeneic BMT in patients with chronic

GVHD [91]. Presentation is with acute or subacute neurological signs related to location of brain damage. Macroscopically, the disease is similar to other forms of vasculitis, showing cortical, nucleobasal, and truncal ischemic lesions, brain infarct, multifocal leukoencephalopathy, and parenchymal hemorrhage [74, 91]. Pathologically, there is subendothelial, intramural, perivascular lympho-monohistiocytic infiltration involving small vessels (i.e., arterioles, precapillaries, and capillaries), similar to the mononuclear perivascular infiltrates found in skin, liver, and renal biopsy specimens of chronic GVHD patients [91]. In a case we observed (Fig. 11.40),

Hemolymphoproliferative Diseases and Treatment-Related Disorders

a

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c

Fig. 11.39a–c Progressive brain hemorrhage in an 11-year-old girl with a renal transplant, clinically exhibiting cyclosporin neurotoxicity. a Axial CT scan. b Axial T1-weighted image. c Axial T2-weighted image. CT scan (A) shows acute hemorrhage in the left cerebral hemisphere, surrounded by marked edema and displacing the midline. MRI, obtained on the following day, show second hemorrhagic focus posteriorly. Additional lesions consistent with PRES are present in the contralateral hemisphere (arrows, c). MR venography (not shown) ruled out sinovenous thrombosis as a possible causal factor. The child died shortly thereafter

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Fig. 11.40a–d GVHD vasculitis in a child with erythrophagocytic lymphohistiocytosis presenting with acute neurological deficits three years after a bone marrow transplant. a–d Axial FLAIR images. At presentation, MRI (a) shows large lesion in the right parietal lobe with surrounding edema, containing a few hypointense areas suggestive of colliquation. There is mass effect with compression of the lateral ventricle and slight midline shift. The patient was put on steroid treatment. After 20 days, MRI (b) shows marked decrease in size of the lesion with residual gliosis and cavitation. The brain has a pseudo-atrophic appearance due to steroid treatment. After 2 years, during acute relapse of neurological compromise. MRI (c) shows new lesion in the posterior left frontal lobe and mild gliosis contralaterally. MRI performed after 15 days of steroid treatment (d) shows marked size decrease of the left frontal lesion, persistence of right white-matter gliosis, and a iatrogenic pseudo-atrophic appearance of the brain

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MRI showed multifocal areas of leukoencephalopathy or cortical ischemia. Although temporary resolution was obtained with cortisone administration, reactivation of disease occurred in different locations; eradication of the process was eventually obtained by means of second autologous BMT. Brain involvement by GVHD should be suspected in BMT patients in whom encephalopathy is seen in the presence of systemic GVHD and in the absence of other causes of CNS dysfunction [74].

11.4 Conclusions Neurological complications of HLD encompass a wide spectrum of disease that can be directly or indirectly related to primary malignancy, or represent side effects of treatment. Most affected patients face a significant risk for developing these complications at some point in their clinical history. Knowledge of basic disease processes has greatly increased in the past few years. MRI plays an important, often pivotal role in the detection of CNS abnormalities [92]. Therefore, familiarity with these conditions and their imaging appearances is crucial for a correct diagnosis. Close collaboration between the clinician and the neuroradiologist is required in order to successfully integrate the clinical, laboratory, and imaging data, so that patients may receive the best possible treatment and enjoy better prognoses.

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Ferrini P. Fatal herpesvirus 6 encephalitis after unrelated bone marrow transplant. Bone Marrow Transplant 1998; 22:285–288. 45. Tiacci E, Luppi M, Barozzi P, Gurdo G, Tabilio A, Ballanti S, Torelli G, Aversa F. Fatal herpesvirus-6 encephalitis in a recipient of a T-cell-depleted peripheral blood stem cell transplant from a 3-loci mismatched related donor. Haematologica 2000; 85:94–97. 46. Ball WS Jr, Prenger EC, Ballard ET. Neurotoxicity of radio/ chemotherapy in children: pathologic and MR correlation. AJNR Am J Neuroradiol 1992; 13:761–776. 47. Sheline GE, Wara WM, Smith V. Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phys 1980; 6:1215– 1228. 48. Rastogi H, Bazan III C, Da Costa Leite C, Jinkins JR. The posttherapeutic cranium. In: Jinkins JR (ed) Posttherapeutic Diagnostic Imaging. New York: Lippincott-Raven, 1997:3–36. 49. Dowling C, Bollen AW, Noworolski SM, McDermott MW, Barbaro NM, Day MR, Henry RG, Chang SM, Dillon WP, Nelson SJ, Vigneron DB. Preoperative proton MR spectroscopic imaging of brain tumors: correlation with histopathologic analysis of resection specimens. AJNR Am J Neuroradiol 2001; 22:604–612. 50. Kinoshita K, Tada E, Matsumoto K, Asari S, Ohmoto T, Itoh T. Proton MR spectroscopy of delayed cerebral radiation in monkeys and humans after brachytherapy. AJNR Am J Neuroradiol 1997; 18:1753–1761. 51. Schlemmer HP, Bachert P, Henze M, Buslei R, Herfarth KK, Debus J, van Kaick G. Differentiation of radiation necrosis from tumor progression using proton magnetic resonance spectroscopy. Neuroradiology 2002; 44:216–222. 52. Suzuki S, Nishio S, Takata K, Morioka T, Fukui M. Radiationinduced brain calcification: paradoxical high signal intensity in T1-weighted MR images. Acta Neurochir (Wien) 2000; 142:801–804. 53. Larson JJ, Ball WS, Bove KE, Crone KR, Tew JM Jr. Formation of intracerebral cavernous malformations after radiation treatment for central nervous system neoplasia in children. J Neurosurg 1998; 88:51–56. 54. Novelli PM, Reigel DH, Langham Gleason P, Yunis E. Multiple cavernous angiomas after high-dose whole-brain radiation therapy. Pediatr Neurosurg 1997; 26:322–325. 55. Pozzati E, Giangaspero F, Marliani F, Acciarri N. Occult cerebrovascular malformations after irradiation. Neurosurgery 1996; 39:677–682. 56. Detwiler PW, Porter RW, Zabramski JM, Spetzler RF. Radiation-induced cavernous malformation (letter). J Neurosurg 1998; 89:167–168. 57. Christie D, Leiper AD, Chessells JM, Vargha-Khadem F. Intellectual performance after presymptomatic cranial radiotherapy for leukaemia: effects of age and sex. Arch Dis Child 1995; 73:136–140. 58. Brown RT, Madan-Swain A, Walco GA, Cherrick I, Ievers CE, Conte PM, Vega R, Bell B, Lauer SJ. Cognitive and academic late effects among children previously treated for acute lymphocytic leukemia receiving chemotherapy as CNS prophylaxis. J Pediatr Psychol 1998; 23:333–340. 59. Kramer JH, Norman D, Brant-Zawadzki M, Ablin A, Moore IM. Absence of white matter changes on magnetic resonance imaging in children treated with CNS prophylaxis therapy for leukemia. Cancer 1988; 61:928–930. 60. Iuvone L, Mariotti P, Colosimo C, Guzzetta F, Ruggiero A, Riccardi R. Long-term cognitive outcome, brain computed

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long-term survivors of allogeneic bone marrow transplantation. Ann Neurol 1998; 43:627–633. 76. Ferrara JL, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991; 324:667–674. 77. Zimmer WE, Hourihane JM, Wang HZ, Schriber JR. The effect of human leukocyte antigen disparity on cyclosporine neurotoxicity after allogeneic bone marrow transplantation. AJNR Am J Neuroradiol 1998; 19:601–608. 78. Beausang-Linder M, Bill A. Cerebral circulation in acute arterial hypertension - protective effects of sympathetic nervous activity. Acta Physiol Scand 1981; 111:193–199. 79. Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, Pessin MS, Lamy C, Mas JL, Caplan LR. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996; 334:494–500. 80. Coley SC, Porter DA, Calamante F, Chong WK, Connelly A. Quantitative MR diffusion mapping and cyclosporine-induced neurotoxicity. AJNR Am J Neuroradiol 1999; 20:1507–1510. 81. Gleeson JG, duPlessis AJ, Barnes PD, Riviello JJ Jr. Cyclosporin A acute encephalopathy and seizure syndrome in childhood: clinical features and risk of seizure recurrence. J Child Neurol 1998; 13:336–344. 82. Pavlakis SG, Frank Y, Chusid R. Hypertensive encephalopathy, reversible occipitoparietal encephalopathy, or reversible posterior leukoencephalopathy: three names for an old syndrome. J Child Neurol 1999; 14:277–281. 83. Pace MT, Slovis TL, Kelly JK, Abella SD. Cyclosporin A toxicity: MRI appearance of the brain. Pediatr Radiol 1995; 25:180–183. 84. Schwartz RB, Bravo SM, Klufas RA, Hsu L, Barnes PD, Robson CD, Antin JH. Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy: CT and MR findings in 16 cases. AJR Am J Roentgenol 1995; 165:627–631. 85. Truwit CL, Denaro CP, Lake JR, DeMarco T. MR imaging of reversible cyclosporin A-induced neurotoxicity. AJNR Am J Neuroradiol 1991; 12:651–659. 86. Dillon WP, Rowley H. The reversible posterior cerebral edema syndrome. AJNR Am J Neuroradiol 1998; 19:591. 87. Debaere C, Stadnik T, De Maeseneer M, Osteaux M. Diffusion-weighted MRI in cyclosporin A neurotoxicity for the classification of cerebral edema. Eur Radiol 1999; 9:1916– 1918. 88. Schaefer PW, Buonanno FS, Gonzalez RG, Schwamm LH. Diffusion-weighted imaging discriminates between cytotoxic and vasogenic edema in a patient with eclampsia. Stroke 1997; 28:1082–1085. 89. Antunes NL, Small TN, George D, Boulad F, Lis E. Posterior leukoencephalopathy syndrome may not be reversible. Pediatr Neurol 1999; 20:241–243. 90. Teksam M, Casey SO, Michel E, Truwit CL. Subarachnoid hemorrhage associated with cyclosporine A neurotoxicity in a bone-marrow transplant recipient. Neuroradiology 2001; 43:242–245. 91. Padovan CS, Bise K, Hahn J, Sostak P, Holler E, Kolb HJ, Straube A. Angiitis of the central nervous system after allogeneic bone marrow transplantation? Stroke 1999; 30:1651– 1656. 92. Rossi A, Biancheri R, Lanino E, Faraci M, Haupt R, Micalizzi C, Tortori-Donati P. Neuroradiology of pediatric hemolymphoproliferative disease. Riv Neuroradiol 2003; 16:221–250.

Infectious Diseases

12 Infectious Diseases Paolo Tortori-Donati, Andrea Rossi, and Roberta Biancheri

CONTENTS 12.1

Introduction 470

12.2 12.2.1 12.2.2 12.2.2.1 12.2.2.2 12.2.2.3 12.2.2.4 12.2.3 12.2.3.1 12.2.3.2 12.2.3.3 12.2.4 12.2.4.1 12.2.4.2 12.2.4.3 12.2.5 12.2.5.1 12.2.5.2 12.2.5.3 12.2.6 12.2.6.1 12.2.6.2 12.2.6.3 12.2.7 12.2.7.1 12.2.7.2 12.2.7.3 12.2.8

Intracranial Congenital Infections 470 Background 470 Cytomegalovirus Infection 471 Clinical Findings 471 Neuropathological Findings 472 Imaging Studies 472 Differential Diagnosis 476 Toxoplasmosis 478 Clinical Findings 478 Neuropathological Findings 478 Imaging Studies 478 Congenital Rubella Infection 480 Clinical Findings 481 Neuropathological Findings 481 Imaging Studies 481 Neonatal Herpes Simplex Virus Infection 482 Clinical Findings 482 Neuropathological Findings 482 Imaging Studies 482 Congenital Human Immunodeficiency Virus (HIV) Infection 483 Clinical Findings 483 Neuropathological Findings 483 Imaging Studies 484 Congenital Syphilis 485 Clinical Findings 485 Neuropathological Findings 486 Imaging Studies 486 Congenital Varicella 486

12.3 12.3.1 12.3.1.1 12.3.1.2 12.3.1.3 12.3.2 12.3.2.1 12.3.2.2 12.3.3 12.3.3.1 12.3.3.2 12.3.3.3 12.3.3.4 12.3.3.5

Bacterial Meningitis 486 Background 486 Neonatal Bacterial Leptomeningitis 486 Acute Bacterial Meningitis in Children 487 Recurrent Bacterial Meningitides 487 Neuropathological Findings 487 Acute Changes 488 Chronic Changes 489 Imaging Studies in Bacterial Meningitis 489 Choroid Plexitis/Ventriculitis 489 Arachnoiditis 490 Vasculitis 490 Cerebral Edema 494 Complications of Meningitis 494

12.4 Intracranial Suppuration 498 12.4.1 Cerebritis and Brain Abscess 498 12.4.1.1 Neuropathological Findings 498

12.4.1.2 Imaging Studies 499 12.4.1.3 Empyemas 504 12.4.1.4 Toxin-induced Neurological Disease 505 12.5 12.5.1 12.5.1.1 12.5.1.2 12.5.1.3 12.5.1.4 12.5.2 12.5.2.1 12.5.2.2

Other Intracranial Bacterial Infections 505 Central Nervous System Tuberculosis 505 Background 505 Tuberculous Meningitis 506 Parenchymal Tuberculomas 508 Tuberculous Abscess 509 Lyme Disease (Neuroborreliosis) 510 Background 510 Imaging Studies 511

12.6 12.6.1 12.6.1.1 12.6.1.2 12.6.1.3 12.6.1.4 12.6.1.5 12.6.1.6 12.6.1.7 12.6.1.8 12.6.2 12.6.2.1 12.6.2.2 12.6.2.3 12.6.2.4

Intracranial Viral Infections 512 Acute Encephalitides 513 Herpes Simplex Virus Encephalitis 513 Human Herpesvirus-6 Infection 515 Acquired HIV Infection 516 Measles 516 Chickenpox 516 Influenza Virus Infection 517 Epstein-Barr Virus (EBV) Infection 518 Mycoplasma Pneumoniae Infection 519 Subacute and Chronic Encephalitides 519 Subacute Sclerosing Panencephalitis 519 Brainstem Encephalitis 522 Rasmussen’s Encephalitis 522 Reye Syndrome 524

12.7 12.7.1 12.7.2 12.7.3 12.7.4 12.7.5

Fungal Infections 525 Cryptococcus 525 Candida albicans 526 Aspergillus 527 Coccidioidomycosis 527 Nocardia 527

12.8 12.8.1 12.8.1.1 12.8.1.2 12.8.1.3 12.8.2 12.8.2.1 12.8.2.2 12.8.3

Parasitic Infections 527 Cysticercosis 527 Clinical Findings 527 Neuropathological Findings 527 Imaging Studies 528 Echinococcosis 531 Echinococcus granulosus 531 Alveolar Echinococcosis 532 Toxocaral Disease 532

12.9 12.9.1 12.9.2 12.9.3

Sarcoidosis 532 Clinical Findings 533 Neuropathological Findings Imaging Studies 533 References 534

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12.1 Introduction

12.2 Intracranial Congenital Infections

The central nervous system (CNS) and its covering membranes may be involved in a variety of infectious processes, either during intrauterine development or in postnatal life [1]. Although the CNS is normally protected by the meninges and blood-brain barrier (BBB), it is more vulnerable to infectious agents than any other tissue, due to the lack of a true lymphatic system, the little resistance to infection offered by the subarachnoid space, and the fact that CSF facilitates infection spread over the brain and spinal cord and into the ventricles [2]. Furthermore, capillaries are absent in the subarachnoid space itself and there are tight junctions between intra- and extracranial venous system (i.e., without valves). Early recognition of CNS infection in the pediatric age group is extremely important due to the great potential for permanent damage in survivors. Magnetic resonance imaging (MRI) has greatly facilitated early diagnosis, and is today the gold standard in imaging of CNS infectious disorders.

12.2.1 Background

Terminology

Cerebritis and myelitis are comparable terms for focal or localized inflammation of the cerebrum and spinal cord, respectively. Encephalitis, on the other hand, refers to diffuse inflammation throughout the cerebral hemispheres with or without involvement of the cerebellum and brainstem; it is distinguished from cerebritis in that encephalitis is not focal. Meningitis may involve either the dura (pachymeningitis) or the leptomeninges (leptomeningitis). Pachymeningitis usually manifests as epidural or subdural empyemas, and occurs much less frequently than leptomeningitis. In leptomeningitis, the inflammatory exudate is usually confined by the pial and arachnoidal membranes. Occasionally, adjacent nervous tissues become inflamed, resulting in meningocerebritis (localized) or meningoencephalitis (diffuse). Abscess refers to a suppurative inflammatory process with central liquefactive necrosis encased by granulation tissue that varies in thickness and integrity. An abscess is the end-stage in the natural history of an untreated cerebritis [3].

Intracranial congenital infections can be transmitted during intrauterine life by transplacental passage (i.e., fetal infection) or during passage through an infected birth canal (i.e., parturitional infection). Causal agents include a host of viruses, protozoa, spirochetes, bacteria, and fungi. Postnatal infection may occur as well. The main infections are often designated by the acronym TORCH, where T stands for toxoplasmosis, O for others (such as syphilis and HIV), R for rubella, C for cytomegalovirus, and H for herpes simplex virus (Table 12.1). The fetal or neonatal stage of development at the time of infection, cellular susceptibility to infecting agent, and host immune response are important factors in determining the effects of CNS infections [4]. Important concepts are that gestational age at the time of the insult is more important than the nature of the agent [5], and that fetuses and neonates mount a different biological response to injury than older children or adults, basically characterized by absent or less marked inflammatory reaction. In general, infections occurring in the first two weeks of intrauterine life lead to abortion. Insults occurring during the first 16 to 20 weeks of gestation, i.e., while the CNS is actively developing, will result in congenital brain malformations, basically involving aberrations of neuronal proliferation and migration [1]. One should remember that astroglial reaction is absent in the immature brain, and that the capacity of astrocytes to react with proliferation and hypertrophy develops after the first half of gestation, with reactive gliosis becoming detectable at around 20 weeks of gestation [2]. Microglia, forming a network of antigen-presenting cells in the CNS with a primary function in immune surveillance, are well differentiated after 35 gestational weeks [2]. Therefore, classic destructive patterns, including varying degrees of inflammation and tissue injury, are due to infections occurring late during the course of pregnancy, generally in the third trimester. However, destructive effects may be difficult to separate from teratogenic effects, because destructive processes often cause coincident tissue loss and subsequent anomalous development [1]. It should be underlined that the conventional means of identifying intrauterine viral infection (i.e., neonatal virus isolation or antibody response) may not be adequate to detect an infection occurring during early brain development. In fact, the fetus becomes capable of mounting a humoral antibody response only at approximately 20 weeks of gestation [6].

Infectious Diseases Table 12.1. Neuropathological findings of intracranial congenital infections Organism

CNS inflammation

Cerebral calcifications

Anomalies of cortical development

Other findings

CMV

Meningoencephalitis (predilection for periventricular region of lateral ventricles)

Periventricular (typical)

Polymicrogyria Lissencephaly Pachygyria Schizencephaly Neuronal heterotopias Microcephaly

Porencephaly Hydranencephaly Hydrocephalus Focal subcortical cysts Impaired myelination Cerebellar hypoplasia

Cortical dysplasia (possible)

Hydrocephalus Porencephaly Hydranencephaly

Diffuse

Toxoplasma gondii

Meningoencephalitis (multifocal necrotizing granulomas) Perivascular infiltrates Multifocal and diffuse necrosis of parenchyma

Diffuse

Rubella

Meningoencephalitis (necrosis of brain parenchyma)

Diffuse

Herpes simplex

Meningoencephalitis (multifocal parenchymal necrosis, occasionally hemorrhagic) Cowdry type A intranuclear inclusions

Periventricular Cerebral cortex

HIV

Meningoencephalitis (multinucleated giant cells)

Basal ganglia White matter Cerebral cortex

Treponema pallidum

Acute or subacute meningitis (mononuclear inflammation) Chronic meningitis, especially in basal meninges

Varicella

Meningoencephalitis

Vasculopathy with focal ischemic necrosis Delayed myelination Neuronal migration disorder (reported in some cases of fetally acquired HSV-1)

Brain swelling Multicystic encephalomalacia Hydranencephaly

Cerebral atrophy (neuronal and myelin loss) Spinal cord myelin loss CNS lymphoma, opportunistic infection, stroke (ischemic and hemorrhagic) Dilatative arteriopathy Vasculitis with cerebral infarction Hydrocephalus Secondary chronic arachnoiditis

yes

Polymicrogyria and focal lissencephaly

Ventricular dilatation Porencephalic cysts Vasulitis with ischemic lesions

Modified from ref. #1,2

12.2.2 Cytomegalovirus Infection Congenital cytomegalovirus (CMV) infection occurs in approximately 1.0%–1.4% of births in the United States [1, 7]. Congenital infection occurs in utero by transplacental passage of the virus that is transmitted to the fetus during a primary (more commonly) or a recurrent maternal infection. Around 30%– 40% of infected mothers pass the infection to their fetus: however, only 19% of infected infants become symptomatic. CNS involvement is more common if fetal infection occurs during the first or second trimester; however, it has been demonstrated also for infection occurring in the third trimester. Partu-

ritional and early postnatal infections may occur during passage through an infected birth canal or through breast milk or blood transfusion during the first 4–8 weeks of life. They usually do not cause neurological injury [1]. 12.2.2.1 Clinical Findings

Most congenitally infected children are asymptomatic at birth [1]. Only around 10% of cases are symptomatic and may show intrauterine growth retardation, hepatosplenomegaly, petechial rash, chorioretinitis, and neurological manifestations (such as seizures, microcephaly, and meningoencephalitis) [1].

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About 95% of infants with neonatal neurological syndrome will show major neurological sequelae, such as mental retardation, seizures, motor deficits, and deafness [1]. Around 16% of cases with systemic neonatal signs, but no neurological manifestations, will develop major neurological signs during follow-up. Although the clinical course is usually static, evidence for progressive disease has been demonstrated in some cases [8]. About 10% to 15% of infected infants who are asymptomatic at birth will develop neurological or developmental abnormalities in the first year of life [1, 7, 9]. Therefore, the possibility of late intrauterine CMV infection should be considered in any patient showing neurological features, such as developmental delay, microcephaly, ataxia, seizures, and hearing loss, in association with white matter involvement and cerebral calcification on imaging, even if the neonatal period was unremarkable [1]. A clinical syndrome characterized by microcephaly, deafness, and behavioral abnormalities has been described in some children infected during the third trimester of pregnancy [10]. Detection of virus in the neonatal urine is the most specific and sensitive test for diagnosing congenital CMV infection [1]. Polymerase chain reaction (PCR) assay may detect the virus in CSF and serum, although the sensitivity and specificity remain to be established [11, 12].

12.2.2.2 Neuropathological Findings

Both inflammatory/destructive and teratogenic effects occur in congenital CMV infection [1] (Table 12.1). Meningoencephalitis is characterized by perivascular infiltrates with inflammatory cells, necrosis

of brain parenchyma (mainly in the periventricular region resulting in the characteristic periventricular calcifications), reactive microglial and astroglial proliferation, and evidence of enlarged neuronal and glial cells with intranuclear inclusions [1]. Severe necrotizing lesions may cause porencephalic cysts or hydranencephaly [1, 2]. Microcephaly due to either encephaloclastic effects or to a disturbance of cell proliferation may be evident at birth or appear later in infancy. Anomalies of cortical development related to the teratogenic potential of CMV include cerebral and/or cerebellar polymicrogyria, pachygyria, lissencephaly, schizencephaly, and gray matter heterotopia [7, 13–18]. A relationship between the timing of cell formation in the germinal zone during gestation and the type and extent of gyral abnormalities has been suggested [7, 18] (Table 12.2). It has been hypothesized that CMV might have a special affinity for the immature, rapidly growing cells within the germinal zone. Thus, the loss of periventricular brain tissue and the abnormalities of cerebral cortex would be the result of injury to the germinal zone itself [7]. However, some debate still exists on this issue, particularly because no neuropathological differences have been found between cortical dysplasia in CMV-infected patients and polymicrogyria from other causes. An alternative hypothesis proposes that the brain injury might be the result of ischemia or chronic perfusion insufficiency [7, 19]. 12.2.2.3 Imaging Studies

Congenital CMV infection causes different neuroradiologic patterns, depending on the timing of infection during gestation (Table 12.2) [7]. However, it is

Table 12.2. Relationship between timing of intrauterine CMV infection and imaging findings Presumed timing of infection

Early infection (before 16-18 weeks of gestation / first half of the second trimester)

Mid infection [18 to 24 weeks of gestation /middle of the second trimester]

Late infection (third trimester / early postnatal period)

Cortical gyral pattern

Lissencephaly (smooth, agyric and thin cortex)

Symmetrical frontotemporal dysplasia Polymicrogyria (typically) Schizencephaly (rarely)

Normal

Cerebellum

Hypoplastic

Mild hypoplasia

Normal

White matter

Lack of formation or destruc- Impaired myelination tion of the white matter

Periventricular damage

Lateral ventricles

Marked ventriculomegaly

Less evident dilatation

Mild ventricular prominence

Calcifications

Periventricular (significant)

Periventricular (possible)

Scattered periventricular

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not always easy to differentiate between early and mid-gestational infection, and some degree of overlapping may occur. • Infections occurring earlier during pregnancy (Fig. 12.1) are characterized by lissencephaly, hypoplastic cerebellum, abnormal myelination, marked ventriculomegaly, and diffuse periventricular calcifications. • Infections occurring in the middle of gestation (Figs. 12.2, 12.3) cause polymicrogyria, impaired myelination, less evident ventricular enlargement, and less prominent cerebellar hypoplasia. • Late congenital infections may determine symmetrical lobar white matter involvement, with or without calcifications. Because neuronal migration and cortical organization are already concluded, no significant cortical abnormalities are found [10,15,22] (Fig. 12.4). White matter involvement may appear either as reduction of its volume due to lack of formation (Fig. 12.5), or as areas of T2 prolongation related to

a

d

b

Fig. 12.1 Congenital CMV infection in a 2-month-old boy (presumed early pregnancy infection). Axial CT scan. The lateral ventricles are enlarged, prevailingly in the posterior portions. There are diffuse periventricular calcifications and some calcified foci in the nucleocapsular regions. The cerebral cortex is diffusely lissencephalic

c

Fig. 12.2a–d Congenital CMV infection in an 8-month-old girl (presumed mid-pregnancy infection). a Axial CT scan. b,d Axial T2-weighted images. c Axial FLAIR image. On CT scan (a), enlarged lateral ventricles and gross periventricular calcifications are seen. MRI shows polymicrogyric features involving almost the whole cerebral cortex and diffuse signal changes of the white matter that appears markedly hyperintense, due to delayed myelination (b,c). A large cystic cavity is clearly recognizable in the left frontal region (asterisk, c). The cerebellum is hypoplastic and shows diffuse cortical dysplasia (d)

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a

b Fig. 12.3a,b Congenital CMV infection in a 15-month-old girl (presumed mid-pregnancy infection). a Axial T2-weighted image. b Sagittal STIR image. The left cerebral hemisphere is globally hypoplastic, with only a minimal sparing of the occipital region, and shows diffuse polymicrogyria. Diffuse signal changes are also recognizable in the white matter of the contralateral hemisphere

Fig. 12.4 Congenital CMV infection in a 22-month-old girl (presumed late pregnancy infection). Axial FLAIR image. Gross hyperintense areas are evident in the parietal white matter bilaterally. Small hyperintense areas are recognizable in the frontal subcortical regions

impaired myelination and/or destruction (Figs. 12.2– 12.4), or again as cystic formations (Fig. 12.2) (see below). Therefore, white matter involvement may be found in infants infected at any gestational time [5], and the type of abnormality grossly depends on the timing of infection during gestation. In particular, the association between delayed myelination and a thin agyric cortex, as well as the presence of cerebellar hypoplasia associated with cortical dysplasia and diminished white matter, should suggest the diagnosis of congenital CMV infection in any child with developmental delay or seizures [7]. Hippocampal dysplasia (Fig. 12.6), characterized by vertical orientation of the hippocampus, has been reported as the result of an arrest of hippocampal development due to the infection, and should perhaps be added to the spectrum of the described cortical gyral abnormalities [7]. Intracranial calcifications appear as high density spots on CT (Figs. 12.1, 12.2, 12.5, 12.7), and may be seen as T1 bright, T2 dark foci on MRI in neonates and young infants [5]. Although they are typically located in the periventricular regions, probably due to the particular affinity of CMV for the germinal zone, other possible locations include the cerebral cortex, white matter, basal ganglia, cerebellum, brain stem, and spinal cord [20]. Though usually widespread, even a single calcified spot may be sufficient to suggest the diagnosis. We have seen a case of holoprosencephaly in which widespread calcifications indicated an associated CMV infection (Fig. 12.8).

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b

a

c

d

Fig. 12.5a–d Congenital CMV infection in a 4-month-old boy. a Coronal T2-weighted image. b Sagittal T1-weighted image. c,d Axial CT scans. The white matter of both cerebral hemispheres is globally absent, and the lateral ventricles are enlarged (a). The corpus callosum is markedly hypoplastic and not easily recognizable (arrowheads, b). The midbrain, pons, and cerebellum are also hypoplastic, and there is a concurrent mega cisterna magna (b). CT scan shows diffuse calcification at the level of the margins of the ventricles and into the parenchyma (c), as well as in the medulla and cerebellar hemispheres (d)

Fig. 12.6 Hippocampal dysplasia in a child with congenital CMV infection (presumed mid-pregnancy infection). Coronal T2-weighted image. Diffuse cortical dysplasia and verticalization of both hippocampi (arrowheads) is associated with signal changes in the temporal white matter bilaterally (asterisk)

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c

a

b

d

Fig. 12.7a–d Different imaging appearance of calcification in different infants with congenital CMV infection. a–d Axial CT scans. a Isolated calcified focus in the left parietal region. b Diffuse periventricular and cortical microcalcification. c Gross calcified foci scattered in the periventricular regions. d Gross calcified confluent foci in the periventricular regions and in the frontal subcortical white matter bilaterally

Subependymal periventricular cystic lesions (Fig. 12.2) may be seen adjacent to the lateral ventricles. They result from the necrotizing inflammatory process. Areas isointense with CSF on both T1- and T2-weighted images may also involve the anterior temporal lobes [4, 7, 21]. Encephaloclastic lesions, such as hydranencephaly or porencephaly, may be the end-result of severe, diffuse destruction of the brain parenchyma lesions [20] (Fig. 12.9). 12.2.2.4 Differential Diagnosis

Fig. 12.8 Holoprosencephaly in a child with congenital CMV infection. Axial CT scan. There is absent cleavage of the anterior brain associated with widespread, coarse calcified spots

The MRI appearance of cortical dysplasia seen in congenital CMV infection should be differentiated from classic lissencephaly and cobblestone complex (Table 12.3). Differentiation between microcephaly due to congenital CMV infection and primitive microcephaly may be difficult on imaging only, in the absence of

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calcification [7]. On imaging, late CMV intrauterine infection, characterized by patchy to confluent abnormal myelination [10, 22] may strongly resemble a metabolic disorder. Therefore, metabolic causes should be considered in the differential diagnosis.

a

Among these, Aicardi-Goutières syndrome is characterized by the association of leukoencephalopathy and calcifications (Fig. 12.10). CSF analysis, revealing the increased lymphocyte count typical of AicardiGoutières syndrome, will clear the view.

b

Fig. 12.9a,b Hydranencephaly in a 2month-old child with congenital CMV infection. a,b CT scans. CT scan shows absence of most of the cerebrum. Small calcified foci (arrowheads, a,b) are recognizable within the residual portions of the antero-inferior frontal lobes. Cortical remnants located in the parasagittal and temporo-occipital regions are visible. Note that also the thalami, albeit atrophic, are identified (arrows, a)

Table 12.3. Differential diagnosis between lissencephaly due to congenital CMV infection, classic lissencephaly, and cobblestone complex Lissencephaly due to early congenital CMV infection

Classic lissencephaly

Cobblestone complex

Thin agyric cortex

Agyric cortex with a thick layer of neurons lying central to a sparse cell layer

Thickening of the cerebral cortex with irregular gyral patterns

Impaired myelination

Normal myelination

Delayed myelination

Cerebellar hypoplasia

Usually normal cerebellum

Cerebellar abnormalities Bundles of dysplastic neurons plunging into the white matter at the gray-white matter junction

a

b

Fig. 12.10a,b Aicardi-Goutières syndrome. a Axial CT scan. b Axial protondensity weighted image. Diffuse calcified foci are present in the basal ganglia, in the periventricular regions, and in the cortico-subcortical regions of the left temporal and right occipital lobes (a). MRI shows diffuse leukoencephalopathy (b). Cortical abnormalities are absent

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12.2.3 Toxoplasmosis Congenital toxoplasmosis is acquired in utero by transplacental passage of Toxoplasma gondii, and its likelihood and severity are closely related to the time of maternal infection [1]. Although fetal infection is more likely later in pregnancy, it is more severe in cases of early infection, and the majority of cases infected in the first trimester shows severe disease with eye and CNS involvement [1]. An unusual susceptibility to severe infection has been related to inadequate cellular defenses [23, 24]. Toxoplasmosis is the second most common TORCH infection after CMV. It is differentiated from the latter basically because cortical malformations are much rarer and cerebral calcifications more peripheral. 12.2.3.1 Clinical Findings

Infants who are symptomatic at birth may show predominantly neurological or systemic manifestations. About two-thirds of infected cases are neurologically symptomatic in the neonatal period with seizures, meningoencephalitis, diffuse intracranial calcifications, hydrocephalus, or, rarely, microcephaly [1]. Actually, head size may help in differentiating between neonates with congenital CMV and those with congenital toxoplasmosis, as the first group is more commonly microcephalic, while the latter is more likely to have hydrocephalus [25]. Bilateral chorioretinitis is present in 90% of these cases. Microphthalmos may be present as well [26]. Patients presenting with predominantly systemic symptoms show hepatosplenomegaly, hyperbilirubinemia, and anemia. Chorioretinitis is evident in two-thirds of these cases. The majority of cases with symptomatic congenital toxoplasmosis also show severe neurological deficits [1]. Asymptomatic congenitally infected children show a relatively high frequency of chorioretinitis and cognitive impairment (ranging from mild to severe mental retardation). 12.2.3.2 Neuropathological Findings

The main neuropathological features of congenital toxoplasmosis are related to tissue inflammation and destruction (Table 12.1). Teratogenic effects causing malformations of cortical development may occur [2], although they are not as typical as in congenital CMV infection [1].

Meningoencephalitis is characterized by multifocal, necrotizing, granulomatous lesions. The main features include focal inflammatory lesions in the meninges, perivascular infiltrates with inflammatory cells, multifocal and diffuse necrosis of the nervous tissues (involving the cerebrum, brain stem, and spinal cord) often associated with widespread calcifications, reactive microglial and astroglial proliferation, and granulomas containing large epithelioid cells and intracellular Toxoplasma organisms [1]. Hydrocephalus frequently occurs due to aqueductal obstruction, related to ependymal inflammation and intraventricular dissemination of Toxoplasma. This also causes immunological reaction resulting in thrombosis and periventricular infarction [1]. Severe diffuse, destructive lesions may cause porencephalic cysts or hydranencephaly [27, 28]. White matter involvement is always prevalent in the temporo-parieto-occipital regions, with marked ex-vacuo dilatation of the atrial portions of the ventricular system. Microcephaly occurs in approximately 15% of cases, and is related to multifocal necrotizing encephalitis, especially of the cerebral hemispheres [1]. Focal areas of destruction of gray and white matter, secondary to vascular thrombosis, may occur [2]. 12.2.3.3 Imaging Studies

The spectrum of severity of the brain involvement in congenital toxoplasmosis ranges from mild cases (Fig. 12.11), with only few periventricular calcifications and mild atrophy, to severe cases, showing marked, diffuse cerebral calcifications and destructive parenchymal lesions (Fig. 12.12) [5]. The cerebral cortex, basal ganglia, and white matter may be involved [2]. Imaging findings show a gross correlation with the period of gestation at which maternal infection occurs (Table 12.4). Calcifications are diffuse and involve the basal ganglia, thalami, periventricular parenchyma, and cerebral cortex (Fig. 12.13) [4, 5, 20]. Generally, albeit not invariably, calcifications tend to be more peripheral than in CMV infection, in which they are more typically periventricular. It has been reported that brain calcifications may resolve after antibiotic therapy [29]. Ventricular dilatation of variable severity and areas of porencephaly may be seen [5]. There is typically a disproportionate dilatation of the posterior portions of the lateral ventricles with respect to the frontal horns, secondary to prevalent white matter destruction in these regions (Figs. 12.12, 12.14). Hydrocephalus secondary to aqueductal stenosis may also

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a

d

a

b

c

Fig. 12.11a–d Congenital toxoplasmosis infection. a,b Prenatal MRI (performed at the 36th week of gestation), axial T2-weighted images. c Axial CT scan during neonatal period. d Axial STIR image obtained at 11 months. Prenatal MRI shows enlargement of the posterior portions of both the lateral ventricles (asterisks, a) as well as a small cystic lesions within the cerebral parenchyma (arrowheads, a,b). Neonatal CT scan shows a small calcification in the right para-atrial region (arrow, c). On postnatal MRI, small cystic foci, already shown on prenatal MRI, are well recognizable (arrows, d)

b Fig. 12.12a,b Congenital toxoplasmosis infection in a 7-month-old boy. a,b Axial CT scans. Enlargement of the lateral ventricles, prevailingly involving the posterior portions, is secondary to parenchymal destruction. Linear calcifications within the thalami and punctuate calcifications in the right frontal lobe are seen (arrows, a). A huge fluid periencephalic collection located in the right temporo-occipital region is evident (asterisks, a). The same child shows microphthalmos and diffuse ocular calcifications bilaterally

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P. Tortori-Donati, A. Rossi, and R. Biancheri Table 12.4. Relationship between timing of intrauterine toxoplasma infection and imaging findings Presumed timing of intrauterine infection

Imaging findings

Before 20 weeks of gestation

Severe ventricular dilatation Areas of porencephaly Extensive calcifications (particularly in the basal ganglia)

Between 20-30 weeks of gestation

Ventricular dilatation Multiple periventricular calcifications

After 30th week of gestation

Small periventricular and intracerebral calcifications Rare ventricular dilatation

Fig. 12.14 Congenital toxoplasmosis infection in a 7-day-old girl. Axial T2-weighted image. Marked enlargement of the lateral ventricles, mainly in the posterior portions. Areas of cortical dysplasia (black arrow) and cystic foci (asterisks) showing peripheral calcification (white arrows) are recognizable. The cerebral mantle is discontinued in the right temporo-parietal region (arrowheads)

a

be found [4, 20]. Multicystic encephalomalacia and hydranencephaly may occur in severe cases [20, 21]. Although, unlike with CMV, malformations of cortical development are not a typical feature of congenital toxoplasmosis [5], cortical dysplasia has been described [20] (Fig. 12.14).

12.2.4 Congenital Rubella Infection

b Fig. 12.13a,b Different imaging appearance of calcification in different children with congenital toxoplasmosis infection. a,b Axial CT scans. a Multiple intraparenchymal punctuate calcifications are the most typical appearance of congenital toxoplasmosis infection. b Periventricular calcification, though more frequently seen in congenital CMV infection, may also be present in cases of congenital toxoplasmosis infection.

Congenital rubella, caused by transplacental passage of the virus, is extremely rare after the widespread use of vaccination. The earlier in pregnancy the maternal infection occurs, the greater the frequency and the severity of the congenital infection [1].

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12.2.4.1 Clinical Findings

Although two-thirds of infected infants are asymptomatic at birth, the majority develops symptoms in the first years of life, due to the prolonged viral replication [1]. Symptomatic neonates show intrauterine growth retardation, hepatosplenomegaly, cardiovascular defects, eye and hearing problems, and signs of meningoencephalitis. Lethargy and hypotonia, subsequently followed by irritability, are the most common initial neurological features. Seizures appear in 10%–15% of cases [1]. The majority of children symptomatic at birth show neurological sequelae that usually are severe. 12.2.4.2 Neuropathological Findings

Meningoencephalitis is characterized by inflammatory cells in the meninges, perivascular infiltrates, necrosis of brain parenchyma, and reactive microglial and astroglial proliferation (Table 12.1). Vasculopathy is a distinctive feature of rubella infection, especially involving the brain. Involvement of the leptomeningeal and intraparenchymal vessels is thought to be associated with focal areas of ischemic necrosis in the cerebral white matter and basal ganglia, resulting in calcification [30].

a

Although inflammation and tissue necrosis are the main pathological features, interference with cellular proliferation (through a disturbance of mitotic activity of fetal cells) during brain development occurs, and is responsible for microcephaly and impaired myelination. Microcephaly may not be clinically overt at birth, but may become apparent after several months due to lack of brain growth [30, 31]. 12.2.4.3 Imaging Studies

The imaging appearance depends on the time of the intrauterine infection [5]. Early infection results in congenital anomalies, whereas late infection produces nonspecific generalized edema or loss of brain tissue. In general, MRI findings are not significantly different from those of other TORCH infections. These include delayed myelination (Fig. 12.15), multifocal areas of prolonged T2 relaxation time possibly resulting from insufficient production of oligodendroglia [4, 32–34], foci of parenchymal necrosis [4, 20], ventriculitis, and ventriculomegaly [4]. Intracranial calcifications (Fig. 12.15), well documented by CT scan, involve the basal ganglia, cerebral cortex, and periventricular white matter [4, 21]. Cortical calcifications occur because the virus tends to preferentially destroy the deep cortical layers [35]. In the most severe cases, brain destruction and microcephaly are observed [5].

b Fig. 12.15a,b Congenital rubella infection in an 18-month-old boy. a CT scan. b Axial T2-weighted image. CT scan shows multiple calcified foci within the lentiform nuclei, the frontal subcortical white matter bilaterally, and the cortico-subcortical junction in the left temporal lobe (a). T2-weighted image shows myelination is globally reduced; high-signal-intensity foci are evident in the paraventricular regions bilaterally (arrows, b)

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12.2.5 Neonatal Herpes Simplex Virus Infection Neonatal herpes simplex infection differs from other congenital TORCH group infections in that it is usually acquired during passage through an infected birth canal, while ascending and transplacental infection are much less common. Postnatal infections have been uncommonly reported [36, 37]. The vast majority of congenital herpes virus infection (about 75%–90%) are caused by the herpes simplex type 2 (HSV2) virus. This represents a notable difference from postnatal (i.e., childhood) herpetic meningoencephalitides, which are caused by the herpes simplex type 1 (HSV1) virus. 12.2.5.1 Clinical Findings

Almost all infected infants are symptomatic in the neonatal period, either from disseminated or localized disease. Disseminated disease is characterized by neurological symptoms, such as lethargy, stupor, irritability, and seizures (often focal), progressing to coma [1]. In addition, hepatomegaly, hyperbilirubinemia, and bleeding may occur. Skin lesions are present in 50% of cases. The outcome is poor. Localized disease may involve the CNS, skin, eye, or oral cavity. Neurological symptoms are similar to those previously described and may occur during the second or third week of life [25]. Any infant with a CSF formula suggestive of encephalitis, i.e., pleocytosis and elevated protein, should be considered to have herpes simplex encephalitis until proven otherwise [1]. Although the virus can be isolated from the CSF, the cultures often are negative early in the course of the disease. PCR assay is the optimal method to rapidly identify the virus in the CSF [1]. Electroencephalography (EEG) is among the most sensitive noninvasive laboratory studies in the diagnostic workup of herpes infections. It usually shows focal or multifocal paroxysmal, periodic or quasiperiodic discharges of repetitive sharp-slow wave complex [38]. 12.2.5.2 Neuropathological Findings

A wide range of CNS injuries has been described, especially related to inflammation and destruction (Table 12.1). Meningoencephalitis is characterized by inflammatory cells in the meninges, inflammatory perivas-

cular infiltrates, severe multifocal necrosis of brain parenchyma that, unlike HSV1 infection, only rarely involves preferentially the temporal lobe, reactive microglial and astroglial proliferation, and intranuclear inclusions (i.e., Cowdry type A) in neuronal and glial cells [1]. A considerable degree of brain swelling, with possible hemorrhagic necrosis due to endothelial involvement, may occur in the early stages of the disease. Since early intrauterine infection by transplacental passage of virus is rare, neonatal microcephaly is a rarity [1]. However, HSV2 has a strong clastic potential that typically manifests with severe brain destruction in the follow-up. Microcephaly commonly develops after the neonatal period, due to failure of brain growth [1]. Multicystic encephalomalacia and hydranencephaly have also been commonly reported as the result of brain destruction [1]. 12.2.5.3 Imaging Studies

Neonatal HSV2 infection (Fig. 12.16) causes diffuse, nonspecific encephalitis characterized by edema and subtle, ill-defined patchy zone of enhancement [35], eventually resulting in widespread brain destruction. Thus, imaging features are different from those of HSV1 infections of older children and adults, characterized by preferential involvement of the temporal and, sometimes, frontal lobes [4, 20, 21, 25]. Despite the diffuse CNS involvement, imaging studies performed during the initial stages of the disease in neonates may show patchy areas of T1 and T2 prolongation on MRI and hypodensity on CT primarily involving the white matter, with relative sparing of the basal ganglia, thalami, and posterior fossa structures [4, 5]. However, other authors have reported a predilection for the cerebellum, basal ganglia, and brainstem [25]. Regardless of the initial location of imaging abnormalities, there is rapid progression towards global brain involvement during the course of disease [5]. The gyri may be hyperintense on noncontrast T1-weighted MR images, possibly because of intrinsic hypervascularity [39, 40]. Both the white and the gray matter may be involved. These features may persist for weeks or even months [5]. Finger-like areas of increased attenuation within the cortical gray matter, associated with an increase in matter lucency, are considered typical CT findings in the first 3 weeks after presentation [4]. Following gadolinium administration, mild leptomeningeal enhancement is seen [5]. Rapid progression of brain destruction eventually leads to diffuse cerebral atrophy (Fig. 12.16) with

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severe cortical thinning, multicystic encephalomalacia, and large, diffuse dystrophic calcifications that are mainly located in the periventricular regions and in the cerebral cortex, but may become very extensive [5, 20, 21, 25]. Vascular thrombosis and hemorrhage may result from inflammatory involvement of the endothelial cells [20, 41]. Unlike CMV or toxoplasmosis, neuronal migration disorders are extremely uncommon. They have been reported in some cases of fetally acquired HSV1 infection [25, 40, 42, 43].

12.2.6 Congenital Human Immunodeficiency Virus (HIV) Infection Transmission of HIV from infected pregnant women to their fetuses may occur through transplacental passage of the virus (especially during the second or third trimester), during passage through an infected birth canal, or by ingestion of maternal blood. Fetal infection accounts for 25% of cases, and parturitional infection for the remaining 75% [1]. Postnatal infection due to transmission of HIV by breast feeding may also occur. 12.2.6.1 Clinical Findings

Patients with congenital acquired immunodeficiency virus (AIDS) usually do not show neurological signs in the neonatal period. Neurological manifestations typically appear between 2 months and 5 years of age [1, 2, 44]. Either a progressive or a static encephalopathy may occur. Progressive encephalopathy, presenting during the first year of life, is characterized by microcephaly, developmental delay, and spastic motor impairment (more rarely extrapyramidal or cerebellar deficits), associated with systemic features of disease. The outcome is extremely poor. Static encephalopathy is characterized by cognitive impairment and mild motor dysfunction. Acute neurological deterioration may be secondary to bacterial infections, opportunistic infections or neoplasm [45].

a

12.2.6.2 Neuropathological Findings

b Fig. 12.16a,b Congenital herpes virus infection (HSV type II). a CT scan at 4 months. b CT scan at 8 months. At presentation (a), CT shows severe cerebral swelling with slit-like lateral ventricles. There is diffuse marked hypodensity of both cerebral hemispheres with loss of gray-white matter demarcation. The basal ganglia are slightly more dense. Follow-up CT (b) shows severe cerebral atrophy with focal hypodense parenchymal lesions, ventriculomegaly, and ex-vacuo subdural collections bilaterally

The main neuropathological features of HIV infection are related to the immune response of the host to the virus (Table 12.1). Meningoencephalitis is less prominent than in infections caused by TORCH organisms. Its most striking feature is multinucleated giant cells, containing the virus, often in syncytial formations. Cerebral atrophy with resulting microcephaly is a prominent feature of HIV infection, and is related to loss of both neurons and myelin [1]. The mechanism leading to neuronal death, particularly evident in the basal ganglia and cerebral cortex, is not completely clear. Experimental studies have suggested the following steps: infection of brain macrophages (and perhaps astrocytes) by HIV, induction of release of “neurotoxins” (such as arachidonic metabolites, cyto-

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kines, reactive oxygen species), increase of cytosolic calcium by toxic action mediated by the coat protein of HIV, gp 120, activation of glutamate receptors, synthesis of nitric oxide and free radicals, and eventual cell death. The gp 120 protein of HIV has been demonstrated to sensitize neurons to glutamate-induced cell death mediated by N-methyl-D-aspartate (NMDA) receptors, thus playing a crucial role in the genesis of brain injury. A protective effect from neuronal death, caused by the action of both HIV coat protein and “toxins” released from infected macrophages, might be played by NMDA and calcium-channel antagonists [46–48]. In addition to these mechanisms, it also has been suggested that dendritic abnormalities could play a role in the pathogenesis of cortical atrophy [49–51]. Myelin loss, either diffuse or multifocal, is a prominent finding of HIV infection. It is caused by a destructive process, more than a disturbance of myelin formation, as demonstrated by the presence of reactive astrocytosis and calcifications. Furthermore, the HIV coat protein gp 120 has shown a destructive action on developing oligodendrocytes in culture [52]. Mineralizing microangiopathy with calcific degeneration of blood vessels (especially involving the basal ganglia and white matter) is a striking feature of HIV infection. It accounts for hemorrhagic or ischemic stroke. Aneurysmal dilatation of the vessels of the circle of Willis is an unusual presentation of arteriopathy [53] that seems to predispose children to thrombosis and embolization [54, 55]. Spinal cord demyelination is particularly evident in the lateral corticospinal tract. This finding is different from the vacuolar myelinopathy of HIV-infected adults, that is more prominent in the posterior columns [56, 57]. Neoplastic lesions or opportunistic infections are rare (about 10%–15% of infants). 12.2.6.3 Imaging Studies

Routine neuroimaging studies in congenital HIVinfected patients may be initially normal [25]. However, progressive mineralizing vasculopathy, revealed by intracranial calcifications (Fig. 12.17) that primarily involve the basal ganglia, may be present at birth [25]. Calcifications are promptly revealed by CT, although they may appear as bright T1 signal on MRI due to the paramagnetic effects of calcium-related ions. These calcifications are a typical feature of infected children, in contrast to adults, in whom they are not a prominent finding [58]. Furthermore, subcortical calcifications (Fig. 12.17) are only found in patients infected in

a

b Fig. 12.17a,b Congenital HIV infection in two different patients. a Axial CT scan in a 13-year-old girl shows diffuse calcification in the striatum bilaterally. b Axial CT scan in a 6-year-old girl shows diffuse, small subcortical calcifications prevailingly in the frontal lobes

utero and prevail in the frontal lobes, although they may be also involve other locations [5]. Cerebral atrophy (Fig. 12.18), usually progressive on serial MRI examinations, is the most common finding in children with congenital HIV infection, and correlates well with the above-described histopathological changes [5, 58]. White matter lesions have been variably described as prevailingly central [53] or subcortical [25]. Intracranial hemorrhage and infarction are uncommon complications of pediatric AIDS, occurring in about 1.3% of children [4, 5], particularly in cases of severe immune thrombocytopenia [55, 58]. Nonhemorrhagic infarction may appear as multifo-

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cal microinfarctions or large areas of encephalomalacia [58]. Both arteriopathy, primarily involving large vessels and thought to be the result of either HIV or other superinfecting organisms [59], and necrotizing encephalopathy [58] have been considered as possible causes of cerebral infarction. Repeated thrombosis, due to vascular injury indirectly mediated by HIV, has also been reported [60]. MRI features consistent with moyamoya syndrome have been reported in a 10-year-old boy with congenital AIDS, presenting with recurrent episodes of hemiparesis [61]. Both intracranial neoplasms and opportunistic infections are rare in congenital HIV-infected infants, as opposed to adults [5]. The most common intracranial neoplasm is lymphoma, typically involving the basal ganglia and thalami [5], while the most common form of infectious disease is progressive multifocal leukoencephalopathy (PML), resulting from lytic infection of oligodendrocytes by the papovavirus JC. PML may occur also in patients with congenital immunodeficiency syndromes and disorders necessitating immunosuppressive therapy [5]. It is characterized by slowly progressive mental deterioration and neurological deficits. The low incidence of PML in HIV-infected children has been related to the early mortality of these patients, so that the improved survival might lead to an increase of its frequency [45]. Multifocal demyelination of the cerebral white matter at the gray–white matter junction, with extension into the deep white matter [45] with intranuclear inclusion bodies in oligodendrocytes is the main

pathological finding [5]. MRI shows single or multiple areas of prolonged T1 and T2 relaxation times in the subcortical white matter, usually without mass effect and enhancement [5]. Demyelinating lesions appear as confluent regions of abnormal white matter signal throughout the cerebral hemispheres, with involvement of both subcortical and periventricular white matter. The frontal and parieto-occipital regions are the most common locations, although lesions may be found anywhere in the white matter of the cerebral hemispheres, brainstem, and cerebellum [5]. Clinical and imaging pictures consistent with posterior reversible leukoencephalopathy (see Chap. 11) have been reported in a perinatal HIV-infected girl [62]. Finally, spinal cord involvement in HIV-infected patients may appear as vacuolar myelopathy, spinal tract degeneration, or myelitis. The rare reports on imaging studies describe nonspecific changes [4, 5, 63]. Advanced MR Imaging

Proton MR spectroscopy (MRS) may be useful even when the routine MRI is normal, showing abnormalities in neonates exposed to HIV in utero, although it does not differentiate between infected and uninfected newborns [25]. In children, the NAA/Cr ratio is normal in cases of static encephalopathy and low in cases of progressive encephalopathy [64, 65]. In addition, a lactate peak in the basal ganglia region has been described, possibly related to HIV-infected inflammatory cells found in this region [66].

12.2.7 Congenital Syphilis Congenital infection with Treponema pallidum occurs by transplacental passage, particularly during the second and third trimesters of gestation. 12.2.7.1 Clinical Findings

Fig. 12.18 Congenital HIV infection in a 2-year-old boy. Axial CT scan. There are enlarged lateral ventricles and diffuse enlargement of the subarachnoid spaces of the convexity

Approximately 65%–90% of infected infants are completely asymptomatic at birth. Clinical symptoms of early stage congenital syphilis (i.e., presenting during the first two years of life) are characterized by skin rashes, hepatosplenomegaly, lymphadenopathy, bone involvement, and neurological symptoms related to meningitis or increased intracranial pressure [1]. Symptoms of late-stage congenital syphilis (i.e., presenting after 2 years of life) include abnormalities of teeth, optic atrophy, sensorineural deafness, paresis, or spinal cord disease.

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12.2.7.2 Neuropathological Findings

12.3 Bacterial Meningitis

CNS involvement in congenital syphilis is usually confined to the meninges (Table 12.1). Acute and subacute meningitis is characterized by inflammatory infiltration of the leptomeninges with mononuclear cells, prevailingly in the basal meninges. Perivascular infiltrates may extend into the brain parenchyma via the Virchow-Robin space, although parenchymal lesions are uncommon [1]. Chronic meningovascular syphilis develops as an extension of the acutesubacute meningitis. Its preferential basal location results in cranial nerve abnormalities and hydrocephalus related to chronic arachnoiditis. If vasculitis is severe, vessel obliteration may produce cerebral infarction, usually between 1 and 2 years of life [1].

12.3.1 Background

12.2.7.3 Imaging Studies

Leptomeningeal enhancement, especially involving the basal meninges, is the main neuroimaging finding. Extension of the infiltration into the brain parenchyma via the Virchow-Robin spaces may rarely result in an enhancing intraparenchymal mass (i.e., gumma) [5]. Cerebral infarction may sometimes complicate congenital syphilis.

12.2.8 Congenital Varicella Congenital varicella syndrome is a rare disorder caused by transplacental passage of the varicella zoster virus associated with maternal viremia, in cases of infection occurring during the first or early second trimester of pregnancy [1, 67]. Unlike CMV infection, the fetal infection is not chronic, and isolation of the virus after birth has not been accomplished [1]. The clinical presentation is characterized by typical cutaneous scars in a segmental distribution, muscle hypoplasia with limb deformity, chorioretinitis, microphthalmia, cataracts, bulbar signs, and seizures [1]. The main neuropathological findings include meningoencephalitis, myelitis, dorsal root ganglionitis, and muscle denervation (Table 12.1). MRI findings are nonspecific, and include microcephaly, ventricular dilatation up to hydrocephalus, porencephalic cysts, and calcifications indicative of a destructive process whose severity is related to the timing of infection [67]. Polymicrogyria or focal lissencephaly, associated with intracranial vascular compromise, have also been described [25].

The term meningitis indicates an inflammatory process involving the dura mater, leptomeninges, and CSF within the subarachnoid spaces [68]. The term meningoencephalitis is used when the underlying brain parenchyma is also involved. Bacterial meningitis is the most common and one of the most severe infectious process in the pediatric age group [5]. Etiologic agents vary with the age of the patient (Tables 12.5, 12.6), as does the clinical presentation. Neuroimaging studies have allowed early and precise diagnosis, monitoring of treatment, and identification of complications, thereby contributing to a significant decrease of morbidity and mortality. Infectious agents may enter the CNS through hematogenous spread, direct implantation (usually traumatic), local extension (secondary to sinusitis, mastoiditis, otitis, brain abscesses), and spread along the peripheral nervous system. 12.3.1.1 Neonatal Bacterial Leptomeningitis

Neonatal leptomeningitis occurs in about 0.4% of births, especially in those preterm or born after dystocic delivery [69], and represents the most common and serious neonatal intracranial bacterial infection. In the majority of cases it is associated with sepsis, so that the term sepsis/meningitis more appropriately describes the consistent association of bacteremia plus inflammatory process of the dura mater, leptomeninges, and CSF. Although presentation is consistently by the first month of life [1], two different clinical entities exist, differing in age of onset, clinical presentation, and prognosis.  Early-onset sepsis/meningitis affects newborns in their first week (usually first 48 hours) of life. Patients often are prematures with a history of obstetrical complications. Systemic manifestations (i.e., sepsis, respiratory disturbances) prevail over neurological abnormalities. The mode of transmission is mother to fetus. The prognosis is poor with elevated mortality.  Late-onset sepsis/meningitis presents after the first 7 days of life. Prematurity and obstetrical complications are uncommon. Neurological symptoms (lethargy, seizures, and coma) are more prominent than in the early-onset type. Other than mother to fetus, possible modes of transmission also include other human or equipment contacts. Prognosis is less dismal with higher survival rate than in the early-onset type.

Infectious Diseases Table 12.5. Bacterial agents implicated in meningitis

Table 12.6. Bacterial etiology of meningitis stratified by age

Bacterium

Organism

Neonates (%)

Children (%)

Adults (%)

Haemophilus influenzae

0-3

40-60

1-3

Neisseria meningitidis Streptococcus pneumoniae Group B streptococcus Other streptococci Escherichia coli Staphylococci Listeria

0-1 0-5 45-50 7-10 15-20 5 2-10

25-40 10-20 2-4 1-2 1-2 1-2

10-35 30-50 5 1-5 5-15 5

Remarks and predisposing conditions

Haemophilus Formerly the most common cause of influenzae (type B) bacterial meningitis in USA Neisseria meningitidis (meningococcus)

Cause of epidemic meningitis

Streptococcus pneumoniae (pneumococcus)

Currently the most common cause of meningitis in USA. Basilar skull fracture, splenectomy, hypoglobulinemia, multiple myeloma, alcoholism, malnutrition, diabetes, chronic liver or renal disease, malignancy, diabetes mellitus

From ref. # 1,2

Listeria monocytogenes

Soil organism. Most important in immunosuppressed; can cause disease in normals.

12.3.1.2 Acute Bacterial Meningitis in Children

Streptococcus agalactiae

Group B streptococcus. Important cause of sepsis and meningitis in newborns. Also in age > 60 years, collagen vascular disease, malignancy, diabetes, renal or liver failure, corticosteroid therapy

After the neonatal period (from the second month of life up to 15 years) the most common agent of acute bacterial meningitis is Haemophilus influenzae (40%– 60% of cases), followed by Neisseria meningitidis (25%–40%) and Streptococcus pneumoniae (10%–20%) (Table 12.6). Type b Haemophilus influenzae (HIB) is a leading cause of purulent meningitis in children between 4 months and 3 years [2]. Irritability, lethargy, vomiting, and fever are the main clinical symptoms after 3 months of age; after 2 years, symptoms of meningeal involvement become more prominent.

Propionibacterium Patients with CNS shunts acnes Staphylococcus aureus

Head trauma, post neurosurgery

Staphylococcus epidermidis

Head trauma, post neurosurgery particularly in patients with CNS shunts

Enterococcus

Underlying disease (e.g. diabetes, liver transplantation)

Escherichia coli

Newborn, head trauma, elderly, immunosuppressed, intestinal infection with Strongyloides stercoralis

Klebsiella pneumoniae

Newborn, head trauma, elderly, immunosuppressed from all causes

Pseudomonas aeruginosa

Newborn, head trauma, elderly, immunosuppressed from all causes

Salmonella

Children < 2 years old in developing countries

Nocardia

Immunosuppressive drugs, malignancy, head trauma, neurosurgery, chronic granulomatous disease, sarcoidosis

Mycobacterium tuberculosis

Meningitis usually from rupture of subependymal tubercle into subarachnoid space, not direct hematogenous spread

Since neonatal meningitis is mainly related to maternal genital flora, Streptococcus agalactiae (group B hemolytic streptococcus) is the most common agent (45%–50% of cases); other common germs are Escherichia coli (15%– 20%) and Listeria monocytogenes (2%–10%). Neonates are particularly susceptible to gram-negatives (such as Escherichia coli), since their neutralization requires IgM that are not produced by neonates [2].

12.3.1.3 Recurrent Bacterial Meningitides

Recurrent meningitides occur in patients with medical and surgical disorders that predispose to infection of the CNS (Table 12.7). Medical conditions basically involve immunodeficiency and hematological conditions, whereas surgical causes include traumatic CSF fistula (see Chap. 19), congenital anomalies of the petrous bone (among which the Mondini deformity) (see Chap. 32), dermal sinuses (with or without associated dermoid cyst) and other spinal dysraphic disorders (see Chap. 39). Most are caused by Streptococcus pneumoniae, whereas a minority involve other bacterial species. Although antibiotic treatment is obviously mandatory, ultimate treatment rests on the identification and correction of the underlying predisposing condition.

12.3.2 Neuropathological Findings The major neuropathological features of bacterial meningitis may be distinguished as acute and chronic changes [1].

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12.3.2.1 Acute Changes

During the acute stage of infection, an orderly pathophysiological cascade of events occurs, basically starting with arrival of the germs to the choroid plexuses, and proceeding with their diffusion to the CSF, leptomeninges, and eventually the parenchyma. These various stages correlate strictly with corresponding neuroimaging features. However, one should be aware that, depending on the aggressiveness of the process and the time of imaging, MRI/CT may display any of these stages at presentation. Stages 1/2: Choroid Plexitis/Ventriculitis. The initial stages of choroid plexitis and ependymitis-ventriculitis are difficult to separate from both a neuropathologic and imaging perspective. Bacteria enter the ventricles via the choroid plexuses [70]. Ependymitis-ventriculitis quickly follows, with inflammatory exudation and bacterial replication in the ventricular CSF. These events are favored in young children by the functional immaturity of the arachnoid villi, allowing longer persistence of bacteria into the CSF [71]. The subependymal layer is damaged and replaced by a thin, highly vascularized and gliotic band showing inflammatory necrosis. At this stage, complications include hydrocephalus, periventricular white matter necrosis, and abscess formation. Stage 3: Arachnoiditis. Arachnoiditis, i.e., infiltration of the arachnoid with inflammatory cells, is

the hallmark of bacterial meningitis in the acute stage, especially in post-neonatal disease. However, one should remember that as many as 75% of cases of early-onset group B streptococcal meningitis (representing the most common etiology of neonatal bacterial meningitis) show little or no evidence of leptomeningeal inflammation at autopsy [1]. In the initial stages, purulent exudation in the subarachnoid spaces diffusely covers the cranial base (involving the cranial nerves, especially 3 through 8) and, sometimes, the cerebral convexity. There may be differences in location of the purulent exudates according to the causal agent: for example, meningitis caused by Haemophilus influenzae is characterized by thick and purulent exudate that tends to create saccular collections, sometimes multilocular, at level of basal cisterns and sulci; conversely, pneumococcal meningitis preferentially involves the hemispheric convexity. Polymorphonuclear leukocytes initially prevail in the inflammatory infiltrate, but are subsequently replaced by monocytes and fibroblasts; collagen bands appear by the end of the second week of disease, resulting into thick leptomeningeal fibrosis that obstructs the basal cisterns and may cause communicating hydrocephalus. Aqueductal obstruction is rare. Stage 4: Vasculitis. Vasculitis is an almost invariable feature of neonatal bacterial meningitis (especially due to group B streptococcal infection), and represents the subsequent stage in the pathophysiologic cascade following arachnoiditis, due to the extension of the inflammatory reaction along the perivascular spaces of Virchow-Robin to involve the walls of the arteries and veins. Arteritis usually causes narrowing of the arterial lumen, whereas phlebitis typically results in a complete obstruction of the involved vessels. Whereas vasculitic changes are particularly prominent by the second and third weeks, cerebral infarction may often be an early event. Lesions are most frequently due to venous occlusion by fibrinoid thrombosis, and are usually multiple and hemorrhagic. Preferential locations are the cerebral cortex and underlying white matter; however, the periventricular white matter and basal ganglia may also be involved. Arterial thrombosis is less common than venous thrombosis, although endoarteritis with intimal thickening and leukocyte infiltration does occurs [5, 71]. Stage 5: Cerebral Edema. Cerebral edema is primarily related to vasculitis, increased permeability of blood vessels, and BBB changes (vasogenic edema), but may be complicated by cytotoxic and interstitial edema [1]. In neonates, edema may be the initial manifesta-

Infectious Diseases

tion of disease because of rapid evolution and greater vulnerability of the immature brain to the infectious agent. Nevertheless, brain herniations are rare, due to the distensibility of the neonatal cranium. In infants and children, herniations can be responsible for vascular or parenchymal compression, infarcts, or thrombosis. In particular, herniation of cerebellar tonsils is potentially responsible for apnea, coma, and sudden death; this tends to occur more frequently after the second/third month of life. Acute-Stage Complications

Parenchymal changes associated with meningitis include diffuse gliosis of regions subjacent to inflammatory exudate (especially cerebral and cerebellar cortex), neuronal loss (namely in the cerebral cortex), and periventricular leukomalacia [1]. Subdural effusions are sterile, liquid collections within the subdural space, often bilateral, most commonly located over the frontal, parietal, or temporal regions. They are due to toxin-induced increased permeability of the capillaries and veins of the internal layer of the dura mater. Sometimes they are not easily differentiated from enlarged subarachnoid spaces [71]. They tend to resolve spontaneously, without need of surgical treatment, unless they are particularly large. They are extremely rare in neonates, as they are more commonly related to infections due to Haemophilus influenzae occurring in infants and children. We have also seen subdural effusions with Streptococcus pneumoniae meningitis. True subdural empyemas are very rare in neonates [1]. Brain abscesses, resulting from superimposed infections of ischemic lesions, are particularly frequent in cases of Citrobacter or Proteus infections [69,72,73].

stages described above. However, these findings may dramatically and rapidly change from initial normal imaging to severe edema in a few days or even hours, and to multiple infarcts, atrophy, or encephalomalacia in few weeks. Such evolution can be more tumultuous in newborns due to the greater vulnerability of the immature brain, so that edema, a late stage in the pathophysiologic chain of events, may in fact be the initial manifestation on imaging. Although MRI is the most sensitive imaging method in the detection of brain involvement in cases of infectious disease, CT is often used as the first examination, especially in emergency situations. Both unenhanced and contrast enhanced scans should be obtained. 12.3.3.1 Choroid Plexitis/Ventriculitis

As was previously stated, choroid plexitis and ventriculitis are the initial stages of infection, due to arrival of germs to the choroid plexuses and colonization of the ependymal lining and CSF. These two stages are difficult to separate from a neuroimaging perspective. Both CT (Fig. 12.19) and MRI (Fig. 12.20) will

12.3.2.2 Chronic Changes

The main long-term neuropathological changes of neonatal bacterial meningitis are hydrocephalus, multicystic encephalomalacia, porencephaly, and cerebral cortical and white matter atrophy [1]. Experimental studies have also shown disturbances of dendritic arborization and synaptogenesis in infant rats [74].

12.3.3 Imaging Studies in Bacterial Meningitis Imaging findings of acute bacterial meningitis in neonates and infants reflect the various neuropathologic

Fig. 12.19 Choroid plexitis/ventriculitis in a 1-month-old baby girl with sepsis/meningitis due to Streptococcus β haemolyticus. Post-contrast axial CT scan. Marked enlargement of the ventricular system showing diffuse signs of ependymitis, characterized by thickening and marked enhancement of the ventricular walls (arrowheads). The choroid glomi are engorged and adhere to the anterior walls of the ventricular trigones (thick arrows). Dependent intraventricular proteinaceous debris are recognizable bilaterally (thin arrows). Periventricular hypodensity is related to edema (E)

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show a characteristic triad, composed of (1) choroid plexus engorgement and adhesion to the ventricular walls, (2) ependymal enhancement, and (3) intraventricular debris layered in the dependent portion of the ventricles, usually the trigones or occipital horns of the lateral ventricle [5]. Hydrocephalus is commonly associated, usually due to obstruction of the cerebral aqueduct or fourth ventricular foramina. Periventricular edema, seen both on CT scan (Fig. 12.19) and MRI (Fig. 12.20,12.21) [1], can be a consequence of unbalanced CSF dynamics [1], but may herald necrosis of periventricular white matter, related either to obstruction of subependymal and periventricular veins or to toxins produced by the bacteria [75]. Brain abscess, usually located in the periventricular white matter (Fig. 12.21), may be a further complication in this line of events. Eventually, multiple ventricular loculations separated by thin septa may occur as a consequence of intraventricular scarring [5]. These cavities may be mutually excluded and may enlarge separately, creating a condition of multiloculated hydrocephalus that often requires placement of multiple shunt catheters.

a

enhancing meninges (Fig. 12.22) may remain completely unseen during the natural history of bacterial meningitides in children, especially those caused by group B streptococci. When present, two distinct patterns of abnormal meningeal enhancement may be observed, i.e. dural enhancement following the inner contour of the calvaria, and leptomeningeal enhancement extending into the depths of the cerebral and cerebellar sulci and fissures [68]. Rapidly developing adhesive arachnoiditis with reactive fibrosis may cause acute communicating hydrocephalus with increased intracranial pressure, accounting for the simultaneous occurrence of imaging signs of edema and hydrocephalus. 12.3.3.3 Vasculitis

Extension of the infectious process along the perivascular spaces leads to involvement of the walls of the arteries (arteritis) and veins (phlebitis/thrombophlebitis).

12.3.3.2 Arachnoiditis

Arteritis

In the early stages of infection, arachnoiditis may be unrecognizable. One should be aware of the fact that the imaging hallmarks of arachnoiditis, i.e., enlargement of the subarachnoid space, and thickened,

This may result in both arterial infarcts (Fig. 12.23), involving either large or small vessels [5], and pseudo-laminar cortical necrosis (Fig. 12.24). On imaging, the diagnosis of vasculitis may not be

b Fig. 12.20a,b Choroid plexitis/ventriculitis in a 1-month-old girl. a Gd-enhanced axial T1-weighted image. b Gd-enhanced sagittal T1-weighted image. There is marked enlargement of the whole ventricular system, showing diffuse signs of ventriculitis characterized by enhancement of the ependymal lining (arrows, a). Both choroid glomi are congested and adhere to the anterior walls of the atria (arrowheads, a) as a manifestation of choroid plexitis. Sagittal image reveals obstruction of the fourth ventricular foramina secondary to adhesive phenomena (arrow, b)

Infectious Diseases

a

c

b

d Fig. 12.21a–d Choroid plexitis/ventriculitis in a 3-month-old boy. a,b Gd-enhanced sagittal T1-weighted images. c Gd-enhanced axial T1-weighted image. d Axial T2-weighted image. There is marked enlargement of the third and lateral ventricles. Proteinaceous debris are recognizable at the level of the aqueduct and of the fourth ventricle (arrows, a). The choroid plexuses are congested and adhere to the ventricular walls (open arrows, b,c). Parasagittal image shows a satellite abscess (arrowhead, b). Marked T1 and T2 prolongation in the white matter (b–d) is related to diffuse cerebral edema

immediate, basically because it is usually difficult to assess arterial narrowing noninvasively, especially when small-caliber vessels are involved. Infarcts tend to be sharply marginated and confined to a specific arterial vascular territory [5]. Either large cortical infarction, due to major vessel involvement, or multiple lacunar-type infarcts in the distribution of perforating vessels in the brainstem, basal ganglia, and white matter may be seen [5]. Cortical laminar necrosis appears as pseudo-gyral T1 and

T2 hyperintensity showing gadolinium enhancement (Fig. 12.24). MRA can show irregularity and narrowing of the arterial lumen when large- to medium-caliber vessels are involved. However, the picture may be deceivingly normal when the process involves small arteries. Digital angiography remains the gold standard in the diagnosis of vasculitis (see Chap. 7). However, this invasive examination is often not performed, especially in young children, and the disease is treated on a clinical basis.

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a a

b Fig. 12.22a,b Arachnoiditis in a 6-month-old girl with Haemophilus influenzae meningitis. a Gd-enhanced sagittal T1weighted image. b Gd-enhanced axial T1-weighted image. Diffuse leptomeningeal enhancement involves both frontal regions (arrowheads, a,b). A right-sided subdural effusion is associated (E, b)

Fig. 12.23a–c Vasculitis in a 1-month-old girl with late-onset Streptococcus agalactiae meningitis. a Gd-enhanced coronal T1-weighted image. b Gd-enhanced axial T1-weighted image. c Axial T2-weighted image. The triangular area of enhancement extending from the cortex to the ventricular ependyma (arrowheads, a,b) is the result of a small infarct with BBB changes. Axial T2-weighted image shows a further small area of infarct at level of the right caudate nucleus and homolateral frontal lobe (arrow, c)

b

c

Infectious Diseases

a

b

Fig. 12.24a–c Vasculitis in a 16-month -old boy with Streptococcus pneumoniae meningitis. a Axial T1-weighted image. b Gdenhanced axial T1-weighted image. c 3D TOF MR angiography, axial MIP. Diffuse pseudo-laminar cortical necrosis in the right fronto-temporo-insular regions is characterized by spontaneous T1 hyperintensity secondary to mild hemorrhagic cortical infarctions (a). Following gadolinium, enhancement is marked and follows a gyriform pattern (b). A further small area of infarct is evident at the level of the head of the homolateral caudate nucleus. MR angiogram (c) shows diffuse high signal in the involved regions because of incorporation of the high signal intensity of the methemoglobin of the hematoma into the image of vascular flow; however, notice paucity of small caliber vessels in the distal right middle cerebral artery territory compared to the normal contralateral side

c

Venous Thrombosis

Although venous thrombosis is an uncommon complication of meningitis, it does occur especially in cases of superimposed dehydration [5]. The imaging diagnosis of venous thrombosis may not be immediate, and the often subtle signs should not be overlooked (Table 12.8). While unenhanced CT is usually unrevealing, contrast material injection is required to bring out the central, less dense thrombus surrounded by the enhancing dural coverings. This is a relatively immediate diagnosis when the superior sagittal sinus is involved (“empty delta sign”), whereas it may be more tricky at level of the transverse and sigmoid sinuses. On MRI (Fig. 12.25), sinus thrombosis may be diagnosed more easily. However, the appearance of the thrombus strongly depends on the age of the clot. Initial signs (acute thrombus)

basically involve absence of the normal flow-void, better seen as isointensity on T1-weighted images. The classical T1 hyperintensity (subacute thrombus) is seen after a few days. MRA is the gold standard in the diagnosis of venous thrombosis (Fig. 12.25) (see Chap. 7). Venous thrombosis may be complicated by venous infarctions (Fig. 12.26), which tend to involve the Table 12.8. Imaging appearance of sinus thrombosis Acute phase

Subacute phase

CT

High density in involved sinus (on noncontrast scan)

“Empty delta sign” (triangle of hypodensity in the posterior portion of the sinus on contrast-enhanced scan)

MRI T1

Isointense

Hyperintense

MRI T2

Hypointense

Hyperintense

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a

b Fig. 12.25a,b Venous thrombosis in a 1-month-old boy with streptococcal meningitis. a Axial T1-weighted image. b 2D TOF MR angiography, axial MIP. Axial T1-weighted image shows high signal intensity in the transverse sinuses (arrows, a). MR angiogram shows almost complete absence of flow within both sinuses (arrows, b)

cerebral cortex and subjacent white matter, but also the central white matter and basal ganglia. Parasagittal infarcts are due to superior sagittal sinus thrombosis, whereas infarcts involving the thalami are due to straight sinus/vein of Galen thrombosis, and infarcts involving the temporal lobe are secondary to thrombosis of the vein of Labbé, transverse, or sigmoid sinus [5]. Around 25% of venous infarcts are hemorrhagic, and range from petechial hemorrhages within the edematous brain parenchyma to large subcortical hematomas [5]. They are usually subcortical and often multifocal with irregular margins [5]. Imaging appearance of linear hematoma (i.e. in and around the vein) is quite specific [5]. Acute infarcts may rapidly evolve into porencephalic cysts. 12.3.3.4 Cerebral Edema

As was previously stated, cerebral edema, while representing a relatively late stage along the pathophysiological cascade of brain injury due to meningitis, may in fact be the initial presentation on imaging studies, especially in newborns and young infants. Cerebral edema is initially vasogenic due to vasculitis and increased permeability of blood vessels, but may become cytotoxic when parenchymal injury ensues. In most instances, CT scan (Fig. 12.27) will show obliteration of the basal cisterns, fissures, and cerebral and cerebellar sulci due to the presence of inflammatory exudate and brain swelling. The latter is characterized by poorly defined or slit-like ventricles, absence of subarachnoid spaces, and blurred

gray-white matter junction. Increased density of the basal cisterns and choroid plexuses may be seen, due to hyperemia and fibrinoid (sometimes hemorrhagic) exudates. 12.3.3.5 Complications of Meningitis Subdural Effusions

On imaging (Fig. 12.22,12.28), subdural effusions are isodense/isointense with CSF (except in presence of high protein content or blood, which may alter their density and signal behavior). Sometimes, they may be associated with enhancement of a portion of their medial surface (Fig. 12.28), probably related to an inflammatory membrane or underlying cortical infarction [5]. Superinfection may result in purulent subdural empyemas. Hydrocephalus

Communicating hydrocephalus is the most common complication of meningitis. It is usually related to impaired CSF flow and resorption caused by the presence of the inflammatory exudate at the level of the subarachnoid spaces and arachnoid villi. Surgical shunting may be necessary in cases of hydrocephalus caused by leptomeningeal fibrosis [68]. Obstructive hydrocephalus (Fig. 12.20) may occur due to exudative obstruction of the aqueduct or fourth ventricular foramina [68]. Hydrocephalus is further discussed in Chapter 21.

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a

b

Fig. 12.26a–c Venous thrombosis in a 34-day-old boy with meningitis due to Streptococcus agalactiae. a Sagittal T1-weighted image. b,c Axial T1-weighted images. High signal intensity involves the transverse sinuses and the posterior third of the sagittal superior sinus (arrowheads, a,b). A cerebellar vein is also hyperintense (arrow, b). Spontaneous hyperintensity at the level of the nucleo-capsular regions bilaterally is due to venous infarctions. Diffuse areas of periventricular necrosis are seen (N, c)

a

c

b Fig. 12.27a,b Cerebral edema in a newborn with streptococcal sepsis/meningitis. a,b Axial CT scans. There is diffuse hypodensity of both cerebral hemispheres, with relative sparing of the right occipital regions (arrows, a,b). Thrombosis of the sinus rectus and sagittal superior sinus is present (arrowheads, a). The lateral ventricles are nearly virtual (b), while the third ventricle and trigones are still recognizable (a)

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Brain Death

Brain death is defined as the cessation and irreversibility of all brain function, including brainstem (i.e., spontaneous respiration and cardiocirculatory activity). Brain death may be the ultimate outcome of bacterial meningitis in children, as well as of a host of other pathologies, such as severe anoxic-ischemic damage. The diagnosis of brain death is crucial for both ethical reasons and identification of potential organ donors. It is based on a number of clinical and paraclinical criteria that were established by an ad hoc commission in the United States in 1981 [76] (Table 12.9). In the recent past, MRI and MR angiography have been Table 12.9. Criteria for establishment of brain death

a

b Fig. 12.28a,b Subdural effusion in an 8-month-old boy with meningitis due to Haemophilus influenzae. a Gd-enhanced axial T1-weighted image. b Axial T2-weighted image. A fluid collection is seen over the left frontal convexity (E, a,b). The effusion is isointense with CSF on both sequences and does not enhance. The thin cortical rim of enhancement could be related to an inflammatory membrane (arrows, a)

Late-Stage Destructive Lesions

As was previously described, parenchymal damage may eventually result in destructive lesions that include multicystic encephalomalacia, porencephaly, and cortical atrophy. On imaging, there are no significant differences from equivalent long-term outcomes of cerebrovascular injury. Parenchymal damage can be particularly severe in group B streptococcal as well as in gram-negative meningitides.

• Unresponsiveness - The patient is completely unresponsive to external visual, auditory, and tactile stimuli and is incapable of communication in any manner. • Absence of cerebral and brain stem function - Pupillary responses are absent, and eye movements cannot be elicited by the vestibulo-ocular reflex or by irrigating the ears with cold water. - The corneal and gag reflex are absent, and there is no facial or tongue movement. - The limbs are flaccid, and there is no movement, although primitive withdrawal movements in response to local painful stimuli, mediated at a spinal cord level, can occur. - Apnea Test: An apnea test should be performed to ascertain that no respirations occur at a PCO2 level of at least 60 mmHg. The patient oxygenation should be maintained with giving 100% oxygen by a cannula inserted into endotracheal tube as the PCO2 rises. The inability to develop respiration is consistent with medullary failure. • Nature of coma must be known - Known structural disease or irreversible systemic metabolic cause that can explain the clinical picture. • Some causes must be ruled out - Body temperature must be above 32 °C to rule out hypothermia - No chance of drug intoxication or neuromuscular blockade - Patient is not in shock • Persistence of brain dysfunction - Six hours with a confirmatory isoelectric EEG or electrocerebral silence, performed according to the technical standards of the American Electroencephalographic Society - Twelve hours without a confirmatory EEG - Twenty-four hours for anoxic brain injury without a confirmatory isoelectric EEG • Confirmatory tests (are not necessary to diagnose brain death) - EEG with no physiologic brain activity - No cerebral circulation present on angiographic examination (is the principal legal sign in many European countries) - Brain stem-evoked responses with absent function in vital brain stem structures From ref. #76.

Infectious Diseases

increasingly used to assist in the determination of brain death. MRI features of brain death (Fig. 12.29) include swelling of the cerebral gyri and cerebellar cortex, showing T1 and T2 prolongation due to hypoxic-ischemic damage, downward displacement of the diencephalon and brainstem (i.e., central and tonsillar herniation), and loss of flow voids in the intracranial portions of both internal carotid arteries [77]. MR arteriography (Fig. 12.29) shows absence of

a

flow in the intracranial arteries above the level of the supraclinoid portion of the internal carotid arteries [77], whereas MR venography shows absent visualization of the intracranial veins and dural sinuses [78]. Diffusion-weighted imaging offers important additional information, showing diffuse hyperintensities involving both cerebral hemispheres associated with corresponding severe drop in the apparent diffusion coefficient [79].

b

c d Fig. 12.29a–d Brain death from meningococcal meningitis in an 11-year-old girl. a Axial CT scan. b Axial T1-weighted image. c Sagittal T2-weighted image. d 3D TOF MR angiography, coronal collapsed view. CT scan (a) shows mild spontaneous hyperdensity of the basal cisterns, probably related to vasal congestion and trasudation of blood components. Subarachnoid spaces are effaced. On MRI, all supra- and infratentorial subarachnoid spaces are virtual, and the ventricles are small. The cortex is swollen, and is hypointense on T1-weighted images (b) and hyperintense on T2-weighted images (c). The deep gray matter nuclei show high T1 signal intensity (b). The cerebellum is swollen, with dislocation of the inferior vermis into the foramen magnum (arrows, c). The brainstem is compressed and flattened against the clivus. MR arteriography (d) shows complete absence of intracranial arterial blood flow.

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12.4 Intracranial Suppuration 12.4.1 Cerebritis and Brain Abscess Focal purulent brain infections are uncommon, devastating, but potentially treatable disease whose earliest stage is called cerebritis. If adequately treated, cerebritis may resolve completely. With inadequate or absent treatment, it will evolve into full-blown disease, represented by brain abscess. Cerebritis/abscess is caused by bacteria entering the CNS through hematogenous spread from distant infection or generalized sepsis, by extension from contiguous infection, by direct traumatic implantation, or in association with cardiopulmonary malfunction [5]. Brain abscesses complicating bacterial meningitis are most commonly related to Citrobacter, Proteus, Pseudomonas, Serratia, and Staphylococcus aureus [80]. The postulated pathogenetic mechanism involves vasculitis and thrombosis, followed by cerebral infarct and infection of the ischemic territory from concurrent bacteremia. They are more common during the neonatal age, where they account for two thirds of cases, while they are rare in early childhood. Other conditions that predispose to the development of cerebritis and abscesses include left-to-right shunts, such as congenital heart disease and hereditary hemorrhagic telangiectasia (see Chap. 17), suppurative pulmonary infections, immunodeficiency, otomastoiditis, and sinusitis. In these cases, the main agents are Staphylococcus aureus, Streptococcus, gram-negatives and anaerobics, Nocardia, Mycobacterium tuberculosis, and fungi [80]. Abscesses occurring in neonates and small infants have a number of peculiarities that distinguish them from those occurring in older children and adults. First, they are usually caused by gram-negative germs. Second, they are relatively large, often multiple, and typically incomplete, i.e., without a well-defined capsule, which favors their rapid enlargement [81]. Neonatal abscesses are located in the cerebral hemispheres, especially in the frontal and parietal lobes, and usually originate in the periventricular white matter, whereas the subcortical white matter and basal ganglia are more common locations in older children [71, 82]. Deeply located abscesses may rupture into the adjacent lateral ventricle [5]. Clinically, affected neonates may present with acute or subacute signs of increased intracranial pressure, such as increasing head circumference, or with seizures, sepsis, and acute fulminating meningitis. Older children usually present with headache, leth-

argy, vomiting, seizures, or focal neurological deficits [5]. Fever is usually present, but unfortunately this is a relatively common condition in hospitalized children. Distinction between cerebritis and abscess is crucial for therapeutic implications. Cerebritis often responds to appropriate antibiotic therapy, while surgery is contraindicated; conversely, surgical approach may be indicated for abscesses in some cases [5]. 12.4.1.1 Neuropathological Findings

Evolution from focal cerebritis to mature abscess with fibrous capsule usually occurs over a 2–3 week period, although such period may vary from a few days in neonates [5] to several months [83]. Four consecutive stages may be identified (Table 12.10) [83–87]. Early cerebritis (days 1–3 following inoculation) is characterized by injury to the microvasculature due to the arrival of bacteria to the cortex or white matter. Spread of the organism across the wall of the injured vessels results in local inflammation with necrosis of the cerebral parenchyma, vascular congestion, petechial hemorrhages, microthromboses, perivascular fibrinous exudate, and surrounding edema [70]. Late cerebritis (days 4–9) is characterized by a necrotic purulent center confined by an irregular layer of inflammatory granulation tissue. In the absence of treatment or with inadequate therapy, formation of an abscess capsule, representing the host response, occurs. The early capsule (days 10–13) is composed of granulation tissue including lymphocytes, plasma cells, monocytes and macrophages, newly formed blood vessels, and collagen fibers. It is initially poorly defined, thicker on its cortical surface and very thin on the ventricular surface, probably related to differences in blood supply [5, 70, 83]. This explains the tendency to expand medially with occasional rupture into the ventricular system that causes acute purulent ventriculitis, potentially responsible for sudden death. In the late capsule stage, when the abscess is wellencapsulated (days 14 and later), five layers may be recognizable: a necrotic center, granulation tissue containing fibroblasts and capillaries, a zone of lymphocytes and plasma cells within granulation tissue, dense fibrous tissue with embedded astrocytes, and surrounding edematous areas of gliosis. White matter edema surrounding the abscess is widespread [5, 83]. Brain abscesses may show variable size and are usually oval and solitary, albeit often multilocular [70]. However, multiple, small secondary abscesses may be seen peripherally to the lesion. In cases of hematogenous dissemination, the abscess is located at

Infectious Diseases Table 12.10. Neuropathological and MR findings during evolution from cerebritis to abscess Stages

Neuropathological findings

MR signal intensity T1-weighted images

T2-weighted images

Enhancement

Stage I (Early cerebritis)

Infiltration of necrotic tissue by inflammatory cells Capsule is absent Edema in the surrounding white matter is marked

Heterogeneous hypointensity

Heterogeneous hyperintensity

Patchy, heterogeneous

Stage II (Late cerebritis)

Better definition of necrotic area surrounded by proliferation of vessels, inflammatory cells, and reticulin leading to encapsulation

Peripheral rim: hyperintense

Peripheral rim: hypointense

Peripheral rim: marked CE

Center: heterogeneous, Center: prevailingly prevailingly hypointense hyperintense

Center: CE on delayed images

Increasing reticulin and collagen forms a wall surrounding the necrotic center of abscess Regression of edema and mass effect

Abscess wall: hyperintense

Abscess wall: hyperintense

Abscess wall: marked CE

Center of abscess: uniformly hypointense

Center of abscess: uniformly hyperintense

Center of abscess: no CE

The collagen capsule is complete (it is thicker on the cortical side than on the ventricular side) Widespread white matter edema

Abscess wall: iso-hyperintense

Abscess wall: markedly hypointense

Abscess wall: marked CE

Center of abscess: hypointense

Center of abscess: hyperintense

Center of abscess: no CE

Stage III (Early capsule formation)

Stage IV (Late capsule formation)

CE, Contrast enhancement

the gray-white matter junction, mainly in the vascular territories of the middle and anterior cerebral arteries where the infection tends to be mechanically limited by the reduction of size of vascular lumen [83]. 12.4.1.2 Imaging Studies Cerebritis

During the early cerebritis stage (Fig. 12.30), MRI shows an ill-defined area of heterogeneously hypointense signal on T1-weighted and hyperintense signal on T2-weighted images. Mass effect is mild, basically with some degree of effacement of the adjacent cortical sulci. Following gadolinium administration, enhancement is patchy and heterogeneous. CT scan may be normal or show a poorly marginated hypodense area. After contrast administration, an ill-defined contrastenhancing area within the edematous region may be seen. The imaging appearance may be confusing, and differentiation from tumor may not be immediate. Close follow-up after high-dose, short-course antibiotics is, therefore, often necessary. A recent paper has suggested that DWI may be a helpful tool, showing restricted water diffusion with ADC values approaching those of true abscesses [87]. In the late cerebritis stage (Fig. 12.31), imaging findings progressively approach those of true abscesses, though with signs of immaturity. The

center of the lesion shows heterogeneous signal intensity both on T1- and T2-weighted images, with prevalent hyperintensity on T2-weighted images. A peripheral, discontinuous rim appears, slightly hyperintense on T1- and hypointense on T2-weighted images. Following gadolinium administration, there is inhomogeneous enhancement that is more marked in the peripheral rim. Delayed sequences may show progressive enhancement increase in the center of the lesion. This pattern stands for cerebritis and absence of collagen layer within the capsule. Peripheral edema can still be absent at this stage. The presence of subacute hemorrhage may be revealed as foci of hyperintensity on T1-weighted images within the edematous region [83, 86]. On CT scan, an irregular enhancing rim surrounding a central hypodense area may be seen. Abscess

During the early capsule stage (Fig. 12.32), the center of the abscess is hypointense on T1- and hyperintense on T2-weighted images, although signal intensity is slightly higher than that of CSF on both sequences. The enhancing ring is still incompletely formed. During the late capsule stage (Fig. 12.33), the capsule is T1 hyperintense, T2 hypointense, and enhances markedly after gadolinium administration, while the center of the lesion more closely resembles the signal intensity of CSF and does not enhance. The enhanc-

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Fig. 12.30a–c Early cerebritis in a 3-year-old boy. a Axial T2-weighted image. b Gd-enhanced axial T1-weighted image. c Gdenhanced axial T1-weighted images obtained after 1 month of antibiotic therapy. Axial T2-weighted image shows an ill-defined hyperintense area extending from the cortex to the lateral ventricle. Within this area, inhomogeneous low-signal-intensity zones are visible (arrowheads, a). The lesion is T1 hypointense, and mass effect is negligible. Following gadolinium, inhomogeneous enhancement, corresponding to the T2 hypointense components, is seen (arrowheads, b). After 1 month of antibiotics administration, MR imaging is back to normal (c)

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Fig. 12.31a–d Late cerebritis due to Proteus mirabilis in a 21-day-old boy. a Axial CT scan. b Axial T1-weighted image. c Axial T2-weighted image. d Gd-enhanced axial T1-weighted image. There is a focal area in the right frontal lobe, hypodense on CT scan (asterisk, a) and slightly hypointense on T1-weighted images (asterisk, b). The margins of the lesion are mildly hyperdense on CT scan (arrowhead, a) and T1 hyperintense (arrowhead, b). On the T2-weighted image, the lesion is diffusely hyperintense with a markedly hypointense, not completely continuous peripheral rim (arrowheads, c). Following gadolinium administration (d), enhancement of the peripheral rim is marked, although less intense than in cases of the capsule of a mature abscess. The center of the lesion also enhances moderately, unlike in mature abscesses

Infectious Diseases

b

a

c

Fig. 12.32a–c Brain abscess: stages III and IV (early and late capsule formation) in a 4-month-old girl. a Axial T1-weighted image. b Axial T2weighted image. c Gd-enhanced axial T1-weighted images. Huge bilocular lesion in the right cerebral hemisphere. On the T1-weighted image, the lesion is characterized by spontaneously hyperintense walls and a hypointense center, whose signal intensity is, however, higher than that of CSF. On the T2-weighted image, the capsule of the anterior lesion component is markedly hypointense, whereas that of the posterior portion is more blurred and shows slightly higher signal intensity (arrowheads, b). Following gadolinium, the walls of the lesion enhance markedly; however, notice that enhancement of the posterior cavity is less marked (arrowheads, c). Perifocal edema surrounds the lesion (asterisk, a–c) and contributes to the marked midline shift. These findings correspond to two different stages of abscess formation, i.e., early capsule formation posteriorly and late capsule formation anteriorly

ing rim is generally thin and smooth, and is usually thicker compared to the thickness of the capsule on unenhanced images. This is related to the granulation tissue that is located medially to the true capsule. Surrounding edema is consistently present, although its extension is variable. The characteristic signal intensity of the rim (i.e., T1 and T2 shortening) seems to be related to the paramagnetic effect of intracellular free radicals released by macrophages during the phagocytosis or to small amounts of hemorrhage [21, 83–86]. Evaluation of the rim on T2-weighted images during follow-up is therefore a good indicator of the response to treatment, since it tends to resolve in parallel with the reduction in phagocytic activity. Conversely, residual contrast enhancement may persist for months after successful therapy [86, 88]. CT scan is also useful in the diagnosis of brain abscess when MRI is not available. It shows a central hypodense area corresponding to the necrotic purulent center, a thin wall of iso-slightly increased density, corresponding to the fibrotic capsule, that enhances markedly with

contrast material administration, and hypodense perifocal edema. The presence of the ring is the most important finding to distinguish cerebritis from abscess. Gas bubbles may be seen within the abscess when it is caused by anaerobic germs. Differentiation between the stages of late cerebritis, early capsule, is very difficult, if not impossible, on CT scan alone [5]. Complications of brain abscess include (1) increased intracranial pressure (Fig. 12.32), possibly responsible for herniation, brainstem compression, and respiratory arrest, and (2) acute subdural empyema due to rupture of the abscess into the subarachnoid spaces. In turn, abscess may represent the complication of a local infections, such as otomastoiditis, in which case sigmoid sinus thrombosis often is associated (Fig. 12.34). One should remember that a “ring-enhancing” mass is a nonspecific feature that may have several etiologies (Table 12.11). The differentiation between an abscess and a necrotic tumor may sometimes be especially difficult, even for the experienced neuroradiologist. Crite-

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a

b

c

d Fig. 12.33a–d Mature brain abscess (late capsule formation). a Axial T1-weighted image. b Coronal T2-weighted image. c Gdenhanced axial T1-weighted image. d Axial CT scan. The typical features of a mature abscess are shown. The lesion has a rounded appearance and is surrounded by abundant vasogenic edema that causes moderate midline shift. The center of the lesion is T1 hypointense (a), T2 hyperintense (b), and does not enhance (c). The peripheral capsule is smooth and regular; it is T1 isointense (a), T2 hypointense (especially on its inner margin (b), and enhances markedly (c). CT scan (d) shows the lesion has a hypodense center and an isodense capsule; enhancement on CT parallels that on MRI (not shown)

ria that are commonly considered to suggest an abscess include presence of fever and high erythrocyte sedimentation rate and a regular, smooth enhancing rim. However, the final impression often remains ambiguous, and decision-making used to be postponed after a high-dose, short-course (i.e., 14 days) antibiotic regimen. While such a strategy remains valid when only conventional imaging is available, advanced imaging modalities play a significant role in such differentiation, allowing for earlier diagnosis and institution of proper treatment. Diffusion-weighted images basically show reduced diffusivity within the abscess core (i.e., giving bright signal on DWI, and dark on ADC) (Fig. 12.35), whereas the opposite behavior is seen in cases of necrotic tumors [89–91]. This restriction of microscopic movement of water molecules occurs as

Table 12.11. Differential diagnosis of ring-enhancing lesions on CT scan Common Some primary brain tumors (e.g. anaplastic astrocytoma) Metastatic brain tumor Abscess Granuloma Resolving hematoma Infarct Less common Thrombosed vascular malformation Demyelinating disease Uncommon Thrombosed aneurysm Other primary brain tumors (e.g. primary CNS lymphoma in AIDS) From ref. # 98

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a

b Fig. 12.34a,b Cerebellar abscess in an 8-year-old boy with otomastoiditis. a Axial T1-weighted image. b 2D TOF MR angiography, coronal MIP. There is a cerebellar abscess secondary to otomastoiditis (asterisk, a), which is also complicated by thrombophlebitis of the sigmoid sinus (arrow, a). MR angiogram (b) shows complete occlusion of the left sigmoid sinus and internal jugular vein.

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d

c

Fig. 12.35a-d Diffusion-weighted imaging (DWI) and MR spectroscopy (MRS) of brain abscess. a Axial FLAIR image shows left occipital abscess surrounded by vasogenic edema, and demonstrates placement of the MRS voxel. b Axial diffusion-weighted image shows lesion gives bright signal, consistent with reduced diffusivity. c ADC map shows corresponding dark signal intensity. d Single voxel MRS (PRESS, TE = 136 ms) shows large inverted lactate peak (Lac), abnormal succinate (Succ) and aminoacid (AA) peaks, and relative decrease of physiologic peaks (Cho = choline, Cr = creatine, NAA = N-acetylaspartate). Case courtesy of Dr. M. Thurnher, Vienna, Austria.

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they are contained inside a complex matrix of proteins, inflammatory cells, cellular debris, and bacteria in high-viscosity pus [92]. Moreover, it is remarkable that abscesses appear slightly larger on diffusion-weighted images than on conventional MR images, probably due to a summation of the necrotic region and the capsule [92]. On MR spectroscopy, a voxel should be placed within the cystic component to minimize volume averaging with adjacent normal parenchyma and CSF. Spectra of abscesses show a complex appearance of multiple abnormal peaks, resulting from lactate and lipids, acetate (1.9 ppm) and succinate (2.4 ppm) from anaerobic glycolysis in bacteria, and amino acids (0.9 ppm) (including valine, alanine, and leucine) due to proteolysis, other than a relative absence of normal metabolites [93,94] (Fig. 12.35). 12.4.1.3 Empyemas

Epidural and subdural empyemas are rare purulent extracerebral collections that frequently occur concurrently. They may follow neurosurgery, trauma, or sinusitis. Rarely, they are secondary to meningitis or hematogenous dissemination. Epidural empyemas (Fig. 12.36) are frequently caused by frontal sinusitis and mastoiditis. Subdural empyemas (Fig. 12.37) are most commonly located over the cerebral convexity, and may rapidly and diffusely spread along the hemispheric surface and into the interhemispheric fissure [70]. Empyemas secondary to meningitis are

commonly located over the frontal convexity, whereas those secondary to sinusitis or otitis are usually located in the interhemispheric fissure, along the tentorium cerebelli, or along the floor of the anterior or middle cranial fossae [5]. On CT and MRI (Figs. 12.36, 12.37), both epidural and subdural empyemas are characterized by purulent collections into the extracerebral space with compression of adjacent sulci. Distinction between the two forms is based on their shape, which is lentiform when epidural and crescentic when subdural, just as with hematomas. They usually appear as a unilateral collection, slightly denser than CSF on CT, slightly more intense than CSF on T1-weighted, and less hyperintense than CSF on T2weighted images. In around 50% of cases, these collections are multilocular [5]. Vasogenic edema usually does not occur. Evidence of low density on CT or T1 and T2 hyperintensity on MRI in the adjacent parenchyma usually results from an associated cerebritis (concurrent with empyemas in around 20% of cases) [95–97]. Less commonly, it is related to venous or arterial ischemia. Contrast enhancement is uncommon in the early stages, whereas marked enhancement, creating a demarcation between the empyema and the subjacent parenchyma, becomes evident after 1–3 weeks [5] (Figs. 12.36, 12.37). In subdural empyemas, both the internal and external inflammatory membranes enhance, while the external membrane is rarely visible on CT scan [68]. In epidural empyemas, dural necrosis may cause secondary subdural empyemas and daugh-

a

b Fig. 12.36a,b Epidural empyema secondary to frontal sinusitis in a 9-year-old boy. a Gd-enhanced sagittal T1-weighted image. b Gd-enhanced coronal T1-weighted image. This child with frontal sinusitis (open arrow, a) has a large frontal epidural and subgaleal collection (E, a,b). The dura is thickened and enhances markedly with gadolinium (arrowheads, a,b). The superior sagittal sinus is dislocated caudally (arrow, b). Notice satellite abscess (asterisk, a) surrounded by huge perifocal edema (O, a,b)

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a

b Fig. 12.37a,b Multilocular subdural empyema in a 7-year-old girl. a Gd-enhanced coronal T1-weighted image. b Coronal T2-weighted image. Multiple subdural empyemas are located in the right fronto-temporal regions (e, a). Both pachymeningitis with thickening of the dura and leptomeningitis close to the empyema are visible (open arrows, a); there also is leptomeningeal enhancement within the adjacent sulci (arrowheads, a). A daughter abscess is seen in the temporal lobe (thin arrow, a). Diffuse edema and swelling of the right temporal lobe are evident (O, b). Note that purulent collections show mixed signal intensity on T2-weighted images (b)

ter abscesses (Fig. 12.36). Daughter abscesses may also complicate subdural empyemas (Fig. 12.37). Unless the lesion is parafalcine and therefore necessarily subdural, it may be difficult to differentiate between epidural and subdural locations on imaging [5]. However, demonstration of a linear hypointensity on T2-weighted images, corresponding to the dislocated dura, stands for epidural empyemas, while the absence of this hypointense rim is typically observed in subdural empyemas. Furthermore, it should be remembered that a diffuse meningeal involvement may coexist in cases of subdural empyema (Fig. 12.37). It should be underlined that it is mandatory to seek a possible source of infection in the sinuses, middle ear, mastoid air cells, orbit, and skull in the presence of an extraaxial fluid collections without history of trauma or meningitis [5]. 12.4.1.4 Toxin-induced Neurological Disease

In addition to direct invasion of the CNS, bacteria can cause neurological damage indirectly by producing neurotoxic substances. A number of neurotoxins have been identified in specific bacterial infections. Diphtheria is the prototypic toxin-induced illness. However, it is now exceptional after widespread introduction of immunization [70]. Neurotoxins are produced by other organisms, such as Clostridium tetani, Clostridium botulinum, Bordetella pertussis, Legionella pneumophila, etc.

Staphylococcus aureus and group A streptococci produce pyrogenic toxins including the toxic shock syndrome toxin-1, the staphylococcal enterotoxins, and the streptococcal pyrogenic exotoxins (synonyms: scarlet fever toxins and erythrogenic toxins), all capable of causing toxic shock syndromes and related illnesses [98]. We have observed a boy presenting with signs of CNS involvement consistent with vasculitis and gray matter encephalitis a few weeks after scarlet fever, probably related to toxin-induced mechanisms due to the streptococcal pyrogenic exotoxins (Fig. 12.38). Although the question regarding differential diagnosis with acute disseminated encephalomyelitis (ADEM) remained open, we nevertheless favored the hypothesis of toxin-induced neurological damage due to the exclusive involvement of the gray matter with substantial sparing of the white matter throughout the brain.

12.5 Other Intracranial Bacterial Infections 12.5.1 Central Nervous System Tuberculosis 12.5.1.1 Background

Tuberculosis is still today the single most important bacterial infection worldwide in both developing and

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Fig. 12.38a–c Vasculitis occurring 20 days after the onset of scarlet fever in a 7-year-old boy (possible toxin-induced mechanism). a,b Axial T2-weighted images; c 3D TOF MR angiography, axial MIP. Diffuse patchy areas of hyperintensity involve the gray matter of both cerebral hemispheres (asterisks, a,b). MR angiogram shows focal areas of absent flow signal at the level of the trifurcation of the left middle cerebral artery and of the M1 segment of the right middle cerebral artery (arrowheads, c), consistent with vasculitis

c

industrialized nations [99, 100]. The incidence of tuberculosis is higher in the pediatric age group, especially between 4–6 years of life [101–103]. A higher frequency of CNS involvement is evident in HIV-related tuberculosis than in patients without AIDS [104–106]. Clinical symptoms of CNS involvement become evident within 6 months of the initial tuberculous infection [107, 108]. Congenital tuberculosis with multisystem involvement has also been reported [109]. CNS involvement results from hematogenous spread from a primary focus (most commonly pulmonary) or, more rarely, from direct spread of infections of the adjacent paranasal sinuses or mastoid air cells [110–112]. The nonspecific inflammatory response occurring at the first exposure to the mycobacterium subsequently evolves into a granulomatous formation [100]. The tuberculous granuloma is typically small and characterized by epithelioid cells, containing the tuberculous bacilli, surrounded by fibroblasts and inflammatory cells [112, 113]. The immunological reaction of the host leads to the transformation from

hard tubercle (containing multinucleate giant cells, termed Langerhans cells) into soft tubercle, the hallmark of tuberculosis (resulting from coagulative and liquefactive necrosis, i.e., caseous necrosis). Several clinicopathologic forms of intracranial tuberculosis, including meningeal and parenchymal lesions, are recognized and will be discussed herein. Spinal tuberculosis is discussed in Chapter 41. 12.5.1.2 Tuberculous Meningitis

Isolated tuberculous meningitis represents less than 5% of childhood bacterial meningitis [114], and most children with tuberculous meningitis also have concomitant miliary brain infection or combined parenchymal/meningeal lesions [110]. Typical symptoms and signs of meningitis may be absent in pediatric tuberculous meningitis. The first stage of disease is characterized by irritability and personality changes, followed by fever, headache, nausea, vomiting, neck

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stiffness, eventually complicated by cranial nerves palsies (of those nerves running through the skull base), seizures, hemiparesis, and coma [101, 111, 115]. Neuropathological Findings

The earliest and predominant locations of tuberculous meningitis are the basal meninges of the interpeduncular fossa at the level of the anterior aspect of the midbrain and pons. The meningeal exudate progressively becomes thicker, gelatinous, and partly fibrotic, and tends to obstruct the basal cisterns, eventually causing communicating hydrocephalus [101, 104, 111, 116, 117]. Rarely, obstruction of the aqueduct or of the fourth ventricular foramina may cause obstructive hydrocephalus. Secondary calcification of basal meninges may occur [118]. Involvement of small cortical vessels and perforating arteries from spread of inflammatory process into the Virchow-Robin spaces causes vasculitis, accounting for infarctions and ischemia [5, 20, 100]. Infarctions are more common in children than in adults [119].

Two mechanisms have been proposed for the pathogenesis of tuberculous meningitis: rupture of small subpial or subependymal granulomas into the CSF, and direct penetration of the meningeal vessels by hematogenous spread [120]. Imaging Studies

Basal leptomeningitis is characterized by obliteration of the basal cisterns by tuberculous exudates (Fig. 12.39). This is visible, albeit with difficulty, on unenhanced CT. After contrast administration, an obvious picture of homogeneous enhancement of the basal meninges is seen. Meningeal enhancement can extend into the ambient, sylvian, and prepontine cistern, around the optic chiasm, and over the surface of the cerebral and cerebellar hemispheres [101, 104, 111, 116, 117, 121, 122]. Hydrocephalus may be present in 45%–87% of cases at time of diagnosis [115]. On MRI, unenhanced T1weighted images show the basal cisterns have higher signal than the normal CSF [20], while on T2-weighted MR images, the exudate may be overlooked due to

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c

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Fig. 12.39a–c Tuberculous meningitis with infarction in a 7year-old boy. a Axial CT scan. b Contrast-enhanced axial CT scan. c Gd-enhanced sagittal T1-weighted image. The basal cisterns are spontaneously hyperdense (a) and enhance markedly following contrast material administration (b). On postcontrast CT scan, a focus of cerebritis (arrowhead, b) is recognizable. Parasagittal MR image shows cortical enhancement secondary to ischemic damage in the fronto-rolandic regions (open arrows, c)

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b Fig. 12.40a,b Tuberculous meningitis of the convexity in a young adult. a Gd-enhanced axial T1-weighted image. b Axial FLAIR image. Gadolinium administration reveals diffuse, mild leptomeningeal enhancement involving the right superior frontal and rolandic sulci (arrowheads, a). The FLAIR image shows mild hyperintensity of the same sulci (arrowheads, b), but also reveals a small intraparenchymal hyperintense area (arrow, b), consistent with a small focus of tuberculous cerebritis

the high intensity of CSF [5]. Following gadolinium administration, diffuse meningeal enhancement of the involved cistern is seen (Fig. 12.40) [5, 106, 110, 123], in association with thickening and distension of the subarachnoid spaces [20]. Either secondary extension of arachnoiditis to vessels or direct vessel invasion may cause vascular fibrinoid degeneration, resulting in infarctions (Fig. 12.39), particularly involving the basal ganglia and thalami, while the cerebral cortex, pons, and cerebellum are less common locations [106, 124]. These infarctions are more common in children than in adults [101, 122, 124]. Granulomatous tuberculous meningitis is a rare presentation of intracranial tuberculosis, characterized by diffuse or circumscribed granulomatous involvement of the basal meninges. CT scan shows basal meningeal enhancement associated with ill-defined mass-like features. On MRI, the granulomatous portion of meninges appears as a mass that is isointense to brain on T1-weighted images and hypointense on T2-weighted images [100]. Following gadolinium administration, enhancement is marked and heterogeneous.

weighted MR images, it appears iso- to hypointense to brain. Marked, homogeneous enhancement of the thickened meninges is seen after contrast administration [100].

12.5.1.3 Parenchymal Tuberculomas

Intracranial parenchymal granulomas (i.e., tuberculomas) may be of variable size (usually smaller than 2 cm, although sometimes >5–6 cm in diameter) [21], located anywhere in the brain (usually at the corticomedullary junction) [20], associated or not with tuberculous meningitis, single (especially if infratentorial) or multiple (particularly if supratentorial) [5]. A higher frequency of infratentorial tuberculomas in children than in adults has been reported [125]. Rarely, tuberculomas may have a dural attachment [126]. Clinical presentation is usually with fever, headaches, seizures, and signs of increased intracranial pressure. Imaging Studies

Pachymeningitis is a rare complication of tuberculous meningitis due to extension of infection to the dura mater. The most common locations are the cavernous sinus, the floor of the middle cranial fossa, the cerebral convexity, and the tentorium [100]. The affected dura appears solid or plaque-like, with or without calcification. Calcification is, obviously, readily appreciable on CT scan. On both T1- and T2-

The imaging appearance depends on the stage of evolution (Table 12.12). As a general rule, central necrosis produces low attenuation, while granulomatous tissue shows higher attenuation on CT scan [21]. On MRI, the degree of necrosis and the presence of free radicals or trace metals accounts for the variable signal intensity [21]

Infectious Diseases Table 12.12. Imaging findings of parenchymal tuberculous granulomas Tuberculous cerebritis

Noncaseating tuberculous granulomas Hard tubercle

Caseating tuberculous granulomas Soft tubercle

CT scan

Hypodense

Iso- slightly hyperdense

Isodense (sometimes hypodense margins) Healed tuberculoma may calcify

MR T1

No signal abnormality

Iso- to hypointense

Iso- hypointense

MR T2

Hyperintense signal

Hypo- to hyperintense

Hypointense rim with hyperintense central dot

Enhancement

Variable on MRI Absent on CT scan

Marked (ring, nodular or irregular)

Variable Marked peripheral enhancement on MRI “Target sign” (i.e. a ring-enhancing lesion with a central area of no enhancement or calcification) occasionally seen on CT scan

Tuberculous cerebritis, evolving into mature noncaseating tuberculous granuloma, is characterized by circumscribed low density with ill-defined enhancement on CT scan (Fig. 12.39). T1-weighted MR images may be normal. On T2-weighted and FLAIR images, the lesion appears as a focal hyperintense area (Fig. 12.40). The degree of enhancement is variable depending on the amount of inflammatory hypervascularity, reactive neovascularity, and BBB breakage [100]. When present, it is a good indicator of the stage of granulomas and response to therapy [100]. Noncaseating tuberculous granulomas (i.e., hard tubercles) (Fig. 12.41) may be nodular or en plaque, single or multiple. On CT scan, they appear as isodense or slightly hyperdense lesions surrounded by edema. On T1-weighted images, they are iso- to hypointense, while on T2-weighted images they are hypo- to hyperintense. Marked nodular enhancement is seen after contrast material administration, both on CT and MRI [100]. Caseating tuberculous granulomas (i.e., soft tubercles) appear as isodense lesions on CT, sometimes with hypodense margins. Enhancement is absent within the central caseation and strong in the periphery, producing a typical ring-enhancing appearance. A variable degree of white matter edema surrounds the lesion. On T1-weighted MR images, they appear as iso- to hypointense lesions, while on T2-weighted images they are hypointense with a central dot-like hyperintensity (corresponding to caseating necrosis), surrounded by irregular edema. Marked ring enhancement is also seen after gadolinium administration. Disseminated tuberculosis is characterized by a diffuse infiltration of brain by small granulomas appearing as multiple, hypo- to hyperintense lesions without central high signal and surrounded by edema on T2-weighted images. Intense nodular enhancement

is seen after contrast administration [100]. Although rarely, these lesions may calcify. 12.5.1.4 Tuberculous Abscess

Tuberculous abscesses are rare manifestations of intracranial tuberculosis, most commonly seen in the immunocompromised population [4]. Most involve the gray-white matter junction supratentorially. Tuberculous abscesses are larger than granulomas, are teeming with tubercular bacilli (while tuberculomas contain only few bacilli), and elicit more vasogenic edema [5, 120]. They are considered to result from liquefactive breakdown of caseated tuberculomas [127]. Although they may be grossly similar to bacterial abscesses, they are more often multiloculated [128, 129]. On CT scan, they appear as hyperdense lesions with a hypodense center. On MRI, T1-weighted images show the center of the abscess to be hypointense, and its wall slightly hyperintense. On T2-weighted images, the center is hyperintense and the wall hypointense. Large, irregular perifocal edema is typically present. Peripheral ring enhancement is evident after contrast administration [100]. Precontrast magnetization transfer (MT) imaging has been reported to improve lesion detection in CNS tuberculosis compared to routine MR images, and to help in differential diagnosis with similar-appearing lesions [130]. On MT spin-echo images, tuberculomas invisible on conventional spin-echo images show a lower transfer of magnetization compared to the surrounding brain parenchyma [130]. Moreover, the MT ratio of tuberculous meningitis is lower than that of pyogenic or fungal meningitis and higher than that of viral meningitis [130]. Furthermore, MT ratios may differentiate between tuberculomas and cysticercus granulomas in the face of a similar appearance on

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a

b

c

d Fig. 12.41a–d Cerebellar tuberculoma. a Axial CT scan. b Contrast-enhanced axial CT scan. c Axial T1-weighted image. d Axial T2-weighted image. On CT, there is an ill-defined, isodense left cerebellar mass showing speckled calcification (arrowhead, a). Contrast material administration reveals a partly solid, partly ring-like enhancement pattern. On MRI, there is slight T1 hyperintensity (arrow, c), and very characteristic low T2 signal intensity (arrow, d). Perifocal edema is marked and causes compression and displacement of the brainstem and fourth ventricle

conventional MRI: T2 hypointense cysticercus granulomas show a significantly higher MT ratio than that of T2 hypointense tuberculomas [130]. MR spectroscopy shows only lipid peaks, with specific components of serine and phenolic lipids that are absent in other intracranial masses [131].

12.5.2 Lyme Disease (Neuroborreliosis) 12.5.2.1 Background

Lyme disease is a tick-transmitted spirochetal disorder caused by the spirochete Borrelia burgdor-

feri, a highly specialized, motile, two-membrane, spiral-shaped bacterium which lives primarily as an extracellular pathogen. Lyme disease is a multisystem disease with extreme clinical variability, characterized by alternating episodes of remission and exacerbation. CNS involvement occurs in 10%–20% of cases, several weeks or months after exposure to infection [20, 21, 100, 132]. The first stage of disease [3–32 days] is characterized by skin lesions (erythema chronicum migrans) and “f lu-like” symptoms; in the second stage (after several weeks to months) neurological symptoms or cardiac involvement are seen; the third stage (weeks up to 2 years after the onset of infection) is characterized by arthritis and chronic neurological symptoms.

Infectious Diseases

Neurological manifestations include meningitis, encephalitis, cranial neuritis (especially facial palsy), headaches, sleep disturbances, mood and memory disturbances, radiculoneuritis, chorea, and myelitis [132, 133]. Both acute neurological pictures and chronic encephalopathy have been described [134]. Moreover, acute onset of unusual neurological symptoms in childhood has been described in some reports: these have included acute transverse myelitis and cranial polyneuritis [135], acute hemiparesis [136, 137], and acute loss of neurological function associated with signs of increased intracranial pressure, mimicking intracranial space-occupying lesion [138]. In the latter case, the presence of CSF cellular pattern identical to that found in CNS involvement from non-Hodgkin lymphoma has been considered to result from blastoid transformation of lymphocytes induced by the antigenic stimulus exerted by the spirochete [138]. Different pathogenetic mechanisms of CNS involvement have been suggested, including direct spirochetal invasion, vasculitis, and an immunomediated process. The latter is supported by the occurrence of focal demyelination with perivascular inflammatory infiltrates similar to those of ADEM [100, 132].

[145–147]. This form has been termed the “European form of Lyme disease” [5]. MRI evidence of ischemic infarction involving the basal ganglia has been reported in two cases presenting with acute hemiparesis [136]. Although rarely, large vessel occlusive disease has been reported in childhood [137]. Thus, neuroborreliosis could be considered in cases of stroke-like episodes of unknown origin. Cerebral atrophy may occur in some cases of chronic neuroborreliosis [148]. Differential Diagnosis

12.5.2.2 Imaging Studies

Differential diagnosis of Lyme disease includes a wide host of entities. White matter involvement may be found in acute disseminated encephalomyelitis (ADEM), vasculitis, ischemic lesions, viral encephalitis, multiple sclerosis, and tumors. Enhancement of the cranial nerves is found in Bell’s palsy, sarcoidosis, viral meningitis, leukemia, CNS lymphoma, HIV infection, ophthalmoplegic migraine, Tolosa-Hunt syndrome, syphilis, demyelinating optic neuritis, postradiation optic neuritis, metastatic disease, and may be physiological in some cases [149]. Finally, multiple cranial nerve involvement can be due to Miller-Fisher syndrome. It is clear that diagnostic investigations other than MRI are required to perform such differential diagnosis. This will often entail CSF analysis.

CT scan is relatively insensitive in detecting the disease [134], although slight hypodensity of the affected regions has been reported [5, 134]. Only about 25% of cases shows positive MRI findings. In fact, imaging may be normal, despite the presence of neurological symptoms [20, 21, 100, 139]. On MRI, white matter involvement (Fig. 12.42) is the most typical finding, appearing as single or multiple, uni-or bilateral, focal areas of high signal intensity on T2-weighted and FLAIR images [5, 140, 141]. Both periventricular and subcortical white matter involvement have been reported [21, 134]. Lesions may be multifocal or confluent [134]. Lesions involving the basal ganglia or thalami [139, 141], the capsular regions [141] (Fig. 12.42), and corpus callosum [143] have been reported. In patients with cranial neuropathy (Fig. 12.43), the affected nerve(s) is thickened [144] and enhances markedly, as a result of hypervascularity of the nerve and perineural tissue and/or hematoneural barrier disruption [5, 144]. Primary leptomeningeal enhancement along the brainstem (Fig. 12.43) and tentorial enhancement without parenchymal lesions have been described

Fig. 12.42 Lyme disease in a 10-year-old girl. Axial T2-weighted image. Small hyperintense area involving the posterior limb of the right internal capsule (arrow). The lesion was not visible on T1-weighted images and did not enhance with gadolinium (not shown)

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a

b

c

d Fig. 12.43a–d Lyme disease in an 8-year-old girl. a–c Gd-enhanced axial T1-weighted images. d Gd-enhanced sagittal T1-weighted image. Following gadolinium administration, the right facial and vestibulocochlear nerve (long arrow, a), the cisternal segments of the abducens nerves (short arrows, a), trigeminal nerves (arrows, b), oculomotor nerves (long arrows, c), and the pre-chiasmatic optic nerves (short arrows, c) all enhance. Sagittal image shows a small area of enhancement in the inferior portion of the medulla oblongata (thin arrow, d). The ventral subpial surface of the cervico-medullary junction also enhances (thick arrows, d)

12.6 Intracranial Viral Infections Background

Viral infections of the CNS may cause a wide spectrum of diseases, including meningitis, acute encephalitis and encephalomyelitis, postinfectious encephalitis, and subacute encephalitides. Meningitis implies infection confined to the leptomeninges, without involvement of the nervous tissue. The most common cause is represented by enterovirus. Imaging studies are usually normal [16].

Encephalitis may result either from direct or indirect viral involvement of the brain tissue. One should note that the term encephalitis refers to diffuse viral brain disease, whereas cerebritis refers to focal bacterial infection. Therefore, the two terms are not interchangeable. Acute primary viral encephalitides are characterized by infection, replication of the virus within the neural tissue, and destruction of neurons and glial cells, mainly resulting in polioencephalitis, i.e., preferential involvement of the cortical gray matter [2]. The most common causative organisms are herpesviruses, although other viruses, such as enterovirus, arbovirus, and rubella may also be involved. Acute para/postinfec-

Infectious Diseases

tious encephalitides occur late in the course of a viral disease or after a vaccination (and less commonly may occur after a Mycoplasma infection). They are characterized by perivascular cuffing and demyelination, in the absence of virus within the brain, suggesting an immunological pathogenesis [2]. The term acute disseminated encephalomyelitis (ADEM) is currently used to refer to these forms [5] (see Chap. 15). Subacute and chronic encephalitides are characterized by a prolonged duration of disease that lasts for months or years [2]. These include, among others, subacute sclerosing panencephalitis and Rasmussen encephalitis. As a general rule, although imaging findings of different viral infections overlap considerably, some may show suggestive features. However, diagnosis is not always straightforward. One crucial point that requires due consideration is that, in our experience, it has often been difficult to differentiate between primary viral encephalitis and ADEM based on imaging alone. Such differentiation is, on the other hand, important in view of different treatment options (i.e., administration or withdrawal of corticosteroids). Clinical history (especially regarding prior history of recent upper airway/gastrointestinal infection or vaccination) and CSF analysis are equally important, if not superior, to MRI findings in this regard.

12.6.1 Acute Encephalitides 12.6.1.1 Herpes Simplex Virus Encephalitis

Herpes simplex virus (HSV) encephalitis is the most common cause of sporadic acute encephalitis in temperate parts of the world [2]; it is particularly common in the pediatric age group [5]. The majority of herpetic encephalitides in children aged 6 months or older are caused by HSV type 1, whereas HSV type 2 is the causative organism in immunosuppressed patients other than, typically, in congenital HSV infection (see above, “Intracranial congenital infections”). Either primary infection or reactivation of a preexisting infection may cause encephalitis [5]. While hematogenous spread seems to be limited to neonatal cases [2], the HSV typically reaches the CNS along the neural pathways. During primary HSV infection, the virus penetrates through the oral or nasal mucosa. Nasal colonization allows direct spread to the CNS along the olfactory route through the cribriform plate. Oral infection allows the virus to climb along the trigeminal branches, reaching the gasserian ganglion where it may remain latent indefi-

nitely. Reactivation, related to various factors, causes retrograde viral spread towards the limbic structures through the roots of the trigeminal nerve, probably on the basis of a specific tropism of HSV for the cells of the limbic system [2, 36, 150]. The whole brain is then rapidly involved by the infection [20]. Clinical Findings

About 60% of children show prodromal symptoms, such as fever, malaise, and behavioral disturbances; symptoms of respiratory infection are evident in 30% of cases. Clinical manifestations characteristic of encephalitic process, such as alterations in consciousness (ranging from lethargy to coma) and seizures (typically focal) appear within several days. Hemiparesis often develops [151]. EEG shows highly suggestive periodic localized or lateralized discharges. Polymerase chain reaction (PCR) in the CSF is typically positive during the first week of infection and up to 5 days into acyclovir therapy, with sensitivity over 95% and specificity approaching 100% [36]. Neuropathological Findings

HSV encephalitis is a necrotizing hemorrhagic meningoencephalitis, usually beginning in the temporal lobes [5, 21]. The most striking pathological finding is widespread, uni- or bilateral, asymmetrical necrosis. The temporal lobes are predominantly involved, especially in the anterior parts of the parahippocampal, inferior, and middle temporal gyri, extending to the superior temporal gyrus, posterior orbital frontal lobe cortex, and insula. The necrosis is not restricted to the neocortex, but involves the white matter, hippocampus, amygdala, putamen, and cingulate gyri. Bilateral involvement of the temporal lobes may be asynchronous. Microscopic changes are initially characterized by necrosis associated with diffuse meningoencephalitis, which is particularly intense in and adjacent to the necrotic tissue. Areas of hemorrhage are frequently present. Reactive microglial hyperplasia follows the disintegration of the necrotic tissue. Intranuclear inclusion bodies may be identified within the neurons or glial cells. Tissue shrinkage, destruction of the cortex, and cyst formation leading to severe cavitation with almost complete destruction of one or both temporal lobes are the chronic histological changes [2]. Imaging Studies

CT scan is typically normal in the first days of disease [5]. The earliest CT findings, reflecting the initial tem-

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poral lobe localization, are poorly defined areas of low density with mild mass effect in the affected regions [5, 16, 20, 21, 99]. Both the cortex and the subjacent white matter are involved [21]. Small hyperdense foci, consistent with hemorrhage, may be occasionally seen within the damaged tissue in the early studies, whereas they are more consistently detected on studies performed later in the course of the disease [5, 99]. Either gyriform or ill-defined, patchy enhancement may be seen after contrast administration [5, 99]. It should be underlined that enhancement is seen only after the appearance of hypodense areas on baseline CT scan [5]. MRI is the gold standard in diagnostic imaging of HSV encephalitis, being more sensitive than CT in detecting early changes and allowing better evaluation of the degree of CNS involvement. MRI (Fig. 12.44) shows prolongation of T1 and T2 relaxation times in the temporal lobe, insular cortex, orbital surface of the frontal lobe, and cingulate gyrus. Occasionally, the parietal lobes may also be involved [21]. Atypical (i.e.,

nontemporal) locations of disease may be found in HIVinfected patients, suggesting that HIV infection can distinctly modify the spatial distribution of herpetic encephalitis. T2-weighted and FLAIR images are most sensitive to areas of inflammatory swelling, appearing as high-signal-intensity lesions involving both the gray and white matter [5, 21]. On T1-weighted images, multiple hyperintense areas representing petechial hemorrhage are commonly seen. Midline shift and tentorial herniation may occur secondary to brain edema [152]. After gadolinium administration there is a variable degree of enhancement, predominantly involving the pial and cortical surfaces with a typical gyriform pattern. Usually, enhancement is not detected earlier than three days after clinical presentation [21]. The MRI appearance rapidly changes during the course of the disease, and evolution of MRI findings may be used for monitoring the response to antiviral therapy [21]. More widespread changes may be seen with disease progression, eventually resulting in atro-

a

c

b

Fig. 12.44a–c Herpes simplex virus type 1 infection. a Axial T1weighted image. b Axial FLAIR image. c Gd-enhanced sagittal T1-weighted image. Axial T1-weighted image shows diffuse hypointensity in the right temporal lobe with patchy areas of spontaneous hyperintensity that prevailingly involve the cortex (arrowheads, a), consistent with hemorrhagic necrosis. FLAIR image shows diffuse signal changes, also involving the white matter. The homolateral amygdala, hippocampus, and gyrus rectus (arrow, b) are also involved. Following gadolinium administration, enhancement is marked both in the corticosubcortical temporal regions and in the insula (arrow, c)

Infectious Diseases

phy, encephalomalacia, and dystrophic calcifications in the burnt-out stage (Fig. 12.45) [16]. In some infants and very young children with HSV type 1 encephalitis, involvement of multiple cerebral lobes has been reported. This has been thought to reflect hematogenous viral spread, producing a multifocal or diffuse involvement that may occur also beyond the neonatal age [153, 154]. Asynchronous involvement of multiple lobes may reflect reinfection (Fig. 12.46). The association of herpes simplex encephalitis and anterior opercular syndrome has been reported in some children [155–158]. Anterior opercular syndrome is characterized by anarthria and impaired mastication and swallowing due to bilateral, focal cortical damage of the anterior opercular region (i.e., the cerebral cortex surrounding the sylvian fissure and covering the insular area). Though unusual, this specific clinical and imaging pattern should be recognized as a possible presenting feature of HSV encephalitis in the pediatric age group. Advanced MR Imaging

Proton MR spectroscopy studies have demonstrated decreased NAA/Cr ratio (reflecting neuronal loss), elevated choline and lipids (reflecting demyelination), and elevated lactate (reflecting anaerobic metabolism) in the acute-subacute stages of disease, with improvement after successful acyclovir treatment, in parallel with neurological recovery [159, 160]. DWI shows bright signal in the affected areas, with mild decrease of ADC with respect to the normal adjacent parenchyma [161]. DWI may be more sensitive

a

than conventional T2-weighted imaging in revealing parenchymal damage. Lower ADC values have been associated with poorer disease outcome [161, 162]. Differential Diagnosis

Although bilateral temporal involvement with the above described imaging appearance is characteristic of HSV encephalitis, similar bitemporal distribution has been reported in gliomatosis cerebri, systemic lupus erythematosus, Hurst’s hemorrhagic leukoencephalitis, and paraneoplastic limbic encephalopathy [163, 164]. Bilateral hippocampal involvement from enteroviruses has been described in patients presenting with encephalitis and CSF PCR studies negative for HSV [165]. 12.6.1.2 Human Herpesvirus-6 Infection

Human herpesvirus-6 (HHV-6) is the causative agent of exanthema subitum, typically occurring in children younger than 2 years of age. Neurological complications include febrile seizures, meningitis, and meningoencephalitis. The outcome is favorable in about half of cases, while the remaining patients show severe sequelae [166, 167]. HHV-6 encephalopathy predominates in Japan. Immunohistochemical studies have shown that both astrocytes and oligodendrocytes are infected by HHV-6, and the susceptibility of glial cells to HHV-6 infection has been confirmed by in vitro studies [168, 169]. Therefore, HHV-6 may cause destruction of oligodendrocytes and demyelination [166].

b Fig. 12.45a,b Herpes simplex virus type 1 infection in a 1-year-old boy. a Axial T2-weighted image. b Sagittal T1-weighted image. Diffuse malacic sequelae of HSV type 1 infection involve the left frontal, insular, temporal and occipital regions. Notice involvement of the mesial portions of the contralateral temporal pole (a)

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a

b Fig. 12.46a,b Herpes simplex virus type 1: reinfection in a 10-year-old girl. a Gd-enhanced axial T1-weighted image. b Coronal T2-weighted image. There is marked swelling of the left temporal lobe with subtle cortical enhancement (a). The amygdala and hippocampus are also involved. Coronal image shows swelling of the whole left temporal lobe and partial involvement of the insula (arrow, b). Signal change involves both the gray and the white matter, and there is mass effect with contralateral midline shift. Also, malacic sequelae of prior contralateral HSV type 1 infection are depicted (asterisk, a,b)

On MRI, multifocal white matter involvement, similar to that observed in ADEM, as well as thalamic, cerebellar, and pontine lesions have been demonstrated [166, 167, 170] (see Chap. 11). 12.6.1.3 Acquired HIV Infection

Acquired AIDS in children is equivalent to that in adults, therefore it is not further discussed here. Congenital HIV infection is described above (see “Intracranial congenital infections”). 12.6.1.4 Measles

Measles may cause acute encephalitis, basically characterized by brain edema. However, this is a rare entity, especially with widespread vaccination. Bilateral striatal necrosis has been described following measles [171]. Subacute sclerosing panencephalitis is related to prior measles infection. It is described below (see “subacute encephalitides”). 12.6.1.5 Chickenpox

Chickenpox is caused by the varicella-zoster virus, belonging to the family of herpetic viruses (Herpesviridae). Chickenpox may be associated with CNS

complications in less than 1% of cases, but immunocompromised children have a higher incidence of CNS complications related to varicella infection. CNS complications may be related either to direct brain invasion by the virus or to immune-mediated processes [172–176]. Although neurological complications usually occur between 2–6 days after the onset of the rash, pre-eruptive varicella encephalitis (up to 2.5 weeks before the onset of the exanthema) which probably occurred during the initial viremia has been occasionally reported [177]. The most common complication of varicella is acute cerebellitis (see below) occurring days to 2 weeks after the exanthema, usually resolving after weeks to months. Delayed onset of neurological deficits, usually characterized by acute contralateral hemiplegia sometimes associated with extrapyramidal symptoms, has been described 1–4 months after primary varicella or herpes zoster infection [170, 173, 178]. The postulated pathophysiological mechanism is a focal vasculitis. MR imaging shows basal ganglia infarcts (Fig. 12.47), commonly unilateral. The putamen and caudate nucleus are more frequently involved [173, 179–181]. Involvement of the basal ganglia is a common feature of a wide host of diverse conditions in the pediatric age (Table 12.13), which may enter the differential diagnosis. MR angiography may either be normal or show unilateral narrowing of the common carotid artery and of proximal branches of the anterior or middle cerebral artery [173].

Infectious Diseases

a

Fig. 12.47a–d Delayed onset of neurological symptoms following chickenpox in a 4-year-old boy (onset of right hemiparesis 1 week after the rash). a Axial T2-weighted image. b Gd-enhanced axial T1-weighted image. c,d 3D TOF MR angiography, axial MIP. MRI performed at the onset of neurological symptoms shows signal abnormality involving the anterior two-thirds of the left lentiform nucleus and the head of the homolateral caudate nucleus (arrows, a). Following gadolinium administration, these lesions enhance (arrows, b). MR angiogram shows narrowing of the left middle cerebral artery (arrowhead, c). The neurological picture worsened in the following days. Three days after, MR angiogram shows complete occlusion of the left middle cerebral artery (arrowhead, d)

b

c Acute Cerebellitis

Acute cerebellitis is characterized by acute onset of signs of cerebellar dysfunction, with or without fever and meningismus. Sometimes a history of recent viral illness may be obtained. Clinical symptoms usually resolve spontaneously over weeks to months, although severe cases showing permanent disability have been reported [5]. Acute cerebellitis may be caused by vasculitis, demyelinating processes, intoxication, cyanide poisoning, and infectious disorders. The main infectious etiologies are summarized in Table 12.14. Chickenpox is the most frequent among these. Cerebellitis presumedly related to prior influenza virus infection has also been reported [182]. Idiopathic forms represent a diagnosis of exclusion. In most cases, presumed cerebellitis is treated on a clinical basis and imaging studies are not performed. When available, imaging findings (Fig. 12.48) include diffuse cerebellar swelling and bilateral, symmetrical areas that are hypodense on CT and show T1 and T2 prolongation on MRI, pref-

d erentially involving the gray matter of the cerebellar hemispheres [5, 183]. Focal edema may cause acute hydrocephalus due to decreased efflux of CSF from the fourth ventricle [5]. In the subacute stage, enhancement may be observed following gadolinium administration. Acute hydrocephalus, secondary to compression of the fourth ventricle by localized edema, may rarely occur [5]. 12.6.1.6 Influenza Virus Infection

Acute encephalitis is an uncommon complication of influenza virus infection. It is still unclear whether CNS involvement is caused by direct invasion by the virus or by an immune-mediated process [184]. Both diffuse and focal brain involvement have been reported [185, 186]. MR imaging may show areas of abnormal signal (hyperintense on T2-weighted and FLAIR images) involving the cerebral cortex and adjacent white matter [184]. Symmetrical thalamic lesions have also been reported [187]. It has also been reported that

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P. Tortori-Donati, A. Rossi, and R. Biancheri Table 12.13. Differential diagnosis of basal ganglia involvement in childhood Anatomic distribution

Acute

White matter involvement

Globus pallidus

Caudate

Putamen

Hypoxia/ischemia Neonate

+

-

+

+/-

Hypoxia/ischemia Older child

+

++

++

+

Hypoglycemia Neonate

+/-

-

-

++

Hypoglycemia Older child

+

+

+

+

Toxins (carbon monoxide, cyanide)

++

+

+

+

Hemolytic-uremic syndrome

+

+

+

+

Osmotic myelinolysis

+

+

+

++ pons

Encephalitis

+

+

+

+

+

Parainfectious encephalomyelitis Tegretol toxicity Chronic Inborn errors of metabolism Mitochondrial disorders

+

+

++

Canavan’s disease

+

-

-

++

GM2 gangliosidoses

-

++

-

+

Glutaric aciduria type I and II

-

+

+

+

Methylmalonic acidemia

+

-

-

+

Propionic acidemia Molybdenum cofactor deficiency

-

++

++

+

L-2-OH glutaric aciduria

++

-

-

++

Wilson’s disease

++

+

++

+

Hallervorden-Spatz disease

++

-

-

++

Biotinidase deficiency MSUD -

Dentatorubral and pallidoluysian atrophy Degenerative disorders Juvenile Huntington disease

++

-

Sequelae of acute insults Basal ganglia calcifications Other disorders Neurofibromatosis type 1

DWI may depict lesions more extensively than conventional MRI [184, 186]. 12.6.1.7 Epstein-Barr Virus (EBV) Infection

EBV may be associated with CNS involvement in 1%–10% of cases. Neurological manifestations may occur before, concomitantly with, or after the symptoms of infectious mononucleosis [188]. Encephalitis, meningitis, transverse myelitis, Guillain-Barré

syndrome, and cranial neuropathies have been described [2]. Both direct invasion of the virus and autoimmune phenomena have been postulated as the pathogenetic mechanisms of the cerebral involvement [189]. Imaging findings may be normal or nonspecific, with decreased signal on T1-weighted images and increased signal on T2-weighted images in the gray or white matter of the cerebrum and cerebellum [188]. Basal ganglia and brainstem involvement [188] and brain atrophy [187] have been reported.

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Infectious Diseases Table 12.14. Different infectious etiologies of acute cerebellitis Varicella-zoster Rubella Pertussis Diphtheria Typhoid fever Coxsackievirus Poliovirus Epstein-Barr virus

12.6.1.8 Mycoplasma Pneumoniae Infection

Mycoplasma pneumoniae infection may be complicated by CNS involvement, including encephalitis, meningitis, ADEM, and cerebral infarction. In children, acute encephalitis is the most common complication, accounting for 1%–10% of cases of acute childhood encephalitis [190]. The pathophysiology of CNS involvement is still unclear. Direct invasion of brain tissue by the organism, production of neurotoxins, and autoimmune mechanisms have been postulated [190–200]. Direct invasion of the brain parenchyma is revealed by the detection of Mycoplasma in the brain tissue or CSF, while an immune mechanism may be postulated in the absence of such finding [190]. Although some Mycoplasma species have been demonstrated to produce neurotoxins in infected mice, no such toxin has been revealed in humans infected by M. pneumoniae [197]. A restricted encephalitis of the striatum has been reported in some pediatric cases, usually aged from 5 to 11 years [194, 195, 201].

Cerebrovascular thromboembolism is a rare complication of M. pneumoniae infection, more frequently involving the anterior circulation but also reported in the posterior cerebral artery territory [196]. Leptomeningeal involvement may be related to immunomediated processes [193], meningeal vasculitis [192], or erythrophagocytosis [191] (Fig. 12.49).

12.6.2 Subacute and Chronic Encephalitides 12.6.2.1 Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a slow virus infection, occurring several years after primary measles infection and resulting from a persistent measles virus that is characterized by a defective genomic RNA [202]. After the introduction of measles vaccination, SSPE has been almost eradicated in developed countries, while it is unfortunately still endemic in many Third World countries. Clinical Findings

Age at presentation ranges from 2 to 21 years, with a peak at 7–9 years. Minor behavioral disturbances, occurring in a previously healthy child, are usually the initial insidious symptoms. Then, myoclonic spasms develop, and progressively increase in frequency. Progressive mental deterioration up to dementia follows; finally, neurovegetative status and death occur. Both slowly progressive and rapid course have been described [151]. Diagnosis is based on clinical fea-

a

b Fig. 12.48a,b Post-varicella cerebellitis in an 8-year-old girl. a Axial T2-weighted image. b Coronal T2-weighted image. Inhomogeneous hyperintense areas involve the cortex of both cerebellar hemispheres. The cerebellum has a swollen appearance

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a

b

c

Fig. 12.49a–c Meningoencephalitis due to Mycoplasma pneumoniae in a 6-year-old boy. a Axial T2-weighted image. b,c Gd-enhanced axial T1-weighted images. Diffuse hyperintense areas involve the basal ganglia and the right fronto-temporal and left mesial temporo-occipital cortex (a). Following gadolinium, there is marked and diffuse leptomeningeal enhancement (b,c)

tures, evidence of the characteristic periodic EEG pattern, and the titer of measles antibodies in the CSF. Neuropathological Findings

The macroscopic appearance of the brain may either be normal or show predominant white matter abnormalities or severe generalized cerebral atrophy, depending on the duration of the disease [2]. Histologically, lymphocytic and plasma cell infiltration in the leptomeninges and perivascular spaces prevails in the early stage of disease, whereas loss of cortical neurons with astrocytic and microglial hyperplasia are evident in the most severely affected cases [2]. Both the gray and white matter are involved [203]. Intranuclear inclusion bodies are present in both oligodendrocytes and neurons, and viral nucleocapsids are demonstrated by electron microscopy examination [2, 204]. The disease initially involves the cortical occipital regions and progressively spreads anteriorly, eventually affecting the subcortical structures, brainstem, and spinal cord [205]. Perivascular edema, lymphocytic inflammatory reaction, and demyelination are consistent with immune-mediated myelin damage, identical to that observed in post-infectious encephalitis and experimental allergic encephalomyelitis [206]. Later subcortical white matter involvement is identical to that observed in cases of other slow virus infections, such as AIDS [207]. In the later stage (i.e., after resolution of inflammation), demyelination, necrosis, and gliosis predominate. Progressive loss of white matter leads to atrophy [206].

Immunofluorescence studies have shown measles antigens within the neurons and glial cells [208] and measles-specific IgM antibody in serum and CSF [209, 210], indicating that SSPE is indeed causally related to measles. However, it is still unclear how the virus may remain dormant for many years and then reactivate to cause SSPE, and also whether the CNS is already invaded by the virus at the time of the primary infection or only later. It has been hypothesized that the measles virus might be changed into a slow virus, modified by another simultaneous viral infection [207]. An alternative hypothesis postulates that cell-associated forms of the virus, naturally occurring during the primary measles infection, may reproduce and spread within the CNS, in relationship to the host immune response [2, 211]. A failure to produce antibodies to a specific virus protein has also been postulated [212]. Imaging Studies

MRI findings evolve depending on the stage of the disease (Table 12.15). A constant pattern of MRI changes progression has been described, as follows: initial normal appearance (i.e., in the first 3–4 months after clinical presentation), followed by evidence of focal, patchy, and asymmetrical T2 hyperintensity (Fig. 12.50), located in the cerebral cortex and subcortical white matter of the parietal and temporal lobes and possibly characterized by mass effect and contrast enhancement. The periventricular white matter and corpus callosum are subsequently involved. In the most advanced stages, T2 prolonga-

Infectious Diseases Table 12.15. Evolution of MRI findings in SSPE Stage of disease

MRI findings

First months

Normal

First year

Asymmetrical gray matter and adjacent subcortical white matter high signal on T2-weighted images, prevailing in the posterior part of the brain. Periventricular white matter and basal ganglia lesions (only in a minority of cases)

Second year

Asymmetrical periventricular white matter high signal abnormalities. Regression of cortical/subcortical lesions Mild atrophy

After the 2nd year

Extensive, symmetrical, diffuse periventricular white matter lesions. Severe cerebral atrophy

tion in the brainstem and diffuse atrophic changes, up to almost total loss of white matter, are observed [5, 207, 213, 214]. The basal ganglia, and especially the putamen, are involved in about one-third of cases [5, 207]; differences in the reported percentage may depend on the timing of imaging evaluation [215]. Migration of basal ganglia involvement from the putamen to both the caudate nuclei has been reported by Sawaishi et al. [215], who suggested that axonal spread of the virus through the nigrostriatal pathway could explain these migratory basal ganglia lesions. In fact, evidence that the measles virus may be transported both anterogradely and retrogradely in axons was recently provided by studies on mice [216]. MR spectroscopy is useful to evaluate the extent of brain involvement, since severe metabolic abnormali-

a

b

c

d Fig. 12.50a–d Subacute sclerosing panencephalitis in a 9-year-old child. a,b Axial T2-weighted images. c,d Diffusion weighted images (DWI). Diffuse areas of abnormal signal intensity involve the cortico-subcortical regions and the white matter in the fronto-rolandic parietal regions bilaterally (a,b). DWI shows corresponding restricted diffusion (c,d). (Case courtesy of Dr. A.M.S. Low, Singapore)

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ties may be shown also in areas where conventional MRI demonstrates only small or no changes [217]. The following abnormalities have been described: decrease in NAA (reflecting severe neuronal loss), increase in inositol (related to active gliosis) and choline (related either to demyelination or inflammation), and presence of lactate peak (indicating macrophagic infiltration) [217]. 12.6.2.2 Brainstem Encephalitis

Selective brainstem encephalitis may be due either to primary viral infection or to an immunomediated process. It is a rare occurrence in the pediatric age group [218]. Viral brainstem involvement mimicking an infiltrating tumor [188] or appearing as a posterior fossa pseudotumor narrowing the fourth ventricle and causing obstructive hydrocephalus [218] has been reported in childhood. It is noteworthy that ADEM may also show similar behavior (see Chap. 15), highlighting the difficult differential diagnosis between viral and postviral conditions. Bickerstaff encephalitis is a brainstem inflammatory disease that often follows a viral illness and is thought to have an immune pathogenesis. Although it is usually a monophasic disease, remitting-relapsing course has been described [219]. The clinical picture includes ataxia, ocular paresis, and impaired osteotendinous reflexes, thus recalling that of MillerFisher syndrome, which is considered to be a variant of Guillain-Barré syndrome (see Chap. 41). Although Miller-Fisher syndrome is a peripheral nervous system disorder and Bickerstaff encephalitis is a CNS disease, some cases of Miller-Fisher syndrome show evidence of concurrent central involvement [220, 221], thus complicating the already controversial issue on the mutual relationships of these disorders. Furthermore, the diagnostic role played by positive anti-GQ1b antibodies is controversial, since they are frequently elevated both in Miller-Fisher syndrome and in Bickerstaff encephalitis [222]. MRI shows areas of hypointensity on T1-weighted images and hyperintensity on T2-weighted images, typically located in the brainstem but sometimes involving also the basal ganglia and thalami. Contrast enhancement is variable (Fig. 12.51).

6–8 years [224]. This disease, occurring in previously normal subjects, is characterized by severe epilepsy, hemiplegia, dementia, and inflammation of the brain. The etiology and physiopathology are still unclear. The main hypotheses suggest a viral infection (such as CMV, herpes simplex virus, Epstein-Barr virus, or slow virus) [225–227], an immune-mediated disease triggered by a viral infection [225], or an autoimmune disease related to autoantibodies to the Glu R3 protein of glutamate receptors [228]. The autoimmune theory postulates that a disruption of the blood-brain barrier (due to viral infection or to other mechanisms) exposes the CNS lymphocytes, causing production of autoantibodies that may activate excitatory amino acid receptors, thereby triggering focal seizures and facilitating the progressive nature of disease [229]. Clinical Findings

Progressive seizures typically represent the first clinical manifestation of the disease. Although generalized seizures may occur at the onset, focal motor seizures are more common, and epilepsia partialis continua (characterized by almost continuous clonic movements of the face or upper limb) is the most common epileptic picture [223, 230]. Seizures are typically refractory to antiepileptic drugs, and epilepsy surgery may represent the only effective therapy. In the absence of effective treatment, progressive motor deficits may lead to hemiplegia, while progressive cognitive deterioration also typically occurs during the course of the disease. Neuropathological Findings

Neuropathological changes are typically restricted to one hemisphere [2]. Perivascular lymphocytic (i.e., T-cell lymphocytes) infiltration, gliosis, and proliferation of “microglial nodules” involve the cortex and white matter of the affected hemisphere. Basal ganglia involvement has been reported in about 65% of cases [2, 231–233]. Histopathological changes are seen also in macroscopically normal areas [2]. Virtually complete loss of neurons, causing diffuse cortical atrophy and ventricular dilatation, is associated with gliosis of the residual white matter in long-standing cases [2, 230]. Imaging Studies

12.6.2.3 Rasmussen’s Encephalitis

Rasmussen’s encephalitis is a progressive disease of childhood or adolescence, affecting patients between 14 months and 14 years [223], with a peak incidence at

Imaging performed at presentation or soon after the onset of disease may be apparently normal [5, 234]. Cerebral swelling associated with focal hypodensity has been described as the earliest imaging finding [235]. With time (Figs. 12.52, 12.53), progres-

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Infectious Diseases

a

b

Fig. 12.51a–c Bickerstaff encephalitis. a Sagittal T2-weighted image. b Gd-enhanced axial T1-weighted image. c Gd-enhanced sagittal T1-weighted image. There is diffuse, inhomogeneous T2 hyperintensity involving the pons and middle cerebellar peduncles (open arrows, a). There is inhomogeneous, patchy enhancement that involves only limited portions of the signal abnormality (arrows, b,c)

c

sive cortical atrophy, either focal or hemispheric, develops. The frontal or fronto-temporal lobes are most commonly involved [5, 236]. Although unilateral involvement is typical, bilateral lesions have been described [237]. Abnormal increased signal intensity on T2-weighted and FLAIR images in the affected cortex may occur in some cases, possibly as a result of gliosis. Basal ganglia involvement appears either as atrophy or increased T2 signal intensity [231, 233]. Pronounced unilateral atrophy of the right caudate nucleus, globus pallidus, and putamen with mildly increased intensity on T2-weighted images, without

associated cortical atrophy, was reported in an 8year-old girl whose clinical features and brain biopsy were consistent with Rasmussen’s syndrome [238]. Advanced MRI Studies

Proton MR spectroscopy studies shows decreased NAA peak (related to neuronal loss) and increased concentration of other metabolites, such as choline (indicating increased cell membrane turnover associated with inflammation), myo-inositol (reflecting glial proliferation), and lactate (related to inflammation and macrophage infiltration) [236, 239–241]. MR spectroscopy may be positive earlier than conven-

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Fig. 12.52 Rasmussen’s encephalitis: intermediate stage in a young adult. Coronal FLAIR image. There is moderate atrophy of the left fronto-temporal regions with associated areas of gliosis. Notice ex-vacuo dilatation of the homolateral ventricle and midline attraction. (Case courtesy of Dr. L. Chiapparini, Milan, Italy)

Fig. 12.53 Rasmussen’s encephalitis: chronic stage in a young adult. Axial FLAIR image. Diffuse atrophy of the left hemisphere with associated ex-vacuo enlargement of the lateral ventricles and marked thinning of the cortex. Notice diffuse hyperintensity of the residual white matter, resulting from gliosis. (Case courtesy of Prof. M. Gallucci, L‘Aquila, Italy)

tional MR imaging [5]. Pathological spectra in the morphologically normal contralateral hemisphere have been reported in a 3-year-old child [239]

In the recent years, the overall incidence of RS has dramatically decreased, perhaps because of more accurate diagnosis of infectious, metabolic, and toxic etiologies [243]. However, others suggest that the warnings about the adverse effects of salicylates in children with viral diseases could have resulted in the reduction of RS cases [246, 249].

Diffusion-weighted imaging demonstrates higher mean ADC values than in the normal parenchyma, probably reflecting high molecular motion in the damaged tissue associated with chronic inflammation [241].

Clinical Findings

12.6.2.4 Reye Syndrome

Reye syndrome (RS), firstly described in 1963 as an acute encephalopathy with fatty degeneration of the viscera [242], is now considered a descriptive term covering a group of heterogeneous disorders [243, 244]. Different etiologies, such as infectious diseases, metabolic disorders, and toxins, have been associated with RS (Table 12.16). The pathogenetic role of an underlying mitochondrial dysfunction has been hypothesized [245]. The hypothetical association with acetylsalicylic acid is still controversial [243, 246]. RS is defined as follows: a child, under 18 years, with: (1) an acute non-inflammatory encephalopathy (without CSF pleocytosis); (2) characteristic liver histology or raised serum transaminases or ammonia values (≥ 3 x normal); (3) no other explanation for the illness [243, 247, 248].

The clinical picture is characterized by sudden onset of signs related to increased intracranial pressure leading to coma, seizures, and other neurological deficits, occurring in a child who is recovering from a viral illness. Different stages of the disease have been described [250]. The outcome is variable; death occurs in 20%–30% of cases [251]. Neuropathological Findings

Severe brain edema, generally cytotoxic in nature, is the main neuropathological finding [2]. Multifocal ischemic changes affecting the cerebral cortex, basal ganglia, diencephalon, and brainstem are associated with cerebral edema [252, 253]. Secondary hypoxic changes may be seen in the cerebral cortex, hippocampus, basal ganglia and cerebellum [2, 252–254].

Infectious Diseases Table 12.16. Different etiologies associated with Reye syndrome Infectious diseases

Metabolic diseases

Toxic disorders/toxins

Influenza A and B

Disorders of fatty acid oxidation and ketogenesis

Aflatoxin

Varicella zoster

Disorders of ureagenesis

Hypoglycin

Parainfluenza

Disorders of carbohydrate metabolism

Margosa oil

Adenovirus

Organic acidurias

Paint thinner

Coxsackie virus

Anti-emetics

Cytomegalovirus

Salicylates

Epstein-Barr virus

Paracetamol

Idiopathic

Valproic acid Zidovudine Outdated tetracycline

Imaging Studies

On CT scan, brain swelling may be associated with hyperemia of cortical vessels [255] and thalamic and/ or cerebellar hypodense lesions [184, 256]. Atrophy typically appears in the later stages of disease [255, 257–259]. On MRI, the acute stage of the disease is characterized by diffusely increased signal of the cerebral cortex and subcortical white matter [260] (Fig. 12.54), associated with swelling of the brain, with compression of sulci and narrow ventricles [261]. The brainstem, basal ganglia, and thalami may also be involved, although this is not the rule [5, 261]. In the chronic stage, curvilinear high T1 signal abnormalities involve the cerebral cortex, with diffuse laminar enhancement after gadolinium administration [260]. This pattern is similar to that of laminar cortical necrosis described in hypoxicischemic brain damage, except for the distribution of cortical changes [262, 263]. In fact, cortical involvement from hypoxic damage predominates in the depths of the sulci, probably reflecting hemodynamic factors. Conversely, signal changes in RS prevails over the surface of the gyri and in the boundary zones of the parieto-occipital cortex [260].

12.7 Fungal Infections Fungal CNS infection is uncommon in children. However, the increased number of immunosup-

pressed patients has led to an increased frequency of CNS fungal infections in the pediatric age group [20]. Cryptococcus, Candida, and Aspergillus are the main etiologies in immunodepressed patients [35]. Cryptococcosis, coccidioidosis, and histoplasmosis are more frequent in the rare immunocompetent children with fungal infection [35]. Meningitis is the most common form of fungal CNS involvement. Meningoencephalitis, thrombophlebitis, and abscesses may occur as well [5, 264, 265]. Since imaging findings are not significantly different from those of the adult age group, they will only be discussed briefly here.

12.7.1 Cryptococcus In cases of Cryptococcus infection, meningeal involvement is more frequent than parenchymal involvement [5, 20]. Hydrocephalus, either communicating or obstructive, may occur [5, 265]. Ventriculitis, due to choroid plexus involvement, may occasionally cause trapping of the temporal horn of the lateral ventricle [5]. In cases of parenchymal involvement, granulomas are iso- to hyperintense on T2-weighted images. Contrast enhancement may be nodular or peripheral [21]. Formation of pseudocysts (i.e., gelatinous fungal collections), localized within the perivascular spaces of the basal ganglia and midbrain, has been described. These pseudocysts show prolonged T1 and T2 relaxation times, without enhancement after gadolinium administration [21, 35, 266].

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a

b Fig. 12.54a,b Reye’s syndrome: acute stage in a 5-year-old boy. a,b Axial T2-weighted images. Diffuse areas of abnormal hyperintensity diffusely involve the cortico-subcortical regions of both cerebral hemispheres; notice that only the periventricular white matter and the frontal portions of the peripheral white matter are spared (b). The pons is also abnormal (arrowhead, a)

a

b Fig. 12.55a,b Aspergillosis in an immunosuppressed 6-year-old boy. a,b Gd-enhanced coronal T1-weighted images. A right frontobasal lesion (arrow, a) and a left parietal cortical lesion (arrow, b) are visible. Both are surrounded by perifocal edema (E, a,b). Only the parietal lesion shows a ring enhancement pattern. (Case courtesy of Dr. I. Nikas, Athens, Greece)

12.7.2 Candida albicans In premature infants or in newborns with congenital malformations, systemic candidiasis may be complicated by CNS involvement resulting in meningitis, diffuse cerebritis, and multifocal microabscesses [5, 265]. Candida meningitis may occur after prolonged antibiotic or corticosteroid therapy or in immunosuppressed patients. It typically involves the basal cisterns, resembling other granulomatous meningiti-

des, with replenishment of the involved cisterns and marked enhancement after gadolinium administration [5]. Candida abscesses, resulting from brain invasion, are very similar to pyogenic abscesses, although they commonly show a thicker wall and are often multiple [5, 265]. The most common location is the gray-white matter junction [35]. Infarction and hemorrhage may occur secondarily to vessels wall invasion [5]. Mycotic aneurysms have also been described [20].

Infectious Diseases

12.7.3 Aspergillus Aspergillus is an angioinvasive fungus causing either multifocal hemorrhagic mycetomas or cerebral infarcts [99]. Brain abscesses caused by Aspergillus are very similar to bacterial abscesses, but with a greater tendency to hemorrhage (causing hypointensity on T2-weighted images) related to vessel wall invasion by the hyphae [265]. CT scans show a hypodense lesion with iso-to hyperdense wall, with moderate to marked ringenhancement [265]. On MRI (Fig. 12.55), lesions may be well demarcated with ring enhancement or may appear as poorly marginated areas of prolonged T1 and T2 relaxation times, with or without mass effect and enhancement [120]. Vasogenic edema usually surrounds the lesion [265]. Occurrence of a hypointense peripheral rim on T2-weighted images has been related to the presence of ferromagnetic elements [267]. Differential diagnosis with bacterial abscess and tuberculous granulomas may be difficult on imaging alone, and is based on clinical grounds and CSF analysis.

12.7.4 Coccidioidomycosis CNS involvement may occur secondarily to hematogenous spread during a systemic infection [5]. The MRI appearance is that of a granulomatous meningitis involving the basal cisterns and other cisternal spaces, showing marked enhancement after gadolinium administration [5]. Although these findings are very similar to those of tuberculous meningitis, the latter usually shows concomitant parenchymal lesions, which are usually absent in coccidioidosis [5]. Communicating hydrocephalus is a common complication. Obstructive hydrocephalus may be caused by ependymitis with obstruction of the cerebral aqueduct or fourth ventricular foramina. Cerebrovascular complications, due to involvement of small penetrating cortical vessels with ischemia and/or infarctions, have also been reported [265].

12.7.5 Nocardia Nocardia may cause multiple cerebral abscesses, whose MR appearance is very similar to that of bacterial abscesses [265]. Most patients are immuno-

compromised from either hemolymphoproliferative or immunodeficient conditions [170].

12.8 Parasitic Infections 12.8.1 Cysticercosis Neurocysticercosis is due to infection of the CNS by the larval stage (cysticercus) of the tapeworm Taenia solium, accidentally ingested by humans from fecalcontaminated substances [5]. The ova are ingested and their coverings are dissolved by gastric secretions. The oncospheres are transported to the bowel, where they penetrate the walls and gain access into the circulatory system. They become larva once they lodge in the brain and other organs. CNS involvement occurs in about 60%–90% of cases, and is now considered the most common parasitic disease of CNS [268, 269]. While it is an endemic disease in developing countries, it is becoming a more common health problem in industrialized countries due to immigrant populations [270]. Due to the long incubation period, neurocysticercosis is less frequent in children than in adults [269, 270]. Spinal cysticercosis is discussed in Chapter 41. 12.8.1.1 Clinical Findings

Clinical manifestations of neurocysticercosis are highly variable, and include seizures, hydrocephalus, and headache [268]. In children, focal seizures represent the most common presentation of this disease [269, 271]. The diagnosis may be confirmed by positive complement fixation test, hemagglutination test, and enzyme-linked immunosorbent assay testing. A definitive, a probable, or a possible diagnosis of cysticercosis may be obtained [272]. 12.8.1.2 Neuropathological Findings

Cysticerci may be located within the brain parenchyma, ventricles, subarachnoid space, spinal cord, or in combined locations. About 50% of patients with cerebral parenchymal lesions will also have meningeal lesions [273]. Actually, cysticercal meningitis and ill-defined encephalitis are not uncommon in children. Cysticercal meningitis may induce a vasculitis resulting in cerebral infarctions.

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Parenchymal cysts represent the most common form. Four pathologic stages have been described [274] (Table 12.17). They may range from 5 to 20 mm in diameter, and are preferentially located in the cerebral gray matter (hemispheres and basal ganglia) due to the greater vascular supply in these areas [268]. The brainstem, cerebellum, and spinal cord are other possible locations [5]. Contrary to adults, most affected children shows a single lesion [269]. Intraventricular cysts are commonly single, although multiple cysts may occur. They may be freely mobile or attached to the choroid plexus or ventricular wall. When located into the subarachnoid space, cysts may occur within the cortical sulci or in the basal cisterns.

12.8.1.3 Imaging Studies Parenchymal Cysts

MRI findings of parenchymal cysts depend on the disease stage (Table 12.17). Vesicular Stage

The cyst appears as a well-marginated lesion whose capsule is not easily identifiable. The signal intensity of the cyst fluid is similar to that of CSF. The scolex may be partially seen as an eccentrically located, T1 hyperintense nodule [275] within the cyst. Both enhancement of the cyst wall and surrounding edema are absent (Fig. 12.56).

Table 12.17. Neuropathological and MRI findings of parenchymal cysticercal cysts Stage

Vesicular

Colloidal vesicular

Neuropathology

The scolex is an eccentric nodule projecting into a small fluid filled cyst Little or no inflammatory response (the cyst is antigenically inert at this stage) The larva may remain in this stage for years, or can undergo the next stage Not visible Clear

Hyaline degeneration of The scolex is mineralized Complete mineralization the larva of the lesion

Capsule Fluid T1 T2 Enhancement Edema

a

Signal intensity of CSF No No

Granular nodular

Nodular calcified

Inflammatory reaction to larval antigens

Thick Turbid ↑ ↑↑ Marked Moderate → marked

Thick and collagenous Reabsorbed ↑ -/↓ Nodular or ring-like Mild

-/↓ ↓ No (occasionally minimal) No

b Fig. 12.56a,b Cysticercosis: vesicular stage. a Sagittal T1-weighted image. b Axial T2-weighted image. There is a large amount of cystic lesions involving the whole brain, characterized by isointensity with CSF and by absence of both enhancement (not shown) and perifocal edema. On T1-weighted image, several of these cysts contain a small punctuate hyperintensity corresponding to the scolex (arrows, a). Lesions are also located in the soft galeal tissues (arrows, b) and in the roof of the orbit (arrowhead, b). (Case courtesy of Dr C.F. Andreula, Bari, Italy)

Infectious Diseases

Colloidal Vesicular Stage

This stage is characterized by a capsule that is visible on T1-weighted images and FLAIR. The cyst fluid is slightly hyperintense on T1-weighted images and markedly hyperintense on T2-weighted images or FLAIR, due to the proteinaceous content. Owing to degeneration, the scolex gradually decreases in size and eventually disappears. Ring enhancement, resulting from inflammatory reaction, is evident (Fig. 12.57). Moderate to marked surrounding vasogenic edema is present. Granular Nodular Stage

The cyst fluid is almost completely reabsorbed and the parasite has become a granulomatous lesion. After gadolinium administration, the lesion shows

nodular or ring-like enhancement (Fig. 12.58). Surrounding edema is less evident than in the previous stage and gradually decreases. Nodular Calcified Stage

This stage is characterized by complete mineralization, appearing as a calcified nodule (Fig. 12.59) or a focal area of gliosis. A minimal residual enhancement may be seen [276]. Surrounding edema is absent. Because the evolution of cysticercal cysts is a dynamic process, it is possible to observe transitions and overlaps from one stage to another [268]. Furthermore, MRI findings of parasite degeneration after specific treatment may differ from those related to the natural degeneration of the parasite [268]. In particular, nodular low intensity and a mixed fluid signal with punctuate low signal on T2-weighted images have been described as specific results of therapy [275]. As it has been estimated that it takes 4 to 7 years for the dead larvae to calcify, calcifications are more commonly seen in adults than in children, while enhancing lesions are more common in children [277]. In childhood, an encephalitic form of cysticercosis, characterized by multiple, small enhancing lesions with diffuse brain edema, has been described [268]. In this form, multiple calcifications represent the late imaging appearance. Intraventricular Cysts

Fig. 12.57 Cysticercosis: colloidal vesicular stage. Gd-enhanced axial T1-weighted image. Three lesions characterized by signal intensity slightly higher than that CSF and by peripheral enhancement are recognizable (arrows). (Case courtesy of Dr C.F. Andreula, Bari, Italy)

a

b

Intraventricular cysts are not easily identifiable on CT, due to their isodensity with CSF. However, they are clearly demonstrable on MRI, showing the scolex as a soft tissue-intensity nodule, particularly visible if T1-weighted images 3 mm or less in thickness are used [5, 268]. The most common location is the fourth ventricle, followed by lateral ventricles and third ventricle

Fig. 12.58a,b Cysticercosis: granular nodular stage in a 14-year old girl. a,b Gdenhanced axial T1-weighted images. Diffuse enhancing nodules are seen. Note the presence of a vesicular stage cyst adjacent to the right frontal horn (arrow, b). (Case courtesy of Dr. I. Nikas, Athens, Greece)

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a

b

[268]. The cyst is more frequently single, although multiple cysts may be seen in the lateral ventricles. After gadolinium administration, ring-like or nodular enhancement, probably related to granular ependymitis, may occur [268]. Improved detection of intraventricular cysts has been reported with the use of three-dimensional constructive interference in steady state [3D-CISS] MR sequences [278]. Intraventricular cysts may cause acute obstructive hydrocephalus. Migration of an intraventricular cyst in or out of the ventricular system (i.e., into the basal cistern and subarachnoid space) has also been reported. Acute ventricular obstruction may cause sudden demise [5]. Racemose Cysts

Racemose cysts are multilobular cysticercal cysts that lack a scolex, located in the subarachnoid space of the

a

Fig. 12.59a,b Cysticercosis: nodular calcified stage in an 8-year-old girl. a,b Contrast-enhanced axial CT scans. Multiple calcified spots involve both frontal lobes (arrowheads, a,b). Note the presence of a second lesion in the granular nodular stage (arrow, b)

basal cisterns (Fig. 12.60), the cerebello-pontine angle, the suprasellar region, or the sylvian fissure [5]. They tend to enlarge, ranging up to several centimeters, and may be associated with leptomeningitis [5]. On MRI, these cysts appear as multiple adjacent cysts clustered together like grapes with intervening septa [5]. It has been suggested that lack of a limiting host response of encapsulation might be responsible for this type of agglomeration [279]. Subarachnoid (Leptomeningeal) Cysticercosis

Subarachnoid (leptomeningeal) cysticercosis is characterized by involvement of the subarachnoid space and adjacent meninges, especially in the basal cisterns. On CT and MRI, soft tissue filling the basilar cisterns and markedly enhancing after gadolinium administration is detected [5]. Hydrocephalus may complicate this form of the disease [5].

b Fig. 12.60a,b Cysticercosis: racemose cyst. a Gd-enhanced axial T1-weighted image. b Gd-enhanced sagittal T1-weighted image. A racemose fronto-basal interhemispheric lesion (asterisk, a,b) causes compression and deformation of the lamina terminalis and elevation of the fornix. (Case courtesy of Dr C.F. Andreula, Bari, Italy)

Infectious Diseases

Granulomas, sometimes calcified, are commonly found within the subarachnoid space [5]. Cerebrovascular Complications

Cerebrovascular complications of neurocysticercosis are not uncommon. The most frequent form is endoarteritis, due to basal exudate involving the small basal vessels and causing lacunar infarctions [268, 280]. Involvement of large vessels, although less common, has been reported in childhood as the result of focal arteritis [280].

12.8.2 Echinococcosis In humans, the two main forms of echinococcosis (hydatid disease) are caused by Echinococcus granulosus and, less frequently, by Echinococcus multilocularis (E. alveolaris). The liver and lungs are the most common locations of the disease, whereas CNS involvement is relatively uncommon, i.e. around 3% with E. granulosus and 5% with E. multilocularis [21, 281, 282]. 12.8.2.1 Echinococcus granulosus

Most hydatid cysts are acquired in childhood and are not diagnosed until the third or fourth decade of life [281]. Although CNS involvement is usually secondary to systemic hydatid disease, brain involve-

a

ment may be primary in the pediatric age group [282]. Cerebral involvement may result in different forms of neurologic dysfunction, including signs of increased intracranial pressure, seizures, hemiparesis, and cranial nerves palsies [281, 282]. The hydatid cyst is usually single, uni-or bilocular; it grows very slowly and may become very large. On imaging, cystic lesions are usually spherical, well-defined, and thin-walled. The surrounding capsule is thin because the host reaction is minimal or even absent before death of the organism occurs [21, 281]. On CT scan, the cyst wall is isodense or hyperdense to brain tissue, while the content is hypodense (Fig. 12.61). Calcification of the wall is rare [281]. On MRI (Figs. 12.61, 12.62), the signal intensity of the intracystic fluid is similar to that of CSF [21]. The peripheral capsule usually appears as a rim of low signal intensity on both T1- and T2-weighted images, and may occasionally calcify [281, 283]. Usually, neither ring enhancement nor perifocal edema are present, unless the hydatid cyst is superinfected [281]. Multiple hydatid cysts, resulting from cyst rupture, are rare. MR spectroscopy studies have shown lactate, pyruvate, alanine, and acetate peaks [282]. The most difficult lesions to differentiate from hydatid cyst are arachnoid cysts, neuroepithelial cysts, and epidermoid tumors. Racemose cysticercosis in the subarachnoid space should be also considered in the differential diagnosis [283], as well as pyogenic or fungal abscess, cystic astrocytoma, and porencephalic cavities [281].

b Fig. 12.61a,b Echinococcus granulosus. a Contrast-enhanced axial CT scan. b Axial T2-weighted image. CT scan reveals a rounded, well-circumscribed hypodense cyst (a). Enhancement is absent. On the T2-weighted image, signal intensity is isointense with CSF (b). (Case courtesy of Dr C.F. Andreula, Bari, Italy)

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a

b Fig. 12.62a,b Echinococcus granulosus. a Axial proton density-weighted image. b Axial T2-weighted image. Multiple cysts separated by thin septa and showing a hypointense rim are isointense with CSF. Perifocal edema (E, a,b) is scant compared to the size of the lesions. (Case courtesy of Dr C.F. Andreula, Bari, Italy)

12.8.2.2 Alveolar Echinococcosis

Alveolar echinococcosis is the form due to Echinococcus multilocularis (alveolaris). The cyst differs from that of E. granulosus in that it grows by external budding of the germinal membrane with progressive infiltration of the surrounding tissue, producing an amorphous multicystic or semisolid structure [281]. CT scan shows a grape-like, multilocular cystic mass with variable density. Calcification may occur. Enhancement is usually present [285, 286]. On MRI, the cyst usually shows heterogeneous signal and positive enhancement [286].The differential diagnosis includes gliomas, metastases, tuberculomas, and fungal infections [281].

12.8.3 Toxocaral Disease Infection with Toxocara canis is a common worldwide human helminthiasis that rarely affects the brain or the spinal cord. The disease is contracted through exposure with soil contaminated by the eggs of the roundworm, which are eliminated in the stools of the primary host, the dog. There are three main forms of the disease: occult, ocular, and visceral. This last one is characterized by generalized illness, abdominal symptoms, a skin rash, and symptoms arising from larval invasion of different organs [287], such as the

liver, lungs, eyes, and CNS [288]. CNS involvement includes eosinophilic meningitis, encephalitis, or a combination of those entities. High seroprevalence is found in developed countries, especially in rural areas, and also in some tropical islands [289]. The diagnosis is based on several findings, including high serum titers of T. canis antibodies [290], eosinophilia in the blood and/or CSF, demonstration of intrathecal antibody synthesis, and close contact with dogs. Clinical and radiologic improvement, as well as normalization of CSF parameters during antihelminthic therapy, supports the diagnosis [291]. MRI reveals multiple focal lesions in the subcortical and deep white matter, showing hypointensity on T1-weighted images, hyperintensity on T2-weighted images, and enhancement with gadolinium administration [292]. In a case we observed, there were multiple high-signal-intensity lesions on T2-weighted and FLAIR images involving the subcortical white matter of both frontal lobes; however, enhancement was not observed (Fig. 12.63).

12.9 Sarcoidosis Sarcoidosis is a systemic granulomatous disorder of unknown origin, characterized by an accumulation of non-caseating epithelioid granulomas [293, 294]. An immune complex deposition triggering a granulomatous response has been considered the pathoge-

Infectious Diseases

a

b Fig. 12.63a,b Toxocaral disease. a Axial FLAIR image. b Coronal FLAIR image. Multiple hyperintense focal abnormalities involve the subcortical white matter of the frontal and parietal lobes bilaterally (a,b). None of the lesions enhanced after gadolinium administration (not shown)

netic mechanism [295]. CNS involvement occurs in about 5%–10% of cases [5, 293].

12.9.1 Clinical Findings Neurosarcoidosis is considered a protean disease, due to the extremely variable clinical manifestations related to the location and size of granulomas [293, 294]. It is uncommon in children. The mean age of occurrence in the pediatric age group is between 9 and 15 years of age [5, 20]. Either acute onset of symptoms (usually seizures, headache, or focal neurological signs) or progressive neurological impairment (cranial neuropathies, pyramidal involvement, psychiatric disturbances) are possible [296, 297]. Involvement of the hypothalamicpituitary axis typically causes diabetes insipidus (see Chap. 18). Facial nerve involvement is the most common among cranial nerve neuropathies, followed by nerves II and VIII [5]. Meningitis, encephalopathy, hydrocephalus, and myelopathy have also been described in childhood [298, 299]. Finally, it is noteworthy that neurological symptoms may occur without any evidence of other systemic features as the presenting manifestations of sarcoidosis [300, 301]. The diagnosis of sarcoidosis has been, and still is, difficult to ultimately establish, and may remain presumptive or of exclusion in a number of cases. The diagnostic value of serum angiotensin converting enzyme in the CSF still awaits ultimate validation.

12.9.2 Neuropathological Findings Histologically, the sarcoid granulomas in the active stage are characterized by a central mass of epithelioid cells surrounded by lymphocytes, monocytes, and fibroblasts. Central necrosis is unusual. The granulomatous changes involve predominantly the leptomeninges, and tend to extend into the brain parenchyma along the Virchow-Robin spaces. Within the brain, granulomas may be confined to the perivascular spaces, but may also involve the periventricular areas and ependymal lining, often surrounded by marked astrocytic proliferation. Secondary hydrocephalus may occur. Large meningeal and/or parenchymatous masses simulating neoplasms may occur secondarily to coalescence of granulomas [302]. The most common locations of neurosarcoidosis include the base of the brain, the posterior fossa, and the suprasellar and hypothalamic regions. However, any part of the CNS may be involved [293]. Vasculitis and perivascular involvement may cause vessel stenosis and infarctions [302].

12.9.3 Imaging Studies Granulomatous leptomeningitis is the most common form of neurosarcoidosis, although pachymeningitis may occur as well [20, 68]. Leptomeningitis may be diffuse or localized into the floor and anterior walls of the third ventricle, the sella turcica and infundibu-

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lum, the optic chiasm, and the base of the frontal lobes [5, 20, 303]. MRI shows leptomeningeal enhancement (nodular or diffuse) that may extend into the parenchyma through infiltration of the Virchow-Robin spaces [20, 304]. Thickening of the hypothalamus and infundibulum, with marked contrast enhancement, is seen in cases of hypothalamus and pituitary stalk involvement [300]. Dural mass lesions appear isointense on T1- and hypointense on T2-weighted images (possibly due to fibrocollagenous component), and enhance uniformly [297]. Meningeal or ventricular granulomas may cause communicating or obstructive hydrocephalus [293]. Parenchymal sarcoid granulomas may appear as multiple or solitary supra- or infratentorial masses [5, 293] that are isointense with gray matter on T1weighted images and iso- to hyperintense on T2weighted images [5]. After gadolinium administration, enhancement is homogeneous [5, 20]. Vasogenic edema is absent [5]. In addition to this appearance, parenchymal lesions may appear as demyelinating lesions, possibly representing the chronic glial sequelae of the previous inflammatory lesions, or as lacunar lesions, resembling those of microangiopathy and consistent with vasculitis [302]. Long-term longitudinal MRI studies should be performed in any patient with parenchymal lesions, due to the possibility of a relapsing course of the disease [305, 306]. Periventricular white matter lesions appearing as hypodense areas on CT scan and prolonged T1 and T2 on MRI are common [5, 307]. Pseudo-tumoral presentation of neurosarcoidosis has been rarely reported in adolescent patients [308– 311]. It has been suggested that intracranial masses may develop secondary to coalescence of parenchymal granulomas, that in turn represent the extension of granulomatous leptomeningitis through Virchow-Robin spaces [305]. In cases of cranial nerve involvement, contrastenhanced MR imaging may show enhancement of the nerve, resulting from sarcoid infiltration [300].

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Metabolic Disorders

13 Metabolic Disorders Zoltán Patay

CONTENTS 13.1

Introduction 544

13.2

General Considerations 544

13.2.1 13.2.1.1

Classification of Metabolic Disorders 544 Classification According to Organ System Involvement 545 Classification According to Cellular Organelle Dysfunction 545 Classification According to the Biochemical Abnormality 548 Classification According to Brain Substance Involvement 549 The Concept of Selective Vulnerability 550 Direct Toxic Effect 551 Indirect Toxic Effect 551 Dysmyelination 551

13.2.1.2 13.2.1.3 13.2.1.4 13.2.2 13.2.2.1 13.2.2.2 13.2.2.3 13.3

Principles of Imaging of the CNS in Metabolic Disorders 552

13.3.1 13.3.1.1 13.3.1.2 13.3.1.3 13.3.1.4

Foundation 552 Imaging Modalities 552 Imaging Strategies 553 Evaluation of MR Images 556 Common MR Imaging Features of Metabolic Disorders 562 Uncommon MRI Features of Metabolic Disorders 562 Misleading Imaging Findings 564 Differential Diagnostic Problems 564 Imaging Patterns in Metabolic Disorders 564 Pathognomonic MRI Patterns 564 Suggestive MRI Patterns 564 Nonspecific MRI Patterns 565 The Concept of Dynamic Imaging Patterns 565 Progressive Atrophy 565 Evolving Structure-Specific Lesions 565 Myelination Abnormalities 565 Advanced MR Techniques in the Diagnostic Work-Up of Metabolic Diseases 565 Diffusion-Weighted MRI 565 MR Spectroscopy 569 Clinical Aspects of Inborn Errors of Metabolism 575 Age of Onset 576 Systemic Manifestations of Metabolic Disorders 576

13.3.1.5 13.3.1.6 13.3.1.7 13.3.2 13.3.2.1 13.3.2.2 13.3.2.3 13.3.3 13.3.3.1 13.3.3.2 13.3.3.3 13.3.4 13.3.4.1 13.3.4.2 13.3.5 13.3.4.1 13.3.4.2

13.3.4.3 13.3.4.4 13.3.4.5 13.3.5 13.3.5.1 13.3.5.2 13.3.5.3 13.3.6 13.3.7 13.3.7.1 13.3.7.2 13.3.7.3 13.3.8

Neurological Abnormalities 577 Psychiatric Manifestations 579 Additional Useful Clinical Features 579 Laboratory and Histopathological Diagnosis in Metabolic Diseases 580 Routine Laboratory Findings 580 Advanced Laboratory Methods 581 Histological Diagnosis 581 Molecular Genetic Aspects of Inborn Errors of Metabolism 581 Management of Metabolic Disorders 583 Prenatal Management 583 Perinatal Management 583 Follow-Up 584 Treatment and Prognosis of Metabolic Diseases 584

13.4

Disease Entities and Imaging Findings in Metabolic Diseases 586

13.4.1 13.4.1.1 13.4.1.2 13.4.1.3 13.4.1.4 13.4.1.5

Organic Acidopathies 586 Propionic Acidemia 586 Methylmalonic Acidemia 589 Ethylmalonic Aciduria 591 3-Methylglutaconic Aciduria 592 3-Hydroxy-3-Methylglutaryl (HMG)-Coenzyme A Lyase Deficiency 595 Glutaric Aciduria Type 1 596 L-2-Hydroxyglutaric Aciduria 599 D-2-Hydroxyglutaric Aciduria 601 Pyroglutamic Aciduria (5-Oxoprolinuria) 602 Isovaleric Acidemia 603 Multiple Carboxylase Deficiency 603 3-Methylcrotonyl-Coenzyme A Carboxylase Deficiency 606 β-Ketothiolase Deficiency 606 α-Ketoglutaric Aciduria 608 Primary Lactic Acidosis 609 Amino Acidopathies 609 Urea Cycle Defects 609 Maple Syrup Urine Disease 610 Phenylketonuria 615 Hyperhomocystinemias 621 Nonketotic Hyperglycinemia 625 3-Phosphoglycerate Dehydrogenase Deficiency 627 Disorders of Carbohydrate Metabolism 628 Galactosemia 628 Fructose Metabolism Abnormalities 628 Disorders of Metal Metabolism 629 Copper Metabolism 629

13.4.1.6 13.4.1.7 13.4.1.8 13.4.1.9 13.4.1.10 13.4.1.11 13.4.1.12 13.4.1.13 13.4.1.14 13.4.1.15 13.4.2 13.4.2.1 13.4.2.2 13.4.2.3 13.4.2.4 13.4.2.5 13.4.2.6 13.4.3 13.4.3.1 13.4.3.2 13.4.4 13.4.4.1

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13.4.4.2 13.4.5

Other Metals 634 Disorders of Mitochondrial Energy Metabolism 634 13.4.5.1 Disorders of Pyruvate Metabolism 634 13.4.5.2 Defects of the Respiratory Chain 638 13.4.5.3 Fatty Acid Oxidation Disorders 648 13.4.6 Lysosomal Disorders 652 13.4.6.1 Mucopolysaccharidoses 652 13.4.6.2 Metachromatic Leukodystrophy 654 13.4.6.3 Multiple Sulfatase Deficiency 657 13.4.6.4 Krabbe Disease (Globoid Cell Leukodystrophy) 658 13.4.6.5 GM Gangliosidoses 662 13.4.6.6 Niemann-Pick Disease 663 13.4.6.7 Gaucher Disease 665 13.4.6.8 Fucosidosis 666 13.4.6.9 Mucolipidoses 667 13.4.6.10 Salla Disease 668 13.4.6.11 Chédiak-Higashi Disease 669 13.4.7 Peroxisomal Disorders 670 13.4.7.1 Zellweger Syndrome 672 13.4.7.2 Neonatal Adrenoleukodystrophy 674 13.4.7.3 Infantile Refsum Disease 675 13.4.7.4 Hyperpipecolic Acidemia 675 13.4.7.5 Rhizomelic Chondrodysplasia Punctata 676 13.4.7.6 Pseudoneonatal Adrenoleukodystrophy 676 13.4.7.7 X-Linked Adrenoleukodystrophy 676 13.4.7.8 Adrenomyeloneuropathy 680 13.4.8 Unclassified Leukodystrophies 682 13.4.8.1 Canavan Disease 682 13.4.8.2 Megalencephalic Leukoencephalopathy with Subcortical Cysts (van der Knaap Disease) 684 13.4.8.3 Vanishing White Matter Disease 686 13.4.8.4 Alexander Disease 688 13.4.8.5 Leukodystrophy with Brainstem and Spinal Cord Involvement and High Lactate 688 13.4.8.6 Aicardi-Goutières Syndrome 690 13.4.8.7 Cockayne Disease 692 13.4.8.8 Pelizaeus-Merzbacher Disease 693 13.4.9 Miscellaneous Metabolic Diseases 695 13.4.9.1 Carbonic Anhydrase II Deficiency 695 13.4.9.2 Persistent Hyperinsulinemic Hypoglycemia (Nesidioblastosis) 696 13.4.9.3 Creatine Deficiency 697 13.4.9.4 Leukoencephalopathy Associated with Polyol Metabolism Abnormality 697 13.4.9.5 Biotin-Responsive Encephalopathies 698 13.4.9.6 Cerebrotendinous Xanthomatosis 698 13.4.9.7 Sjögren-Larsson Syndrome 700 Acknowledgments 702

13.1 Introduction Although individual disease entities may not be frequently encountered in the practice of general radiology, the group of (known and yet unidentified or poorly defined) neurometabolic disorders accounts for a considerable percentage of central nervous system (CNS) pathologies seen, especially in the pediatric population. The prevalence of metabolic diseases is increasingly recognized as being actually higher than previously believed. Furthermore, since most of the metabolic diseases are genetically determined and show autosomal recessive inheritance, in communities where consanguinity is high (i.e., Amish families in Pennsylvania, some Jewish communities, North-American Indian and Saudi tribes, etc.), certain otherwise rare or even exceptional inborn errors of metabolism may be quite common. Indeed, metabolic diseases often exhibit specific ethnic or geographical preponderance, but epidemiological studies indicate that many of them are pan-ethnic and may occur sporadically anywhere [1–9]. Increasing availability of sophisticated diagnostic methods (including advanced imaging techniques of the CNS and laboratory, histopathological, and molecular genetic investigational tools) facilitates early and accurate diagnosis and helps to progressively elucidate the underlying pathological processes. Although inborn errors of metabolism are commonly perceived as therapy-resistant and relentlessly devastating diseases, introduction of new, early diagnostic and therapeutic options has already modified the prognosis of many of the diseases, and further progress in this domain is anticipated in the near future. Awareness of the different entities and their clinical and imaging manifestations is, therefore, mandatory for the radiologist in order to raise or directly reach the diagnosis of these often underrecognized or misdiagnosed diseases.

References 702

13.2 General Considerations 13.2.1 Classification of Metabolic Disorders Metabolic disorders are classically divided into inborn (or congenital) errors of metabolism and acquired metabolic diseases.

Metabolic Disorders

Acquired metabolic diseases usually occur in specific or highly suggestive clinical settings, such as hypovitaminosis in malnutrition (Wernicke encephalopathy, subacute combined degeneration of the spinal cord), ketoacidosis in diabetes mellitus, or neonatal hypoglycemia in premature infants. Benign forms of hyperbilirubinemia are common in neonates and usually resolve without sequelae; however, delayed or inappropriate treatment of the more severe forms may lead to lesions within the deep gray matter structures (kernicterus). Toxic encephalopathies (alcohol, lead, drug and chemotherapy induced) are special, exogenous forms of acquired metabolic diseases, most usually encountered in specific social or clinical contexts and many occurring almost exclusively in adults. Inborn errors of metabolism represent a vast and complex group of genetically determined pathologies. Many attempts have been made to set up classification schemes, none of which, however, is universally applicable, for reasons of failing to fulfill the distinctly specific practical criteria of use in clinical, pathological or radiological settings. Their knowledge is, however, useful, since each of them points to one of the many essential aspects of these pathologies. 13.2.1.1 Classification According to Organ System Involvement

This is mainly a clinically oriented classification, which takes into account the pattern of organ system involvement. A few of the inborn errors of metabolism exclusively, others preferentially or occasionally, and again others never, present with involvement of the CNS. Diseases without Involvement of the CNS

The best known of the diseases in this group are the so-called glycogen storage disorders (von Gierke, Pompe disease, etc.). Their typical clinical manifestations include hepatosplenomegaly, renal failure, (cardio)myopathy, and hypoglycemia (the latter, however, may have occasionally secondary adverse effects on the brain). Diseases with Systemic and CNS Involvement

These diseases may present with visceral involvement (e.g., cardiac, musculoskeletal, and hepatic abnormalities in mucopolysaccharidoses) and/or systemic metabolic derangements (lactic acidosis), in conjunction with CNS involvement.

Diseases with Exclusive Involvement of the CNS

In this group, the metabolic abnormality manifests with signs and symptoms of CNS involvement only [10]. In the strict sense of the term, this group of pathologies is referred to as neurometabolic disorders (although, somewhat erroneously, such term is often used to encompass all of the metabolic disorders with CNS involvement as well). The best known of these pathologies are L-2-hydroxyglutaric aciduria, type 1 glutaric aciduria, 4-hydroxybutyric aciduria, αketoglutaric aciduria, phenylketonuria and N-acetyl aspartic aciduria (Canavan disease). The Nondiseases

A peculiar group of inborn errors of metabolism is composed of genetically determined biochemical derangements which are actually nondiseases, with affected individuals remaining healthy and clinically asymptomatic. The best known examples are benign familial hyperlysinemia (2-aminoadipic semialdehyde synthetase deficiency), essential fructosuria (fructokinase deficiency), and, probably, also glutaric aciduria type 3 (glutaryl coenzyme A oxidase deficiency), a presumably peroxisomal disorder [11–13]. 13.2.1.2 Classification According to Cellular Organelle Dysfunction

The cellular organelles have distinctly different metabolic functions: mitochondria are mainly involved in energy metabolism, lysosomes in the degradation of macromolecules (lipids, lipoproteins, mucopolysaccharides), and peroxisomes in both anabolic and catabolic processes. The Golgi complex has a role in the terminal phase of glycosylation (synthesis of Nglycans). Mitochondrial Disorders

This term is somewhat confusing as many metabolic disorders are due to enzyme deficiencies within the mitochondria (some of the urea cycle defects and organic acidopathies, such as type 1 glutaric aciduria or propionic acidemia, etc.) and, therefore, could be referred to as mitochondrial disorders as well. However, in the strict sense of the term, true mitochondrial disorders comprise abnormalities of mitochondrial energy metabolism only, notably oxidative phosphorylation, fatty acid oxidation, ketogenesis, and ketolysis. Although mitochondrial dysfunction is often generalized, clinical manifestations are most

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frequently related to involvement of muscle and brain tissue, probably because of their high energy requirements. For this reason, diseases in this group are also called mitochondrial encephalomyopathies. The best known entities in this group are MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), MERRF (myoclonic epilepsy with ragged-red fibers), Kearns-Sayre syndrome (progressive external ophthalmoplegia, retinitis pigmentosa, and cardiac conduction block), Leigh disease (subacute necrotizing encephalomyelopathy), and Leber hereditary optic neuropathy (LHON). Lysosomal Disorders

Lysosomes are cellular organelles which contain various enzymes, notably proteases, nucleases, lipases and glycosidases. The primary role of these enzymes is the breaking down of macromolecules (proteins, nucleic acids, lipids, lipoproteins, and polysaccharides) in normal (physiological cell constituent turnover) and abnormal (inflammation) conditions. The degradable intracellular macromolecules enter the lysosomes, where the actual hydrolytic process takes place. Deficiency of lysosomal enzymes (failure to catabolize macromolecules) leads to abnormal intralysosomal accumulation of specific macromolecules. This progressively interferes with the normal function of lysosomes and subsequently of the entire cell, and a so-called lysosomal storage disease develops. Depending on the function of the deficient enzyme and abnormally accumulated macromolecules, several types and subtypes of lysosomal storage diseases are known. Some of them present with central and/ or peripheral nervous system involvement (leukodystrophy, polyneuropathy), while others have skeletal (dysostosis), visceral (e.g., hepatosplenomegaly, renal, cardiac and pulmonary disease), and cutaneous manifestations [14]. Mucopolysaccharidoses These diseases are caused by the impaired degradation of acid mucopolysaccharides (also called glycosaminoglycans). Mucopolysaccharides are composed of polysaccharide chains bound to proteins, forming a complex macromolecular structure. Depending on the polysaccharide composition, several types of mucopolysaccharides exist. The breakdown of each of them requires a specific hydrolase enzyme, deficiency of which leads to abnormal, progressive accumulation of specific mucopolysaccharides in various tissues and organs and, hence, distinctly different disease entities develop.

Mucopolysaccharidoses include at least six subgroups; within some of these, further subdivisions exist depending on the enzyme deficiency and resultant storage abnormality (Table 1). The most common clinical and imaging features of mucopolysaccharidoses are skeletal (dysostosis multiplex) and visceral (hepatosplenomegaly) abnormalities. These are followed by manifestations of CNS involvement, related to excessive intraneuronal and perivascular storage of mucopolysaccharides. Sphingolipidoses Sphingolipids are essential constituents of membranes. Sphingolipids include cerebrosides, sphingomyelins, and gangliosides. Therefore, sphingolipidoses represent a heterogeneous group that includes cerebrosidoses, gangliosidoses, mixed, and a few other individual entities. Cerebrosidoses

This group includes metachromatic leukodystrophy (sulfatide accumulation in oligodendrocytes and Schwann cells due to arylsulfatase A deficiency) and globoid cell leukodystrophy, better known as Krabbe disease (cerebroside accumulation in oligodendrocytes due to galactosyl ceramidase deficiency). Gangliosidoses

The deficient enzyme is β-galactosidase in GM1 gangliosidosis and β-hexosaminidase A (classical and juvenile Tay-Sachs disease) or β-hexosaminidase A and B (Sandhoff disease) in GM2 gangliosidoses. GM1 gangliosidosis typically presents with prominent visceral involvement and variable neurological manifestations. In GM2 gangliosidosis neurological signs dominate. Other Mixed or Individual Entities

Multiple sulfatase deficiency is due to deficiency of several sulfatase enzymes which, individually, cause various cerebrosidoses or mucopolysaccharidoses. Therefore, the resultant mixed storage disorder is characterized by accumulation of both mucopolysaccharides and sulfatides. The disease is often referred to as Austin disease. Niemann-Pick disease (accumulation of sphingomyelin in neurons) is caused by deficiency of lysosomal sphingomyelinase, while Gaucher disease (accumulation of glucocerebroside) results from deficiency of acidic β-glucosidase enzyme.

Metabolic Disorders Table 13.1. Classification of the mucopolysaccharidoses according to the underlying enzyme deficiency and the urinary secretion of abnormal glycosaminoglycans MPS type

Disease entity

Enzyme deficiency

Accumulated metabolites (glycosaminoglycans)

MPS-I

Hurler

α-L-Iduronidase

Dermatan sulfate, heparan sulfate

Iduronate-2-sulfatase Heparin sulfamidase α-N-Acetylglucosaminidase α-Glucosaminide-N-acetyltransferase N-Acetylglucosamine 6-sulfatase N-Acetylgalactosamine-6-sulfatase, Galactose-6-sulfatase β-Galactosidase N-acetylgalactosamine 4-sulfatase β-Glucuronidase

Dermatan sulfate, heparan sulfate Heparan sulfate

MPS-IV

Scheie Hurler-Scheie Hunter Sanfilippo A Sanfilippo B Sanfilippo C Sanfilippo D Morquio A

MPS-VI MPS-VII

Morquio B Maroteaux-Lamy Sly

MPS-II MPS-III

Other rare individual entities include Fabry disease (glycosphingolipid accumulation due to α-galactosidase deficiency) and Farber disease (acid ceramidase deficiency). Oligosaccharidoses (Glycoproteinoses) The membrane-associated proteins are almost invariably glycosylated, which means that different oligosaccharide chains are attached to protein backbones. Oligosaccharide chains may contain mannose, fucose, galactose, N-acetylgalactosamine, N-acetylneuramic acids (sialic acids), and N-acetylglucosamine. Impairment of synthesis of oligosaccharides (defects of glycosylation) partly belongs to Golgi complex abnormalities. On the other hand, enzyme deficiencies involved in degradation of oligosaccharides result in oligosaccharidoses (i.e., glycoprotein storage disorders). This group consists of several neurovisceral storage disorders, which are classified according to nonor partially-degraded oligosaccharide substances. These include α- and β-mannosidosis (α- and β-mannosidase deficiency), α-fucosidosis (fucose accumulation in neurons due to acidic α-L-fucosidase deficiency), type 1 and 2 sialidosis (α-neuraminidase deficiency), galactosialidosis (“protective protein” deficiency), and aspartylglycosaminuria (aspartylglycosaminidase deficiency), which share many clinical and imaging similarities with mucopolysaccharidoses and other lysosomal storage disorders.

Keratan sulfate, chondroitin-6-sulfate Keratan sulfate Dermatan sulfate Dermatan sulfate, heparan sulfate, chondroitin sulfate

Mucolipidoses Lysosomal enzymes contain oligosaccharide chains, and a terminal mannose-6-phosphate is used for their labeling and intracellular identification. The Nacetylglucosamine-1-phosphotransferase is responsible for binding the phosphate group onto oligosaccharide units of the lyosomal enzymes. If this enzyme is deficient, several lysosomal enzymes–after being properly synthesized within the endoplasmatic reticulum–are not recognized as such, hence are unable to enter the lysosomes. As a result, multiple lysosomal enzyme deficiencies may develop, which are referred to as mucolipidoses. Mucolipidoses, therefore, comprise diseases with multiple lysosomal enzyme deficiencies (similarly to multiple sulfatase deficiency, see earlier), in contrast to the majority of lysosomal storage disorders which are related to a single enzyme deficiency. Defects of intracellular targeting are increasingly recognized as a likely pathomechanism in several mitochondrial, lysosomal, and peroxisomal disorders [15]. Miscellaneous This group includes cystinosis and Wolman disease, which typically have no neurological manifestations, and Salla disease (infantile sialic acid storage disease), which usually presents with mental retardation and extrapyramidal movement disorder clinically and white matter disease by imaging.

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A special form of lysosomal disorder is ChédiakHigashi syndrome [16], which is related to a peculiar structural abnormality of lysosomes (fusion disorder of the primary lysosomes) and may present with white matter disease. Peroxisomal Disorders

Peroxisomes are cellular organelles, which are present in all human cells, except erythrocytes. These contain several dozen enzymes involved in different metabolic pathways. Unlike lysosomes, peroxisomes have both anabolic and catabolic functions [17]. The term “peroxisome” refers to the presence of a catalase enzyme responsible for the conversion of hydrogen peroxide into oxygen and water. One of their primary anabolic roles is biosynthesis of phospholipids (plasminogens), which are essential components of myelin. On the other hand, very long chain fatty acids (peroxisomal β-oxidation of fatty acids is a functional duplicate of the mitochondrial system) and glutaric, phytanic, and pipecolic acids are also degraded within peroxisomes. Cholesterol is both synthesized and catabolized within peroxisomes. Since peroxisomes are specifically involved in lipid metabolism, they are indispensable in normal myelination process. The number of peroxisomes and their enzymatic activity vary accordingly as a function of the specific and tissular metabolic requirements. For example, peroxisomes in oligodendrocytes are significantly more abundant in neonates and infants during active myelination than later in life. Therefore, peroxisomal diseases typically present with involvement of CNS with predilection of the white matter. Additional characteristic features of peroxisomal disorders are craniofacial abnormalities (dysmorphias), skeletal abnormalities (rhizomelic shortening of the limbs, epiphyseal

calcifications), ocular abnormalities (retinopathy, cataract, optic nerve dysplasia), and hepatobiliary dysfunctions (hepatomegaly, hyperbilirubinemia, cholestasis). Some of them may be compatible with life, while others are not. Peroxisomal diseases are characterized by total or partial absence of peroxisomal activity and represent a real continuum of diseases, whose clinical manifestations are heavily dependent on the age of onset (Table 13.2). Golgi Complex Disorders

These are rare disorders characterized by defect of glycosylation. The first two steps in the synthesis of N-glycans (oligosaccharides essential to the synthesis of N-linked glycoproteins) take place in the cytosol and endoplasmic reticulum; however, the final processing is accomplished within the Golgi complex by N-acetylglucosaminyl transferase II. Patients with deficiency of this enzyme present with facial dysmorphia, growth retardation, and encephalopathy (behavioral disorders, mental retardation and epilepsy). 13.2.1.3 Classification According to the Biochemical Abnormality

This classification provides some help for the radiologist, since disease groups, such as the various organic acidurias or aminoacidemias, have common, sometimes suggestive clinical and imaging features. However, there is also some overlap between these two groups of diseases. Abnormalities along the breakdown pathways of L-lysine and L-leucine (both are amino acids) often present with organic acidurias (type 1 glutaric aciduria, 3-methylglutaconic aciduria, propionic acidemia, methylmalonic

Table 13.2. The typical age of onset of the most common peroxisomal diseases Neonatal

Early infantile

Zellweger syndrome Neonatal adrenoleukodystrophy

Infantile Refsum disease X-linked adrenoleukodystrophy Adrenomyeloneuropathy Pseudo-infantile Refsum Classical Refsum disease disease

Pseudo-neonatal adrenoleukodystrophy Rhizomelic chondrodysplasia punctata Bifunctional enzyme deficiency Pipecolic aciduria Mevalonic aciduria Trihydroxycholestanoic acidemia

Late infantile-juvenile

Juvenile-adult

Metabolic Disorders

acidemia). Aminoacidurias may be associated with organic acidemias (e.g., the association of homocystinuria with methylmalonic acidemia). Carbohydrate metabolism abnormalities represent another distinct but common group of metabolic diseases. Disorders of metal transport represent a peculiar group of pathologies, which is quite difficult to fit into any classification scheme. Organic Acidopathies

The best known organic acidopathies are primary lactic acidosis, propionic, methylmalonic, and isovaleric acidemias, glutaric aciduria type 1, 3-methylglutaconic, 4-hydroxybutyric, and L-2-hydroxyglutaric acidurias, and HMG-coenzyme A lyase deficiency. Some organic acidurias, such as L-2hydroxyglutaric aciduria, glutaric aciduria type 1, 4-hydroxybutyric aciduria, α-ketoglutaric aciduria, and N-acetylaspartic aciduria (Canavan disease) present with CNS involvement only. Others have systemic manifestations too (e.g., acidosis, ketosis, or ketoacidosis). Aminoacidopathies

The best known diseases in this group are phenylketonuria, nonketotic hyperglycinemia, maple syrup urine disease (branched-chain amino aciduria), hyperhomocystinemia, tyrosinemia, alkaptonuria, and a group of diseases (carbamyl phosphatase synthetase deficiency, ornithine transcarbamylase deficiency, argininosuccinate synthetase deficiency, argininosuccinate lyase deficiency, and arginase deficiency) referred to as urea cycle defects. Disorders of Carbohydrate Metabolism

Glycogen storage disorders, as mentioned earlier, do not have central or peripheral nervous system manifestations. Other entities in this group may present with CNS involvement. These include disorders of galactose (galactosemia) and fructose metabolism and persistent hyperinsulinemic hypoglycemia (nesidioblastosis). Disorders of Metal Metabolism

The best known of these diseases are those related to copper transport (Menkes disease and Wilson disease). Other metals which may be involved in inherited metabolic diseases are iron, magnesium, selenium, zinc, manganese, and molybdenum.

13.2.1.4 Classification According to Brain Substance Involvement

This classification takes into account the dominance of substance involvement (gray matter, white matter, or both) within the brain. Classification of inherited neurometabolic diseases–according to the primarily involved substance–into leukodystrophies, poliodystrophies, or pandystrophies is a helpful diagnostic imaging concept. This classification serves best the purposes of the radiologist but, as a trade-off, sometimes at the price of lack of specificity. Leukodystrophies

Diseases presenting with white matter abnormalities are referred to as leukodystrophies. The underlying metabolic abnormalities, however, span over a wide range, and include peroxisomal disorders (e.g., X-linked adrenoleukodystrophy) or lysosomal storage disorders (e.g., metachromatic leukodystrophy, Krabbe disease). In many other so-called classical leukodystrophies, the underlying metabolic abnormality is not known (Alexander disease, vanishing white matter disease, van der Knaap disease, AicardiGoutières syndrome). Furthermore, there are others which are not classically referred to as leukodystrophies but, from an imaging perspective, present with predominantly white matter abnormalities (GM2 gangliosidosis, L-2-hydroxyglutaric aciduria, many aminoacidopathies, and some forms of congenital muscular dystrophy) [18, 19]. In leukodystrophies or leukodystrophy-like conditions, the underlying pathological process may be quite different, notably delayed myelination, dysmyelination, or demyelination, or quite frequently a combination of them. The differentiation between these categories may be difficult or impossible by imaging; nevertheless, the concept is important [20]. Myelination is a very much an energy and nutrient dependent process, and any systemic (cardiac, respiratory, etc.) or CNS disease (meningoencephalitis, neurometabolic disease, etc.) occurring during the most active period of myelination (from birth to the age of 18 months) may lead to delay in the normal myelination. In these cases, however, the myelin composition is normal. In dysmyelinating processes, the histochemical structure of myelin is abnormal, leading to reduced and fragile myelin, which is then prone to breakdown resulting in partial or complete loss of the myelin. Absence of one of the essential constituents of myelin leads to dysmyelination. In Pelizaeus-Merzbacher

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disease, the so-called proteolipid protein is deficient, while in 18q- syndrome the myelin basic protein is absent. These conditions, therefore, represent examples of dysmyelination, with hypomyelination and secondary demyelination. The term demyelination refers to loss of a primarily normal or abnormal myelin. Possible causes of demyelination include a wide range of pathologies, notably inflammatory, toxic, metabolic, and many other diseases. Dysmyelination is also a possible cause of demyelination. Poliodystrophies

This group comprises diseases which present with predominant gray matter abnormalities. Some degree of white matter involvement, however, is often present. Classical disease categories are respiratory chain disorders (so-called mitochondrial diseases), some storage disorders, and organic acidopathies. Pandystrophies

In fact, the majority of metabolic disorders fall into this category, since exclusive involvement of gray or white matter structures is quite rare. Even some of the classical leukodystrophies present with clinical or imaging evidence of gray matter involvement. Typical neuroimaging findings of Canavan disease and Krabbe disease are pallido-thalamic lesions and putaminal lesions, respectively. Conversely, poliodystrophies (e.g., neuronal ceroid lipofuscinosis, mitochondrial diseases) may also be associated with more or less extensive white matter disease and, in some instances, even mimic leukodystrophy. It is, however, difficult to determine whether white matter abnormalities in “poliodystrophies” are primary or secondary to neuronal degeneration and, conversely, whether signal changes within basal ganglia in classical “leukodystrophies” represent just myelin breakdown or genuine neuronal damage.

13.2.2 The Concept of Selective Vulnerability Some of the metabolic disorders present with rather unremarkable, “generic” features from an imaging standpoint, such as atrophy and hypo- or delayed myelination. Nevertheless, one of the most striking imaging and pathological characteristics of many metabolic disorders is the highly variable pattern of involvement of the CNS parenchyma. Depending on the disease entity, some brain structures may be

severely damaged, whereas others appear to be completely normal. This is to a great extent explained by selective vulnerability of different structures to different noxae, especially in the developing brain [21]. The involved or spared structures define patterns (often referred to as “gestalt”) which, at times, may be consistent enough to be suggestive of or specific to certain disease entities. There is, however, increasing evidence to suggest that the nature of the metabolic disorder, in particular the type and quantity of the specific lacking or excess metabolites, as determined by the underlying molecular genetic disorder (genotype) and degree of resultant enzymatic dysfunction (biochemical phenotype), age of onset (maturity of the brain), and distinct histo-biochemical properties of different anatomical and functional systems, all have a potentially significant impact on the clinical manifestations (clinical phenotype) and may also be reflected by the magnitude and topographic distribution of imaging abnormalities (radiological phenotype). The specific energy and nutrient requirements of certain structures (myelinating white matter, basal ganglia), as a function of age, have a definite influence on selective vulnerability. The cerebral white matter is particularly vulnerable before the 32nd week of gestation, whereas basal ganglia are most prone to injury during the last three gestational months and during the first 3 years of life because of their particularly high metabolic rate. This may explain why hypoxicischemic episodes lead to periventricular leukomalacia in preterm, and to basal ganglia disease in term infants [22]. Similarly, since organic acidurias with postnatal onset (propionic aciduria, 3-methylglutaconic aciduria, methylmalonic aciduria, primary lactic acidosis, α-ketoglutaric aciduria) are often characterized by disturbances of amino and fatty acid supply to the citric acid cycle and, hence, by impairment of energy production, these preferentially present with basal ganglia disease, although white matter disease (demyelination) may also develop, especially in advanced stages of the disease. In neonatal maple syrup urine disease, selective involvement of actively myelinating and already myelinated white matter structures (vacuolating myelinopathy) results in a strikingly characteristic and consistent pathological-radiological lesion pattern. Conversely, in the late onset (or intermittent) form of maple syrup urine disease, pallidal and thalamic changes are usually more conspicuous. In some metabolic disorders (glutaric aciduria type 1, L-2-hydroxyglutaric aciduria, propionic and methylmalonic acidemias, and certain mitochondrial diseases) CSF levels of abnormal metabolites exceed

Metabolic Disorders

those within the plasma, which may also have a role in development of specific brain lesion and related neurological symptomatology [23]. It is also noteworthy that isomers of the same abnormal metabolite (L-2-hydroxyglutaric aciduria and D-2-hydroxyglutaric aciduria) may result in distinctly different clinical and imaging phenotypes (see below). While some aspects of the biochemical (direct or indirect toxic effects) and histopathological (dysmyelination) background of the phenomenon of selective vulnerability in neurometabolic disorders are progressively elucidated, others remain unclear or hypothetical. 13.2.2.1 Direct Toxic Effect

In some diseases a direct toxic effect by a specific abnormal metabolite has been identified. For example, in urea cycle defects hyperammonemia is the most likely cause of brain edema. Increased blood concentration of homocystine in homocystinuria is known to be destructive to fibrillin in connective tissues, a typical manifestation of which is lens subluxation. Homocystine is also believed to be toxic to the vascular endothelium, hence predisposing to thrombus formation [24]. Excitotoxicity is a peculiar direct toxic mechanism, which is particularly relevant to some of the metabolic diseases. Excitotoxicity refers to the detrimental effect of an otherwise normal neurotransmitter on neural cells, if it is present in excessive quantities (due to increased production or decreased elimination) or in case of activation (sensitization) of the receptors by energy depletion. Glutamate, probably the best known of the potentially excitotoxic substances, can cause transient or permanent cellular damage or death through the mechanism of excitotoxicity or “glutamate suicide” [25, 26]. 13.2.2.2 Indirect Toxic Effect

Other known indirect mechanisms include enzyme inhibition by an abnormal metabolite and activation of alternative metabolic pathways for an excess metabolite, resulting in synthesis of another toxic metabolite. Enzyme Inhibition

Excess propionyl and methylmalonyl coenzyme A in propionic and methylmalonic acidurias is known to

have an inhibitory effect on multiple metabolic processes. Methylmalonyl coenzyme A reduces the activity of pyruvate carboxylase and methylmalonic acid inhibits succinate dehydrogenase, both of which are important enzymes in gluconeogenesis. The result is hypoglycemia and ketosis, which have well-known detrimental effects on brain parenchyma. Propionyl coenzyme A also inhibits pyruvate dehydrogenase. At the same time, hepatic glycine cleavage system may also be impaired, leading to hyperglycinemia. Furthermore, the urea cycle is also affected through inhibition of carbamyl phosphatase synthetase enzyme, and this leads to toxic hyperammonemia. Inhibition of gluconeogenesis also occurs in HMG coenzyme A lyase deficiency. In glutaric aciduria type 1, inhibition of glutamate decarboxylase by glutaric acid causes glutamate accumulation within glial cells, possibly leading to glutamate excitotoxicity [25]. Succinic semialdehyde in 4-hydroxybutyric aciduria may cause impairment of oxidative phosphorylation. Activation of Alternative Metabolic Pathways

Hyperammonemia in urea cycle defects leads to increased synthesis of glutamate, which is believed to be an excitotoxic metabolite to brain parenchyma [26]. Excess tryptophan in glutaric aciduria type 1 may be degraded through an alternate catabolic pathway towards quinolinic acid, which is also believed to be toxic to basal ganglia, providing one of the possible explanations for basal ganglia damage in this disease. 13.2.2.3 Dysmyelination

Some of the metabolic disorders (L-hydroxyglutaric aciduria, homocystinuria) present with a peculiar pattern of retrograde demyelination. It is hypothesized that in metabolic diseases with postnatal onset, myelin produced after birth may be abnormal, hence fragile and prone to early degradation. Conversely, myelin and premyelin synthesized before the onset of the metabolic derangement is normal and, therefore, more resistant. This leads to a lesion pattern within the brain, somewhat reminiscent of neonatal or early postnatal myelination pattern, with the oldest myelin structures (brainstem, cerebellum, central corticalspinal tracts) being intact and other, younger white matter structures showing imaging evidence of demyelination.

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13.3 Principles of Imaging of the CNS in Metabolic Disorders 13.3.1 Foundations Health care centers specializing in the management of neurometabolic diseases benefit from considerable expertise, and the specific diagnosis is often established or at least strongly suggested based on clinical manifestations and results of sophisticated laboratory screening studies. The role of neuroimaging in such settings is often limited to initially providing a baseline “inventory” of CNS lesions, and then, occasionally, to performing follow-up studies in order to monitor disease progress and possible response to therapy. Somewhat paradoxically, the diagnostic burden is often heavier on radiologists working in general neuroimaging practices. These institutions are more likely to be involved in primary screening, and the referral diagnoses may not be suggestive of neurometabolic diseases. A high index of suspicion, knowledge of basic imaging semiology of neurometabolic diseases, and a systematic approach to image analysis and interpretation is mandatory under such circumstances. More importantly, it is indispensable to obtain an appropriately performed magnetic resonance imaging (MRI) study, taking full advantage of available technical options, in order to enhance sensitivity and specificity and identify definite, probable, and possible neurometabolic diseases and warrant further, targeted investigations. Imaging strategies in inborn errors of metabolism rely heavily on the concepts of selective vulnerability and pattern recognition. The imaging workup of patients with suspected metabolic disorders needs to be designed so as to obtain the best possible visualization and characterization of lesions within the CNS. This is the most important prerequisite of application of the concept of pattern recognition in the process of image analysis. The individual lesions represent imaging substrates of selective vulnerability, and the sum of the lesions with the resultant lesion patterns correspond to imaging phenotypes of various disease entities. 13.3.1.1 Imaging Modalities Conventional X-rays

Conventional X-ray studies have a very limited role in the diagnostic imaging workup of metabolic disorders. These may be used to demonstrate involvement of the skeletal system in peroxisomal disorders, for

example, in Zellweger disease, rhizomelic chondrodystrophia punctata, or Gaucher disease. X-rays of the head show deformities of the skull and sella or abnormalities of bony elements of the cranio-cervical junction, and spine X-rays are used to diagnose vertebral body changes in mucopolysaccharidoses. Ultrasound (US)

Some of the neurometabolic diseases, especially those which are associated with morphological brain abnormalities, may have a highly characteristic or suggestive appearance on cranial US images; therefore, the diagnosis may be suggested even before appearance of clinical signs and symptoms. Transcranial US has been found to be useful in demonstration of morphological changes, such as bilateral Sylvian fissure abnormalities in glutaric aciduria type 1 or germinolytic cysts in Zellweger syndrome [27, 28]. In infantile leukodystrophies presenting with macrocephaly, US may have an important role in ruling out hydrocephalus and orienting the diagnosis towards a possible neurometabolic disease. Furthermore, cranial US may allow differentiation between different leukodystrophies (Canavan vs. Alexander disease) by differences in echogenicity of affected white matter [29, 30]. Metabolic diseases, in particular lysosomal storage disorders, presenting with hydrops fetalis (Gaucher disease, Niemann-Pick disease, mucopolysaccharidoses IV and VII, GM1 gangliosidosis) may also be suspected by prenatal US examination [31]. Rhizomelic chondrodysplasia punctata was successfully diagnosed by prenatal US at 19-week gestational age, based on detection of classical skeletal abnormalities (punctate epiphyseal calcifications, shortening of femur) [32]. Computed Tomography (CT)

In clinically suspected neurometabolic diseases, the role of CT in the imaging workup is usually secondary, since its overall sensitivity and specificity is inferior to MRI. In rare and specific situations, however, CT performed as a complementary study can enhance diagnostic specificity. The demonstration of rather typical hyperdense basal ganglia (in Krabbe disease) and thalami (in GM2 gangliosidoses) by CT can be helpful to support the MRI suspicion [33;34]. CT is particularly useful in the demonstration of calcifications. This is important because calcifications are not always conspicuous on MR images, and their

Metabolic Disorders

appearance may be inconsistent. Theoretically, calcifications present with hyposignal on both T1- and T2-weighted images; however, due to variations of the crystalline structure, they may occasionally be hyperintense on T1-weighted images. The demonstration of basal ganglia calcifications by CT also has diagnostic implications in Cockayne syndrome, Aicardi-Goutières syndrome, and some mitochondrial encephalopathies [35, 36]. In malignant biopterin-dependent form of phenylketonuria or carbonic anhydrase II deficiency, CT presentation with extensive subcortical calcifications may be highly suggestive. In acute metabolic crisis and stroke or stroke-like presentations, CT may also be used as an emergency imaging modality to rule out vascular etiologies, i.e., ischemia or intracerebral bleeding. Some metabolic disorders, and in particular organic acidemias (propionic, methylmalonic, isovaleric acidemias), may be associated with thrombocytopenia, causing hemorrhagic diathesis with possible subarachnoid and intraparenchymal, mainly cerebellar, bleedings [37, 38]. Frequent subdural hematomas in Menkes disease or in glutaric aciduria type 1 may also be readily diagnosed and followed up by CT. Positron Emission Tomography (PET)

PET is a powerful functional imaging modality, which may be used in metabolic disorders as a complementary tool to assess functional abnormalities. The most robust and frequently used technique is 18 Fluoro-2-deoxyglucose (18FDG-PET), which is very sensitive in demonstrating metabolic changes in gray matter, notably within cerebral or cerebellar cortex, basal ganglia, and thalami. Hypometabolism within these structures–presenting with decreased uptake of the radiopharmaceutical–may be a more sensitive indicator of an ongoing disease process than MRI in some cases, especially during the early stage of the disease (Fig. 13.1).

tive, or occasionally even disease-specific, patterns may be identified. Nowadays, MRI is the technique of choice in the imaging evaluation of inborn errors of metabolism. 13.3.1.2 Imaging Strategies

The actual brain MRI protocol in patients with suspected or known metabolic disorders should always be adapted to the specific needs of the imaging evaluation of various, potentially relevant brain structures and underlying pathological phenomena. The most important prerequisites for lesion detection are selection of the optimal imaging planes and high spatial and contrast resolution. Optimal Imaging Plane

Accurate assessment of different anatomical structures of brain requires appropriate imaging plane selection. For example, the cerebellar white matter and dentate and subthalamic nuclei are best visualized in the coronal plane (Fig. 13.2). The basal ganglia, in general, are well appreciated in the axial plane; nevertheless, involvement of the body of the caudate nucleus may also require coronal cuts. The cerebellar vermis and corpus callosum are most adequately outlined in sagittal images. Optimal Spatial Resolution

Some brain structures are fairly well visualized in low spatial resolution (256 matrix) images, because of their considerable volume (basal ganglia, thalami, centrum semiovale). Other structures, however, such as cerebral and cerebellar cortex, claustra, brainstem structures, subcortical U-fibers, etc., are smaller; therefore, use of high resolution (512 matrix) techniques is indispensable for their accurate evaluation.

Magnetic Resonance Imaging (MRI)

MRI has inherently high sensitivity in demonstrating normal or abnormal myelination, differentiating white and gray matter structures, and detecting structural and signal changes within brain. The usual criticism about MRI is its “low specificity,” since most abnormalities present with prolonged T1 and T2 relaxation (i.e., hyposignal on the T1- and hypersignal on the T2-weighted images). This undeniable shortcoming of MRI may be, however, significantly compensated by a systematic application of the concept of pattern recognition, through which sugges-

Optimal Sequence Selection and Contrast Resolution

T1-Weighted Imaging T1-weighted imaging is essential in evaluation of normal or abnormal myelination and in assessment of the pattern of a demyelinating process. The T1 contrast can be enhanced by use of real inversion recovery (rIR) techniques. Since this technique prominently highlights the myelinated structures with respect to nonmyelinated areas, it is particularly useful in the assessment of the myelina-

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a

b

c

d

e

f

Fig. 13.1a–f. MRI and 18FDG-PET correlations in glutaric aciduria type 1. Axial T2-weighted fast spin-echo and PET images at the level of the deep gray matter structures. a, b Images of a 3-month-old male patient diagnosed with glutaric aciduria type 1 at birth and successfully treated afterwards. Normal MRI appearance and metabolic activity of basal ganglia and thalami. Note the relatively decreased (age-related) cortical uptake of the radiopharmaceutical within both cerebral hemispheres. c, d Images of an 11-year-old female patient with the naturally mild form of the disease. On the MR image, moderate signal changes are seen within the posterior parts of the putamina with ambiguous signal alterations within the head of the left caudate nucleus. The PET image shows total loss of the metabolic activity within both putaminal and the left caudate lesion, confirming the MRI findings. The cortical and thalamic metabolic activity is preserved. e, f Images of a 7-year-old male patient (brother of patient shown in Fig. 13.1a, b) with the riboflavin dependent form of the disease, in whom diagnosis and treatment were delayed. Severe, necrotic changes within the basal ganglia bilaterally, with corresponding total lack of metabolic activity on the PET image, are shown. There is decreased metabolic activity within the thalami and the right subinsular cortex

tion process and is recommended in children under 12 months of age (by which myelination appears to be grossly accomplished on T1-weighted images). Furthermore, inversion recovery sequences provide T1-weighted images with exquisite contrast resolution between white and gray matter structures. In the mature brain, this allows relatively easy identification of cortical dysplasias or gray matter heterotopias. T1-weighted, and in particular, rIR imaging may also be a sensitive indicator of demyelination and allows accurate assessment of involvement or sparing of specific white matter structures of the brain.

Subcortical U-fibers may be involved in some leukodystrophies (Canavan disease, Alexander disease, Krabbe disease) or spared in others (X-linked adrenoleukodystrophy, metachromatic leukodystrophy) (Fig. 13.3). Sparing of perivascular white matter may be observed in metachromatic leukodystrophy or in Pelizaeus-Merzbacher disease. In some instances, however, conventional T1weighted spin-echo images yield better results. Notably, abnormal hyperintensity of basal ganglia in cases of hepatic encephalopathy, Krabbe disease, or GM2 gangliosidosis may be more conspicuous on conven-

Metabolic Disorders

a

b Fig. 13.2a, b. Optimal visualization of subthalamic and dentate nucleus lesions in the coronal plane in metabolic disorders. a Coronal T2-weighted fast spin-echo image in an 18-month-old male patient with history of prolonged postnatal hyperbilirubinemia, leading to kernicterus. The abnormal hyperintensity within the subthalamic nuclei (thin arrows), as well as the globi pallidi (open arrows) and the substantia nigra (arrowheads) is clearly demonstrated. b Coronal T2-weighted fast spin-echo image in a 9-year-old male patient with propionic acidemia after acute metabolic crisis. The abnormal hyperintense appearance of the dentate nuclei (open arrows) and of the cerebellar cortex is best appreciated in the coronal plane

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tional T1-weighted spin-echo than on IR images. Furthermore, signal enhancement after intravenous contrast injection is easier to interpret on T1-weighted spin-echo than on IR images. T2-Weighted Imaging Differences in histochemical properties (water and lipid content) between immature (newborns and infants) and mature (children and adults) brain requires appropriate adjustment of some parameters of conventional spin-echo or fast spin-echo sequences. To compensate for longer T2 relaxation

Fig. 13.3a,b. MR imaging visualization of sparing or involvement of subcortical U-fibers in leukodystrophies. a Axial T1weighted inversion recovery image in a 2.5-year-old female patient with metachromatic leukodystrophy. The subcortical U-fibers are preserved. b Axial T1weighted inversion recovery image in an 11-month-old female patient with globoid cell leukodystrophy (Krabbe disease). The subcortical U-fibers are involved in the demyelinating process

time (due to high water and lower myelin/lipid content) of brain parenchyma in the newborn and infant, longer repetition (TR) and echo (TE) times are used in T2-weighted imaging. T2-weighted imaging is useful in assessment of both gray and white matter at any age in normal or pathological conditions. T2-weighted imaging is considered to be the gold standard for depiction of parenchymal lesions characterized by T2 prolongation. Conventional spin-echo technique is perhaps more sensitive than fast spin-echo, but the trade-off is a definite time penalty.

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T2-weighted imaging is also essential in assessment of myelination pattern, especially in the 12 to 18 months age range, where T1-weighted (and IR) images are already more or less insensitive. Furthermore, in the neonate and young infant T2-weighted images often allow better assessment of the cortex and more accurate depiction of cortical abnormalities than T1-weighted images (Fig. 13.4). The modular inversion recovery (mIR) technique allows accurate delineation of small lesions within the brainstem and deep gray matter nuclei. Using a high resolution matrix, accurate topographical localization of lesions within deep gray matter structures or the brainstem is further enhanced, providing necessary information for disease-specific pattern recognition. Fluid-attenuated inversion recovery (FLAIR) technique may be helpful in demonstrating cystic lesions within a markedly abnormal white matter, for instance in van der Knaap or Alexander diseases. FLAIR imaging, however, is less frequently used in children than in adults. Especially in brainstem lesions, its sensi-

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tivity is inferior to that of conventional T2-weighted imaging (Fig. 13.5). 13.3.1.3 Evaluation of MR Images

The evaluation of MR images in metabolic disorders is based on the application of the concept of pattern recognition [19, 39]. Pattern recognition means recognition of imaging manifestations of selective tissue or structure vulnerability within the CNS. Detection and identification of lesions within specific anatomical structures is a key element in pattern recognition. Some abnormalities are easily recognized; others may be more subtle and require sophisticated imaging techniques and meticulous evaluation. In order to obtain the most complete data set for pattern recognition, a systematic and extensive evaluation of brain structures is mandatory [40]. The most relevant white or gray matter structures of the brain to be analyzed are listed in Table 13.3.

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Fig. 13.4a,b. Cortical gyral abnormalities (polymicrogyria) in a 5-month-old female patient with Zellweger disease. a Axial T1weighted fast inversion recovery image. The bilateral polymicrogyria-like cortical abnormalities around the Sylvian fissures are hardly visible. b Axial T2-weighted fast spin-echo image. The cortical abnormalities are easier to detect on this image because of the better gray-white matter contrast resolution on the T2-weighted images at this age

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Fig. 13.5a,b. Brainstem abnormalities in a 6-year-old female patient with glutaric aciduria type 1. a The axial modular inversion recovery image shows bilateral, symmetrical signal abnormalities within the central tegmental tracts. Ill-defined faint hyperintensities are also demonstrated within the ventral part of the pons, which clearly outline the unaffected pyramidal tracts, presenting normal hyposignal. b The axial FLAIR image at the same level fails to provide the above information

Metabolic Disorders Table 13.3. The most important white and gray matter structures of the brain to be analyzed in metabolic disorders White matter structures

Gray matter structures

Cerebral (lobar) white matter Subcortical U-fibers Extreme capsule External capsule Internal capsule Medullary laminae Corpus callosum Anterior commissure Mammillary bodies Central tegmental brainstem tract Cortical-spinal tract Cerebellar white matter

Cerebral cortex Claustrum Caudate nucleus Putamen Globus pallidus Thalamus Subthalamic nucleus Red nucleus Substantia nigra Dentate nucleus Cerebellar cortex

White Matter Structures

The cerebral white matter is assessed in different lobes (frontal, parietal, occipital, and temporal) separately. Their involvement may be different or similar in various diseases. Depending on the magnitude

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of involvement in different lobes, antero-posterior or postero-anterior gradients of the disease process may be identified. Similarly, central and peripheral white matter structures may show different degrees of damage; therefore, centripetal or centrifugal progression patterns may also be found (Fig. 13.6). Special attention should be paid to subcortical Ufibers, whose sparing or involvement may be characteristic of specific disease entities (metachromatic leukodystrophy vs. Canavan disease). The deep white matter layers are also important to analyze. The internal capsule may be entirely or partially affected; therefore, anterior limb, genu, and posterior limb have to be evaluated separately. The external and extreme capsules may also be normal or abnormal. The medial and lateral medullary laminae separate the pars medialis of the globus pallidus (medial pallidal segment) from the pars lateralis (lateral pallidal segment), and the pars lateralis of the globus pallidus from the putamen, respectively, and may (e.g., L-2-hydroxyglutaric aciduria, fucosidosis) or may not be involved in white matter diseases (Fig. 13.7).

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Fig. 13.6a–d. Various progression patterns in leukodystrophies on axial T1-weighted inversion recovery images. a Antero-posterior gradient of the white matter disease in van der Knaap disease. b Postero-anterior gradient of the white matter disease in Krabbe disease. c Centripetal progression pattern in L-2-hydroxyglutaric aciduria. The subcortical structures are completely demyelinated; the central white matter is preserved. d Centrifugal progression pattern in X-linked adrenoleukodystrophy. In this case, an additional postero-anterior gradient is also conspicuous

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The mammillary bodies are also prone to damage; the best-known example is Wernicke encephalopathy. The corpus callosum usually reflects the magnitude and the possible progression gradient of the involvement of hemispheric white matter. The corpus callosum should be assessed for signal abnormalities and volume changes (swelling or atrophy) (Fig. 13.8). To date, no data are available about possible involvement of the anterior commissure in demyelinating processes (Fig. 13.8), but it is probably because little or no attention has been paid to this potentially important structure so far. The central tegmental structures of the pons are frequent lesion sites in metabolic and neurodegenerative processes. These are totally nonspecific, but still useful in raising the possibility of a metabolic disorder (Fig. 13.5). The corticospinal tracts should be carefully analyzed from the precentral gyrus all the way down to the decussation at the level of the medulla oblongata, including their course through the posterior limbs of the internal capsules and cerebral peduncles. The cerebellar hemispheric white matter is perhaps less frequently involved than the cerebral white matter in metabolic diseases, but presence of signal abnormalities and their distribution can be useful in pattern recognition (Fig. 13.9). Gray Matter Structures

The cerebral cortex is quite difficult to assess for atrophic changes; nevertheless, in some diseases (GM2 gangliosidosis, van der Knaap disease, Canavan disease) thinning of the cortex may be obvious on MRI. Occasionally, cortical dysplasia may be associated with inborn errors of metabolism (Zellweger disease, fumaric aciduria).

Fig. 13.7a,b. Involvement or sparing of deep white matter structures. Axial modular inversion recovery images in a 21year-old female patient with L-2-hydroxyglutaric aciduria. a On this image, the abnormal hyperintense appearance of the external and extreme capsule well delineates the claustra. The anterior limbs of the internal capsules are partially demyelinated; this is obvious, when compared to the spared posterior limbs and knees. The poor delineation of the interface between the putamina and the lateral pallidal segment indicates involvement of the lateral medullary laminae. b Sparing of the anterior commissure and of the medial medullary laminae

Deep gray matter structures should be assessed for morphological changes (swelling, atrophy) and signal abnormalities. In the acute phase of organic acidopathies, swelling of the basal ganglia is a typical finding, whereas in the chronic stage atrophy is characteristic. These changes are associated with abnormal, increased signal intensity on T2-weighted images (Fig. 13.10). Hypointense appearance on long TR images (especially on T2-weighted gradient echo images) is suggestive of calcifications or premature iron depositions, which are more characteristic of neurodegenerative diseases, but are quite typical also of Wilson disease. In metabolic diseases presenting with basal ganglia lesions, the claustra may be spared (L-2-hydroxyglutaric aciduria) or involved (Wilson disease). The thalami are less frequently abnormal in inherited metabolic disorders. The subthalamic nuclei are abnormal in kernicterus and in Leigh disease. The red nuclei are often spared in metabolic disorders, but involvement of the surrounding white matter structures and of the substantia nigra with hypersignal on T2weighted images results in the so-called giant panda face appearance, which may be seen in Wilson disease or glutaric aciduria type 1 (Fig. 13.11). The dentate nuclei may be involved in all kinds of metabolic diseases, especially in organic acidopathies, probably more frequently than previously thought. In the acute phase, when swelling is associated with hypersignal on the T2-weighted images, depiction of abnormalities is easy; however, in the atrophic stage, when volume loss is present with less prominent signal changes, identification of the lesions may be quite challenging. Lesions of the dentate nuclei are frequent and characteristic in cerebrotendinous xanthomatosis. The cerebellum as a whole, but the cerebellar cortex in particular, often shows atrophic changes in

Metabolic Disorders

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d Fig. 13.8a–d. Patterns of involvement of the corpus callosum in various leukodystrophies. a Sagittal T1-weighted spin-echo image in a 2-year-old female patient with metachromatic leukodystrophy. At this stage of the disease the anterior parts of the corpus callosum exhibit some swelling, whereas posteriorly atrophy and ill-defined hypointensities (arrow) are seen. This is consistent with the known postero-anterior progression gradient of the demyelinating process. b Sagittal T1-weighted spin echo in the same patient at 4 years of age. By this time, the entire corpus callosum shows atrophy and signal changes, which are, however, more prominent posteriorly. c Sagittal T2-weighted gradient echo image in a 19-month-old female patient with van der Knaap disease. The most prominent signal changes are seen at the level of the inferior aspect of the body of the corpus callosum; the upper margin as well as the knee and the splenium show partial sparing. Note the sparing of the anterior commissure (arrowhead). d Sagittal T2-weighted fast spin-echo image in a 12-year-old male patient with X-linked adrenoleukodystrophy. At this stage of the disease, the signal changes involve the splenium and the posterior part of the body only (arrow). Note the signal abnormalities within the anterior commissure (arrowhead)

metabolic diseases. The vermis may be more severely involved than the rest of the cerebellum (Fig. 13.12). Rarely, signal abnormalities are present along the cortical-subcortical interface. Spinal Cord Involvement

To date, the spinal cord has not been systematically assessed in congenital or acquired metabolic diseases; therefore, published data on the imaging

findings of spinal cord and cauda equina lesions are sparse [41, 42]. This may be partially explained by technical reasons, as the small size of anatomical structures renders accurate evaluation of the spinal cord for possible gray or white matter abnormalities difficult, although not necessarily impossible, by currently available MRI techniques. For example, a peculiar white matter tract involvement has been described in a newly discovered leukodystrophy presenting with brainstem and spinal cord involvement

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Fig. 13.9a–f. Patterns of involvement of cerebellar white matter on coronal T2-weighted fast spin-echo images in various leukodystrophies. a 10-month-old male patient with Canavan disease. The central and the peripheral white matter structures are equally involved in the cerebellum. No cerebellar atrophy is seen. b 11-month-old male patient with globoid cell leukodystrophy (Krabbe disease). Diffuse involvement of the cerebellar white matter, somewhat less prominent than in Canavan disease and associated with atrophy. c 7-year-old female patient with van der Knaap disease. Moderate signal abnormalities within the deep cerebellar white matter structures, including the hili of the dentate nuclei. The subcortical white matter is spared. No cerebellar atrophy is seen. d 10-year-old male patient in the advanced stage of metachromatic leukodystrophy. The pattern of the cerebellar white matter involvement is quite similar to that seen in van der Knaap disease, except for the associated atrophy, which is clearly shown in this case. e 2-year-old male patient with metachromatic leukodystrophy (saposin B deficient). In this stage of the disease, only very subtle central white matter signal changes are suggested (sometimes better appreciated on FLAIR images, not shown here). Mild atrophy is, however, already conspicuous. f 12-year-old male patient with X-linked adrenoleukodystrophy (same patient as Fig. 13.8d). No signal abnormality or atrophy is seen at the level of the cerebellum

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Fig. 13.10a,b. Bilateral basal ganglia lesions in acute, subacute, and chronic stages of 3-methylglutaconic aciduria on axial T2-weighted fast spin-echo images. a 1-year-old female patient with 3-methylglutaconic aciduria during acute metabolic decompensation. Signal abnormalities are seen within the globi pallidi, heads of the caudate nuclei and within the anterior parts of the putamina. The putaminal lesions are associated with swelling. b 10-year-old male patient after several metabolic crises. The putamina exhibit prominent atrophy and marked hypersignal, consistent with necrosis. The caudate nuclei and globi pallidi are also abnormal, but signal and volume changes are less marked on this image

Metabolic Disorders

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Fig. 13.11a, b. The “giant panda face” appearance of the upper mesencephalon on T2-weighted fast spin-echo images in metabolic diseases. a 1-year-old male patient with glutaric aciduria type 1. The cerebral peduncles, the red nuclei and the tectum are normal (hypointense), whereas the substantia nigra and the periaqueductal white matter exhibit increased signal. b 16-year-old male patient with Wilson disease. Similar findings as on Figure 13.11a

Fig. 13.12a–c. Progressive atrophy of the cerebellar vermis on sagittal T1weighted spin-echo images in a male patient with 3-methylglutaconic aciduria. a The examination at the age of 1 year shows a normal cerebellum. b At the age of 18 months, the follow-up study reveals definite atrophy of the cerebellar vermis. c The follow-up study at the age of 2 years shows further progression of cerebellar atrophy

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and high lactate [43]. It is reasonable to presume that the spinal cord may also be involved in more disease entities than reported so far. Histopathological data suggest that both white matter tracts and gray matter structures are prone to damage in a series of diseases, including Canavan disease, Cockayne disease, Krabbe disease, GM2 gangliosidosis, nonketotic hyperglycinemia, cerebrotendinous xanthomatosis, carbohydrate-deficient glycoprotein syndrome, glutaric aciduria type 2, and cobalamin and methyltetrahydrofolate deficiency (hyperhomocystinemia). Based on these data, variable patterns of involvement within different spinal cord structures and, in particular, in white matter tracts may be anticipated in these diseases. Lesions within the spinal cord, identical to those seen in brain, have been demonstrated by diffusion-weighted imaging in maple syrup urine disease (personal observation). The spinal cord may, however, be spared in cases of apparent involvement of the brain, for example, in L-2-hydroxyglutaric aciduria [44]. Other Imaging Abnormalities

Identification of additional gross morphological abnormalities may also be useful in the process of pattern recognition. Macrocephaly, for example, in some leukodystrophies (van der Knaap disease, Canavan disease, Alexander disease), type 1 glutaric aciduria, GM2 gangliosidosis, and L-2-hydroxyglutaric aciduria, is an important pattern element. Other metabolic disorders present with microcephaly (Zellweger disease, Aicardi-Goutières syndrome, Cockayne disease, Pelizaeus-Merzbacher disease). Bony abnormalities in the spine are typical and very characteristic in some forms of mucopolysaccharidoses. 13.3.1.4 Common MR Imaging Features of Metabolic Disorders

Metabolic disorders have many common, although individually nonspecific, features, whose awareness and recognition is important for raising the possibility of such a disease in as yet unknown CNS pathologies. Atrophy

Atrophy of different brain structures is common in metabolic diseases. Atrophy may be diffuse or focal, and affect specific structures (basal ganglia, cerebellar vermis, corpus callosum). Cerebellar atrophy is consistently associated with some specific metabolic

disease entities (neuronal ceroid lipofuscinosis, 3methylglutaconic aciduria, carbohydrate-deficient glycoprotein syndrome, many lysosomal storage disorders, Menkes disease, mitochondrial diseases) [39]. However, the association of prominent brainstem and cerebellar atrophy is perhaps more suggestive of neurodegenerative disease (e.g., olivopontocerebellar degeneration). Atrophy is often progressive and may be the sole indicator of an insidious metabolic disorder (Fig. 13.13). It is, nevertheless, important to note that during an acute metabolic crisis, or active ongoing demyelination, swelling of gray or white matter structures is also typical. Symmetry

In metabolic disorders, symmetry of the lesions is a characteristic, although not consistent, feature. Gray matter structures (basal ganglia, dentate nuclei) are almost always symmetrically involved. Very rarely, asymmetrical involvement of the basal ganglia may be present in metabolic diseases, especially during the early stages of the disease [45] (Fig. 13.1). The white matter lesions in metabolic diseases may be patchy, but in extensive diseases, and in particular in leukodystrophies, lobar white matter involvement typically shows a fairly symmetrical pattern. Symmetry is, however, not unusual in some inflammatory (acute disseminated encephalomyelitis) or infectious diseases (subacute sclerosing panencephalitis) either. Symmetry is also common in neurodegenerative diseases and in toxic and hypoxic-ischemic encephalopathies. Myelination Abnormalities

In infants, during the most active period of myelination, delay or hypomyelination is frequently associated with metabolic disorders. These are, again, nonspecific but important abnormalities. In some diseases (Zellweger disease, nonketotic hyperglycinemia) it can be very severe; in others, such as Pelizaeus-Merzbacher disease, the imaging findings suggest an arrest of the myelination process. 13.3.1.5 Uncommon MRI Features of Metabolic Disorders Contrast Enhancement

Intravenous contrast injection is usually not indicated in inborn errors of metabolism, since pathological contrast uptake is quite exceptional and rarely increases

Metabolic Disorders

specificity. Exceptions exist, however. In X-linked adrenoleukodystrophy, if present, contrast enhancement in the actively demyelinating, inflammatory zone is practically pathognomonic. Contrast enhancement in the brain is a hallmark diagnostic feature in Alexander disease [46]. In Krabbe disease, patchy enhancement may occasionally be present within the periventricular white matter (Fig. 13.14). Enhancement of cauda equina roots has also been described in Krabbe disease [41]. Malformations

Dysmorphic features (especially in the craniofacial area) are frequent manifestations of inherited meta-

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bolic disorders, especially in lysosomal storage disorders and peroxisomal diseases [47]. Conversely, the incidence of true brain malformations is surprisingly low in metabolic diseases. This may be explained by the typically postnatal onset of most diseases. Conversely, intrauterine onset of the metabolic disorder (especially if energy metabolism is affected, as in peroxisomal, fatty acid oxidation, and respiratory chain defects) may lead to malformations or disturbed development of the CNS (and of other organs), as demonstrated by the characteristic bilateral perisylvian polymicrogyria in Zellweger disease. Diffuse polymicrogyria and open opercula have also been described in fumaric aciduria [48]. Pachygyria has been observed

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Fig. 13.13a–c. Progressive cerebral atrophy in a male patient with biotinidase deficiency. Axial T2-weighted fast spin echo images. a The initial MR imaging study at the age of 1 year shows mild, predominantly frontal brain atrophy. b First follow-up examination at the age of 2 years. Interval progression of the atrophy. c Second follow-up study at the age of 4 years. Very prominent corticalsubcortical brain atrophy

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Fig. 13.14a–c. Enhancement patterns on postcontrast images in leukodystrophies. a Gd-enhanced axial T1-weighted spin-echo image in a 1-year-old male patient with Krabbe disease. Patchy enhancement is seen in the deep, periventricular white matter. b Gd-enhanced axial T1-weighted spin-echo image in a 12-year-old boy with X-linked adrenoleukodystrophy. The image shows typical peripheral enhancement around the demyelinated central, burned-out zone. c Gd-enhanced coronal T1-weighted spin-echo image in a 3-year-old female patient with Alexander disease. Enhancement is seen in the frontal periventricular white matter and at the level of the basal ganglia (courtesy of Dr. K. Chong, London, United Kingdom)

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in glutaric aciduria type 2 and in nonketotic hyperglycinemia [49, 50]. Cerebellar dysgenesis was reported in one case of type 4 3-methylglutaconic aciduria [51]. Callosal abnormalities (hypo- or dysplasia) are always seen in nonketotic hyperglycinemia, and callosal dysgenesis or hypoplasia may be seen in glutaric aciduria type 2, 3-phosphoglycerate dehydrogenase deficiency, pseudoneonatal adrenoleukodystrophy, Salla disease, and mucolipidosis type IV [49, 52–54]. In glutaric aciduria type 1, the almost invariably present bilateral open Sylvian fissures (disturbed opercularization) also suggest a prenatal disease onset. In siblings with ethylmalonic aciduria, Chiari I malformation and tethered cord have been described [55]. More subtle changes, probably not detectable by MRI, suggestive of incomplete development of the brain, have also been demonstrated by histopathological evaluation in methylmalonic aciduria [56]. Some of the maternal metabolic disturbances or intoxications during pregnancy may lead to fetal malformations. The best known etiological factors are phenylketonuria, diabetes, alcohol and drug abuse, folate and riboflavin deficiency [57, 58]. 13.3.1.6 Misleading Imaging Findings

Some imaging findings may be misleading. Prominent bilateral subdural hematomas, for example, are frequently seen in glutaric aciduria type 1 and Menkes disease, and may be misinterpreted as a sign of child abuse [59]. Awareness of this possible complication and recognition of other imaging or clinical hallmarks of the respective diseases help to avoid a misdiagnosis. As mentioned earlier, symmetrical involvement of different cerebellar, brainstem, and cerebral structures is often an important element and diagnostic clue in the imaging presentation of neurometabolic diseases. Asymmetrical or scattered lesions, however, by no means rule out the possibility of inborn errors of metabolism, especially in early stages of the diseases. 13.3.1.7 Differential Diagnostic Problems

Differentiation of lesions related to inborn errors of metabolism from nonmetabolic ones is important but sometimes difficult [60]. Differential diagnostic considerations in neurometabolic disorders essentially presenting with a white matter disease include periventricular leukomalacia, vasculitis, progressive multifocal leukoencephalitis, demyelinating dis-

eases, human immunodeficiency virus encephalitis, brucellosis, toxic and postirradiation encephalopathy. Basal ganglia involvement in inherited metabolic diseases may be challenging to differentiate from other nonmetabolic causes, such as subacute sclerosing panencephalitis, extrapontine myelinolysis, carbon monoxide intoxication, and sequelae of prolonged hypoxemia or anoxia [36].

13.3.2 Imaging Patterns in Metabolic Disorders Individual lesions in metabolic diseases, by themselves, are usually nonspecific. However, compiling positive and negative structure-specific findings during the process of image analysis may result in lesion patterns. Unfortunately, many of them are nonspecific too; nevertheless, these are still important since they may be useful in raising the possibility of a metabolic disorder along with other differential diagnostic alternatives. In some instances, however, the lesion pattern may be suggestive of a specific disease entity or group of diseases, whereas occasionally the imaging pattern is actually pathognomonic. 13.3.2.1 Pathognomonic MRI Patterns

This category includes L-2-hydroxyglutaric aciduria, glutaric aciduria type 1, neonatal maple syrup urine disease, Zellweger disease, X-linked adrenoleukodystrophy, Canavan disease, Alexander disease, van der Knaap disease, leukodystrophy with brainstem and spinal cord involvement and high lactate, and some mucopolysaccharidoses presenting with perivascular depositions. 13.3.2.2 Suggestive MRI Patterns

The best known of these metabolic diseases are methylmalonic aciduria (mut0, mut-, CblA and CblB forms), 3-methylglutaconic aciduria (type 1 and 4), β-ketothiolase deficiency, late onset forms of maple syrup urine disease, homocystinuria, biotin-responsive basal ganglia disease, nonketotic hyperglycinemia, Krabbe disease, metachromatic leukodystrophy, GM2 gangliosidosis, fucosidosis, mucolipidosis type IV, Pelizaeus-Merzbacher disease, vanishing white matter disease, many of the “mitochondrial diseases” (Leigh disease, MELAS, Kearns-Sayre disease), cerebrotendinous xanthomatosis, Menkes disease, and Wilson disease.

Metabolic Disorders

13.3.2.3 Nonspecific MRI Patterns

All other metabolic disorders fall into this group. It is, nevertheless, worthwhile to mention that it comprises many relatively frequent disorders, notably propionic acidemia, ethylmalonic acidemia, HMG-coenzyme A lyase deficiency, biotinidase deficiency, phenylketonuria, homocystinuria, and the so-called urea cycle defects.

13.3.3 The Concept of Dynamic Imaging Patterns

gressive diffuse brain atrophy. In most cases simple visual image analysis without volumetric studies is sufficient (Fig. 13.13). Progressive trophic changes may affect certain brain structures more selectively, such as the cerebellar vermis, optic nerves, or basal ganglia, which may be important elements in pattern recognition. 13.3.3.2 Evolving Structure-Specific Lesions

Structure-specific lesions in given metabolic disorders may appear in a multiphasic, sequential fashion. It means that certain structures may be affected early during the disease course, while others become abnormal later. In biotin-responsive basal ganglia disease, the dentate nuclei may be affected first, followed by the putamina several months later. In 3-methylglutaconic aciduria, the involvement of the globi pallidi precedes that of the caudate nuclei and putamina. In metachromatic leukodystrophy, the subcortical U fibers are initially spared, while later they undergo demyelination as well. This phenomenon may be responsible for substantial pattern changes in time. Rarely, structural lesion may improve or completely disappear on follow-up studies in patients under treatment (Fig. 13.15).

Follow-up studies in inborn errors of metabolism suggest that imaging patterns are dynamic rather than stable during the disease evolution. This is quite conceivable, since clinically they also often present as progressive diseases. During the early (“subclinical”) and late (“burned out”) stages of a given disease, the imaging patterns may be nonspecific or atypical. The “full-blown” imaging features of a metabolic disease, describing occasionally a suggestive or pathognomonic pattern, may be detected only within a shorter or longer period of time. This means that imaging patterns during the course of a given metabolic disease may shift from nonspecific to suggestive or even pathognomonic and then back to nonspecific again. Clinical signs often precede imaging manifestations; therefore, at the onset of the disease imaging findings may be unremarkable and, hence, noncontributory [61]. In the early stage of the disease the imaging study can be even normal, which makes early diagnosis and more effective treatment difficult or impossible. This is particularly true in early infancy, when detection of lesions within nonmyelinated white matter may represent a real challenge, especially for the less experienced reader. Longitudinal follow-up studies may, therefore, increase both sensitivity and specificity. Appropriately timed follow-up examinations are, therefore, used to demonstrate evolution of the imaging phenotype. The most frequently detected interval changes on follow-up imaging studies of metabolic diseases are progressive atrophy and emerging or vanishing structural lesions, as well as myelination abnormalities.

13.3.4 Advanced MR Techniques in the Diagnostic Work-Up of Metabolic Diseases

13.3.3.1 Progressive Atrophy

13.3.4.1 Diffusion-Weighted MRI

The interval enlargement of extra- or intracerebral CSF spaces on follow-up studies, which is a frequent finding in metabolic disorders, characterizes pro-

Diffusion-weighted imaging (DWI) is a truly functional imaging technique at the cellular level (see Chap. 24). The phenomenon of diffusion (according

13.3.3.3 Myelination Abnormalities

Myelination abnormalities include delayed and/or hypomyelination or progressive demyelination. Interestingly enough, in patients with delayed or hypomyelination, the process of brain myelination may progress, although often at a very low pace, even in poorly controlled or relentlessly progressive metabolic disorders. Nevertheless, it typically remains delayed or unaccomplished (Fig. 13.16). The process of demyelination appears to be rather rapid in some diseases (Canavan disease, Krabbe disease), whereas in others it is very slow (Fig. 13.17).

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Fig. 13.15a,b. Total resolution of basal ganglia lesions on the follow-up study. Axial T2-weighted spin-echo images in a female patient with propionic acidemia. a Prominent basal ganglia signal abnormalities at the age of 3 years, immediately after a metabolic crisis. b The follow-up study 1 year later shows practically total disappearance of the basal ganglia changes

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Fig. 13.16a,b. Follow-up MR studies in nonketotic hyperglycinemia. a Axial T1-weighted inversion recovery image in a 10 month-old male patient. Diffuse paucity of the myelin, with severe delay, especially peripherally. b Axial T1weighted inversion recovery image at the age of 3 years. Some progression of the myelination is well appreciated (compare the signal intensity within the optic radiations, or within the frontal lobes), but overall the myelination remains unaccomplished and severely delayed

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Fig. 13.17a,b. Follow-up MR studies in a male patient with L-2-hydroxyglutaric aciduria. a Axial T1-weighted inversion recovery image at the age of 12 years, showing the typical centripetal demyelination pattern of the disease. b Axial T1-weighted inversion recovery image 2 years later, showing an unchanged, stable appearance of the demyelinating process

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to Fick’s law) is the net movement of molecules due to a concentration gradient. In biological specimens, however, diffusion is more complex: it is actually referred to as apparent diffusion, since besides concentration gradients, pressure and thermal gradients as well as ionic interactions also intervene. Available volume fractions and space tortuosity probably play some role as well. DWI of biological specimens relies on detection of differences in water diffusion properties of various tissues. The signal on diffusion-weighted images is the product of a T2-weighted echo-planar “background” image, modified (typically attenuated) by the rate of apparent diffusion in the direction of the applied diffusion gradient. This means that decreased water diffusion presents with hypersignal and, conversely, increased water diffusion with hyposignal on diffusion-weighted images. Because of the rather heavily T2-weighted echo-planar “background” image, diffusion-weighted images always contain some T2 information. For this reason, tissues or lesions with very long T2-relaxation time may “contaminate” diffusion data, and “shine through” the images, giving the false impression of a water diffusion abnormality. This potential problem can be reduced or eliminated by the use of strong b values and correlation with the so-called apparent diffusion coefficient (ADC) map images which, by definition, contain exclusively diffusion information and, hence, are free of any T2 contamination effect. DWI has been available since the beginning of the 1990s. However, clinically it has become widely available since the introduction of echo-planar imaging, which radically shortened acquisition times (compared to earlier spin-echo techniques) and made examinations feasible even in poorly cooperative and critically-ill patients. To date, DWI has been mainly used in diagnostic imaging evaluation of normal and abnormal conditions of the CNS, in particular of the brain. Indeed, diffusion-weighted MRI was initially used in early diagnosis of cerebral ischemia. More recently, it has proved useful in evaluation of the brain maturation process, normal and abnormal functional neuroanatomy, as well as other pathologies of the CNS, including metabolic disorders. In the mature brain under normal conditions, water diffusion is grossly isotropic in gray matter and markedly anisotropic within white matter. The latter is called physiological anisotropy and it is mainly determined by axonal directions (water diffusion is relatively free along and restricted across the axons). In addition to axonal direction, however, axolemmal flow, extracellular bulk fluid flow, intracellular streaming and even capillary blood flow may also

contribute to the apparent anisotropy of water diffusion in white matter. Anisotropy of cerebral white matter is the result of the brain maturation process, particularly myelination during infancy. In the neonatal brain, water diffusion is mainly isotropic within the cerebral white matter except for those structures which show some degree of myelination in the newborn already (e.g., internal capsules, posterior brainstem tracts, etc.). As myelination progresses, water diffusion becomes increasingly anisotropic within the white matter. Animal studies suggest that measurable diffusion anisotropy develops somewhat earlier than the beginning of the actual myelination process; therefore, nonstructural (sodium-channel activity) changes may have a role in the development of premyelination anisotropy [62]. Abnormal water diffusion in the brain may present in essentially two ways. In both situations there is loss of physiological anisotropy; therefore, isotropic water diffusion within the white matter in the mature brain is always abnormal. On the one hand, water diffusion may increase isotropically; on the other hand it may be restricted, again isotropically. These changes are easily demonstrated by diffusion-weighted images and constitute the basis for differentiation of various types of brain edema, which has great clinical significance. Edema is a nonspecific reaction of brain parenchyma to different noxae. Depending on the underlying pathophysiological mechanisms in various pathological processes, different types of edema may develop. Neuropathologically, four edema types are known. They are vasogenic, interstitial, cytotoxic, and the so-called myelin edemas. The first two are characterized by isotropically increased water diffusion and conversely, the latter two by isotropically restricted water diffusion. The development of edema is typically related to loss of structural or functional integrity of specific anatomical barriers. Cytotoxic Edema

Cytotoxic edema is usually associated with cerebral ischemia. In a wider sense, it is due to an energetic failure within the cells (secondary to hypoxia or other endo- or exotoxic mechanisms resulting in impairment of oxidative phosphorylation). Initially the functional (Na/K pump) and later the structural integrity of the cellular membrane is lost, leading to an abnormal shift of extracellular fluid into the intracellular space and, eventually, disintegration of the entire cell. In such situations, the apparent iso-

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tropic restriction of water diffusion within the lesion is related to either shrinkage or increased viscosity within the extracellular space, or to restricted diffusion of excess water within cells; the latter may be due to limited space availability and intracellular obstacles or, most probably, to both processes. The restriction of water diffusion within extra- and intracellular spaces results in hypersignal on diffusionweighted images, and hyposignal on ADC maps. Myelin Edema

Myelin edema typically develops in white matter diseases (“myelin breakdown”), presenting histopathologically in some conditions as a vacuolating (or spongiform) myelinopathy. In vacuolating myelinopathy, small fluid-containing vacuoles develop within or under myelin layers due to loss of integrity of the myelin sheet itself. It is suggested that, within the vacuoles, water diffusion is restricted; hence, on diffusion-weighted images it presents with hypersignal and on ADC maps with hyposignal, similar to cytotoxic edema, despite the substantial difference between the underlying pathological phenomena. However, vacuolating myelinopathy may not be the only cause of what may be referred to as “myelin edema” on diffusion-weighted images, and other histopathological mechanisms may also be considered. Vasogenic Edema

Vasogenic edema is encountered in perilesional edemas (around tumors, abscesses), and in some forms of toxic encephalopathies. It involves essentially the cerebral white matter. Vasogenic edema is related to loss of integrity of the blood-brain barrier; hence, abnormal migration of water from the intravascular into the extracellular space occurs. The excess water within the expanded extracellular space diffuses relatively freely and randomly (leading to isotropically increased water diffusion) and on diffusion-weighted images presents with hyposignal, on ADC maps with hypersignal. Interstitial Edema

Interstitial edema is found in acute hydrocephalus, mainly in the periventricular white matter of the cerebral hemispheres, and is related to transependymal permeation of cerebrospinal fluid (CSF). Loss of the integrity of the ependyma is the underlying pathological phenomenon in such cases. The excess water (actually CSF), similar to what happens in vasogenic edema, diffuses freely and randomly within the

interstitial space and presents with hyposignal on diffusion-weighted images and hypersignal on ADC maps. In the DWI evaluation of metabolic diseases, differentiation between vasogenic versus cytotoxic and vasogenic versus myelin edema has the greatest importance. In metabolic disorders, cytotoxic edema is encountered in acute gray matter disease, whereas active demyelination is usually associated with myelin edema. Therefore, these disease processes may be detected easily with DWI by their hypersignal. Acute vasogenic edema may also occur in some metabolic disorders, especially during metabolic crises. On conventional MR images, this may be impossible to differentiate from cytotoxic or myelin edema; nevertheless, with DWI this is usually quite straightforward. Therefore, compared to conventional MRI techniques, notably with long TR imaging, DWI enhances specificity rather than sensitivity. To date, it is not yet known whether DWI abnormalities precede or follow T2 relaxation time changes (such as in acute ischemia) in cytotoxic or myelin edema of metabolic origin. As mentioned above, acute involvement of deep gray matter structures (e.g., the basal ganglia, dentate nuclei, and brainstem nuclei), which is typically associated with organic acidopathies and some of the socalled mitochondrial diseases, is easily depicted on diffusion-weighted images by their prominent hypersignal. Follow-up studies may show propagation of the disease to involve other structures, while the old lesion progressively become iso- and later hypointense, consistent with isotropically increased water diffusion, related to tissue necrosis (Fig. 13.18). In leukodystrophies or other metabolic disorders presenting predominantly with white matter involvement (e.g., amino acidopathies, some lysosomal storage disorders), diffusion-weighted images may show increased signal intensity (isotropically restricted water diffusion) within actively demyelinating areas (“myelin edema”). After demyelination is accomplished, physiological anisotropy of the parenchyma is lost and diffusion-weighted images show iso- or hyposignal (Fig. 13.19). DWI is, therefore, valuable in detection of disease activity and monitoring of disease progression in leukodystrophies. In conclusion, since both acute (cytotoxic and myelin edema) and chronic histopathological changes (necrosis and myelin loss) present with hypersignal on conventional T1- and T2-weighted images, but are distinctly different on diffusion-weighted images (cytotoxic and myelin edema are hyperintense, whereas necrosis and fully accomplished demyelination pres-

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Fig. 13.18a, b. The timely evolution of diffusion-weighted imaging changes in basal ganglia disease in 3-methylglutaconic aciduria (same patients and studies as in Fig. 13.10). a Axial echo-planar diffusion-weighted image (b = 1000s) during the acute phase of the basal ganglia disease. The hypersignal indicates isotropically restricted water diffusion within the involved deep gray matter structures (globi pallidi, heads of the caudate nuclei, and anterior parts of the putamina). b Axial echo-planar diffusion-weighted image (b = 1000s) showing the burned-out stage of the basal ganglia disease (necrosis). The deep gray matter structures are isointense, except the left putamen, which exhibits a faint linear hyposignal, consistent with isotropically increased water diffusion suggesting tissue necrosis

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Fig. 13.19a, b. The timely evolution of diffusion-weighted imaging changes in presumed (not laboratory confirmed) globoid cell leukodystrophy (Krabbe disease). a Axial echo-planar diffusion-weighted image (b = 1000s) in an 11-month-old patient. In the periphery of the demyelinating process (centrifugal pattern) the prominent hyperintensities suggest myelin edema due to acute myelin breakdown (vacuolating myelinopathy?). The deep, already demyelinated white matter exhibits hyposignal, consistent with isotropically increased water diffusion in the areas of myelin loss. b Axial echo-planar diffusion-weighted image (b = 1000s) in the same patient at the age of 20 months. Only faint patchy residual hyperintensities are seen, indicating an almost fully accomplished demyelinating process in the cerebral white matter

ent with hyposignal), DWI is useful in the differentiation between the active and the burned-out stage of the disease in both polio- and leukodystrophies. 13.3.4.2 MR Spectroscopy

Magnetic resonance spectroscopy (MRS) is a technique which allows in vitro or in vivo detection of

various normal and abnormal metabolites in tissue specimens (see Chap. 23). For this reason, it has a role in the diagnostic work-up of many pathologies of the CNS, including metabolic diseases [63, 64]. Recent feasibility studies indicate that proton MRS may be applicable in the prenatal diagnosis of metabolic alterations in the fetal brain [65, 66]. The technique takes advantage of the presence of small but detectable differences in resonance frequen-

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cies of normal and abnormal molecules within brain tissue which, therefore, can be identified individually and their relative amounts displayed graphically on the so-called spectra. On the spectra, deviations from the baseline (negative or positive “peaks”) represent different substances characterized by slightly different Larmor frequencies (chemical shifts), which reflect differences in the molecular environment within which protons are found. Depending on the employed resonance frequency range, MRS experiments may be based on signals generated by nonwater H (proton), 13C (carbon) or 31 P (phosphorus) atoms. Proton MRS

In routine clinical settings, proton (1H) MRS is the most widely employed technique, since it can be performed on any commercially available high field (1.5 T or higher) MRI unit without specific hardware requirements. Because of the abundance of protons in the brain tissue, the signal-to-noise ratio is satisfactory. The most important drawback of the technique is the narrow chemical shift range, which unfavorably influences identification and quantitative analysis of metabolites. Hence, only a limited number of compounds are detectable by 1H MRS. The most commonly used forms of 1H MRS are single voxel and multivoxel, chemical-shift imaging (CSI) techniques. Single-voxel 1H MRS is a robust technique capable of producing high quality spectra of a selected area (volume) of brain within a reasonably short acquisition time (in the range of 4 to 6 min). Multivoxel CSI produces metabolic maps of the brain in selected slice levels. Different brain metabolites have different T2 relaxation properties. Their detectability may depend on, and their orientation (phase) with respect to the baseline may be modified by, the applied echo time. Long echo-time (135 and 270 millisecond) techniques, such as point-resolved spectroscopy (PRESS), show fewer metabolites but a less noisy background, allowing for more accurate peak analysis. Short echo-time (20–30 ms) acquisition techniques, such as the most frequently employed stimulated echo acquisition method (STEAM), demonstrate more metabolites but the background is noisier. Peak locations of the most relevant metabolites on proton MR spectra are shown in Table 13.4 [67]. Normal Metabolites in the Brain Three prominent positive metabolic peaks are invariably detected in normal brain: N-acetyl aspartate (NAA, a neuronal marker), creatine (Cr, an energy

metabolism marker), and choline (Cho, a myelin marker). Using short echo-time techniques, myoinositol (mI, of undetermined significance) is typically seen also. Absolute and relative concentrations of metabolites show age-dependent variations, which have to be taken into account when interpreting MR spectra in very young infants [68, 69]. NAA in the neonate is a rather small peak, whereas Cho is the most prominent. After birth, the NAA peak increases and, by the age of 4 months, becomes the most prominent peak. On the other hand, Cho progressively decreases and becomes the smallest of the three major metabolic peaks on spectra using PRESS technique at 135 ms echo time. By the age of 6 months, the spectrum reaches its mature, grossly “adult” appearance. Less marked changes still continue to occur even beyond the age of 16 years [68]. The time evolution of relative metabolite concentrations is believed to reflect the maturation process and, in particular, progress of myelination within the developing brain (Fig. 13.20).

Table 13.4. Peak locations of the most relevant metabolites in inborn errors of metabolism on proton MR spectra of the brain Metabolite

Peak location (ppm)

Acetate Acetoacetate Acetone Acetylcarnitine Alanine Arabitol Choline (trimethyl) Creatine (methyl, trimethyl) Creatinine Galacticol Glutamate Glutamine Glutarate Glycine Isoleucine Isovalerylglycine Lactate Leucine Methylmalonate Myo-inositol N-Acetyl aspartate (methyl) Propionylcarnitine Propionylglycine Pyruvate Ribitol Tiglylglycine Valine 2-oxoglutarate

1.92 2.29, 3.45 2.24 2.15, 2.61, 3.2, 3.67, 3.9 1.48 3.75 3.21 3.04, 3.93 3.05, 4.08 3.67–3.74 2.11–2.35, 3.76 2.14–2.46, 3.78 1.80, 2.21 3.55 0.92, 1.01, 1.33, 1.70, 3.68 0.94, 2.04, 2.19, 3.77 1.33, 4.12 0.96, 1.67, 2.13, 3.70 1.27, 3.20 3.54 2.02 1.11, 2.46, 2.62, 3.20, 3.63 1.13, 2.33, 3.76 2.4 3.75 1.80, 1.87, 4.04, 6.57 0.99, 1.04, 2.29, 3.62 2.48, 3.02

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Abnormal Brain Metabolites Some of these metabolites are present also in normal brain, but in small quantities and under normal conditions they are undetectable by in vivo 1H MRS. Their appearance and identification on the spectra may be an indicator of a pathological process. Some of these “abnormal” metabolites are nonspecific (such as lactate and glutamine-glutamate complexes), but in certain settings they may be suggestive or even pathognomonic of metabolic disorders or other pathologies. Lactate

Lactate is an important metabolite, easily detected by 1H MRS. As a general rule (except for premature infants and during the fi rst couple of weeks of life, when a small amount of lactate may be found even in term neonates), the presence of lactate should be considered abnormal. It is a nonspecific, but potentially useful and sensitive, indicator of impaired (anaerobic) tissue glucose metabolism and subsequent cerebral lactic acidosis.

Fig. 13.20a–d. Age-related relative metabolic changes in the brain in early infancy demonstrated by single-voxel proton MR spectroscopy (PRESS technique, TE: 135 ms, sampling voxel size: 2x2x2 or 2x2x3 cm, placed on the basal ganglia on the right side in all cases) in presumed normal patients. a This spectrum is obtained in a 14-day-old male patient. The most prominent peak is choline (3.21 ppm), followed by creatine (3.04 ppm) and N-acetylaspartate (2.02 ppm). A small myo-inositol peak (3.55 ppm) is also present. b In a different patient, the spectrum obtained at the age of 35 days shows relative increase of NAA and decrease of Cho; the creatine peak is stable. The myo-inositol peak is still detectable, but is very small and remains so on the subsequent spectra. c In another patient, at the age of 4.5 months, NAA is already the most prominent peak. Choline continues to decrease. d At the age of 15 months, the “adult” pattern of the spectrum is demonstrated

In primary lactic acidosis, high brain lactate is typically associated with high plasma and CSF lactate. At times, blood and CSF lactate levels do not reflect accurately brain lactate level, and 1 H MRS is the most reliable method to monitor brain lactate [70]. Studies using combined 1H MRS and 18FDG-PET to assess two aspects of glycolysis (glucose uptake and lactate deposition) demonstrated that defects in oxidative phosphorylation cause an increase in glycolysis to cover energy requirements, with subsequent accumulation of lactate in brain tissue [71]. Lactate, as measured by 1H MRS, represents both intra- and extracellular and perhaps even intravascular lactate pools to some extent; therefore, increased lactate may be related to various pathological processes (systemic lactic acidosis, hypoperfusion, inflammation) besides specific intracellular metabolic disorders. The greatest value of the demonstration of lactate within brain parenchyma is found in cases of clinically suspected mitochondrial diseases (Kearns-Sayre disease, Leigh disease, MELAS,

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MERRF, LHON). 1H MRS has been used effectively to monitor therapy in Leigh disease and appears to be a better measure of response than CSF or plasma lactate [72]. Regional variation in the concentration of cerebral lactate has also been demonstrated in a host of metabolic disorders, including mitochondrial diseases, leukodystrophies, etc. [73–75]. Occasionally, lactate has been detected in areas of brain thought to be “normal” on conventional MRI [70]. In secondary lactic acidosis (e.g., propionic acidemia, HMG coenzyme A lyase deficiency, multiple carboxylase deficiency, maple syrup urine disease, nonketotic hyperglycinemia, urea cycle defects, Zellweger disease, etc.) lactate is also frequently demonstrated within the brain parenchyma by 1H MRS. Glutamine-Glutamate Complexes

Abnormal quantities of glutamine and glutamate substances are frequently seen in urea cycle defects and in other neurometabolic diseases, such as propionic acidemia, hepatic encephalopathy or even after hypoxic-ischemic brain damage [76, 77] (Fig. 13.21). Their demonstration has great clinical value, since it suggests increased neuroexcitatory activity, which is known to have a deleterious effect on neurons, often referred to as glutamate “excitotoxicity” or “suicide” [26, 78]. Miscellaneous

Other metabolites appear only in specific disease entities (e.g., phenylalanine in phenylketonuria, branched-chain amino acids in maple syrup

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urine disease, glycine in nonketotic hyperglycinemia); therefore, in appropriate clinical settings their detection may be practically pathognomonic (Fig. 13.21). In a recently identified inborn error of metabolism affecting the metabolism of polyols, abnormal D-arabinitol and ribitol were identified in brain and body fluids by 1H MRS [79]. Quantitative Abnormalities Quantification of normal or abnormal metabolites in brain is possible but usually not feasible in routine clinical settings. Nevertheless, relative changes of concentrations may also have diagnostic value; therefore, ratios between the most common brain metabolites (NAA/Cho, NAA/Cr, Cho/Cr, etc) are frequently used instead of absolute quantitative analysis. In some instances, however, quantitative changes are so prominent that their pathological character is easily ascertained. Two rare but specific disease entities constitute a special subset in this group, notably the pathological increase of NAA in Canavan disease (Fig. 13.22) and the absence of creatine in guanidinoacetate methyltransferase deficiency. Many metabolic disorders present with abnormal MR spectra, but findings are nonspecific. This “nonspecific pattern” is characterized by a decrease of the NAA peak (loss of neuro-axonal integrity) and increase or decrease of Cho peak (increased myelin turn-over, indicating demyelination). The Cr peak may be normal or decreased. Occasionally, the mI peak may increase (unknown significance) (Fig. 13.22) and various amounts of lactate (impaired energy metabolism) may also be present (Fig. 13.23).

Fig. 13.21a,b. Demonstration of abnormal brain metabolites by single-voxel proton MR spectroscopy. a Proton MR spectrum in a 12-day-old male patient with urea cycle defect (PRESS technique, TE: 135 ms, sampling voxel size: 2x2x2 or 2x2x3 cm, placed on the basal ganglia on the right side). All of the “normal” metabolite peaks are reduced, NAA most markedly. At approximately the 2.35 and 3.76 ppm levels, rather prominent “abnormal” peaks are present, which correspond to glutamate. b Proton MR spectrum in a 1-month-old female patient newly diagnosed to have maple syrup urine disease (STEAM technique, TE: 20 ms, sampling voxel: 2x2x2 cm, placed on the basal ganglia on the right side). At the 0.8–1.1 ppm level the prominent peak is believed to represent “abnormal” branched-chain amino acids (leucine, isoleucine, valine)

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b Fig. 13.22a,b. Proton MR spectroscopic findings in a 1-year-old male patient with Canavan disease. a On the MR spectrum (PRESS technique, TE: 135 ms, sampling voxel 2x2x3 cm, positioned on the centrum semiovale in the right fronto-parietal region) the choline and creatine peaks are decreased; conversely, the NAA peak is markedly increased. b On this spectrum (STEAM technique, TE: 20 ms, sampling voxel size and positioning as before) the findings are similar, except that a prominent myo-inositol peak is shown at the 3.54 ppm level

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Technical Considerations in 1H MRS Appropriate selection of the acquisition technique (short or long echo-time) and positioning and size of the sampling voxel are important technical aspects in clinical 1H MRS of brain. Acquisition Technique

The findings by conventional MRI and clinical data influence the strategy of 1H MRS. To demonstrate mI, glutamine-glutamate complexes, and branched-chain amino acids, short echo-time (20–30 ms) MRS is the technique of choice, despite the fact that this technique provides a noisier baseline, rendering identification of small peaks difficult. NAA, Cho, and Cr are well assessed on both 135 and 270 ms echo-time spectra. This technique

Fig. 13.23a,b. Nonspecific proton MR spectroscopic findings in metabolic diseases. a Proton MR spectrum in a 3-year-old female patient with metachromatic leukodystrophy (PRESS technique, TE: 135 ms, sampling voxel 2x2x3 cm, positioned on the centrum semiovale in the right frontal region). All peaks are decreased, the choline peak somewhat less markedly than the others. A small amount of lactate (negative peak doublet) is also demonstrated at the 1.3 ppm level. b Proton MR spectrum in a 30-year-old male patient with adrenomyeloneuropathy (PRESS technique, TE: 135 ms, sampling voxel 2x2x2 cm, positioned on the right cerebellar hemisphere). The choline and creatine peaks are quite unremarkable here; the NAA peak is markedly decreased. A small amount of lactate is also suggested in this case

provides a fairly flat baseline, but only a smaller number of metabolites may be detected. Glycine is best identified on the 135 ms spectrum, since on the spectra with short echo-time it overlaps with mI at the 3.55 ppm level (Fig. 13.24). Lactate has a peculiar presentation on long echotime 1H MRS. At 135 ms echo-time it presents as a negative peak doublet, whereas at 270 ms echotime as a positive peak doublet. This is called the J-coupling phenomenon (Fig. 13.25). Voxel Positioning and Size

In some metabolic disorders (organic acidopathies, aminoacidopathies), theoretically the sampling voxel may be placed anywhere in the brain, since abnormal metabolites are presumably present diffusely everywhere within the brain parenchyma. Focal lesion areas, if present, should

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Fig. 13.24a, b. Identification of glycine on proton MR spectra in a 9-month-old female patient with nonketotic hyperglycinemia. a On the short echo-time spectrum (STEAM technique, TE: 20 ms, sampling voxel: 2x2x2 cm, positioned on the basal ganglia on the right side) the NAA and choline peaks are markedly decreased. At the 3.55 ppm level a rather prominent peak is seen. This could correspond to either myo-inositol or glycine, since both substances exhibit same chemical shifts (see also Fig. 13.22b). b On the long echotime spectrum (PRESS technique, TE: 135 ms, sampling voxel: 2x2x2 cm, positioned on the basal ganglia on the right side) the peak at 3.55 ppm remains visible, indicating that it is actually glycine (myoinositol usually disappears on the spectra with longer echo times). The NAA and choline peaks are also decreased on this spectrum

Fig. 13.25a, b. The J-coupling phenomenon on single-voxel proton MR spectroscopy (PRESS technique, sampling voxel: 2x2x2 cm, positioned on the basal ganglia on the right side) of the brain in a 5month-old female patient with respiratory chain defect (Leigh disease). a The spectrum at 135 ms echo-time shows a prominent negative peak doublet at the 1.3 ppm level. b The spectrum at 270 ms echo-time shows inversion of the peak. This is the Jcoupling phenomenon, a characteristic MR spectroscopic feature of lactate. The creatine and NAA peaks are decreased on both spectra

preferably be avoided whenever possible, since severely damaged (e.g., necrotic) tissue samples are no longer representative of the metabolic status of the rest of the brain. Furthermore, in visible lesion areas, smaller or larger amounts of lactate are almost always present, due to impaired energy metabolism. This should not be misinterpreted as an indicator of “mitochondrial disease” (Fig. 13.26). Calcified, hemorrhagic or cystic-necrotic lesion areas should be avoided whenever possible, since these cause significant magnetic field inhomogeneity, which results in excessively noisy or uninterpretable spectra. If the voxel size is too small, the baseline of the spectrum may be rather noisy as well; hence, small peaks may not be identified. Usually a

2x2x2 cm or larger voxel provides adequate quality spectra. Occasionally, more than one MRS study is performed using the same technique, but with voxels positioned on different brain areas in order to demonstrate regional differences in the distribution of metabolites. This is more efficiently done by CSI, if available, which provides a true metabolic map of the brain. Phosphorus MRS 31

P MRS is technically also feasible on 1.5 T MRI units. Spectral resolution is much wider than that of 1 H MRS and assignment of detected metabolites is more straightforward but, because of specific hardware (dedicated coils) and software requirements,

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this technique is not widely used in routine clinical practice. Nevertheless, this is a potentially useful diagnostic tool, since it allows noninvasive in vivo assessment of brain energy metabolism. This has been found particularly relevant in mitochondrial diseases. Studies carried out on clinically symptomatic and nonsymptomatic patients with various mitochondrial cytopathies demonstrated derangements of oxidative phosphorylation in both groups [80]. Demonstration of decreased levels of brain phosphocreatine detected by 31P MRS in patients with mitochondrial diseases confirmed that mitochondria are affected not only in muscle but in brain tissue as well [81]. Since direct in vivo tissue pH determinations are also possible with 31P MRS, the technique has great potential in organic acidurias, especially during metabolic decompensations and in monitoring of response to therapy. Carbon MRS

Carbon MRS typically requires high magnetic field strength because of the low natural abundance of the 13C isotope (about 1%) in the brain. Nevertheless, a technique referred to as proton observed carbonedited spectroscopy may be implemented on commercially available 1.5 T systems. Its use is currently limited to specialized experimental centers. The unique potential of carbon MRS lies in the possibility of administering 13C-labeled metabolites (glucose, amino acids, choline, creatine, etc.), whose regional distribution and metabolism can, thereafter, be monitored in vivo. This may help, for example, to better understand the function of such basic biochemical pathways as the citric acid cycle in human brain under different abnormal metabolic conditions.

Fig. 13.26a,b. Proton MR spectra (both with the PRESS technique, TE: 135 ms, sampling voxel: 2x2x2 cm) from two different regions of the brain in a 1-year-old male patient with globoid cell leukodystrophy (Krabbe disease). a This spectrum was obtained with the sampling voxel positioned on the abnormal, severely demyelinated centrum semiovale in the posterior frontal region. It shows markedly decreased NAA, creatine and choline peaks and a prominent negative peak doublet at the 1.3 ppm level, corresponding to lactate. b When the sampling voxel is positioned on the normal-appearing basal ganglia within the same hemisphere, the obtained spectrum is normal

13.3.5 Clinical Aspects of Inborn Errors of Metabolism Systematic application of the concept of pattern recognition in diagnostic imaging evaluation of neurometabolic diseases has resulted in a more accurate description of various distinct lesion patterns in many known neurometabolic disorders [19]. Nowadays, the concept of pattern recognition in diagnostic imaging is further expanded to involve data from other imaging modalities, such as DWI and PET. In a wider sense, 1H MRS may also be integrated into the process of “pattern recognition,” and this approach has helped to identify or further characterize new diseases, such as vanishing white matter disease, guanidinoacetate methyltransferase deficiency, leukodystrophy with brainstem and spinal cord involvement and high lactate, and polyol metabolism abnormality. The concept of pattern recognition is not exclusive to neuroimaging. Integration of imaging and clinical data has led to identification of several new clinical-radiological entities during the past one or two decades, such as L-2-hydroxyglutaric aciduria, biotin-responsive basal ganglia disease, infantile onset encephalopathy with swelling and discrepantly mild clinical course (van der Knaap disease), familial leukodystrophy with adult onset dementia and abnormal glycolipid storage [82], hypomyelination with atrophy of the basal ganglia and cerebellum (HABC) [83], and leukodystrophy with ovarian dysgenesis [84]. The emergence of further entities may also be anticipated. Clinical diagnosis in neurometabolic diseases is based on recognition of specific clinical signs and symptoms characterizing more or less distinct clini-

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cal patterns (clinical phenotypes). The integration of clinical data (gender, age of onset and type of clinical manifestations, clinical evolution, physical or ophthalmological stigmata), imaging abnormalities (lesion types and patterns) and MRS findings defines the concept of clinical-radiological pattern recognition. This further enhances specificity of the entire diagnostic workup. 13.3.4.1 Age of Onset

The age of onset of metabolic diseases is a very useful clinical pattern element. Depending on age of onset of the clinical disease, the following categories may be used: neonatal (from birth to 1 month), early and late infantile (1–6 months and 6 months to 3 years), early and late childhood-juvenile (3–6 and 6–16 years), and adult (16 and over). However, the onset of the clinical signs and symptoms does not necessarily correspond to the onset of the metabolic derangement. As a clear manifestation of their considerable phenotypic variations, almost all neurometabolic diseases have several clinical forms depending on the age of onset. Within the same disease category, earlier onsets usually suggest a more profound metabolic derangement, whereas later onset forms often represent clinically milder but not necessarily benign variants. The differences in the age of onset among various peroxisomal disease entities–as a function of the severity and complexity of the underlying metabolic abnormality–well illustrate this concept. Lysosomal storage disorders are rarely apparent at birth. Most of them typically present in early (TaySachs, Sandhoff disease, Hunter) or late (fucosidosis, Hurler, Maroteaux-Lamy syndromes) infancy. Many lysosomal storage diseases (Gaucher disease, metachromatic leukodystrophy, multiple sulfatase deficiency, Krabbe disease, GM1 and GM2 gangliosidoses, neuronal ceroid lipofuscinoses) have various (neonatal, infantile, juvenile and adult) forms. Hurler-Scheie and Scheie syndromes have late infantile or juvenile forms. Fabry disease is of juvenile or adult onset. Most organic acidemias present either during the first few days of life (primary lactic acidosis, urea cycle defects, propionic acidemia, methylmalonic aciduria, isovaleric acidemia) or infancy (glutaric aciduria type 1, biotinidase deficiency), or may have more than one clinical phenotype. In mitochondrial diseases, the age of onset shows significant variations also. MELAS may appear from early infancy to adulthood, LHON is of late juvenile or adult onset and Kearns-Sayre syndrome is typically seen in the juvenile age group.

Significant, sometimes extreme deviations from the above outlined forms, presenting especially with unusual late onset, are increasingly identified. However, the term “late onset” is relative. It may be appropriately assigned to propionic aciduria developing in a 5-year-old child, as well as to MELAS in a 60-yearold or neuronal ceroid lipofuscinosis in a 64-year-old patient [85–87]. Metabolic disorders of neonatal onset deserve special attention, since most of them fall into the category of so-called devastating metabolic diseases of the newborn. This is a special category of inborn errors of metabolism, and awareness of this group of diseases and their clinical aspects is important because of potentially deleterious consequences, if not diagnosed and treated early. The underlying metabolic derangements typically result in global brain toxicity (encephalopathy), leading to diffuse brain edema and neurological manifestations reflecting varying patterns and degrees of white or gray matter involvement. The term “devastating metabolic disorders” refers to a fairly well-defined clinical syndrome. The newborn is typically normal at birth. The prodrome, a few days later, is characterized by refusal to feed and vomiting. This may be occasionally misinterpreted as pyloric stenosis. This is followed by lethargy and coma, which may mimic CNS infection, notably meningitis. Seizures and changes in muscle tone (hypoor hypertonia) are often present. If the disease is not diagnosed and treated promptly, it then further progresses and leads to irreversible neurological deficit or death [88]. Most devastating metabolic diseases of the newborn are organic or amino acidopathies (Table 13.5). 13.3.4.2 Systemic Manifestations of Metabolic Disorders

One of the most common features of inborn errors of metabolism of early onset is what is often referred to under the rather generic term of “failure to thrive.” The most frequent groups of metabolic diseases which present with failure to thrive among other neurological or nonneurological manifestations during the first 6 months of life are organic acidurias, urea cycle defects, respiratory chain defects, and carbohydratedeficient glycoprotein syndrome. As discussed earlier, many metabolic disorders presenting with CNS involvement also have systemic manifestations. These typically include dysmorphic features, organomegaly, or skeletal abnormalities. Cardiomegaly is often associated with “mitochondrial diseases”, and hepatosplenomegaly with storage disorders or peroxisomal diseases. Skeletal abnor-

Metabolic Disorders Table 13.5. Devastating metabolic diseases in the newborn Organic acidopathies

Amino acidopathies

Propionic acidemia Urea cycle defects Methylmalonic aciduria Maple syrup urine disease Isovaleric acidemia Nonketotic hyperglycinemia HMG-CoA lyase deficiency Multiple carboxylase deficiency 3-Methylglutaconic aciduria Glutaric aciduria type 2 Primary lactic acidosis Pyroglutamic aciduria

malities are common in mucopolysaccharidoses and peroxisomal diseases. Systemic complications in metabolic disorders are frequent. Patients with metabolic diseases are particularly prone to intercurrent infections, including infections of the CNS, notably meningitis or meningoencephalitis [89]. Since devastating metabolic diseases of the newborn may present with meningitis-like signs on the one hand, and an intercurrent infectious disease often triggers clinical deterioration and episodes of metabolic crisis on the other, complex association between metabolic diseases and infections may cause challenging clinical situations and differential diagnostic problems. Hematological abnormalities are quite characteristic of certain metabolic diseases. Neutropenia and thrombocytopenia are typically seen in organic acidopathies (propionic acidemia, methylmalonic acidemia, isovaleric acidemia). In Gaucher disease, anemia and thrombocytopenia are common. Hemolytic anemia is a characteristic complication of 5-oxoprolinuria. Acute pancreatitis is a relatively underrecognized complication in some organic- and aminoacidopathies, such as propionic acidemia, methylmalonic acidemia, isovaleric acidemia, HMG coenzyme A lyase deficiency, homocystinuria, maple syrup urine disease, and cytochrome c oxidase deficiency [90–94]. It usually occurs during an acute ketoacidotic crisis. Acute pancreatitis is otherwise rare in children, and in a few cases occurs before the diagnosis of an underlying metabolic disease is established. Inborn errors of metabolism and, in particular, branched-chain organic acidemia, should be considered in children with pancreatitis of unknown origin. Clinical phenotypes (age of onset, clinical presentation) are sometimes atypical. Misleading or nonspecific clinical pictures suggestive of encephalitis, sequelae of perinatal hypoxemia, acute occlusive arterial or dural venous sinus disease, or even intracranial space-occupying lesions, are also well known [87, 95]. Environmental factors such as minor head

Others Zellweger disease Neonatal adrenoleukodystrophy Menkes disease Nesidioblastosis

injury have been suggested as possible initial triggering factors in some leukodystrophies, such as X-linked adrenoleukodystrophy and the vanishing white matter disease [95–98]. 13.3.4.3 Neurological Abnormalities

Neurometabolic diseases may present as an acute or chronic encephalopathy. Metabolic disorders with lactic acidosis (pyruvate carboxylase, pyruvate dehydrogenase deficiency), ketosis (isovaleric acidemia, propionic acidemia, methylmalonic acidemia, 3-methylglutaconic aciduria) or ketoacidosis (multiple carboxylase deficiency, ethylmalonic aciduria) are most likely to present with acute metabolic decompensation and neurological manifestations (coma, hypotonia, seizures, metabolic stroke with rapid onset of extrapyramidal movement disorders) [10, 99]. Amino acidemias (neonatal maple syrup urine disease, nonketotic hyperglycinemia) and urea cycle defects are also frequently associated with deleterious acute metabolic crises. Reye syndrome (initially described as a childhood devastating clinical condition of unknown etiology and pathomechanism, characterized by a prodromal viral illness, acute encephalopathy, profuse vomiting and fatty degeneration of the viscera) (see Chap. 12) is still a vaguely outlined clinical entity. In a high percentage of cases, Reye syndrome is due to an underlying inborn error of metabolism, most frequently fatty acid oxidation disorders, respiratory chain defects, urea cycle defects, and organic acidopathies [100]. Other organic- and aminoacidopathies (glutaric aciduria type 1, 4-hydroxybutyric aciduria, hyperhomocystinemia, classical phenylketonuria, α-ketoglutaric aciduria), lysosomal storage diseases, late onset peroxisomal diseases, biotinidase deficiency, and some mitochondrial diseases exhibit a more insidious course and result in a chronic progressive encephalopathy with more or less severe neurological crippling.

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Mixed forms characterized by progressive encephalopathy and occasional metabolic deteriorations are also known. Pyramidal signs usually predominate in leukodystrophies, whereas in basal ganglia diseases extrapyramidal movement disorders (dyskinesis, choreoathetosis, tremor) are prominent [18, 60, 101]. Irritability, lethargy, and behavioral changes may be seen in both. Seizures

Seizures are frequent but nonspecific complications of metabolic disorders. Inborn errors of metabolism cause first-time seizures in 16% of infants under the age of 6 months [102]. Seizures reflect structural or functional involvement of the cerebral cortex in the pathological process. Epileptic seizures are difficult to recognize in the neonate and young infant, because these often have subtle or atypical manifestations (eye deviation, staring and involuntary jerky movement). Seizures are often myoclonic in neonates, in particular with urea cycle defects, nonketotic hyperglycinemia, and organic acidopathies. Tonic-clonic seizures are rare in early infancy and usually occur after 6 months of age. In some metabolic diseases, especially in early infancy (e.g., fatty acid oxidation disorders, nesidioblastosis), epileptic seizures are typically related to hypoglycemia. Pyramidal Signs

Pyramidal signs are usually seen in metabolic diseases associated with predominant white matter involvement, and are often progressive. The extent and magnitude of white matter changes may not always correlate well with the severity of neurological abnormalities [103–105]. Some inherited metabolic disorders may present with pyramidal signs in a more acute form. These often misleading clinical events may be related to true strokes (ischemic or hemorrhagic) or stroke-like episodes. Stroke-like episodes probably represent episodes of regional metabolic decompensation with subsequent functional disturbances within brain parenchyma [106–108] and corresponding neurological deficit. There is a probable overlap in the pathomechanisms leading to true strokes or strokelike events, since metabolic decompensation within the brain parenchyma may involve the vascular endothelium as well, which then predisposes to occlusive arterial or venous disease. Some organic acidopathies, notably propionic, isovaleric and methylmalonic acidemias, have

been reported to cause hemorrhagic stroke, especially during metabolic crises [37, 38, 92, 109]. It is unclear if this is due to direct vessel-wall lesions or coagulation abnormalities (e.g., thrombocytopenia, a frequent hematological complication of organic acidopathies). Systemic hemorrhagic complications have been characteristically found in ethylmalonic aciduria [110]. Ischemic complications (i.e., true infarctions) are common in some aminoacidopathies, such as homocystinuria, ornithine transcarbamylase deficiency, L-carnitine and carbamyl phosphatase synthetase deficiency [107, 111–114]. Organic acidopathies, such as HMG-coenzyme A lyase deficiency and 3-methylcrotonyl-coenzyme A carboxylase deficiency, are rare but possible causes of ischemic stroke [115–117]. Stroke due to a true ischemic complication has been described in lysosomal storage disorders, notably in Fabry disease and cystinosis. Both ischemic and hemorrhagic complications may occur in Fabry disease, since endothelial damage (glycosphingolipid deposit within the endothelium) leads initially to occlusive arterial disease with possible infarctions, followed later by bleeding from overloaded collaterals, as seen in moyamoya syndrome. Additional rare causes of ischemic stroke are Menkes disease, sulfite oxidase deficiency (molybdenum cofactor deficiency), and carbohydrate-deficient glycoprotein syndrome [106, 118, 119]. Stroke-like episodes are characteristic in “mitochondrial disorders” such as MELAS, but may also occur in MERRF and Kearns-Sayre disease. Familial hemiplegic migraine and alternating hemiplegia in children are also believed to represent peculiar clinical manifestations of a mitochondrial disorder. Extrapyramidal Signs

Extrapyramidal signs are characteristic in basal ganglia diseases. Patients with basal ganglia lesions usually present with dystonia, choreoathetosis, or tremor [101]. Onset of these neurological abnormalities may be insidious or sudden and the latter, again, may mimic stroke. Metabolic “stroke” with acute onset of an extrapyramidal syndrome usually occurs in organic acidurias, such as glutaric aciduria type 1 and methylmalonic academia, and are found to be associated with severe basal ganglia disease, in many cases probably necrosis [120]. Acute basal ganglia necrosis may occur without acute metabolic decompensation [85, 93]. As a general guideline, involvement of basal ganglia (globi pallidi, caudate nuclei and putamina) without thalamic involvement is typical of meta-

Metabolic Disorders

bolic diseases. Conversely, the thalami and posterior parts of putamina are usually affected in perinatal hypoxic-ischemic brain damage. Clinically, however, both present with extrapyramidal “cerebral palsy.” Visual Abnormalities

Leukodystrophies (X-linked adrenoleukodystrophy) involving the optic radiations present with progressive visual disturbances. Degeneration of other components of the optic pathways (retinal degeneration, optic nerve atrophy) may be seen in some lysosomal storage disorders (Krabbe disease, metachromatic leukodystrophy) and mitochondrial diseases (LHON).

13.3.4.4 Psychiatric Manifestations

Many metabolic disorders have neuropsychiatric manifestations, especially during acute metabolic crisis situations or end-stage of the disease. Psychiatric symptoms as initial clinical manifestations may masquerade the underlying disorder, leading to delay in correct diagnosis and treatment. This is particularly relevant in late (adult) onset forms of metabolic disorders, such as acute intermittent porphyria, Wilson disease, and metachromatic leukodystrophy [121, 122]. 13.3.4.5 Additional Useful Clinical Features

Tone Abnormalities

Odor

Hypotonia is characteristically seen in primary lactic acidosis, respiratory chain defects, multiple carboxylase deficiency, propionic acidemia (ketotic hyperglycinemia), 3-methylglutaconic aciduria, combined methylmalonic acidemia and homocystinuria, nonketotic hyperglycinemia, neonatal peroxisomal disorders (e.g., Zellweger syndrome), Menkes disease, sulfite oxidase deficiency, and urea cycle defects [57]. In propionic acidemia and nonketotic hyperglycinemia, this is probably due to increased blood glycine levels, since glycine is known to have an inhibitory effect on ventral motor neurons in spinal cord. Patients with Canavan disease are usually hypotonic. In fatty acid oxidation disorders, affected children are hypotonic because of associated myopathy. Hypertonia is a typical feature of methylmalonic and isovaleric acidemia. The exact pathomechanism of this is not known. Hypertonia (contractures) is also characteristic in rhizomelic chondrodystrophia punctata. In Krabbe disease, hypertonia is usually found on neurological examination; this is a useful clue in differentiation from Canavan disease, both for the radiologist and the clinician. Alternating hypo- and hypertonia (presenting with opisthotonus) is characteristic of maple syrup urine disease.

Some metabolic disorders present with a characteristic odor (e.g., “smelly cheese” or “sweaty feet” in isovaleric acidemia and glutaric aciduria type 2, “sweet syrup” in maple syrup urine disease, “cat urine” in multiple carboxylase deficiency, “rotten cabbage” in tyrosinemia). The urine of patients on carnitine treatment usually has a smell of “rotten fish” due to therapy-induced excessive trimethylamine formation and urinary excretion.

Peripheral Neuropathy

Besides involvement of the CNS, peripheral neuropathy is characteristic of lysosomal storage disorders (Krabbe disease, metachromatic leukodystrophy, Farber disease), but also occurs in peroxisomal diseases (adrenomyeloneuropathy) and galactosemia.

Facial, Eye, and Cutaneous Stigmata

Patients with organic acidopathies (e.g., propionic acidemia, methylmalonic aciduria, isovaleric acidemia, 3-methylglutaric aciduria) often have a typical “organic acidemia face.” This includes depressed nasal bridge, epicanthic folds, and short or long philtrum. Facial dysmorphia is often present in peroxisomal disorders and characteristic facial changes are also seen in mucopolysaccharidoses. Alopecia has been described in D-2-hydroxyglutaric aciduria. Alopecia associated with skin rashes is often seen in biotinidase deficiency. Erosive, desquamative dermatitis and hair loss have been reported in methylmalonic acidemia (cblC). Skin pigmentation and scleroderma may be present in phenylketonuria. Patients with Cockayne disease have skin hypopigmentation associated with photosensitivity. Some lysosomal storage disorders are associated with generalized angiokeratomas, notably Fabry disease (angiokeratoma corporis diffusum universale), fucosidosis, and sialidosis. Congenital ichthyosis is a cardinal clinical sign of Sjögren-Larsson syndrome. Dietary restrictions in treated metabolic diseases may also predispose to cutaneous infections [123].

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Nipple abnormalities (inverted, hypoplastic, supernumerary) may be found in propionic acidemia patients. Ophthalmological abnormalities are not infrequent in metabolic disease and may provide useful additional clues to the diagnosis [124]. 1. Corneal clouding is found in many lysosomal storage disorders, notably in most mucopolysaccharidoses (except MPS II and III), multiple sulfatase deficiency, Fabry disease, Farber disease, in some oligosaccharidoses (α-mannosidosis, aspartylglucosaminuria, galactosialidosis, mucolipidoses), and cystinosis. 2. Lens opacities or cataracts are characteristic in galactosemia but may occur in other metabolic disorders, such as isovaleric acidemia, 4-hydroxybutyric aciduria, cerebrotendinous xanthomatosis, rhizomelic chondrodystrophia punctata, and Cockayne disease. 3. The Kayser-Fleischer ring in Wilson disease is another highly characteristic ophthalmological finding. 4. Lens dislocations are typical of homocystinuria and sulfite oxidase deficiency [125]. 5. Cherry-red spots (lipid depositions within ganglion cells around the fovea) on funduscopic examination are typical in GM gangliosidoses, NiemannPick disease, Farber disease, some mucolipidoses, and in metachromatic leukodystrophy. 6. Retinitis pigmentosa (retinal degeneration) is found in many peroxisomal and mitochondrial disorders, as well as in neuronal ceroid lipofuscinosis and abetalipoproteinemia. 7. Electroretinographic abnormalities are common in poliodystrophies (primary neuronal diseases with involvement of sensory retinal epithelium) and exceptionally rare in primary leukodystrophies. This is, therefore, a helpful differential diagnostic tool. Head Circumference

Head circumference abnormalities (macro- and microcephaly) are frequent in metabolic disorders. Macrocephalic metabolic diseases include some organic acidopathies (type 1 glutaric aciduria), amino acidopathies (L-2-hydroxyglutaric aciduria), leukodystrophies (Canavan disease, van der Knaap disease, vanishing white matter disease, Alexander disease), and lysosomal storage disorders (GM2 gangliosidosis, mucopolysaccharidoses). The pathogenesis of macrocephaly, however, differs in these diseases. Early (neonatal or infantile) onset of brain swelling, as in infantile leukodystrophies or storage

disorders, is a common etiological factor. On the other hand, hydrocephalus (mucopolysaccharidoses) or intracranial arachnoid cysts (glutaric aciduria type 1) associated with metabolic disease may also account for development of macrocephaly. Microcephaly indicates an abnormal development of the brain. It may be present from birth or “develop” progressively (arrested head growth) during the disease course. Examples of the latter are the “microcephalic” leukodystrophies (Cockayne disease, Aicardi-Goutières disease, Pelizaeus-Merzbacher disease). In Zellweger disease, head circumference is usually normal at birth, but the percentile curve shows progressive downward deviation from the normal afterwards.

13.3.5 Laboratory and Histopathological Diagnosis in Metabolic Diseases The positive and specific diagnosis of inborn errors of metabolism may be established or confirmed by laboratory and/or histological examinations. Therefore, laboratory analysis of body fluids (blood, urine, CSF) is an essential part of the diagnostic workup of metabolic diseases. Routine biochemical findings are often nonspecific but may be suggestive or characteristic of certain disease groups or even diseases entities. Analysis of blood pH, glucose, ammonia, lactic acid, urine ketone bodies, and hepatic profile provide useful baseline information and orient further diagnostic workup. 13.3.5.1 Routine Laboratory Findings Hyperammonemia

One the most important laboratory tests in newborns with a suspected metabolic disorder is blood ammonia level determination. It is usually normal or borderline elevated in maple syrup urine disease. Markedly elevated levels are found in both urea cycle defects and organic acidemias. These two groups can be differentiated from each other by determining the blood pH, which will reveal respiratory alkalosis in the former and metabolic acidosis in the latter. Metabolic Acidosis

Metabolic acidosis can further be characterized by the presence or absence of lactic acidosis and ketosis. Blood sugar level assessment completes the routine laboratory workup.

Metabolic Disorders

Lactic Acidosis Lactic acidosis with hypoglycemia is typically seen in HMG CoA lyase deficiency [126], in some subtypes of 3-methylglutaconic acidemia, in glutaric aciduria type 2, and in medium- and long-chain fatty acid oxidation disorders. Lactic acidosis with normoglycemia may be present in oxidative phosphorylation diseases (primary lactic acidosis). Determination of the pyruvate-lactate ratio may be helpful in identifying different forms, such as pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, and cytochrome c oxidase deficiency. Acidosis without Lactic Acidosis or Ketosis Severe metabolic acidosis without lactic acidosis and ketosis is seen periodically in 5-oxoprolinuria. Hypoglycemia

deficiency), galactosemia, and fructosemia. It may also be found in other systemic diseases, such as sepsis, adrenal insufficiency, dehydration, and acute gastrointestinal problems (vomiting, diarrhea). Ketosis with hyperglycemia is found in diabetic ketoacidosis. Hepatic Dysfunction

Hepatic function is frequently altered in inborn errors of metabolism. Clinical and laboratory evidence of liver disease is typically present in fatty acid oxidation and oxidative phosphorylation disorders. High plasma levels of phytanic, pipecolic, and very long-chain fatty acids (VLCFA), as well as bile acid intermediates, are common findings in peroxisomal diseases. 13.3.5.2 Advanced Laboratory Methods

Hypoglycemia is a severe complication of many metabolic disorders, especially during metabolic crisis situations. It is always present in fatty acid oxidation disorders, holocarboxylase synthetase deficiency, and neonatal onset 3-methylglutaconic aciduria, and is frequent in HMG coenzyme A lyase deficiency. It may also be encountered in pyruvate carboxylase deficiency and in propionic, methylmalonic, ethylmalonic, and isovaleric acidemias. It is never present in β-ketothiolase deficiency, 4-hydroxybutyric aciduria, later onset 3-methylglutaconic aciduria, biotinidase deficiency, glutaric aciduria type 1, and late onset forms of maple syrup urine disease [127]. The most important differential diagnostic element in hypoglycemia is determination of ketones in blood and urine. In general, ketotic hypoglycemia is usually less severe and causes less adverse effects than nonketotic hypoglycemia. Hypoglycemia with hypoketosis (nonketotic hypoglycemia) is characteristic of fatty acid oxidation defects and also occurs in HMG coenzyme A lyase deficiency. It can also be a sign of hyperinsulinemic state in patients with persistent hyperinsulinemic hypoglycemia (nesidioblastosis), in newborns from diabetic mothers, or in patients on insulin treatment. Hypoglycemia with ketosis is discussed under ketosis below.

More sophisticated biochemical techniques, in particular gas chromatography/mass spectrometry (GC/ MS) of the urine, high pressure liquid chromatography (HPLC), and tandem mass spectrometry (tandem MS) of the blood, may also be required in order to reach a specific diagnosis [128, 129]. Specific enzyme activity studies of fibroblast or peripheral blood cell cultures or biopsy specimen (e.g., glutathione reductase assay of red blood cells in 5-oxoprolinuria, propionyl CoA carboxylase or HMG CoA lyase assay of white blood cells in propionic acidemia and HMG CoA lyase deficiency, and pyruvate carboxylase or cytochrome c oxidase assay in liver or muscle biopsy specimens in oxidative phosphorylation disorders) may also be performed.

Ketosis

13.3.6 Molecular Genetic Aspects of Inborn Errors of Metabolism

Ketosis with hypoglycemia (ketotic hypoglycemia) can be encountered in defects of gluconeogenesis, glycogenolysis, organic acidemias (isovaleric, propionic and methylmalonic acidemia, and in β-ketothiolase

13.3.5.3 Histological Diagnosis

Histological diagnosis may be obtained from peripheral nerve (metachromatic leukodystrophy, Krabbe disease), muscle (mitochondrial disease), skin, mucosa, or liver biopsy (storage diseases, Wilson disease) in some diseases. In others, brain biopsy or autopsy may confirm the correct diagnosis (Alexander disease).

The clinical phenotypes of inherited neurometabolic diseases span over a wide spectrum. These features

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include age of onset, clinical manifestations, disease course, therapeutic response, and final outcome. Heterogeneity of imaging findings in inborn errors of metabolism is also well documented. There is growing evidence that the explanation of the remarkable heterogeneity of clinical and imaging phenotypes within biochemically identical or similar entities most probably lies in the underlying molecular genetic abnormalities. The molecular genetic basis of inborn errors of metabolism is increasingly elucidated. Most metabolic diseases are autosomal recessive; a few are autosomal dominant (adult-form of Pelizaeus-Merzbacher disease, pigmentary orthochromatic leukodystrophy) or X-linked recessive (X-linked adrenoleukodystrophy, ornithine transcarbamylase deficiency, Hunter disease, Fabry disease, Pelizaeus-Merzbacher disease, Löwe syndrome, type 2 3-methylglutaconic aciduria, Menkes disease, pyruvate dehydrogenase E1α deficiency). Some of the so-called mitochondrial disorders have a peculiar inheritance pattern. The genetic abnormality is encoded in mitochondrial DNA, and since spermatocytes do not contain mitochondria, the diseases show a maternal transmission. The underlying mutations have been identified in many disease entities. These data provide evidence of genotypic heterogeneity in metabolic disorders. In methylmalonic aciduria about 30, and in glutaric aciduria type 1 at least 20 different mutations have been identified, all presenting with similar biochemical features [130, 131]. The genetic heterogeneity may be reflected in phenotypic variations within the same disease entities. In the Saudi population, for example, four fairly well-defined clinical phenotypes of glutaric aciduria type 1 (naturally mild, riboflavin dependent, leaky, and therapy-resistant) have been identified. Within each of these, different mutations (on exons 9, 6, and 10) were found. Mutations influence the molecular structure and, hence, the function of glutaryl coenzyme A dehydrogenase enzyme in different ways, explaining the heterogeneity of clinical phenotypes. Mutations affecting the association of enzyme subunits or cofactor binding site are typically associated with relatively mild clinical presentations, whereas changes at the catalytic site of subunits result in severe disease. Occasionally, even biochemical and clinical phenotypes may differ from each other. For example, undetectable glutaryl CoA dehydrogenase activity was found in fibroblasts (homogeneity of biochemical phenotypes) of both clinically symptomatic and asymptomatic patients (heterogeneity of clinical phenotypes) with glutaric aciduria type 1 [132]. In a case

of methylmalonic acidemia (mut-), significant discrepancy between severe biochemical phenotype and mild clinical course was reported [133]. These observations indicate the highly multifactorial nature of clinical disease manifestations and the possible compensatory role of alternative metabolic subsystems in inherited neurometabolic disorders. Important clinical phenotypic variations have been reported in several other inherited neurometabolic diseases, including 3-methylglutaconic aciduria, HMG-coenzyme A lyase deficiency, and in the vanishing white matter disease related to different mutations [134–138]. On the other hand, the same clinical entity, such as Leigh disease, may have several causes (e.g., cytochrome-c oxidase deficiency, pyruvate dehydrogenase deficiency and various mitochondrial DNA mutations) and conversely, the same enzymatic abnormality (cytochrome-c oxidase deficiency) may present with fundamentally different imaging phenotypes, i.e., with basal ganglia disease in the classical form of Leigh disease or with leukodystrophy [139]. The clinical heterogeneity of metabolic disorders is often reflected in the age of onset of the disease. This is well illustrated, for example, in metachromatic leukodystrophy, which has neonatal, infantile, juvenile, and adult onset forms. The disease is usually caused by insufficiency of arylsulfatase A enzyme, but several different mutations are known which may encode totally inactive enzymes, active but unstable (resulting in decreased half-life) enzymes, or so-called pseudodeficient enzymes (see later, under metachromatic leukodystrophy). Homozygotes or heterozygotes for the pseudodeficient enzyme are clinically normal, and this is explained by the fact that homoor heterozygotes for the pseudodeficient enzyme have sufficient (more than 10% and up to 50%) residual enzyme activity and the disease usually manifests only in patients with less than 10% residual enzyme activity [140, 141]. Within the clinically symptomatic group, patients with 2%–5% residual enzyme activity have juvenile- or adult-onset disease, and patients with less than 2% present with infantile onset. The importance of residual enzyme activity in explaining significant differences of the onset and clinical course of the disease has been demonstrated in other neurometabolic diseases, such as propionic aciduria, Canavan disease, and mitochondrial diseases [85, 142–144]. Similar to observations in metachromatic leukodystrophy, higher residual enzyme activities are typically associated with later onset, milder clinical course or clinically asymptomatic “biochemical disease.” However, catabolic stress situations (infection, excessive protein intake) may

Metabolic Disorders

potentially lead to acute decompensation in previously asymptomatic neurometabolic diseases. This is probably explained by mutations leading to borderline residual enzyme activities. Other, yet poorly understood factors may also intervene, since variability in clinical and radiological phenotypes is not always correlated with biochemical abnormalities (as demonstrated by blood, urine or CSF tests), as shown in siblings with L-2-hydroxyglutaric aciduria presenting with clinical heterogeneity despite a remarkable biochemical homogeneity [145]. Furthermore, patients with definite biochemical abnormalities, and even with brain lesions, may rarely be clinically asymptomatic [146]. To understand the molecular genetic background, inheritance pattern, and other possible factors determining the clinical phenotypes constitutes the foundation of genetic counseling (including identification and protection of carriers at risk), which is a key element in the complex clinical management of inherited neurometabolic diseases [147]. Other factors may play additional roles in determining the clinical phenotype and explaining the remarkable individual differences among patients affected by the same disease. These include environmental, nutritional, alternative metabolic, and other as yet unknown factors.

13.3.7 Management of Metabolic Disorders The social and economic burden of neurometabolic diseases is considerable. Their complex management extends over pre-, peri-, and postnatal periods, and requires a multidisciplinary approach with close collaboration from obstetricians, pediatricians, geneticists, biochemists, and radiologists. Regular followups, usually during the entire life of affected patients, are also necessary. 13.3.7.1 Prenatal Management

Genetic counseling is the first step in prenatal management of metabolic diseases in affected families, since the statistical recurrence rate is 25% in diseases with autosomal recessive (Mendelian) inheritance. Prenatal diagnosis is possible in many neurometabolic disorders, including propionic acidemia, Menkes disease, peroxisomal diseases, urea cycle defects, and disorders of oxidative phosphorylation, through demonstration of deficient enzyme activity in cultured amniocytes and chorionic villous samples and/or of abnormal metabolites in amniotic fluid.

Emerging new techniques, allowing preimplantation diagnosis by direct identification of gene and chromosome abnormalities or sex determination (in families with high risk for X-linked genetic disorders), represent new promising options in prenatal management of inborn errors of metabolism. Besides anecdotal reports, imaging techniques have not been used systematically in the prenatal diagnosis of inborn errors of metabolism. Occasionally, in utero US studies of the fetus have been reported to be suggestive or diagnostic in a few hereditary metabolic disorders of prenatal onset (see earlier under “ultrasound”) [31, 32]. With the increasing use of intrauterine MRI this may change, and diseases presenting with malformations or other prominent morphological abnormalities of the brain (Zellweger syndrome, glutaric aciduria type 1, nonketotic hyperglycinemia) may be depicted prenatally. Fetal 1H MRS may provide additional biochemical information. 13.3.7.2 Perinatal Management Postnatal Screening

In high-risk communities (e.g., high consanguinity), systematic screening of neonates for metabolic diseases is recommended. Tandem mass spectrometry of urine and blood samples, a cost-effective and reliable laboratory screening method, allows for immediate diagnosis of a wide range of inborn errors of metabolism with neonatal onset and early, preclinical diagnosis (hence possible prevention) of metabolic diseases with later onset, such as glutaric aciduria type 1, classical phenylketonuria, homocystinuria, both types of tyrosinemia, and histidinemia [148]. Immediate Postnatal Care

Optimally, high-risk pregnant women (with previous family history of metabolic diseases) should be encouraged to deliver in hospitals that have experience with and are prepared to manage inborn errors of metabolism. This allows for immediate postnatal diagnostic workup and, in positive cases, appropriate therapeutic measures without delay. The imaging workup is an integral part of the postnatal management process. In this respect, US and CT have a definite role, especially in ruling out other nonmetabolic pathologies, such as hydrocephalus in neonates with progressive increase of head size and intracerebral bleeding in neonates with lethargy or coma.

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13.3.7.3 Follow-Up

Many neonatal metabolic disorders present with nonspecific MRI findings during the early postnatal period. Characteristic imaging findings (basal ganglia disease, dys- or delayed myelination, white matter disease) often develop only at a later stage. Therefore, in cases of nonconclusive initial workup, follow-up MR examinations may be advised in order to monitor possible evolution of imaging abnormalities (from nonspecific to suggestive or pathognomonic). On the other hand, noninvasive monitoring of the effects of therapeutic measures by conventional MRI (e.g., progress of myelination) or 1H MRS (e.g., decrease of brain concentration of abnormal substances) is another important indication for followup studies (Fig. 13.27) [76, 149, 150].

13.3.8 Treatment and Prognosis of Metabolic Diseases Prognosis of metabolic disorders is highly variable, sometimes unpredictable. Genotypic heterogeneity in conjunction with multiple other known or poorly understood intrinsic and extrinsic factors account for remarkable clinical and imaging phenotypic variations within sometimes even biochemically similar disease entities. Many inborn errors of metabolism are untreatable and relentlessly progressive, leading to major neurological crippling and eventually to death through a shorter or longer course. Neonatal peroxisomal disorders, severe phenotypes of propionic acidemia and maple syrup urine disease, pyruvate dehydrogenase, and cytochrome c oxidase deficiencies are incompatible with life and invariably lead to early

a

death. Neonatal variants of 3-methylglutaconic aciduria, nonketotic hyperglycinemia, pyruvate carboxylase deficiency, glutaric aciduria type 2, and holocarboxylase synthetase deficiency are also usually fatal, although exceptionally treatable cases may be encountered. In other diseases, current, often experimental therapeutic efforts are limited to symptomatic treatment (dietary control, medical treatment of movement disorders and epilepsy, etc.). Occasionally, disease progression may be arrested or slowed down. However, if damage to the CNS has already occurred, it can rarely be reverted. Increasing clinical experience suggests, however, that, if diagnosed early, appropriate and aggressive therapy may favorably influence the disease course and even prevent development of clinical manifestations of the disease. Indeed, some metabolic diseases respond well to treatment (Wilson disease, naturally mild and riboflavin-dependent forms of glutaric aciduria type 1, phenylketonuria, 3-phosphoglycerate dehydrogenase deficiency, guanidinoacetate methyltransferase deficiency, etc.), although subtle neurological or imaging abnormalities may be seen even in clinically stable patients [151]. Mild phenotypes of propionic acidemia, most cases with methylmalonic and isovaleric acidemia, HMG coenzyme A deficiency, urea cycle defects, and both classical and intermittent forms of maple syrup urine disease may have good prognosis: in some cases outcome is excellent, allowing normal development and lifestyle. MRI and MRS have a definite role in monitoring therapeutic trials and identifying clinically useful or ineffective treatment protocols [76, 150, 152, 153]. A more causal management of inborn errors of metabolism may be achieved by bone marrow transplantation or other forms of enzyme substitution. New therapeutic options may be anticipated from

b Fig. 13.27a, b. Nonquantitative proton MR spectroscopic monitoring of metabolic changes in a female patient with maple syrup urine disease before and during treatment (both spectra obtained with the STEAM technique, TE: 20 ms, sampling voxel: 2x2x2 cm, positioned on the centrum semiovale on the right side). a At the age of 2 months the spectrum shows a prominent peak at the 0.7–1.1 ppm range, corresponding to branched-chain amino acids (see also Fig. 13.21b). b After 3 months of treatment, follow-up MR spectroscopic study shows the peak is still present, but significantly decreased

Metabolic Disorders

other emerging technologies, including somatic gene therapy and fetal neuronal transplants [154]. Bone marrow transplantation in lysosomal storage diseases (metachromatic leukodystrophy, Krabbe disease, some mucopolysaccharidoses) is increasingly used in humans [155–157]. The rationale of this therapy is based on peculiarities of synthesis and transport of lysosomal enzymes. In order to be recognized and transported into lysosomes, “lysosomal” enzymes are labeled within the Golgi apparatus. Most (but not all) enzymes enter the lysosomes within the same cell; however, about 30% may be “excreted” and taken up and used by other cells elsewhere in the organism. By repopulating the bone marrow of the patient with healthy pluripotential donor cells, normal lysosomal enzymes in sufficient amounts may be transferred into enzyme-deficient peripheral cells (fibroblasts, macrophages, monocytes), and perhaps even into glial cells. These cells may eventually be replaced by donor-derived cells exhibiting normal enzyme activity, provided that these can migrate

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through the blood-brain barrier [158]. Since approximately 10% of normal enzyme activity is sufficient (e.g., in metachromatic leukodystrophy) to prevent clinically manifest disease, this may lead to stabilization of the disease or, in some cases, to improvement in clinically symptomatic patients [159, 160]. In metachromatic leukodystrophy, therapeutic results are significantly better in younger recipients and if the disease is diagnosed and treated before appearance of the clinical symptoms, when damage to brain parenchyma is minimal or absent. In Krabbe disease, hemopoietic stem-cell transplantation resulted in reversal of clinical and MRI abnormalities even in the late juvenile form, and development of clinically symptomatic disease could be prevented in a patient with the infantile form [161]. MRI and MRS have, therefore, a significant role in screening affected families and in identifying prospective candidates for bone marrow transplantation, as well as in postprocedural follow-up to monitor response to therapy (Fig. 13.28).

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Fig. 13.28a–d. Monitoring response to therapy (bone marrow transplantation) in a male patient with X-linked adrenoleukodystrophy by conventional MR imaging. a Initial MR examination at the age of 4 years shows ill-defined hyperintensities on T2-weighted fast spin-echo image within the splenium of the corpus callosum and the deep occipital white matter (arrowheads). b Gadolinium-enhanced T1-weighted spin-echo image shows faint signal enhancement within the splenium (arrowheads). c One-year follow-up examination shows shrinkage of lesion area on T2-weighted fast spin-echo image. d At the same time, contrast-enhanced T1weighted spin-echo image fails to show signal enhancement

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Organ transplantation (renal and liver or both) may be necessary to manage late systemic complications of some of metabolic disorders (e.g., in Wilson disease or in methylmalonic acidemia).

tonia, choreoathetosis) [101]. White matter involvement may also be present, although it is usually less prominent. Occasionally, organic acidopathies have a leukodystrophy-like presentation on MRI (e.g., L2-hydroxyglutaric aciduria), but even in such cases, gray matter lesions are always conspicuous.

13.4 Disease Entities and Imaging Findings in Metabolic Diseases

13.4.1.1 Propionic Acidemia

13.4.1 Organic Acidopathies Many organic acidopathies fall into the group of devastating metabolic diseases of the newborn, while others have a later and often insidious onset (Table 13.6). From a clinical standpoint, organic acidopathies typically present with either acute or chronic encephalopathy, or both. Episodes of acute metabolic decompensation are characteristic of ethylmalonic aciduria, HMG coenzyme A lyase deficiency, pyroglutamic aciduria, isovaleric acidemia, holocarboxylase synthetase deficiency, β-ketothiolase deficiency, and malonic aciduria [162]. Chronic progressive encephalopathy (with pyramidal or extrapyramidal signs) is typically seen in L-2-hydroxyglutaric aciduria, N-acetylaspartic aciduria (Canavan disease), and 4hydroxybutyric aciduria [163]. Acute metabolic crises with interval progressive encephalopathy occur in propionic academia, methylmalonic academia, and glutaric aciduria type 1. In organic acidopathies, gray matter abnormalities, in particular basal ganglia disease, typically dominate the imaging findings. This is usually associated with extrapyramidal signs (rigidity, dysTable 13.6. Typical age of onset in the most common organic acidopathies Disease entity

Neonatal Infantile Juvenile

Propionic acidemia Methylmalonic acidemia Ethylmalonic acidemia 3-methylglutaconic aciduria HMG-coenzyme A lyase deficiency Glutaric aciduria type 1 L-2-hydroxyglutaric aciduria D-2-hydroxyglutaric aciduria Pyroglutamic aciduria Isovaleric acidemia Multiple carboxylase deficiency β-ketothiolase deficiency α-ketoglutaric aciduria

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This is a complex metabolic disorder with autosomal recessive inheritance. It is a “mitochondrial” disease, since the deficient enzyme–propionyl coenzyme A carboxylase–is located within the mitochondria. The enzyme is composed of α- and β-subunits. Encoding genes have been found on both chromosome 3q21-q22 (β-subunit) and 13q32 (α-subunit). Propionyl coenzyme A carboxylase is a biotindependent enzyme; biotin is bound to the α-subunits. It catalyzes conversion of propionyl coenzyme A into methylmalonyl coenzyme A. This is before the last step on the catabolic pathway of isoleucine and valine. Since propionyl coenzyme A inhibits pyruvate dehydrogenase (energy production and gluconeogenesis), N-acetyl-glutamate synthetase (urea cycle), and the glycine cleavage system, the disease typically presents with acidosis (metabolic and lactic), hypoglycemia, hyperammonemia, and ketosis in conjunction with increased glycine levels (similar to methylmalonic acidemia, see later in methylmalonic acidemia). The latter explains why propionic acidemia is also referred to as ketotic hyperglycinemia. Increased ammonia levels may erroneously suggest a urea cycle defect, especially in the neonate. Because the cofactor of the enzyme is biotin, other enzyme defects related to biotin deficiency (impairment of the holocarboxylase synthetase or biotinidase, see in multiple carboxylase deficiency) may cause differential diagnostic problems. As is common in branched-chain organic acidurias (methylmalonic and isovaleric acidurias), propionic acidemia has severe neonatal (60%) and milder infantile (40%) onset clinical variants. In the severe neonatal form, skin rashes, hypotonia, lethargy, dehydration, seizures, and irregular breathing are seen in the newborn before severe acidosis develops, potentially leading to coma and death. Prognosis in the late onset form is much better. The patients present with recurrent episodes of ketoacidotic metabolic decompensations. Neurologically, these lead to development of spasticity and extrapyramidal movement disorders (dystonia, choreoathetosis), related to basal ganglia disease. If the metabolic crises (often triggered by infection, fasting, constipation, or high protein intake) are successfully managed or prevented,

Metabolic Disorders

affected patients may live to adult age; the cognitive and, particularly, motor performances of the patients remain below normal [164]. Intercurrent infections are frequent complications in propionic aciduria, affecting up to 80% of patients during the course of the disease [89]. Rarely, the disease may have unusual clinical phenotypes. Acute hemiplegia without underlying structural cortical or deep gray matter lesion was the initial clinical presentation of propionic acidemia in a 10-month old infant during metabolic crisis [165]. Bilateral, symmetrical basal ganglia necrosis may develop without acute ketoacidotic crisis, characterizing a so-called neurologic, nonmetabolic clinical phenotype of the disease [93, 166]. The onset of the disease may also be unusually late. Fatal basal ganglia necrosis without metabolic acidosis or hyperammonemia has been described in a 6-year-old child [85]. Exceptionally, propionic acidemia may have an adult onset and present as a chronic progressive disease with dementia and chorea [167]. Neuropathologic examination of the brain usually shows spongiform changes in the white matter, which is already present in patients dying before the age of 1 year. Later, basal ganglia (globus pallidus, caudate nucleus, and putamen) lesions become common and consist of neuronal loss, gliosis and occasionally mineralizations. The cerebral cortex and neurons within the cerebellum also show abnormalities indicating particular vulnerability of gray matter structures in the disease [92].

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Imaging Findings

Patients with propionic acidemia are mainly encountered in two characteristic situations, notably during acute metabolic crisis and afterwards, in the chronic stage of the disease, with an extrapyramidal syndrome. The most typical imaging finding in propionic acidemia is bilateral basal ganglia disease with or without dentate nucleus involvement. In the neonate with propionic acidemia, diffuse brain edema without focal lesions is the most typical finding. Later in life, in well-controlled and metabolically stable patients, basal ganglia changes may be absent. Some degree of brain atrophy and delayed myelination are, however, almost always present. Diffuse brain swelling is seen during metabolic crises. Basal ganglia and dentate nuclei show abnormal hypersignal on T2-weighted images [92, 168]. Subtle signal changes may be present within the pulvinar of the thalami. The cerebral and cerebellar cortex is also affected. The involved gray matter structures are markedly swollen at this stage. White matter lesions may also be present, mainly subcortically, including subinsular areas (external and extreme capsules). The corpus callosum, internal capsule, and corticospinal tracts appear to be spared (Fig. 13.29). Differential diagnostic possibilities in the acute stage of propionic acidemia are hypoxic-ischemic brain damage, primary lactic acidosis, Leigh disease, or other organic acidopathies (ethylmalonic aciduria,

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Fig. 13.29a–c. MR imaging findings in propionic acidemia in acute metabolic crisis. Axial T2-weighted fast spin-echo images in a 6-year-old female patient, immediately after the first metabolic decompensation of her life. a Prominent, abnormal hyperintensities within the dentate nuclei, but ill-defined signal changes are also seen within the pons. b Symmetrical signal abnormalities are present within the heads of the caudate nuclei, putamina and the pulvinar of the thalami. c Dominantly subcortical white matter changes within the cerebral hemispheres (note similar changes on other images as well). The cerebral cortex appears to be abnormally hyperintense too

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3-methylmalonic aciduria). In hypoxic-ischemic brain damage, findings can be quite similar to propionic acidemia, and only the clinical setting and laboratory findings may allow differentiation between the two. Lesions in primary lactic acidosis and ethylmalonic aciduria may be indistinguishable from those in propionic acidemia from an imaging standpoint. In Leigh disease, upper brainstem abnormalities are common; these are absent in propionic acidemia. In 3-methylglutaric aciduria, the cerebellar vermis is almost always markedly atrophic; this is either absent or less conspicuous in propionic acidemia. Occasionally, if medical treatment has been early and adequate, an almost total normalization of both gray and white matter changes with mild residual atrophy only may be found [92]. After multiple metabolic decompensations, diffuse brain atrophy develops. The basal ganglia and dentate nuclei may show permanent signal changes, sometimes conspicuous even on the T1-weighted images, usually but not always associated with atrophy. Abnormalities, similar to acute-stage findings,

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are typically symmetrical. Basal ganglia abnormalities constitute the imaging substrate of the extrapyramidal syndrome (choreoathetosis, dystonia), which is the typical neurological manifestation of the disease at this stage. Occasionally, patchy white matter lesions are present within the cerebral hemispheres on T2-weighted or FLAIR images (Fig. 13.30). DWI studies during acute metabolic decompensation usually show moderate signal increase within involved gray matter structures and subcortical white matter. In the chronic stage, basal ganglia lesions may be somewhat hypointense on the diffusion-weighted images. These findings suggest tissue damage, probably necrosis. 1 H MRS demonstrates lactate within lesions during the episode of metabolic decompensation, consistent with impairment of energy metabolism resulting in anaerobic glycolysis. Nevertheless, small amounts of lactate may be demonstrated within the brain parenchyma also in treated, metabolically compensated patients. This is believed to represent a permanent, “low-grade” alteration of mitochondrial functions in

Fig. 13.30a–d. MR imaging findings in patients with propionic acidemia in the chronic stage of disease. a Axial T2weighted fast spin-echo image in a 6-yearold female patient. Marked enlargement of the extra- and intracerebral CSF spaces, consistent with diffuse brain atrophy. Within the basal ganglia only very subtle signal changes are suggested without atrophy. b Axial T1-weighted inversion recovery image in the same patient as Figure 13.30a. Paucity of the myelin within the cerebral hemispheres, especially peripherally with significant global volume loss of white matter. c Axial T2-weighted fast spinecho images in a 9-year-old male patient. The heads of the caudate nuclei and the putamina are atrophic and exhibit abnormal hypersignal. Mild enlargement of the frontal horns of lateral ventricles. d Axial T1-weighted inversion recovery image in the same patient as Figure 13.30c. Subtle signal changes within the anterior parts of the putamina are also conspicuous on this image. There is a slight volume loss of cerebral white matter with some diffuse paucity of myelin

Metabolic Disorders

between metabolic crises [169]. In chronic patients with brain atrophy, decreased NAA/Cho ratios were found with long-echo time (TE: 270 ms) 1H MRS [169]. Decrease of NAA and mI and increase of glutamate/glutamine were also found with short echotime (TE: 20 ms) 1H MRS (STEAM), but no diseasespecific metabolites have been identified [77].

hypertonia, is found. As a severe neurological complication during acute metabolic crisis, cerebellar hemorrhage may also occur [37]. Systemic complications in methylmalonic aciduria include pancytopenia, renal complications, pancreatitis, and cardiomyopathy [172, 173]. Progressive kidney failure may require renal transplantation [174, 175].

13.4.1.2 Methylmalonic Acidemia

Intracellular Cobalamin Utilization Disorders

Methylmalonic acidemia is a complex autosomal recessive metabolic disorder. In fact, methylmalonic aciduria is a biochemically and clinically heterogeneous group of diseases [170]. It has cobalamin unresponsive and cobalamin responsive clinical phenotypes. Methylmalonyl Coenzyme A Mutase Deficiency

Most cobalamin unresponsive variants are related to primary deficiency of methylmalonyl coenzyme A mutase. The encoding gene of mutase enzyme is located on chromosome 6p21. Two mutations of methylmalonyl coenzyme A mutase (mut0 and mut-) are known; mut0 leads to total, and mut- to partial, enzyme deficiency. In both forms, conversion of methylmalonyl coenzyme A into succinyl coenzyme A (the last step of the L-leucine breakdown pathway) is impaired. As a result, methylmalonyl coenzyme A is found in excessive quantities in plasma and urine. This causes secondary inhibition of propionyl coenzyme A carboxylase and, therefore, propionic acid and its metabolites accumulate. Methylmalonyl coenzyme A inhibits pyruvate carboxylase, and methylmalonic acid itself inhibits succinate dehydrogenase complex; both are important enzymes in gluconeogenesis. Impaired succinate dehydrogenase activity is believed to be one of the major causes of basal ganglia disease in methylmalonic acidemia [171]. Propionyl coenzyme A inhibits multiple other systems that are also involved in gluconeogenesis (pyruvate dehydrogenase), urea cycle (N-acetylglutamate synthetase), fatty acid oxidation, and glycine cleavage system in liver (but not in brain, unlike nonketotic hyperglycinemia). For these reasons, the mutase deficient form of methylmalonic acidemia shares many similarities with propionic acidemia (see also in propionic acidemia) from the biochemical point of view, and it typically presents also with hypoglycemia, ketoacidosis, hyperammonemia and hyperglycinemia. The disease presents during the first few days of life or in early infancy. From the clinical point of view, presentation can also be confusing, with the exception of tone differences: in propionic acidemia hypotonia, while in methylmalonic aciduria usually

Cobalamin responsive and some cobalamin unresponsive forms of methylmalonic acidemia are related to intracellular utilization disorders of cobalamin (NB: cobalamin absorption and extracellular transport defects cause different disease entities, such as pernicious anemia). Cobalamin, in the form of adenosylcobalamin and methylcobalamin, is a cofactor of methylmalonyl coenzyme A mutase and of methionine synthetase, respectively; therefore, combined adenosyl- and methylcobalamin deficiency leads to a “dual” disease characterized by both methylmalonic acidemia and homocystinuria. These conditions are referred to as cblC, cblD, and cblF. The most common form is cblC, which has two clinical phenotypes. Most patients present during the immediate postnatal period or early infancy with microcephaly, poor feeding, failure to thrive, seizures, and hypotonia [176– 178]. Hemolytic-uremic syndrome may also occur. Cutaneous lesions (erosive, desquamative dermatitis, hair loss) may also occur [179,180]. Later, choreoathetosis and multiorgan abnormalities (pancytopenia, renal and hepatic failure, and cardiomyopathy) may also develop [180]. Hydrocephalus, presumably nonresorptive, has been described in several instances, the exact pathomechanism of which is poorly understood [176–178,181]. Ophthalmological changes, including progressive pigmentary retinopathy, and atrophic maculopathy are also quite characteristic of cblC. Prognosis for the early-onset form is poor and survivors of acute metabolic crises usually have significant neurological disturbances. Rarely, the disease may manifest in adolescence or adulthood with confusion, dementia, and spastic quadriplegia related to myelopathy [181, 182]. Isolated adenosylcobalamin (cblA and cblB) or methylcobalamin (cblE and cblG) deficiencies also exist. Defects, leading to impairment of the functional integrity of adenosylcobalamin only, lead to secondary mutase enzyme deficiency; therefore, cblA and cblB are clinically reminiscent of mutase deficiency and present with acidosis, ketosis, hyperglycinemia, and hyperammonemia during the neonatal or early infantile period of life. CblA is believed to be related

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to a reductase deficiency and cblB to a mitochondrial adenosyltransferase defect. Both of these forms are cobalamin responsive; prognosis is, however, much better in cblA than in cblB. Isolated functional methylcobalamin deficiencies (cblE and cblG) are related to methionine synthetase reductase and methionine synthetase defects. Clinically, these present with megaloblastic anemia. Imaging Findings

In the mut0, mut-, CblA, and CblB forms of methylmalonic aciduria, the most characteristic MRI finding is bilateral globus pallidus lesions [120, 183–186]. In the neonate, the disease presents with rather unremarkable or nonspecific MRI findings. Mild swelling of the brain may be seen, in conjunction with T2 prolongation within nonmyelinated white matter structures, most probably related to vasogenic edema. Myelinated white matter structures (in brain-

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stem, posterior limbs of the internal capsules, etc.) are spared. No basal ganglia or cortical abnormalities are seen in the newborn. In one case, hypoplasia of the cerebellar vermis was observed. During acute metabolic crises, the most typical and often sole abnormality is symmetrical density (CT) or signal (MRI) changes within the globi pallidi, which are associated with swelling [120, 187]. Contrast uptake within lesion areas has also been reported [120, 188]. The putamina and the thalami are spared (Fig. 13.31). In the chronic stage of the disease, globus pallidus lesions undergo necrotic changes; these are markedly atrophic but continue to exhibit hypodensity on CT and hypersignal on T2-weighted MR images [120, 183, 188] (Fig. 13.32). Extra- and intracerebral CSF spaces show mild to moderate enlargement. Sometimes, mild cerebellar atrophy may be present and subtle signal changes within dentate nuclei suggest some damage also. In early onset cases delayed myelination is frequently seen.

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Fig. 13.31a–d. Imaging findings in a 3year-old female patient with methylmalonic acidemia (during the first acute metabolic decompensation). a Axial CT image of the brain, showing bilateral hypodensities within the globi pallidi (arrowheads). b Axial T2-weighted fast spin-echo image 2 days after the CT examination. Within the posterolateral parts of the globi pallidi bilateral symmetrical hyperintensities are seen (arrowheads). The rest of the basal ganglia are spared. c Axial diffusionweighted echo planar image (b=1000s). The lesions within the globi pallidi are markedly hyperintense (arrowheads), suggesting cytotoxic edema. d Axial apparent diffusion coefficient (ADC) map image. The lesions are hypointense (arrowheads), confirming decreased water diffusion

Metabolic Disorders

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Fig. 13.32a–c. MR imaging findings in the chronic stage of methylmalonic acidemia in a 4-year-old female patient, who had an episode of acute metabolic decompensation in early infancy. a Axial T2-weighted modular inversion recovery image. The globi pallidi exhibit a slit-like appearance and are markedly hyperintense (arrowheads) (identical to CSF). b Axial diffusion-weighted echo-planar image. The lesions (lateral to the posterior limbs of the internal capsules) are hypointense (arrowheads), consistent with isotropically increased water diffusion, suggesting tissue necrosis. c Apparent diffusion coefficient (ADC) map image. The lesions are hyperintense (arrowheads), consistent with isotropically increased water diffusion

DWI shows hypersignal within the globi pallidi during the acute phase [189] (Fig. 13.31). In one patient, shortly after kidney transplantation but without metabolic decompensation, stroke-like lesions were found within the brainstem, whose acute nature was suggested by diffusion-weighted images [175]. In the chronic stage of the disease, lesions are hypointense, consistent with tissue necrosis [175] (Fig. 13.32). 1 H MRS may show decreased NAA and abnormal lactate within the lesions. No disease-specific metabolites are demonstrated [189]. Clinically, the presence of globus pallidus lesions is almost invariably associated with abnormal extrapyramidal manifestations. However, in one patient with neonatal onset of methylmalonic acidemia, bilateral, but asymmetrical globus pallidus lesions were demonstrated after several episodes of metabolic decompensation but without corresponding neurological abnormalities [146]. In patients with clinically and neurologically mild phenotypes or successfully treated preventively, MRI findings can be normal [185]. Differential diagnoses in bilateral globus pallidus disease without involvement of other basal ganglia components include kernicterus and carbon monoxide intoxication. In kernicterus, lesions of the subthalamic nuclei are associated with globus pallidus lesions [190]. Carbon monoxide intoxication is usually encountered in suggestive clinical settings. In severe, early-onset combined form of methylmalonic aciduria (cblC), imaging abnormalities consist

of a combination of the findings in classical homocystinurias and the mutase deficient methylmalonic acidemia [177, 178, 180–182]. In the neonate or young infant, diffuse brain swelling is present. The initial periventricular but later diffuse cerebral hemispheric white matter signal changes probably represent delayed myelination with hypo- or dysmyelination and with subsequent demyelination. This is believed to be secondary to impairment of the methylation potential within the CNS, resulting in defective synthesis of myelin basic protein or other essential lipid constituents of the myelin sheath (see later in hyperhomocystinemia). Progressive loss of the volume of cerebral white matter and occasionally subtle signal changes within globi pallidi also develop throughout the course of the disease. 13.4.1.3 Ethylmalonic Aciduria

Ethylmalonic aciduria is a rare organic acidopathy of autosomal recessive inheritance. Mass spectrometry of the urine reveals increased levels of ethylmalonic and methylsuccinic acids. However, increased ethylmalonic acid excretion in the urine has been described in patients with various metabolic disorders, notably in short-chain acyl-coenzyme A dehydrogenase deficiency, glutaric aciduria type 2, and cytochrome c oxidase deficiency, but the underlying biochemical cause of the disease is poorly understood. It may be related to a defect in mitochondrial fatty acid oxidation, respiratory chain, or isoleucine metabolism [191–196].

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Patients have a more or less typical organic acidemia facies (broad, depressed nasal bridge, epicanthal folds). Possible clinical presentations include neonatal onset with acute metabolic crisis and early or late infantile onset with slowly progressive encephalopathy, with or without metabolic decompensations. During metabolic crises, lactic acidosis and mild hypoglycemia are found without ketosis [110, 195]. Hypotonia and seizures, occasionally presenting with status epilepticus, are common. Patients with the slowly progressive phenotype present with neuromotor delay, pyramidal and extrapyramidal signs, ataxia, and dysarthria. The most prominent systemic manifestation of the disease is vasculopathy (tortuous retinal veins, usually appearing after a few months of life), widespread recurrent cutaneous petechiae and ecchymoses, orthostatic acrocyanosis, as well as persistent microhematuria and chronic diarrhea [110]. The disease leads to death by early childhood in most cases, although milder forms with probably better prognosis may exist as well. The major cause of death is complications related to vasculopathy. Imaging Findings

On MRI, ethylmalonic aciduria typically presents with basal ganglia disease, but patchy white matter lesions may also be present within the cerebral and cerebellar hemispheres [55, 195, 197]. Signal changes within the caudate nuclei and the putamina are somewhat patchy and heterogeneous; this peculiar pattern may help to raise the possibility of the disease and differentiate it from other organic acidopathies. The globi pallidi and the dentate nuclei may be involved, but lesions in these locations are sometimes absent

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(Fig. 13.33). CNS malformations have been described in two patients with ethylmalonic aciduria: one patient had a Chiari I malformation, and another a lipomatous filum terminale [55]. On diffusion-weighted images the basal ganglia lesions appear to be quite unremarkable (iso- or faintly hypointense). 1 H MRS shows a nonspecific pattern with decreased NAA, somewhat increased Cho, and rather markedly increased lactate. 13.4.1.4 3-Methylglutaconic Aciduria

This is a heterogeneous group of four biochemically and clinically distinct entities [134, 198, 199]. The inheritance pattern in type 1 is autosomal recessive, in type 2 is X-linked, and in types 3 and 4 is also probably autosomal recessive. In type 1 3-methylglutaconic aciduria, the underlying abnormality is 3-methylglutaconyl coenzyme A hydratase deficiency, resulting in impairment of conversion of 3-methylglutaconyl coenzyme A into 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), which is the fifth step on the L-leucine breakdown pathway. The resultant disease usually presents in infancy or childhood with mild mental retardation, macrocephaly, and speech disturbance [200]. A more severe clinical phenotype, presenting with failure to thrive, spastic quadriplegia and dystonic movement disorder, hypotonia, and seizures has been described [201, 202]. In the other forms (type 2, 3 and 4) the enzyme deficiency is yet to be identified, hence the source of excreted 3-methylglutaconic acid is unknown. Since in 3-methylglutaconic aciduria the most severely

Fig. 13.33a,b. MR imaging findings in ethylmalonic aciduria in a 10-month-old male patient. a Axial T2-weighted fast spin-echo image. Inhomogeneous, patchy hyperintensities are demonstrated within the basal ganglia bilaterally. b Axial T1weighted inversion recovery image. Basal ganglia abnormalities are well appreciated on this image. Diffuse paucity of the myelin within cerebral hemispheres (delayed and hypomyelination)

Metabolic Disorders

affected organs are typically the brain and heart, and sometimes the liver and skeletal muscles, it is possible that the primary defect is in the mitochondrial respiratory chain. The increased excretion of 3-methylglutaconic acid may be an epiphenomenon or a biochemical marker for a group of unspecified energy metabolism disorders [51, 203]. Type 2 of 3-methylglutaconic aciduria (Barth syndrome) is an X-linked variety of the disease, whose gene is mapped to Xq28 [204, 205]. The clinical syndrome is defined as an X-linked cardiac and skeletal myopathy with short stature and neutropenia [206, 207]. Since no enzyme deficiency is identified on the L-leucine pathway in this disease, but patients excrete increased levels of 3-methylglutaconic acid and other branched-chain amino acid products, it may actually be due to an overload of this pathway or to an unspecified mitochondrial disorder. The disease does not have neurological manifestations, but it may still be fatal in infancy, as a result of cardiac failure. Type 3 of the disease (Behr and/or Costeff syndrome), presenting with optic, pyramidal, and extrapyramidal signs (optic atrophy, ataxia, nystagmus, extrapyramidal signs, spasticity, urinary incontinence, mental retardation) of juvenile or adult onset, has been described in Iraqi Jews [208, 209]. The disease may be misdiagnosed as cerebral palsy [210]. The so-called unspecified, type 4 of the disease comprises several different clinical-biochemical phenotypes, whose only common feature is that they do not fit into the three other categories. One of them presents in the neonate with severe acidosis and hypoglycemia. In this subtype, mitochondrial ATP synthetase deficiency and multiple respiratory chain abnormalities have been identified as possible causes [211, 212]. Another phenotype is characterized by insidiously developing neurological signs (mainly extrapyramidal), without overt acidosis or hypoglycemia (“silent” or “neurologic” organic acidemia) [51, 199, 213]. In this phenotype, hepatic dysfunction, cardiomyopathy, and dysmorphic features may also be present. Increased excretion of 3-methylglutaconic acid has also been found as a rather consistent marker of Pearson syndrome, a respiratory chain defect caused by mitochondrial genome deletions [214]. This disease usually has an infantile onset, presents with aplastic anemia, neutropenia, thrombocytopenia, and sometimes with additional episodes of severe lactic acidosis and hypoglycemia. Another biochemical phenotype of 3-methylglutaconic aciduria associated with hypermethioninemia but without hepatic failure has been described recently [215].

Imaging Findings

In type 2 (Barth syndrome) and type 3 (Costeff and/or Behr syndrome) 3-methylglutaconic aciduria, brain MRI studies are usually unremarkable, although occasionally atrophy may be found. However, in a patient whose clinical presentation was highly suggestive of Behr syndrome, MRI examination at the age of 2 years showed ventricular dilatation and bilateral putaminal signal changes, in conjunction with extensive cystic lesions within the subcortical white matter [216]. Cystic lesions were demonstrated by cranial US already at the age of 6 months. In both type 1 and type 4 3-methylglutaconic aciduria (and in the uncategorized phenotype with hypermethioninemia), the most characteristic imaging presentation is symmetrical bilateral basal ganglia disease with cerebellar atrophy [199, 213, 217, 218]. No reports are available on the MRI findings in the neonatal age group in 3-methylglutaconic aciduria. In patients in whom the disease presents in infancy, initially the basal ganglia are usually swollen and exhibit high signal on diffusion-weighted images, suggestive of cytotoxic edema. In this stage, the globi pallidi, caudate nuclei, and sometimes the anterior parts of putamina, are involved. This pattern may coincide with a metabolic crisis with lactic acidosis, but it may also be observed in silent forms. During the metabolic crisis, the cerebellar cortex and dentate nuclei may also show swelling and signal abnormalities. With progression of the disease, putaminal abnormalities may become complete. Rarely, when gray matter disease is initially limited to the globi pallidi, differential diagnostic problems with methylmalonic acidemia may arise from an imaging standpoint. In some cases, illdefined diffuse cerebral white matter signal changes are also present. Cerebellar atrophy is a characteristic imaging finding, with the vermis being usually more affected than the cerebellar hemispheres. This may be present already during the first metabolic crisis, but sometimes develops later as brain damage progresses. Conversely, occasionally it may be present without imaging evidence of basal ganglia damage. The association of prominent cerebellar atrophy and basal ganglia disease–if present–is a suggestive imaging pattern of 3-methylglutaconic aciduria (Fig. 13.34). In the chronic phase of the disease, the basal ganglia are atrophic and hypointense on diffusionweighted images. Cerebellar atrophy also progresses and can become very prominent. Diffuse cerebral atrophy also ensues [201] (Fig. 13.35). On 1H MRS the findings are nonspecific. Lactate is present within the lesion areas in the acute phase, but no disease-specific metabolites are identified.

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Fig. 13.34a–d. MR imaging studies in a male patient with 3-methylglutaconic aciduria (with hypermethioninemia). a Sagittal T1-weighted spin echo image at the age of 1 year, showing marked cerebellar atrophy. b Axial T2-weighted fast spin-echo image at the same age. Bilateral basal ganglia disease. The globi pallidi and the heads of the caudate nuclei show moderate hypersignal and atrophy already (burned-out disease). The anterior parts of the putamina are swollen (the small punctuate signal voids are most probably enlarged vessels) and markedly hyperintense, whereas the posterior parts of the putamina appear to be normal. c Sagittal T1-weighted spin-echo image at the age of 2 years. Subtle, but clear interval progression of cerebellar atrophy. d Axial T2-weighted fast spin-echo image at the same age. The basal ganglia changes also show progression. The anterior parts of the putamina are less swollen, but the posterior parts are abnormal and the intermediate zone is still apparently normal. Mild diffuse brain atrophy and delayed myelination

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Fig. 13.35a,b. Coronal T2-weighted fast spin-echo MR images in a 7-year-old female patient with 3-methylglutaconic aciduria in the chronic phase of the disease. a The basal ganglia are atrophic and markedly hyperintense. Very marked enlargement of the extra and in particular of the intracerebral CSF spaces, characterizing diffuse brain atrophy. b Very prominent atrophy of the cerebellum

Metabolic Disorders

In type 4 3-methylglutaconic aciduria without neonatal acidosis, cerebellar dysgenesis was described in one case [51]. In another patient presenting with a very slowly progressive encephalopathy (misdiagnosed initially as “cerebral palsy”) only scattered white matter lesions were seen within the cerebral hemispheric white matter, without basal ganglia abnormality [219]. In a patient with presumed type 4 disease (mitochondrial DNA depletion with partial complex II and IV deficiencies and 3-methylglutaconic aciduria), brain atrophy and extensive white matter disease were found [220]. 13.4.1.5 3-Hydroxy-3-Methylglutaryl (HMG)-Coenzyme A Lyase Deficiency

3-Hydroxy-3-methylglutaryl coenzyme A (HMG coenzyme A) is a mitochondrial and peroxisomal enzyme. In mitochondria, it is involved in the catabolism of HMG coenzyme A into acetoacetate and acetyl coenzyme, the final step of the L-leucine breakdown pathway. Deficiency at this level leads to a specific disease entity referred to as HMG coenzyme A lyase deficiency. Its role in peroxisomes is unknown. The disease has an autosomal recessive inheritance. The gene is mapped to 1pter-p33, and several mutations have been identified [221]. HMG coenzyme A lyase deficiency has other adverse biochemical consequences. Most importantly, it causes impairment of ketone body synthesis from HMG coenzyme A, an intermediate metabolite on the fatty acid oxidation pathway. Acetoacetyl coenzyme A (see fatty acid oxidation defects) is first converted into HMG coenzyme A by HMG coenzyme A synthetase. HMG coenzyme A–similarly to the Lleucine breakdown pathway–is further metabolized into acetyl coenzyme A (which can already be used for energy production through the tricarboxylic cycle) and acetoacetate (a ketone body used in the mitochondria of extrahepatic tissues for energy production). Therefore, if the catabolic pathway of HMG coenzyme A is interrupted, patients are unable to perform adequate ketogenesis due to a lack of the necessary precursors. Additionally, excess HMG coenzyme A inhibits normal intrinsic gluconeogenesis, which further aggravates global metabolic fuel depletion. Patients with HMG coenzyme A lyase deficiency accumulate 3-hydroxyisovaleric, 3-methylglutaconic, 3-methylglutaric, and 3-hydroxy-3-methylglutaric (HMG) acids in tissues and blood, which are subsequently excreted in the urine. The disease is diagnosed by the detection of increased concentrations of carnitine esters of these compounds in blood

tandem MS or by their identification in urine. HMG coenzyme A lyase can be also assayed in leukocytes and fibroblasts [137]. Ketone bodies are important sources of energy for the brain and myocardium, and their synthesis takes place in the liver. In patients with HMG coenzyme A lyase deficiency, unavailability of endogenously synthesized ketone bodies and glucose may potentially lead to a life-threatening acute encephalopathy in cases of insufficient extrinsic alimentary supply (e.g., fasting, vomiting) or high utilization of glucose (e.g., intercurrent illness). The disease therefore presents with acute metabolic crises with hypoglycemia and acidosis but without ketosis. The Saudi phenotype of the disease typically (70%) presents in neonates, but elsewhere the disease is characterized by infantile onset [126, 136, 137, 222]. The child experiences peripheral shock with coma and expires within hours if no appropriate treatment is initiated. If treated promptly, the patient will recover rapidly. Such metabolic decompensations occur mainly during the first 5 years of life and are rare later, although these may be still lethal. Despite dramatic episodes of decompensation, most patients under treatment will grow to be normal children. In one patient, the association of HMG coenzyme A lyase deficiency with VATER syndrome (vertebral defects, anal atresia, tracheo-esophageal fistula with atresia, radial upper limb hypoplasia and renal defects) has been described [223]. Imaging Findings

MRI usually reveals clear, but nonspecific gray and white matter abnormalities. Since the disease usually starts in the early postnatal period or in early infancy, gray matter abnormalities are initially easier to depict, because white matter is not myelinated yet. Later, as brain myelination progresses, white matter changes (which most probably correspond to dys- and demyelination) become increasingly obvious. Due to considerable individual and age-related phenotypic variations on MRI, lesion patterns in HMG-CoA lyase deficiency are nonspecific. In a 14-day-old neonate with confirmed HMG coenzyme A lyase deficiency, no definite abnormality was detected by conventional MRI. In patients undergoing MRI examination during infancy or childhood, mild frontal atrophy and ventricular enlargement, as well as bilateral basal ganglia and dentate nucleus and multiple patchy or confluent white matter lesions, are seen [222]. Deep gray matter abnormalities are rather subtle in most cases and, if the disease is appropriately treated, may actually disappear on follow-up studies.

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In the Saudi phenotype, white matter lesions appear to be predominantly periventricular and subcortical U-fibers are typically spared (Fig. 13.36). In cases reported from elsewhere, white matter lesions were found in both periventricular and subcortical, or in exclusively subcortical, locations, with or without involvement of the arcuate fibers [135, 136, 222, 224]. DWI shows faint hypersignal within the involved gray or white matter structures. 1 H MRS of the brain demonstrates disease-specific changes invariably and throughout the disease course, in all ages, with two abnormal positive peaks at the 1.3 and the 2.4 ppm levels [222, 224]. These peaks probably correspond to HMG itself. The MRS data, therefore, upgrade the nonspecific conventional MRI pattern into an overall pathognomonic MRI/ MRS presentation (Fig. 13.37). 13.4.1.6 Glutaric Aciduria Type 1

Glutaric aciduria type 1 is an autosomal recessive disorder of degradation of lysine, hydroxylysine, and tryptophan. It is caused by deficiency of glutaryl-

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coenzyme-A dehydrogenase, which is a “mitochondrial” enzyme [225]. Glutaryl-coenzyme A dehydrogenase enzyme is a flavoprotein and its cofactor is flavin adenine dinucleotide (FAD). Glutaryl-coenzyme A dehydrogenase oxidizes glutaryl-coenzyme A (a catabolite of L-lysine, L-hydroxylysine, and Ltryptophan) through a FAD-linked reaction to glutaconyl-coenzyme A and, subsequently, to crotonylcoenzyme A. From the biochemical point of view, the disease is characterized by increased levels of glutaric acid and its breakdown products, 3-hydroxyglutaric acid and glutaconic acids in body fluids. The gene of glutaryl-coenzyme A is located on chromosome 19p13.2 and contains 11 exons. The catalytic site of the enzyme is at glutamate414 at exon 10. Many different mutations exist in glutaric aciduria type 1 [131]. Comparative analysis of genetic and clinical data suggests that mutations at exon 10 typically present with a severe disease course, which is probably due to proximity of the mutation sites to the active catalytic center of the enzyme. Mutations at other exons (in more remote locations from the catalytic site, such as at exons 6 and 9 in Saudi, and at exon 7 and 11 in non-Saudi mutants) present with

Fig. 13.36a–d. MR imaging manifestations in HMG coenzyme A lyase deficiency. a Axial T2-weighted fast spin-echo image in 3-year-old female patient after an episode of metabolic decompensation (parental neglect of dietary restrictions). Both gray and white matter lesions are present. The heads of the caudate nuclei and the anterior parts of the putamina are slightly swollen and exhibit ill-defined hyperintensities. Ill-defined white matter signal abnormalities are also present in the left occipital region; the subcortical U-fibers appear to be spared. b Axial T2-weighted fast spin-echo image in the same patient. On this image, white matter abnormalities are more extensive and prominent. c Axial T2-weighted fast spin-echo image in another, 4-year-old female patient. In this case, the basal ganglia are normal, except for very subtle signal changes suggested within the globi pallidi. d Axial T2-weighted fast spin-echo image in the same patient. White matter signal changes are more extensive, and the subcortical U fibers appear to be involved as well

Metabolic Disorders

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Fig. 13.37a,b. Single voxel proton MR spectroscopic findings in HMG coenzyme A lyase deficiency. a MR spectrum of a 6month-old male patient (PRESS technique, TE: 135 ms, sampling voxel: 2x2x2 cm, positioned on basal ganglia on the right side). The NAA peak is slightly smaller than usual for the age of the patient, and the choline peak is increased. Two abnormal positive peaks are present at the 1.3 and 2.4 ppm levels. b MR spectrum of an 11-year-old female patient (PRESS technique, TE: 270 ms, sampling voxel: 2x2x2 cm, positioned on centrum semiovale on the right side). Two abnormal, pathognomonic peaks are again clearly identified

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variable, but usually less severe clinical phenotypes (naturally mild, “leaky” and treatable forms). The pathogenesis of CNS lesions in glutaric aciduria type 1 is poorly understood. According to one hypothesis, excess glutaric acid inhibits glutamic acid decarboxylase activity, which is involved in synthesis of γ-aminobutyric acid (GABA, an inhibitory neurotransmitter) and leads to GABA deprivation in basal ganglia. Decreased neuronal inhibition by GABA leaves the exciter glutamate activity unbalanced, which causes neuronal damage. This pathomechanism is often referred to as glutamate excitotoxicity or “glutamate suicide” [26, 78, 226]. Animal studies, however, suggest that it is 3-hydroxyglutaric acid (rather than glutaric acid), which indirectly (through energy deprivation) activates NMDA receptors (a subtype of ionotropic glutamate receptors, that interact with N-methyl-D-aspartate), which causes neurodegeneration [227]. Another hypothesis is based on the observation that in glutaric aciduria type 1 initial neurological manifestations often appear after viral infection and/or the disease may be aggravated by intercurrent infectious diseases. Viral infections are known to stimulate production of interferon, which induces monoamine 2,3 dioxygenase, leading to formation of quinolinic acid from tryptophan (in glutaric aciduria type 1 the breakdown of tryptophan is impaired, as discussed above, therefore it is available in excessive amounts) through the alternative 3hydroxy-anthranilic acid pathway. Quinolinic acid is also known to be a highly neurotoxic substance. Glutaric aciduria type 1 is a disease of prenatal onset; however, infants usually remain asymptomatic during the first 3–12 months of life or present with mild psychomotor retardation only. Acute encephalopathy typically develops following a viral infection or an acute catabolic state (fasting, vomiting in gastrointestinal problems). The episode of acute metabolic crisis

is commonly associated with seizures. Rigidity and dystonia ensue a few days later, leading eventually to severe choreoathetosis and dementia [228–230]. Extrapyramidal signs often appear abruptly in the form of a stroke-like presentation, but dystonia-dyskinesia may develop insidiously [231]. Pyramidal tract signs (progressive quadriparesis) are also present occasionally. In some patients, subdural hematoma can be the presenting sign of the disease [59, 232]. Early, preferably immediate, postnatal diagnosis of glutaric aciduria type 1 is important, since if the disease is treated before onset of metabolic decompensation, neurological crippling may be prevented in 90% of cases (depending probably on genetically determined clinical phenotype) [233]. Conversely, if the patient undergoes neurometabolic crisis, usually irreversible lesions of the basal ganglia occur. If treatment is started after that, only arrest or slowing of progression of the disease may be achieved. In cases of therapy-resistant clinical phenotypes, progression is always unrelenting despite appropriate treatment. Routine blood, urine, and CSF laboratory tests are not always diagnostic and may even be misleading in glutaric aciduria type 1 [234]; hence, imaging investigations have an important role in the initial diagnostic workup. Imaging Findings

Since residual activity of glutaryl-CoA dehydrogenase is closely linked to the site and type of mutation, it is not surprising that the magnitude of basal ganglia and cerebral white matter abnormalities, as demonstrated by MRI, shows a wide spectrum but tends to correlate with genetically determined clinical phenotypes. The primary target organ in glutaric aciduria type 1 is the brain (a true neurometabolic disorder);

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therefore, in clinically symptomatic cases the most severe acquired lesions are seen at the level of basal ganglia [235]. In clinically severe disease phenotypes (therapy resistant, some of the leaky and the nontreated riboflavin dependent forms) imaging examinations show bilateral basal ganglia disease (globi pallidi, caudate nuclei, putamina) but sparing of thalami. The affected deep gray matter structures appear to be atrophic-necrotic. Abnormalities are often seen within the upper brainstem, and the pattern of signal changes are reminiscent of the so-called giant panda face. It is characterized by hyposignal of red nuclei and tectum and increased signal within the substantia nigra and tegmentum on T2-weighted images. The dentate nuclei may also be abnormal, and show hypersignal on T2-weighted and FLAIR images. White matter signal abnormalities are also frequent. These are typically seen within the cerebral hemispheres in subcortical locations. These changes are usually patchy and scattered. The central

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tegmental tracts along the floor of the fourth ventricle often show bilateral symmetrical hypersignal too. Infants with glutaric aciduria type 1 often develop progressive fronto-temporal atrophy (Fig. 13.38). In clinically mild phenotypes (naturally mild, treated riboflavin-dependent forms) similar but less prominent, or no parenchymal lesions may be seen. Patients with type 1 glutaric aciduria are usually macrocephalic at birth [236]. Both CT and MRI typically show enlargement of CSF spaces of the temporal fossa and, in particular, of the Sylvian fissures [237– 241]. These are usually bilateral, but not necessarily symmetrical. The abnormality is rarely unilateral. These may correspond to arachnoid cysts or disturbed and incomplete opercularization, or perhaps to both. These changes may be detected prenatally or in the early postnatal period by US [27]. Macrocephaly and Sylvian fissure abnormalities are present in both clinically benign and malignant phenotypes, and are not affected by medical treatment (Fig. 13.39).

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Fig. 13.38a–d. MR imaging findings in a 3year-old female patient with glutaric aciduria type 1, who had an episode of acute encephalopathy and subsequent extrapyramidal movement disorder at the age of 7 months. Axial modular inversion recovery images of brain. a Subtle signal changes are seen within dentate nuclei, pons, and especially within central tegmental tracts. b At the level of mesencephalon the “giant panda face” lesion pattern is shown. c Subtle signal changes are suggested within the thalami. The basal ganglia are clearly abnormal; signal changes within the globi pallidi and the heads of the caudate nuclei are moderate, while they are more prominent at the level of putamina. d Incomplete bilateral opercularization and atrophy of the posterior parts of the putamina

Metabolic Disorders

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Fig. 13.39a, b. MR imaging findings in patients with glutaric aciduria type 1 (riboflavin dependent clinical phenotype). a Axial T2-weighted fast spin-echo image in a 7-year-old male patient diagnosed with glutaric aciduria type 1 only in childhood, when he already had severe extrapyramidal movement disorder. The image shows severe bilateral, basal ganglia lesions as well as patchy white matter lesion. The open operculum sign is present only on the right side. b Axial T2-weighted fast spin-echo image in the cousin of the previous patient at the age of 5 years. He was diagnosed to have the disease by neonatal screening and received appropriate care immediately. Although his psychomotor development was normal, he was macrocephalic and the image shows typical bilateral open opercula

Prominent brain atrophy may also develop during the course of the disease, especially in patients with more severe clinical phenotypes. Similar to Menkes disease, chronic subdural hematomas are relatively frequent in type 1 glutaric aciduria without any evidence of significant head trauma in the patient’s clinical history [59].These should not be mistaken for imaging evidence of child abuse (Fig. 13.40). Although none of the imaging findings is specific for glutaric aciduria type 1, the presence of open Sylvian fissures and temporo-polar arachnoidal cysts in conjunction with bilateral basal ganglia lesions in a macrocephalic child presenting with dystonia is highly suggestive, if not pathognomonic of the disease, both by CT and MRI [236, 238, 240, 242–244]. However, the aforementioned abnormalities without basal ganglia lesions in an infant should also raise the possibility of the disease, and should prompt further laboratory workup in order to prevent the devastating consequences of a possible metabolic crisis and the resultant damage to the basal ganglia [121, 236, 245]. 1 H MRS may show lactate within basal ganglia during the acute stage of the disease. Although the possible role of glutamine-glutamate complexes in the pathogenesis of basal ganglia disease has been raised (glutamine excitotoxicity), increased glutamine-glutamate levels could not be demonstrated within basal ganglia by in vivo 1H MRS.

The functional status of the basal ganglia–as in other organic acidopathies–is, however, best evaluated and monitored by 18FDG-PET (Fig. 13.1). 13.4.1.7 L-2-Hydroxyglutaric Aciduria

L-2-hydroxyglutaric aciduria is an organic aciduria of unknown etiology. Inheritance of the disease is autosomal recessive. The underlying biochemical abnormality is believed to be related to a deficiency of glutarylcoenzyme A dehydrogenase, which is found on the catabolic pathway of lysine and tryptophan. The diagnosis of the disease is based on laboratory findings, which are dominated by enormous excretion of 2-hydroxyglutaric acid in urine, but lysine is always elevated in blood and CSF [246, 247]. Sophisticated laboratory procedures need to be used in order to identify the stereoisomer of the 2-hydroxyglutaric acid [248–250]. This is important, since distinct disease entities related to either or both optical isomers (L-2-hydroxyglutaric aciduria, D-2-hydroxyglutaric aciduria, and a combined form) are known [251]. It is also noteworthy that 2-hydroxyglutaric acid may be excreted in urine in glutaric aciduria type 2 as well. L-2-hydroxyglutaric aciduria is a slowly progressive metabolic disorder. The disease usually starts in

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Fig. 13.40a, b. Chronic subdural hematomas in patients with glutaric aciduria type 1. Axial T2-weighted fast spin-echo images. a 3-year-old macrocephalic female patient. Left-sided fronto-temporal subacute subdural hematoma without history of head trauma. Bilateral basal ganglia disease and open Sylvian fissure on the right side. b 2-year-old male patient. Multicompartmented chronic subdural fluid collections bilaterally. The patient had several surgical interventions in the past for subdural hematomas. Bilateral basal ganglia signal abnormalities. Extensive white matter hyperintensities in conjunction with diffuse brain atrophy

late infancy or early childhood but is typically diagnosed in late childhood or early adolescence. Very rarely it might manifest after birth or, conversely, in adulthood [252, 253]. The reason for the relative delay in diagnosis is the rather unremarkable initial clinical presentation. Patients present with delayed development of motor milestones and speech, as well as learning difficulties [254]. Cerebellar signs (gait disturbance, extremity and truncal ataxia, dysarthria, dysmetria, intentional tremor) and seizures complete the clinical picture [246, 255]. Absolute or relative macrocephaly is common. The disease course is relatively benign and protracted; affected patients usually survive into adulthood. There may be an increased occurrence of brain tumors in patients with L-2-hydroxyglutaric aciduria [247, 255, 256]. Imaging Findings

Since clinical presentation is typically mild and nonspecific, MRI examination of brain often precedes the metabolic workup. It reveals rather prominent brain abnormalities, the overall pattern of which is practically pathognomonic of the disease [257–260]. At first glance, L-2-hydroxyglutaric aciduria presents with a leukodystrophy-like appearance on MRI. White matter abnormalities exhibit a typical centripetal and slightly antero-posterior gradient; the subcortical U-fibers are most severely affected. Conversely, the periventricular white matter, and in

particular the central corticospinal tracts and corpus callosum, are spared for quite a long time during the course of the disease. The extreme and external capsules, as well as the anterior limb and genu of the internal capsules, are abnormal. The cerebellar white matter is usually spared. White matter abnormalities within the brain correspond to a spongiform encephalopathy (Fig. 13.41). The gray matter structures are also involved. The basal ganglia are always abnormal, but this is less prominent than in other organic acidopathies. The thalami are normal. The dentate nuclei are also always abnormal. Interestingly, the involved gray matter structures are somewhat swollen (Fig. 13.42). With progression of the disease, atrophic changes develop, but much more slowly than in most metabolic disorders and, in particular, in organic acidopathies. The atrophic changes involve both the cerebral hemispheres and cerebellum. Diffusion-weighted images are usually rather unremarkable in L-2-hydroxyglutaric aciduria. The most markedly abnormal peripheral hemispheric white matter structures are hypointense. No definite hypersignal is seen elsewhere in white matter to suggest myelin edema. This is consistent with a very slowly progressive demyelinating disease, which histologically corresponds to a spongiform encephalopathy. 1 H MRS shows decreased NAA and Cho peaks. Increased mI has been described, but its significance is poorly understood [261]. Typically, no lactate is demonstrated within the brain parenchyma.

Metabolic Disorders

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Fig. 13.41a–c. a, b Coronal FLAIR images in 21-year-old female patient with L-2-hydroxyglutaric aciduria. a The subcortical U-fibers exhibit a markedly hypointense appearance, almost identical to CSF signal intensity. This suggests complete demyelination. b The centripetal gradient of the demyelinating process is well demonstrated. Below the hypointense subcortical U fibers, a hyperintense zone is seen, which probably corresponds to partial demyelination. The deep white matter and diencephalic and brainstem structures are normal. c Coronal T2-weighted image in a 4-year-old girl with L-2-hydroxyglutaric aciduria (courtesy of Dr. P. Tortori-Donati, Genoa, Italy). White matter changes involve the subcortical white matter and spare the central white matter and corticospinal tracts. The globi pallidi and external capsules are also involved

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Fig. 13.42a–c. Axial modular inversion recovery images in a 7-year-old male patient with L-2-hydroxyglutaric aciduria. a Both dentate nuclei are swollen and exhibit a prominent hypersignal. b The basal ganglia are abnormal, but the thalami are spared. The most marked signal abnormalities are seen at the level of the pars lateralis of the globi pallidi in this case. Extensive, leukodystrophy-like white matter changes, exhibiting a centripetal character. The subinsular white matter (extreme and external capsules) and the anterior limbs of internal capsules are involved. c The centripetal gradient of white matter changes is again well appreciated, but the central corticospinal tracts are spared, even peripherally (retrograde demyelination pattern)

As a possible related skeletal abnormality, spinal canal stenosis has also been described in two cases of L-2-hydroxyglutaric aciduria [262]. 13.4.1.8 D-2-Hydroxyglutaric Aciduria

This disease appears to be of autosomal recessive inheritance. The underlying biochemical abnormality has not been elucidated yet. Since increased γ-aminobutyric acid (GABA) levels are found in CSF, the disease may be related to a defect of D-2-hydroxyglutaric

acid transhydrogenase. This enzyme catalyzes the breakdown of D-2-hydroxyglutaric acid into 2-oxoglutarate and, at the same time, converts 4-hydroxybutyric acid into succinic semialdehyde. Succinic semialdehyde is also a catabolic product of GABA; therefore, the enzyme defect may lead to accumulation of both D-2-hydroxyglutaric acid and GABA (through a block by accumulation of succinic semialdehyde). GABA is a well-known potent neurotransmitter in the CNS. Another possible defective metabolic pathway potentially leading to D-2-hydroxyglutaric aciduria is found at the level of D-2-hydroxyglutaric acid–2-

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oxoglutarate conversion. This may be catalyzed by another enzyme, notably mitochondrial enzyme D2-hydroxyglutaric acid dehydrogenase. Since 2-oxoglutarate is an intermediate metabolite of glutamate, altered levels of this neuroexcitatory compound may occur in dehydrogenase deficiency [263]. The disease seems to have two different clinical phenotypes [105, 264]. In the severe form, disease onset is early postnatal. Seizures start during the first hours or weeks of life and are initially myoclonic, but very soon become generalized tonic-clonic. The infant may also present with severe vomiting, misdiagnosed as pyloric stenosis and treated surgically [263]. Other characteristic clinical findings are facial dysmorphia, lethargy, hypotonia, involuntary movements, loss of vision, and severe developmental delay [265, 266]. Progressive microcephaly and cardiomyopathy are inconsistent but frequent features. Skeletal myopathy has also been described [267, 268]. The milder clinical phenotype is characterized by normo- or macrocephaly, less severe mental retardation, and hypotonia. Epilepsy, if it occurs at all, is of later, usually early infantile onset. An unusual form of D-2-hydroxyglutaric aciduria has also been reported [269]. Clinically, its presentation was quite similar to the severe phenotype; the imaging findings, however, were very different (see below). Imaging Findings

Despite more severe presentation and earlier onset of the disease in comparison with L-2-hydroxyglutaric aciduria, imaging findings may be quite unremarkable in early infancy [265]. MRI usually shows atrophy with ventriculomegaly, due to loss of white matter volume. Myelination may be initially normal but becomes increasingly delayed for the age of the patient and, eventually, may be totally arrested [263, 265, 267]. Delayed gyration and incomplete opercularization are common findings, but cortical dysplasia in the occipital regions has also been described [264]. In patients examined before the age of 6 months, subependymal (germinolytic) cysts were invariably found around the frontal horns of the lateral ventricles; they may later disappear. Gliotic changes in occipital white matter, scattered patchy cerebral white matter changes, and contrast enhancement on both CT and MRI of unknown significance, have been also described. Subdural effusions may also be present. The overall imaging pattern is somewhat reminiscent of that seen in glutaric aciduria type 1. Additionally, cerebrovascular abnormalities (aneurysms, occlusive cerebral arterial disease) have also been described [105, 268].

In an unusual form of the early onset, severe form of the disease, peculiar MRI findings were described. The findings, with periaqueductal, bilateral substantia nigra, thalamic, hypothalamic, caudate nucleus, putamen and globus pallidus lesions, were different from the above described pattern, but fairly reminiscent of the MRI manifestations of some of the mitochondriopathies [269]. Interestingly, the difference between imaging manifestations of the severe and mild clinical phenotypes is quite indistinct [105]: the latter have essentially similar but less prominent abnormalities. L- and D-2-hydroxyglutaric acidurias represent a unique example of how substantially different biochemical, clinical, and imaging phenotypes can be found in metabolic disorders presenting with optical isomers of the same substance. 13.4.1.9 Pyroglutamic Aciduria (5-Oxoprolinuria)

In the classical form, the underlying enzyme abnormality is glutathione synthetase deficiency. It is an autosomal recessive disease; the encoding gene is located on chromosome 20q11.2. Glutathione synthetase deficiency leads to accumulation of 5-oxoproline (precursor of glutathione) and, subsequently, acidosis without ketosis or lactic acidosis. Unavailability of glutathione causes membrane fragility of the erythrocytes, predisposing to hemolytic anemia. The resultant hemolytic-acidotic crises may be seen in both neonates and infants. Besides hemolytic anemia, the disease may also manifest with a slowly progressive encephalopathy, mental retardation, and seizures later in childhood. However, red blood cell glutathione deficiency by itself (with or without glutathione synthetase defect) does not necessarily cause 5-oxoprolinuria [270]. A rare form of the disease is related to 5-oxoprolinase deficiency. Affected patients present with anemia, microcephaly, failure to thrive, and mental retardation. Transient or constant 5-oxoprolinuria is a nonspecific laboratory finding that can occur without defect in the γ-glutamyl cycle (e.g., in GM2 gangliosidosis, homocystinuria, urea cycle defects, tyrosinemia type 1, methylmalonic and propionic acidemias) [271, 272]. Imaging Findings

Imaging findings in 5-oxoprolinuria have not been reported yet. In a personal observation of 5-oxoprolinuria in a 13-year-old boy, both conventional MRI and 1H MRS were normal.

Metabolic Disorders

13.4.1.10 Isovaleric Acidemia

This is one of the metabolic diseases related to abnormalities of the L-leucine breakdown pathway. The third step of L-leucine catabolism is conversion of isovaleryl coenzyme A into 2-methylcrotonyl coenzyme A by the mitochondrial enzyme isovaleryl coenzyme A dehydrogenase. Deficiency at this level results in isovaleric acidemia. The disease is autosomal recessive and the gene is located on chromosome 15q14-q15. Isovaleryl coenzyme A dehydrogenase deficiency results in accumulation of L-leucine catabolism byproducts, and subsequently leads to excessive urinary excretion of N-isovalerylglycine, isovaleric, 3-hydroxyisovaleric, 4-hydroxyisovaleric, methylsuccinic, mesaconic, 3-hydroxyisoheptanoic, and N-isovalerylglutamic acids, as well as of N-isovalerylalanine and N-isovalerylsarcosine. Toxic amounts of isovaleric and 3-hydroxyisovaleric acid and the secondary carnitine deficiency (endogenous carnitine reserves are rapidly depleted due to increased utilization for detoxification of the aforementioned abnormal metabolites) are probably the main causes of the clinical symptomatology in isovaleric acidemia. Hence, therapeutic attempts are aimed at offering alternative metabolic pathways for isovaleryl coenzyme A by administration of glycine (converting isovaleryl coenzyme A into nontoxic isovalerylglycine) on the one hand, and reloading carnitine stores (facilitating conversion of isovaleryl coenzyme A into nontoxic isovaleryl carnitine) on the other [273, 274]. The disease has two phenotypes. The more common, severe form of the disease presents in the neonate or in early infancy and is characterized by severe ketosis, lactic acidosis, and hypoglycemia (due to lack of gluconeogenesis), rapidly leading to coma. Affected patients have a peculiar “sweaty feet” odor. Thrombocytopenia, as part of frequent pancytopenia, may present clinically with disseminated intravascular coagulopathy. Patients with the other, chronic intermittent form are asymptomatic but may present with episodes of acute decompensation in the context of intercurrent infection, catabolic states (intensive physical exercise), or high protein intake, occasionally in adulthood for the first time [275]. Laboratory workup usually reveals hyperglycemia, hyperammonemia, neutropenia, and thrombocytopenia. Imaging Findings

In a case of a 20-day-old newborn with isovaleric acidemia, brain atrophy with fronto-temporal predominance was already present. Delayed myelination was

also suggested. On T2-weighted images, symmetrical signal abnormalities were seen within the posterior parts of putamina (Fig. 13.43). Follow-up examinations may show delayed myelination with a possible element of demyelination. In others patients, no abnormalities may be found at all (Fig. 13.44). Although metabolic abnormalities were clearly demonstrated in urine samples of a patient with isovaleric aciduria, no abnormality was demonstrated by 1H MRS using 135 and 270 ms echo times in a 5-month-old patient with isovaleric acidemia and normal MRI findings [67,276]. 13.4.1.11 Multiple Carboxylase Deficiency

Multiple carboxylase deficiency is a multifactorial, complex metabolic disease group. Four enzymes are involved in multiple carboxylase deficiency: (i) 3-methylcrotonyl coenzyme A carboxylase, responsible for the conversion of 2-methylcrotonyl coenzyme A into 3-methylglutaconyl coenzyme A, the fourth step on the L-leucine breakdown pathway; (ii) pyruvate carboxylase, responsible for the conversion of pyruvate into oxaloacetate (see in oxidative phosphorylation); (iii) propionyl coenzyme A carboxylase, responsible for the conversion of propionyl coenzyme A into methylmalonyl coenzyme A (see in propionic acidemia); (iv) acetyl coenzyme A carboxylase, responsible for the conversion of acetyl coenzyme A into malonyl coenzyme A (see in fatty acid synthesis). For all of these enzymes, biotin (a water soluble vitamin) is an essential cofactor. Multiple carboxylase deficiency develops in conditions characterized by unavailability of biotin, whose main cause is biotinidase or holocarboxylase synthetase deficiency. Acquired biotin deficiency (hypovitaminosis due to malabsorption, long-term anticonvulsant therapy and hemodialysis) also exists and leads to multiple carboxylase deficiency, but is very rare. Biotinidase has a twofold enzymatic function. It is responsible for recycling biotin after it is released from various carboxylase enzymes through a proteolytic breakdown and bound to lysine and biotinyl peptides. Additionally, it catalyzes detachment of biotin from proteins through which exogenous (alimentary) biotin enters the body. Holocarboxylase synthetase, on the other hand, is a biotin carrier responsible for binding of biotin onto inactive apocarboxylases, which converts them into active holocarboxylase enzymes.

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b Fig. 13.43a–d. MR imaging findings in a 15-day-old (term) male patient with isovaleric aciduria. a, b. Axial T2-weighted fast spin-echo images. Subtle and ill-defined hyperintensities are seen within the posterior parts of putamina (arrowheads). The brain appears to be underdeveloped; note the immature cortical gyral pattern in the frontal and temporal regions. The white matter in the frontal lobes exhibits an increased signal intensity. Only traces of myelin are seen within the ventrolateral thalamic nuclei and tectum on these images. c, d Axial T1-weighted inversion recovery images. These images confirm the very poor overall myelination of brain. Practically no myelin is seen within the posterior limbs of the internal capsules, which indicates delayed myelination

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Holocarboxylase Synthetase Deficiency

Holocarboxylase synthetase deficiency is an autosomal recessive disorder; the encoding gene is located on chromosome 21q22.1. Several mutations are known, some affecting the biotin binding center of the enzyme, and others causing decreased activity without changing the affinity of the enzyme to biotin [277]. These mutation differences and their consequences on the functional integrity of the holocarboxylase synthetase enzyme may explain the phenotypic variations of the disease (the principle is somewhat similar to that seen in glutaric aciduria type 1, see above) [278]. The disease usually presents in neonates or in infancy, rarely in childhood. The neonatal onset form is part of the devastating metabolic conditions of the newborn (see above), presenting with hypotonia, lethargy, vomiting, seizures, and respiratory abnormalities (tachypnea,

dyspnea, hyperventilation) [279]; later onset forms may also present with acute metabolic crisis [280–283]. Laboratory workup reveals metabolic acidosis with lactic acidosis and ketosis, hyperammonemia, and organic aciduria (3-hydroxypropionic acid, 3-hydroxyisovaleric acid, methylcitric acid, 3-methylcrotonylglycine). If undiagnosed and not treated promptly, the disease rapidly leads to coma and death. On the other hand, response to adequate treatment is usually favorable [279, 280]. For this reason, screening for the disease in pregnancies at risk and preventive treatment of the mother with biotin is advocated [284, 285]. Imaging Findings

Reports of imaging studies in holocarboxylase synthetase deficiency are sparse. In an infant with holocarboxylase synthetase deficiency, subependymal

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cysts were identified on cranial US and MRI. On the 6-month follow-up after biotin treatment, MRI of the brain showed complete resolution of the cysts, and the patient was neurologically normal [286]. Biotinidase Deficiency

Biotinidase deficiency also shows an autosomal recessive inheritance; the gene is located on chromosome 3p25. Again, several mutations are known, some causing severe, others partial enzyme deficiency. Biotinidase deficiency usually has a later onset than holocarboxylase synthetase deficiency, typically in infancy or rarely in childhood or even during adolescence [287, 288]. It manifests with a more insidiously developing progressive encephalopathy (spastic paraparesis, limb muscle weakness, visual disturbances), although early infantile onset of the disease with severe, acute clinical presentation (lethargy, hypotonia, seizures, lactic acidosis) is also known [289–291]. The laboratory findings are less relevant, since metabolic acidosis and organic aciduria may be minimal or absent during the early stage of the disease.

Fig. 13.44a–d. MR imaging findings in a 14-month-old male patient with treated isovaleric aciduria. a, b Axial T2-weighted fast spin-echo images at the level of the deep gray matter structures. No basal ganglia abnormality is seen (a). Diffuse paucity of the myelin within the cerebral hemispheres, mainly peripherally (note the dense myelin within the corpus callosum). Subtle signal inhomogeneities are seen within the centrum semiovale (b). c, d T1-weighted inversion recovery images. These images suggest some sparing of the subcortical U fibers, which suggests a demyelinating element in the white matter disease, in addition to hypo- and delayed myelination

Because of possible multiple enzyme involvement in biotinidase deficiency (and in holocarboxylase synthetase deficiency as well), and since different enzymes in different organs (brain, liver, kidney) may be affected to different extents, various clinical phenotypes may develop, but usually neurological complications dominate the clinical picture. Typically, the disease presents with developmental delay, hypotonia, seizures, ataxia, hearing loss (usually irreversible), optic atrophy, alopecia, and skin rashes; the latter are important clues to the diagnosis [292, 293]. CNS abnormalities and resultant neurological signs and symptoms are attributed to cerebral accumulation of lactate [294]. In extremis, if pyruvate carboxylase is the most severely affected enzyme, the disease may even present clinically and histopathologically as subacute necrotizing encephalomyelopathy (Leigh disease) [295]. Response to biotin administration is usually prompt and dramatic. Seizures, skin changes, and metabolic changes rapidly resolve; other abnormalities (even hearing loss) may also prove to be reversible [289, 290].

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Imaging Findings

MRI studies in early infancy show mild diffuse brain atrophy and delayed myelination [290, 296, 297]. Subtle basal ganglia abnormalities may also be found (Fig. 13.45). On biotin treatment atrophic changes were found to be reversible and myelination also normalized [290, 296, 297]. Without treatment the atrophy progresses and becomes prominent (Fig. 13.13). In one patient, basal ganglia calcifications without associated neurological deficit were described by CT at the age of 29 months [298]. In a patient with associated severe combined immune deficiency and bone marrow transplantation, brain atrophy (parallel to neurological deterioration) was progressive, despite adequate biotin supplementation [296]. In an 8-yearold child with biotinidase deficiency and multiple episodes of metabolic decompensation, both CT and MRI studies were normal [299]. 1 H MRS showed decreased NAA/Cr ratio and abnormal lactate within the brain parenchyma before treatment with biotin [290]. On follow-up study six weeks after treatment, both abnormalities disappeared (interestingly, CSF 3-hydroxyvaleric acid and lactate levels returned to normal) [290]. 13.4.1.12 3-Methylcrotonyl-Coenzyme A Carboxylase Deficiency

An isolated (biotin nonresponsive) 3-methylcrotonylcoenzyme A carboxylase deficiency also exists [2].

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Clinically, the disease exhibits a broad phenotypic spectrum, with patients developing severe metabolic decompensation (hypotonia, vomiting, lactic and metabolic acidosis, hyperammonemia, and hypoglycemia) in infancy on one end of the spectrum, and totally asymptomatic adults on the other, although the biochemical phenotype of the disease is quite consistent (increased urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine) [2, 117, 300, 301]. In a 16-month-old patient, metabolic stroke causing permanent hemiparesis was reported [117]. Imaging Findings

In mild cases, imaging studies of the brain may be normal [302]. Occasionally, delayed myelination and mild brain atrophy may be detected (Fig. 13.46). Reports of imaging findings in clinically severe cases are not available. 13.4.1.13 β-Ketothiolase Deficiency

β-ketothiolase deficiency is a defect of mitochondrial 2-methylacetoacetyl-coenzyme A thiolase. This is an autosomal recessive disorder and the defective gene is located on chromosome 11q22.3-q23.1. Ketone bodies (acetoacetate and 3-hydroxybutyrate) are important secondary metabolic fuels and are synthesized in liver mainly from fatty acids, but also from amino acids such as leucine (see also fatty acid oxidation defects and HMG coenzyme A lyase deficiency).

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Fig. 13.45a–c. MR imaging findings in biotinidase deficiency. a Axial T1-weighted inversion recovery image in a 9-month-old female patient. The myelination is delayed for the age of the patient. Even in the occipital regions, the peripheral myelination is very poor. b Axial T2-weighted fast spin-echo image in a 17-month-old male patient. The myelination is far from being accomplished, the peripheral white matter is very poorly myelinated in all areas, but the anterior limbs of the internal capsules are hypomyelinated too. c Axial T2-weighted fast spin-echo image in a 3-year-old male patient. Diffuse paucity of the myelin within the cerebral hemispheres. Subtle signal abnormalities within the lateral parts of the putamina bilaterally in conjunction with slight atrophy

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Fig. 13.46a–d. MR imaging findings in 3methylcrotonyl-coenzyme A carboxylase deficiency. a, b Axial T1-weighted inversion recovery images in a 3-month-old female patient. Only traces of myelin are seen within the optic radiations and splenium of corpus callosum, indicating delayed myelination. c, d Axial T2-weighted fast spin-echo images in a 15-month-old female patient. Mild fronto-temporal brain atrophy with some paucity of myelin (note the slight atrophy and faint hypersignal of splenium of corpus callosum)

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In the mitochondria of end-user extrahepatic tissues (brain and muscle), acetoacetate is converted into acetoacetyl coenzyme A. Acetoacyl coenzyme A is converted into acetyl coenzyme A; the latter is then used for ATP production in the tricarboxylic cycle. This last reaction on the ketolytic pathway is catalyzed by mitochondrial 2-methylacetoacyl coenzyme A thiolase. In liver, this enzyme has other metabolic functions. It is involved in ketogenesis (conversion of acetyl coenzyme A into acetoacyl coenzyme A) and degradation of isoleucine (conversion of 2-methylacetoacetyl coenzyme A into propionyl coenzyme A and acetyl coenzyme A). In β-ketothiolase deficiency the metabolic derangement is, therefore, quite complex, and is the sum of the various functions and organ expressions of the enzyme. The typical laboratory presentation of β-ketothiolase deficiency during metabolic decompensation is metabolic acidosis with ketosis, which indicates that ketolytic function is more dominant than ketogenetic. Excreted organic acids in urine are 2-methyl-acetoacetate, 2methyl-3-hydroxybutyrate, and tiglyl-glycine. The disease may have a neonatal onset form, but the infantile form is more common [303–305]. Vomiting and signs of encephalopathy (seizures, decreased

level of consciousness) characterize the acute ketoacidotic metabolic crisis. Otherwise, the disease presents with developmental delay, hypotonia, ataxia, and pyramidal signs, sometimes even before the first metabolic decompensation. No extrapyramidal signs have been described in the disease so far. Some of the neurological abnormalities appear only during metabolic crisis and are reversible; others deteriorate through repeated episodes of decompensation [306]. Imaging Findings

The most characteristic imaging findings in βketothiolase deficiency are bilateral lesions of the putamina. The lesions involve the posterior part of the putamina and, by the time of the imaging workup, usually exhibit an atrophic character. These lesions often present with hyposignal on both T1- and diffusion-weighted images and indicate necrosis. Additionally, dentate nucleus abnormalities are also quite common. In some cases, the dentate nuclei exhibit swelling, in others these are hardly detectable, which may correspond to atrophy and necrosis (Fig. 13.47). Usually, no white matter involvement is noted,

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Fig. 13.47a–c. MR imaging findings in β-ketothiolase deficiency. a Axial T2weighted fast spin-echo image in a 14-month-old male patient. Ill-defined and rather faint but clear signal abnormalities within the posterior parts of putamina bilaterally (arrows), at this stage without atrophy. Suggestion of delayed and hypomyelination. b Axial T2-weighted fast spin-echo image in a 7-year-old female patient. Similar findings as in the previous patient (arrows), but the lesions exhibit an atrophic character. c Coronal T2-weighted image in the same patient as on image b. Somewhat atrophic and abnormal hyperintense appearance of the dentate nuclei (arrowheads)

although rather extensive hemispheric white matter abnormalities have also been reported [306]. Overall, the combination of dentate nucleus and posterior putaminal lesions constitute a rather suggestive imaging pattern, although other diseases, in particular biotin-responsive basal ganglia disease (see later) may present with similar features. On diffusion-weighted images the swollen dentate nuclei are isointense, while the putaminal lesions are either iso- or hypointense. 1 H MRS may show lactate within the lesion areas, occasionally with increase of the Cho peak.

associated with partial, and another with total enzyme deficiency. The disease related to the partial enzyme deficiency presents with slowly progressive neurological manifestations in infancy or early childhood but without systemic metabolic disturbances. The clinical picture is dominated by extrapyramidal signs, notably tremor and choreoathetosis [307, 308]. Seizures, swallowing difficulties, and hypotonia have also been described. Total absence of enzyme activity was associated with severe systemic lactic acidosis, the overall clinical picture being quite similar to pyruvate dehydrogenase deficiency [309]. This form may lead to death in late infancy.

13.4.1.14 α -Ketoglutaric Aciduria

Imaging Findings

α-ketoglutaric aciduria is a rare disorder of the tricarboxylic cycle. The underlying metabolic abnormality is partial or complete deficiency of α-ketoglutarate dehydrogenase. The disease has two clinical phenotypes, one

MRI reveals bilateral basal ganglia disease, but illdefined signal changes may be present within the thalami as well (Fig. 13.48). In milder forms, only the putamina may be affected. In severe cases, the heads of the caudate nuclei are atrophic too. The latter leads

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Fig. 13.48a–c. MR imaging findings in an 11-year-old male patient with α-ketoglutaric aciduria. a–c Axial T2-weighted fast spinecho images. In this patient, only partial putaminal lesions are present, while the caudate nuclei and the thalami are spared. Signal abnormalities and atrophic changes involve the lateral and the posterior parts of the putamina

to enlargement of the frontal horns of the lateral ventricles. There is also mild diffuse brain atrophy [307].

zures) and electrophysiological (EEG) signs also suggest gray matter involvement.

13.4.1.15 Primary Lactic Acidosis

13.4.2.1 Urea Cycle Defects

Primary lactic acidosis represents a complex group of pathologies, some belonging to respiratory chain defects and others to disorders of pyruvate metabolism. Lactic acid is a product of anaerobic metabolism of glucose. Lactic acidosis is frequently found in inborn errors of metabolism (primary or secondary lactic acidosis), but may be acquired as well. Primary lactic acidosis is caused by impairment of lactate and pyruvate oxidation and disorders of the Krebs cycle or of the respiratory chain. Secondary lactic acidosis is present in several other metabolic diseases, notably in organic acidemias, urea cycle and fatty acid oxidation defects. Acquired causes of lactic acidosis include cardiopulmonary disease, severe anemia, malignancy, diabetes mellitus, hepatic failure, and postconvulsion status; lactic acidosis can also be drug-related. Mitochondrial enzyme defects that cause primary lactic acidosis include pyruvate transcarboxylase, pyruvate dehydrogenase, and cytochrome c oxidase deficiencies. These are discussed in greater detail among disorders of mitochondrial energy metabolism.

This group includes carbamylphosphatase synthetase, ornithine transcarbamylase, argininase (hyperargininemia), argininosuccinic acid lyase (argininosuccinic aciduria), and argininosuccinic acid synthetase (citrullinemia) deficiencies. Carbamyl phosphatase synthetase and ornithine transcarbamylase are “mitochondrial” enzymes, whereas argininosuccinate synthetase, argininosuccinate lyase and argininase are found within the cytosol. Ornithine transcarbamylase deficiency has an X-linked recessive inheritance; the other diseases are autosomal recessive. The mutant genes are located on chromosome 2q35 in carbamylphosphatase synthetase, on 9q34 in argininosuccinic acid synthetase, on 7cen-p21 in argininosuccinic acid lyase, and on Xp21.1 in ornithine transcarbamylase deficiency. The urea cycle is a complex metabolic process. It is involved in the synthesis of arginine and in the elimination of excess nitrogen, through conversion of toxic ammonia into nontoxic urea. Impairment of the urea cycle has significant consequences:

13.4.2 Amino Acidopathies Amino acidopathies usually present preferentially with white matter disease; however, clinical (sei-

1. Arginine becomes an essential amino acid (except in hyperargininemia). 2. Severe hyperammonemia develops. Besides its direct toxic effect, it leads to disequilibrium between excitatory (glutamate) and inhibitory (GABA) neurotransmitters through stimula-

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tion of glutamate synthesis from glutamine and ammonia at the presynaptic level. Although the exact mechanism of resultant damage to neurons (“glutamate suicide”) is still poorly understood, this is felt to be one of the major factors behind development of the devastating effects on brain parenchyma in urea cycle defects (and in some organic acidurias such as glutaric aciduria type 1, see earlier). Alternatively, deleterious consequences of increased influx of tryptophan into the brain (in exchange for overproduced glutamate due to hyperammonemia) have also been advocated [310]. The most common metabolic derangements in all of the disease entities referred to as urea cycle defects are hyperammonemia and impaired metabolism of various amino acids (alanine, glutamine, citrulline, and arginine). Some urea cycle defects typically present in neonates as devastating metabolic diseases. Ornithine transcarbamylase deficiency, carbamylphosphatase deficiency, and citrullinemia usually occur very shortly after birth; argininosuccinic aciduria usually has onset a few days later. In urea cycle defects, hyperammonemia leads to diffuse brain edema, responsible for signs of raised intracranial pressure on physical and neurological examination (lethargy, hypotonia, vomiting, hypothermia, seizures, bulging fontanel, and rapidly increasing head circumference). Hyperventilation results in characteristic respiratory alkalosis [311]. Immediate postnatal diagnosis and treatment of urea cycle defects is of utmost importance, since delay in appropriate management leads to death or severe and irreversible neurological deficit [310]. If the disease is of later onset (infantile, juvenile, or adult forms), it may manifest with neurological signs and symptoms of acute or chronic encephalopathy (ataxia, abnormal behavior). In hyperargininemia, the typical presentation is a slowly progressive encephalopathy. Imaging Findings

CT and MRI findings in neonates with urea cycle defects are dominated by prominent brain swelling and white matter signal changes related to vasogenic edema [312, 313]. The myelinated white matter is less severely affected than nonmyelinated structures. This is in sharp contrast to maple syrup urine disease and is, therefore, a useful differential diagnostic clue in MRI. Gray matter structures (basal ganglia, cortex) may also be involved in the most severe cases (Fig. 13.49).

MRI studies during metabolic crises in the later (infantile, adult) onset forms of some of the urea cycle defects (ornithine transcarbamylase deficiency, citrullinemia) often show multiple abnormal signal intensity lesions within the cerebral hemispheres associated with swelling. The lesions, which involve both cortical and subcortical structures, exhibit a strokelike appearance, but these are of metabolic, rather than ischemic origin, somewhat similar to lesions in MELAS [76, 107, 112, 314]. Stroke-like lesions are quite extensive in infants and sometimes involve the entire hemisphere; in adults they are more limited. Occasionally, subtle lesions may be present within the deep gray matter structures as well. In chronic stage of the disease, ill-defined white matter changes and diffuse brain atrophy are found (Fig. 13.50). Diffusion-weighted images in neonates with urea cycle defect show signal heterogeneities with some prominence of hypointensities within the lesion areas, consistent with vasogenic edema. 1 H MRS in urea cycle defects usually shows decreased mI but, more importantly, increased glutamine-glutamate peak complexes in the brain parenchyma, the latter indicative of hyperammonemia [76, 313, 315]. Glutamine is usually easier to demonstrate with short echo time (20 ms), but high concentrations may also be detectable at longer echo times (135 ms) (Fig. 13.21). Lactate is frequently shown in ornithine transcarbamylase deficiency. Additional 1H MRS abnormalities include decreased NAA, Cho, and Cr. Similar changes may occur in hepatic encephalopathy; therefore, these are nonspecific, but highly suggestive findings in appropriate clinical settings. 13.4.2.2 Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) is an autosomal recessive disorder. It is related to deficiency of branched-chain α-keto acid dehydrogenase enzyme, converting 2-oxoisocaproic, 2-oxo-3-methyl-N-valeric and 2-oxoisovaleric acids into isovaleryl coenzyme A, 2methylbutyryl coenzyme A, and isobutyryl coenzyme A (the second step on the L-leucine, isoleucine, and valine breakdown pathway). The encoding genes of the three enzyme subunits are located on chromosomes 19q13.1 and 6p21-p22 (E1 α- and β-subunits), 1p31 (E2-subunit) and 7q31-q32 (E3-subunit). The E3-subunits of pyruvate dehydrogenase (see later in pyruvate dehydrogenase deficiency), α-keto acid dehydrogenase (defective in α-ketoglutaric aciduria, a metabolic disease with late infantile or childhood onset), and branched-chain αketo acid dehydrogenase (in MSUD) are identical and encoded by the same gene in prokaryotic cells [316].

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Fig. 13.49a–h. MR imaging findings in metabolic crisis in urea cycle defect (carbamylphosphatase synthetase deficiency) in a 15-day-old male neonate. a–d Axial T2-weighted fast spin-echo images. Diffuse brain edema with extensive white matter signal changes, with relative sparing of myelinated structures (e.g., posterior brainstem structures). Abnormal hyperintensities are suggested within the thalami and the anterior part of the putamen on the right side. e–h Axial T1-weighted inversion recovery images. The relative sparing of the myelinated structures in the brainstem is better appreciated on these images. In some areas the cerebral cortex appears to be involved

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Fig. 13.50a–h. MR imaging findings in the chronic stage of urea cycle defects. a–d Axial T2-weighted fast spin-echo (a, b) and T1weighted inversion recovery (c, d) images in a 1-year-old female patient with argininosuccinic aciduria. Subtle signal abnormalities are seen within the globi pallidi and heads of the caudate nuclei. Diffuse hypomyelination with an element of delayed myelination affecting mainly peripheral white matter structures. e–h Axial T2-weighted fast spin-echo images in a 5-year-old male patient with citrullinemia. Extensive, predominantly subcortical white matter lesions associated with atrophy. In the subinsular and occipital regions, cortical structures appear to be involved. Subtle signal changes are suggested within the heads of the caudate nuclei, perhaps even within the globus pallidus on the right side. Note severe atrophy of the splenium of the corpus callosum (f, g)

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Due to the underlying enzyme defect, the metabolism of the aforementioned intermediate metabolites in the breakdown of L-leucine, L-isoleucine, and L-valine is interrupted in MSUD. As a result, increased concentrations of branched-chain amino acids (leucine, valine, and isoleucine) and their keto-acid and 2-hydroxy derivatives appear in blood, urine, and CSF. The biochemical effects of marked elevation of branched chain keto acids and amino acids in body f luids include impairment of the metabolism of neurotransmitters and of other compounds, which are important in energy metabolism (pyruvate and glucose) and in the synthesis of proteins and myelin. Four clinical phenotypes of MSUD are distinguished: classical, intermediate, intermittent, and thiamine responsive forms. The most severe form is classical MSUD, characterized by early postnatal onset and rapidly progressive neurological deterioration. The disease typically presents between the fourth and seventh day after birth with poor feeding, vomiting, ketoacidosis, hypoglycemia, lethargy, seizures, fluctuating ophthalmoplegia, alternating muscle tone changes, coma, and a characteristic odor of maple syrup. If untreated, the disease leads to death. The main cause of death during acute metabolic decompensation is brain edema, whose exact pathomechanism is not fully understood [317]. Notably, it is unclear whether the deleterious effect of the disease on the developing brain is due to direct toxic effects of abnormal metabolites or secondary mechanisms (sequelae of hypoxia, hypoglycemia, and/or acidosis) intervene as well. The accumulation of the abnormal intermediate metabolites may impair the blood-brain barrier; this may be the cause of severe vasogenic edema. Toxic amounts of leucine may interfere with normal myelin metabolism. As suggested by electrophysiological data, it is probably the abnormal myelin build-up, rather than demyelination, that is responsible for the neurological sequelae in MSUD. Early diagnosis and an appropriate dietary regimen improve long term outcome in MSUD patients, but intercurrent decompensation is always a possible life-threatening complication even later in life. If treatment was early (preferably preventive) and efficient, affected children may develop normally, but residual neurological deficit (spasticity, psychomotor delay) is quite common. The intermediate and intermittent forms of MSUD have a more insidious clinical pattern. The first metabolic crisis may appear in late infancy or early childhood. The thiamine responsive form is encountered in all age groups.

Imaging Findings

Both CT and conventional MRI show diffuse swelling of the brain [318]. This is partially due to extensive vasogenic edema which involves nonmyelinated white matter structures. On the other hand, prominent signal changes and swelling are also present within myelinated brain areas (schematically, posterior brainstem tracts, central cerebellar white matter, posterior limbs of the internal capsules, and central corticospinal tracts within the cerebral hemispheres), representing “myelin” edema, believed to be secondary to vacuolating myelinopathy [319–321] (Fig. 13.51). In neonates and young infants, germinolytic cysts in periventricular location are frequently found within cerebral hemispheric white matter (Fig. 13.52). Identification and differentiation of the two coexisting pathological processes and the resultant distinctly different edema types is straightforward with DWI. Myelin edema presents with isotropically restricted water diffusion, hence appears to be hyperintense on all directional anisotropy images. On the contrary, vasogenic edema is characterized by isotropically increased water diffusion which causes hyposignal on diffusion-weighted images. On ADC map images, areas of myelin edema are hypointense [322, 323]. The sharp contrast between the signal properties of these two edema types and peculiar distribution of the pathological hypersignal (strictly limited to myelinated white matter structures) result in a practically pathognomonic imaging pattern on diffusion-weighted images (Fig. 13.53). 1 H MRS may also have a role in the diagnostic work-up. The protons of methyl groups of branchedchain amino acids resonate at 0.9–1.0 ppm, whereas in healthy subjects no detectable peak is found. However, in patients with MSUD, and especially during the acute metabolic decompensation when plasma, CSF, and cerebral levels of branched chain amino acids and keto acids are elevated, a more or less prominent peak appears at 0.9–1.0 ppm on both short- and long echo-time spectra [323, 324] (Fig. 13.21). This provides further support to the diagnosis and may warrant specific laboratory tests and adequate treatment. Frequently, an elevated lactate peak is found at 1.3 ppm, which reflects the impairment in energy metabolism and utilization of pyruvate in the citric acid cycle. The NAA peak may also be low during acute decompensation. The imaging findings in the intermittent and intermediate forms of MSUD are somewhat less characteristic. Typically, brain atrophy, delayed myelination, and pathological signal changes within upper brain-

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Fig. 13.51a–d. Axial T1-weighted spinecho images in an 8-day-old female patient immediately after the onset of maple syrup urine disease. a–d Both myelinated and nonmyelinated white matter structures exhibit an abnormal, hypointense appearance. In this case the brain edema is rather mild

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Fig. 13.52a–c. Germinolytic cysts in an 8-day-old female patient with maple syrup urine disease (same patient as in Fig. 13.51). a On the axial T2-weighted fast spin-echo image, periventricular cysts are not conspicuous. Increased signal within the pyramidal tracts is suggested, consistent with myelin edema. b On the T1-weighted spin-echo image, the cysts are faintly visualized. c FLAIR image enables easy identification, due to sharp contrast between fluid-filled cavities and adjacent brain parenchyma. The extensive vasogenic edema within the nonmyelinated white matter is well appreciated on all image types

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stem structures, thalami, globi pallidi, and centrum semiovale are observed [321]. Diffusion-weighted images show hyperintense signal abnormalities in the aforementioned areas, but they are usually rather subtle. From an imaging standpoint, the intermittent form of MSUD may, therefore, be somewhat reminiscent of Canavan disease in early stage, but the clinical context and the laboratory findings allow easy differentiation between them (Fig. 13.54). In treated MSUD cases, CT findings suggested reversibility of the abnormalities [318]. However, on conventional MRI and DWI, findings almost never return to completely normal [320, 323]. Usually, more or less prominent residual abnormalities, including diffuse brain atrophy, delayed myelination, and deep gray matter structural lesions, are noted. The pattern of the structural lesions is very similar to those observed in the intermittent form of MSUD; occasionally, additional abnormalities are also present, notably in hypothalamic structures, dentate nuclei, and cerebellar or cerebral hemispheric white matter (Fig. 13.55). Subtle DWI abnormalities may be present in treated and well-compensated patients. In therapy responsive cases, 1H MRS also shows improvement [324, 325], but total normalization of the branched-chain amino-acid peak complex may not be achieved, since branched-chain amino acids are essential (not synthesized in the human body) and, therefore, total dietary withdrawal is not possible (Fig. 13.27). 13.4.2.3 Phenylketonuria

Phenylalanine is an essential amino acid. Impairment of the phenylalanine hydroxylating system (i.e., block in the conversion of phenylalanine into tyrosine) results in insufficient breakdown and decreased blood concentration of tyrosine and increased blood concentration of phenylalanine (hyperphenylalaninemia), which leads–through an alternate metabolic pathway–to increased excretion of phenylketones and phenylamines in urine, i.e., phenylketonuria (PKU). Two forms of PKU are known. The more frequent “classical” PKU (98%) is caused by deficiency of hepatic phenylalanine hydroxylase enzyme. Depending on residual enzyme activity, three clinical phenotypic subgroups are identified. Type 1 is the classical PKU with infantile onset and the lowest residual enzyme activity (less than 1%), type 2 is the milder variant of the same (1%–5% residual enzyme activity), and type 3 is called persistent hyperphenylalaninemia (more than 5% with serum phe-

nylalanine levels inferior to 600 μM/l). The other, more “malignant” and rare form of the disease is related to deficiency of tetrahydrobiopterin (BH4), which is a cofactor of the hydroxylase enzyme and as such, is also indispensable in the breakdown of phenylalanine into tyrosine. In the malignant form, either synthesis or recycling of tetrahydrobiopterin is impaired through a number of possible enzyme (guanosine-triphosphate-cyclohydrolase, 6-pyruvoyltetrahydropterin-syntethase, dihydropteridine reductase, tetrahydropterin carbinolamine dehydratase) deficiencies. Blood phenylalanine levels in this form are usually above 1200 μM/l. PKU is a common metabolic disorder characterized by an autosomal recessive inheritance pattern. The defective genes are located on chromosome 12q24.1 in the classical type, and on chromosome 4p15.31 in the malignant type. The complex pathomechanisms through which clinical, histopathological, and imaging abnormalities develop in PKU are progressively revealed [326]. Hyperphenylalaninemia is associated with increased brain phenylalanine concentrations. Parallel to this, tyrosine and tryptophan content of brain decreases. This is believed to be due to a competition for a saturable common transporter of large neutral amino acids through the blood-brain barrier, to which phenylalanine seems to have a greater affinity than the others. Increasing evidence suggests that it is intracerebral depletion of tyrosine and tryptophan which causes the secondary CNS abnormalities, rather than increased cerebral concentration of phenylalanine. Intracerebral unavailability of the aforementioned amino acids causes impairment of protein, and hence, myelin synthesis. The reduced amount of synthesized myelin is probably also abnormal (dysmyelination), presumably due to reduction of the sulfatide content. This causes fragility of myelin basic protein in particular, with subsequent increased myelin breakdown (demyelination). Phenylalanine itself may also have a direct toxic effect on some oligodendrocytes (so-called phenylalanine-sensitive oligodendrocytes residing in areas which myelinate after birth, as opposed to phenylalanine-insensitive oligodendrocytes, which are found in areas which myelinate prenatally), leading to decreased myelin producing activity (hypomyelination) [327]. Another possible pathomechanism in the development of neurological complications in PKU is impairment of biosynthesis of neurotransmitters (dopamine, noradrenaline, and serotonin) due to the unavailability of their precursors, tyrosine and tryptophan. The resultant neuropathological changes in untreated PKU patients are in keeping with the above

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Metabolic Disorders Fig. 13.53a–l. Conventional and diffusion-weighted imaging of the different edema types in maple syrup urine disease. a–d Axial T2-weighted fast spin-echo images. Both types of edema (vasogenic and myelin) present with hypersignal on these images. The myelin edema however, which involves the myelinated white matter structures appears to be somewhat more prominently hyperintense (note the increased signal within the pyramidal tracts (e.g., within the posterior limbs of the internal capsules) with respect to the rest of the centrum semiovale (c, d). e–h Axial diffusion-weighted echo-planar images (b = 1000s). On these images, the myelin edema presents with marked hypersignal, whereas vasogenic edema is hypointense. The hyperintensities provide an accurate myelination map of the brain (posterior brainstem tracts, central cerebellar white matter, optic radiations, pyramidal tracts). i–l Apparent diffusion coefficient (ADC) map images. These images confirm the restriction of water diffusion within the areas of vacuolating myelinopathy (hyposignal) and the increased water diffusion in the areas of vasogenic edema (hypersignal)

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Fig. 13.54a–h. Conventional and diffusionweighted MR imaging findings in a 2-yearold male patient with intermittent maple syrup urine disease. a–d Axial T2-weighted fast spin-echo images. Mild fronto-temporal brain atrophy in conjunction with rather extensive gray and white matter signal abnormalities. The most markedly involved structures are the upper brainstem, diencephalon (including thalami), globi pallidi, optic radiations, and central centrum semiovale (note sparing of subcortical U fibers). e–h Axial diffusion-weighted echo-planar images (b = 1000s). The signal abnormalities are less prominent than in the neonatal onset form, but correlate well with T2-weighted imaging findings

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Fig. 13.55a–h. Follow-up MR imaging findings in patients with treated maple syrup urine disease. a–d Axial T2-weighted fast spin-echo (a, b) and diffusion-weighted echo-planar (c, d) images in a 2.5-year-old female patient. Rather unremarkable residual abnormalities are seen, notably faint hypersignal within the tegmentum of the pons, at the level of the globi pallidi, and within subinsular white matter structures. On diffusion-weighted images, very subtle hypersignal is suggested within the globi pallidi. e–h Axial T2-weighted fast spin-echo (e, f) and diffusion-weighted echo-planar (g, h) images in a 14-month-old female patient who had late diagnosis and delayed treatment. Prominent residual signal changes are seen on both conventional and diffusion-weighted images within the brainstem, thalami, and globi pallidi. Very severely delayed overall myelination

Metabolic Disorders

[328]. These show evidence of defective myelination (hypomyelination) and myelin maintenance (demyelination). The most severely affected areas are those which myelinate postnatally. In addition to white matter abnormalities, histopathological studies suggest impairment of postnatal development of cerebral cortex as well. These observations provide explanation for some of the most common neurological manifestations of PKU, notably mental retardation and seizures, which cannot be explained exclusively by white matter disease. PKU is a “pure” neurometabolic disease. Clinical and imaging manifestations of classical and malignant forms of PKU are, however, different. Classical PKU

In classical, type 1 form, the disease usually starts in early infancy. Microcephaly, hypopigmentation, delayed development, and infantile spasms are common early clinical features of the disease. Later, pyramidal and extrapyramidal signs, generalized tonic-clonic seizures, behavioral changes, and mental retardation develop. After childhood, further progression is usually very slow but, occasionally, rapid deterioration may also occur in young adulthood. In early-treated patients with type 1 disease, ultimate neuropsychological and neurological outcome is not completely normal. Affected patients have a lower IQ than age-matched controls and subtle pyramidal (fine motor skills) and extrapyramidal (tremor) abnormalities are detectable on careful neurological assessment [151]. In the type 3 form of the classical disease, affected patients are totally asymptomatic and, therefore, do not require dietary restrictions [329]. Imaging Findings

In the mild form (type 3) of classical PKU, MR examinations may be totally normal, even on repeated follow-up studies [330]. In early treated patients with type 1 and type 2 PKU, MR images often show mild to moderate supratentorial white matter signal abnormalities. Typically, these changes appear in parieto-occipital periventricular regions lateral to optic radiations, as ill-defined hyperintensities on T2-weighted images [151, 330, 331]. The subcortical U fibers are often, but not always, spared (Fig. 13.56). In noncompliant or untreated patients, patchy or confluent white matter changes are present, initially in the occipital periventricular region, and later extending anteriorly to the frontal and temporal regions

of the brain [330]. The subcortical U-fibers and the corpus callosum may also be involved [332, 333]. The internal capsules, brainstem, and cerebellar structures are typically, but not always, spared. If brainstem or cerebellar abnormalities are present, these are usually associated with more severe supratentorial imaging manifestations [334]. The severity and extent of the white matter lesions, according to several reports, tend to correlate with the efficacy of dietary control (in particular blood phenylalanine level), including patient compliance [330, 333–336]. On the other hand, no consistent correlation exists between the magnitude of the white matter changes and the presence and degree of mental retardation [334, 337]. On appropriate treatment, white matter changes may show improvement; after cessation of dietary control, these may deteriorate again [330, 338]. No macroscopic structural imaging abnormalities are found within the cortex and deep gray matter structures, despite compelling pathological evidence of structural cortical changes. Occasionally, cortical atrophy may be present [332]. DWI data in classical PKU suggest that two different types of histopathological changes may occur within the cerebral white matter, probably representing different stages of white matter injury [339, 340]. Cerebral periventricular white matter lesions were found to exhibit either high signal intensity on diffusion-weighted images associated with decreased ADC value (dysmyelination), or an iso- or hypointense appearance and increased ADC value (demyelination) (Fig. 13.56). Conventional 1H MRS in treated patients may be normal as far as the usual metabolites and their relative ratios are concerned (in the upfield portion of the spectrum, from 0–4 ppm) [330, 334, 341]. However, in the downfield portion of the spectrum (4–10 ppm), which is usually not assessed in routine spectroscopic studies, the presence of intracerebral phenylalanine and its dynamics with respect to plasma phenylalanine level changes may be directly demonstrated, even at 1.5 T field strength [341, 342]. The phenylalanine peak appears at the 7.37 ppm level. Quantitative analysis showed that brain concentration of phenylalanine is always lower than serum levels, but show a linear correlation at lower plasma concentration levels. If plasma concentration is higher than 1300 μM/l, brain concentrations do not increase further, supporting the hypothesis of the saturable blood-brain barrier transport mechanism as discussed earlier [343]. Malignant PKU

In the malignant form, microcephaly and delayed development are also typical but the disease–if not

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Fig. 13.56a–h. MR imaging findings in treated classical phenylketonuria in a 10-year-old male patient. a–d Axial T2weighted fast spin-echo images. Extensive, mild hyperintensities within the cerebral hemispheric white matter (compare with the spared, hypointense subcortical U fibers in the frontal regions). More prominent signal changes are seen in frontal and parieto-occipital periventricular areas. Posteriorly, the volume of the white matter is reduced. e–h Axial diffusion-weighted echo-planar images (b = 1000s). The periventricular lesion areas are hyperintense

Metabolic Disorders

treated–often leads to death in early childhood. Neurologically, the patients present with prominent early-onset extrapyramidal signs (infantile Parkinsonism, choreoathetosis) as well as myoclonic and grand mal seizures. Additionally, truncal hypotonia with increased tone within the limbs and progressive pyramidal and bulbar signs develop in conjunction with severe cognitive deterioration [344].

ization or hypoxic-ischemic changes (cortical laminar necrosis) [346]. Improvement of the changes on follow-up imaging studies has been documented even in this form of PKU, underlying the importance of early diagnosis and treatment [344]. 13.4.2.4 Hyperhomocystinemias

Imaging Findings

In the biopterin-dependent form of PKU, the most characteristic, albeit not constant, CT imaging abnormalities consist of calcifications at the level of the putamina and/or globi pallidi as well as along the cortical-subcortical junction area in the frontal regions [345, 346] (Fig. 13.57). It is somewhat similar to what may be seen in carbonic anhydrase II deficiency (see later). Otherwise, progressive atrophy and white matter changes are noted; the latter are occasionally discrepantly mild with respect to the clinical presentation [344]. MRI studies show signal changes within the calcified areas, appearing hyperintense on T1- and hypointense on T2-weighted images [345]. Additionally, white matter lesions are also demonstrated; sometimes they are diffuse and prominent, in other cases focal, with cystic degeneration in the parietaloccipital regions [344, 345]. In this form, the posterior limbs of the internal capsules are often affected. Gyral hyperintensities along the cortical ribbon on T1-weighted images have also been reported; it is, however, unclear whether these represented mineral-

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Hyperhomocystinemias develop in several different conditions due to the complexity of the homocysteine metabolism. Disorders in this group include cystathionine β-synthetase enzyme deficiency (homocystinuria), methionine synthetase (also called 5methylhydrofolate:homocysteine methyltransferase) deficiency, folate deficiency, defect of folate metabolism (5,10-methylene-tetrahydrofolate reductase deficiency), cobalamin (vitamin B12) deficiency, and defects of cobalamin metabolism (methionine synthetase deficiency in isolated methylcobalamin and combined methyl- and adenosylcobalamin deficiencies (see earlier in methylmalonic acidemia). The three key enzymes in the pathogenesis of hyperhomocystinemia are cystathionine β-synthetase, methionine synthetase, and 5,10-methylene-tetrahydrofolate reductase (MTHFR), but at the cofactor level other substances, notably folate, as well as B12 (cobalamin) and B6 (pyridoxine) vitamins, also play an important role. The metabolism of homocysteine is closely linked to that of methionine [347]. In fact, metabolism of methionine into homocysteine is a particularly important

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Fig. 13.57a–c. CT abnormalities in “malignant” biopterin dependent form of phenylketonuria in an 11-year-old male patient. a–c Unenhanced axial CT images of brain show prominent calcifications at the level of basal ganglia and subcortical white matter structures. Faint hyperdensities are also seen within the cerebellum

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biochemical process, often referred to as the methyltransfer pathway. Through this multi-step metabolic process, important methyl groups are transferred to other essential acceptor molecules (DNA, neurotransmitters, proteins, phospholipids, polysaccharides). The end product of the methyl-transfer pathway is homocysteine. The latter may be further metabolized through two different pathways. On the one hand, it may be remethylated and hence “recycled” into methionine (remethylation pathway) or, alternatively, it may be catabolized into cystathionine, cysteine, and eventually sulfate (transsulfuration pathway). 1. Defect of the Transsulfuration Pathway

Cystathionine β-synthetase (converting homocysteine into cystathionine) is involved in the transsulfuration process. Cystathionine β-synthetase deficiency is the most frequent cause of homocystinuria. Patients with cystathionine β-synthetase deficiency present with hyperhomocystinemia and, because of the secondary impairment of the transmethylation pathway, with hypermethioninemia as well. 2. Defects of the Remethylation Pathway

The so-called remethylation pathway may be impaired by deficiency of methionine synthetase or of 5,10-MTHFR enzyme, or also by unavailability of methylcobalamin or folate. Methionine synthetase (together with betainehomocysteine methyltransferase) is responsible for remethylation of homocysteine, or in other words, recycling of homocysteine into methionine. Resynthetized methionine will, therefore, be again available on the aforementioned methyl-transfer pathway as a potent methyl group donor. Methylcobalamin is an essential cofactor of methionine synthetase. The conversion of homocysteine into methionine through transfer of a methyl group by the methionine synthetase enzyme requires 5-methyltetrahydrofolate as a cosubstrate (it is the actual methyl group donor). 5-methyltetrahydrofolate is an intermediate product of folate cycle, whose synthesis is catalyzed by the 5,10-MTHFR enzyme from 5,10-methylene-tetrahydrofolate. Folate is an indispensable precursor in the folate cycle. Patients with methylcobalamin (and cobalamin) or the rare isolated methionine synthetase enzyme deficiency, as well as with 5,10-MTHFR (and folate) deficiency, present with hyperhomocystinemia without hypermethioninemia. Methylcobalamin and adenosylcobalamin are synthesized from cobalamin; the latter is exclusively of dietary origin. It is noteworthy that adenosylcobalamin is a cofactor of methylmalonyl-coenzyme

A mutase, patients with cobalamin and combined methyl- and adenosylcobalamin deficiency present with a “dual” metabolic disorder, notably hyperhomocystinemia and methylmalonic aciduria (see more in detail in methylmalonic aciduria) [178]. The major clinical manifestations of hyperhomocystinemias are ophthalmological, vascular, and neurological. The ophthalmological complications consists of dislocation of the lens. It is believed to be secondary to the destructive effect of homocysteine on fibrillin in connective tissues. Vascular complications consist of occlusive vascular disease affecting both arteries and veins. The pathomechanism of atherosclerosis and thrombosis is not fully understood; nevertheless, direct toxic injury by homocysteine to the endothelium through oxidation, as well as other factors (reactive proliferation of smooth muscle cells, enhancement of certain coagulation factors and platelet aggregation, oxidation of low-density lipoproteins) predisposing to subsequent thrombosis particularly in areas of endothelial damage, are the most likely contributing factors [24,348]. Neurological complications in hyperhomocystinemias are mainly related to myelination abnormalities within the brain and spinal cord. The pathogenesis of hypo-, dys-, and demyelination in hyperhomocystinemias and in combined methylmalonic acidemia and homocystinuria is being progressively elucidated. Clinical and biochemical evidence suggests that impairment of the methyl-transfer pathway causes abnormalities of CNS, manifesting through myelination abnormalities. Appropriate function of the methyl-transfer pathway and in particular, availability of S-adenosylmethionine (which is an intermediate metabolite on the methyl-transfer pathway and as such, the universal methyl-group donor in mammalians) is indispensable for the myelination process, since phospholipids are among the acceptor molecules of transferred methyl groups [349, 350]. Decreased levels of S-adenosylmethionine in CSF was found to be associated with demyelination, and restoration of the normal concentration by betaine administration (betaine is an alternative methyl group donor for remethylation of homocysteine) resulted in apparent remyelination [351]. Clinically, folate and cobalamin deficiencies, as well as defects of the cobalamin metabolism, are also associated with hematological disorders, notably megaloblastic anemia. Maternal folate and 5,10 methylene-tetrahydrofolate reductase deficiencies are also known to be associated with increased occurrence of neural tube defects in neonates.

Metabolic Disorders

Homocystinuria

Homocystinuria is the most common form of hyperhomocystinemias and is related to a defect of cystathionine β-synthetase enzyme. The disease shows an autosomal recessive inheritance and at least 92 mutations have been identified [352, 353]. The onset is typically infantile. The appearance of the patients resembles Marfan syndrome. Especially, B6 vitamin-responsive patients are often mentally retarded. Lens luxation and thromboembolic events are frequent, while osteoporosis and seizures are less common complications of the disease [111]. In nontreated patients, occurrence of both lens dislocation and thromboembolic events is age-dependent [354]. Lens dislocations first manifest after the age of 2 years and, by the age of 10, have developed in about 50% of patients. Similarly, although somewhat delayed, age dependency was demonstrated with regard to the less frequent vascular complications. The chances of a vascular event are 25% by the age of 16 years and 50% by the age of 29 years. The most frequent vascular complications are occlusive peripheral venous and arterial disease (51% and 11%, respectively), followed by cerebrovascular events in 32% of patients. Myocardial infarction occurs in 4%. Venous complications, especially intracranial dural sinus thrombosis or pulmonary embolism, may be fatal [355, 356]. Recently, it has also been shown that occlusive arterial or venous complications may occur in cystathionine β-synthetase deficiency without other clinical symptoms of homocystinuria [357]. Rarely, neurological dysfunctions may also occur in cystathionine β-synthetase deficiency. Dystonia and other extrapyramidal abnormalities without imaging or autopsy evidence of basal ganglia involvement were described in several patients [358, 359]. Imaging Findings

MRI in cystathionine β-reductase deficiency can be very characteristic and, hence, suggestive. Dislocation of the lens, if present, is a highly suggestive imaging feature of the disease and is usually easily detected on T2-weighted MR images (Fig. 13.58). On the other hand, brain atrophy and multiple cortical-subcortical and lacunar infarctions both within the cerebral and cerebellar hemispheres may be detected [111]. In case of dural sinus thrombosis, MRI may show areas of venous infarction [360]. The disease may also present with nonspecific, diffuse white matter involvement, whose pattern is occasionally suggestive of a “retrograde” demyelination [351] (Fig. 13.59).

On adequate treatment, white matter changes may be reversible, indicating effective remyelination. Tetraventricular hydrocephalus internus in association with early neurological abnormalities were described as the presenting symptom in two patients with 5,10-MTHFR deficiency. MR angiography is useful in demonstrating occlusive arterial or venous disease, affecting large cerebral arteries or intracranial dural sinuses [111, 360]. 5,10-MTHFR Deficiency

5,10-methylene-tetrahydrofolate reductase (MTHFR) deficiency is the best known of the defects of folate metabolism, through which it affects the remethylation process of homocysteine [361]. The disease has an autosomal recessive inheritance. Severe and mild enzyme deficiencies are known. In the severe form nine different mutations, while in the mild form only one mutation, have been identified. The onset of the severe form of the disease is variable; infantile onset is the more frequent, but a juvenile onset form is also known. A good genotype-phenotype correlation was demonstrated with regard to severity of the enzyme deficiency and age of onset of the disease. Homozygous patients with 0%–3% residual enzyme activity present with early onset during the first year of life, with microcephaly and severe clinical manifestations usually leading to death during the first year of life, if untreated [362]. Patients (usually compound heterozygotes) with 6%–20% residual enzyme activity have a later onset of the disease, usually during the second decade of life, with milder clinical abnormalities. Neurologically, developmental delay, mental retardation, motor and in particular, gait disturbances, hypotonia, and seizures are the most frequent manifestations in conjunction with signs of spinal cord (combined degeneration of the cord) and peripheral nerve involvement. In the case of a 2-year-old female patient, besides funicular myelosis, extrapyramidal symptoms (in the form of Parkinsonism) also appeared, without detectable lesions of basal ganglia at autopsy [363]. Vascular complications also occur in 5,10-MTHFR deficiency, affecting both arterial and venous sides of the cerebral circulation [356]. The mild form is probably due to a mutation causing thermolability of the enzyme, whose possible role in early atherosclerosis-related occlusive arterial disease has been implicated [24, 361]. Imaging Findings

MRI in the severe, early onset form of 5,10-MTHFR deficiency may show rather prominent abnormalities

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b Fig. 13.58a,b. Lens dislocation in homocystinuria (cystathionine β-synthetase deficiency). a, b Axial T2-weighted fast spin-echo images in a 19-year-old female patient with homocystinuria. Posterior dislocation of the lens bilaterally

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Fig. 13.59a–d. MR imaging findings in homocystinuria (cystathionine β-synthetase deficiency) in a female patient. Initial MR imaging study at the age of 8 years was essentially normal (not shown); after that examination, the patient dropped out from the metabolic clinic. a–d Follow-up study 4 years later, when the patient showed up again in a severely crippled status. Axial T2-weighted fast spin-echo images. Extensive demyelination is seen within the cerebral hemispheres (brainstem and cerebellum are normal, not shown here). The most severely involved structures are the subcortical U-fibers. Conversely, corpus callosum, internal capsules, pyramidal tracts, and optic radiations are relatively spared. Subtle signal abnormalities are also seen within the caudate nuclei, putamina, and even thalami, although the ventrolateral nuclei are spared. Overall, the pattern of residual myelinated structures is reminiscent of the early postnatal myelination status, characterizing a retrograde demyelination process

Metabolic Disorders

in brain. Regional or diffuse atrophy may be present. The cerebral white matter is diffusely abnormal; lesions involve the corpus callosum, external and extreme capsules, medullary laminae, and anterior limbs of the internal capsules, with sparing of the posterior limbs. The cortico-spinal tracts within the centrum semiovale, the subcortical U fibers in the occipital regions, and the optic radiations are also spared. The basal ganglia and thalami are normal, but the globi pallidi show increased signal intensity on T2-weighted images. Subtle signal changes may be present within the mesencephalon (hypersignal within the substantia nigra and the periaqueductal regions) and central tegmental tracts of the pons. The cerebellar white matter is not involved. The findings may cause differential diagnostic problems with leukodystrophies (Fig. 13.60). In some other cases, MRI abnormalities are milder and present with delayed-, hypo-, or demyelination [153]. On therapy, white matter lesions and atrophic changes show improvement. In later onset forms, both diffuse white matter changes and “vascular” lesions may be demonstrated

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by CT or MRI [356, 364]. Vascular lesions consist of areas of recent or old infarctions as well as diffuse leukoaraiosis. Diffusion-weighted images in the early onset form show hypersignal within the white matter lesions, suggestive of vacuolating myelinopathy. Diffusionweighted abnormalities (similar to conventional MRI findings) may remain visible on follow-up studies even after several years. 1 H MRS of brain in a 10-month-old girl showed decreased NAA/Cho ratio, consistent with immaturity. Prominent peaks were found in the macromolecular range, which were interpreted as lipids, indicative of demyelination [153]. 13.4.2.5 Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia is an autosomal recessive disease caused by a defect of the glycine cleavage system. The glycine cleavage system is composed of four proteins; P protein (pyridoxal phosphate-

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Fig. 13.60a–d. Conventional and diffusion-weighted MR imaging findings in a 5-year-old male patient with 5,10-methylene-tetrahydrofolate reductase deficiency. a,b Axial T2-weighted fast spinecho images. White matter abnormalities show a fairly similar pattern to that seen in cystathionine β-synthetase deficiency (see Fig. 13.59). Perhaps the globus pallidus lesions are more prominent. c,d Axial diffusion-weighted echo-planar images. White matter lesion areas are hyperintense, suggestive of active demyelination with myelin edema

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dependent glycine decarboxylase), H protein (lipid acid-containing protein), T protein (tetrahydrofolaterequiring enzyme), and L protein (lipoamide dehydrogenase). In the majority (87%) of cases the disease is related to deficiency of P protein, in the remainder to a defect of T protein. The glycine cleavage system is expressed in liver, kidney, and CNS, and its defect leads to an accumulation of glycine in body fluids without ketoacidosis (in contrast to ketotic hyperglycinemia, notably propionic acidemia). The presence of the defect in the CNS and the resulting accumulation of glycine are thought to be critical in neurotoxicity. There appear to be two neurotransmitter roles for glycine in the CNS, one inhibitory and the other excitatory. The classic glycine receptor is inhibitory and located in spinal cord and brainstem. The second glycine receptor site is associated with the NMDAreceptor channel complex. Glycine acting at this site is excitatory and probably potentiates the action of glutamate, leading to glutamate-induced excitotoxic neuronal death [365]. Nonketotic hyperglycinemia has four known clinical phenotypes: neonatal, infantile, late onset, and transient. In the neonatal form, enzyme activity is undetectable or extremely low; in the later onset forms, some residual activity still exists, and these data provide a fairly consistent genotypic-phenotypic correlation. The neonatal form (often referred to as classical, the others as atypical) is by far the most common. It presents within the first 2 days of life as a devastating metabolic disorder, with encephalopathy, lethargy, breathing difficulties leading to respiratory failure, multifocal myoclonic seizures (showing burst-suppression pattern on the EEG) and, characteristically, hiccups [366]. The pronounced hypotonia may be related to the inhibitory effect of glycine on the anterior horn cells within the spinal cord. On the other hand, the excitatory effect of glycine seems to be responsible for the devastating effect of the metabolic disorder in the newborn (and most probably in the fetus as well). Laboratory diagnosis is made with the ratio of the concentration of glycine in CSF to that in the plasma, that ranges from 0.1 to 0.3 (control values approximately 0.02). Prenatal diagnosis is also possible from the chorionic villi by both genetic and enzymatic studies. The disease is usually resistant to treatment. Most children die in the first year of life, while others display severe neurodevelopmental delay but may survive for many years. The late onset forms, in which some residual glycine cleavage system activity is present, have a milder and rather nonspecific clinical presentation. Exceptionally, survival into adulthood may also occur [367].

Imaging Findings

The imaging hallmarks of nonketotic hyperglycinemia are callosal abnormalities and delayed or arrested myelination [368, 369]. Assessment of the corpus callosum may be challenging in the neonate (due to its small size and lack of myelin). The spectrum of morphological changes of the corpus callosum ranges from rare true callosal dysgenesis to frequent callosal hypogenesis or hypoplasia, but some degree of abnormality is always present (Fig. 13.61). The delay in myelination is increasingly evident with the age of the infant and is probably associated with hypo- or dysmyelination (resulting from inappropriate synthesis of myelin precursors). It seems that initially the myelination process progresses fairly normally, approximately until the age of 4 months; thereafter it slows down and, eventually, may become totally arrested [368]. The myelination abnormalities are, therefore, more prominent supratentorially (Fig. 13.16). Diffuse white matter volume loss of is another characteristic imaging finding in nonketotic hyperglycinemia. This develops earlier supratentorially; the posterior fossa structures may be initially spared, but in older infants brainstem and, in particular, cerebellar atrophy are frequent [368]. In the chronic stage of the disease severe global atrophy of the brain develops. Cortical gyral abnormalities and cerebellar hypoplasia have also been described in nonketotic hyperglycinemia [370]. Acute hydrocephalus may contribute to the severe clinical picture [371]. In two cases of neonatal onset nonketotic hyperglycinemia, intracranial hemorrhagic complications (intraventricular bleeding and subdural hematoma) were reported [366]. In another case of the neonatal onset form, true pyloric stenosis requiring surgery occurred in a 3-week-old boy [372]. DWI data in nonketotic hyperglycinemia were found to be suggestive of myelin vacuolation within the pyramidal tracts, middle cerebellar peduncles, and dentate nuclei [373]. 1 H MRS is a useful adjunct to the MR work-up of patients with suspected nonketotic hyperglycinemia, since the concentration of glycine is particularly elevated in the brain and 1H MRS allows noninvasive, direct demonstration of glycine. However, at a short echo time (e.g., 20 ms), the peak generated by protons of glycine overlaps with the normal mI signal, since both glycine and mI resonate approximately at the same ppm level (3.56 ppm). In normal subjects, glycine accounts for less than 20% of the 3.56 ppm signal. However, since mI has a much shorter T2 relaxation

Metabolic Disorders

time than glycine, its signal significantly decays or disappears at longer echo times (e.g., 135 ms), whereas in patients with nonketotic hyperglycinemia, an abnormal peak at 3.56 ppm remains conspicuous, allowing reliable differentiation between the two metabolites (Fig. 13.24). Cerebral concentrations of glycine correspond more reliably to the clinical findings than CSF and plasma levels [150]. Serial 1H MRS studies are useful in following the therapeutic response to drugs aimed at reducing glycine in the CNS (e.g., sodium benzoate and dextromethorphan, which have been shown to have beneficial effects in some infants with nonketotic hyperglycinemia) [150, 374]. a

13.4.2.6 3-Phosphoglycerate Dehydrogenase Deficiency

This is a recently described inherited metabolic disorder [375]. Two peculiar aspects of the disease make it rather remarkable. On the one hand, this is the only known aminoacidopathy which affects the anabolism rather than the catabolism of amino acids. On the other hand, the disease appears to be at least partially treatable. Deficiency of 3-phosphoglycerate dehydrogenase leads to impairment of serine biosynthesis. Serine is necessary for synthesis of membrane lipids, some of which (glycosphingolipids and sphingomyelin) are particularly important for normal myelin build-up. Besides low serum and CSF concentrations of serine, laboratory workup of body fluids reveals decreased amounts of glycine and 5-methyltetrahydrofolate as well; the latter is also known to adversely affect normal myelin maintenance. The disease is usually diagnosed in childhood, except in one patient in whom the disease was identified at the age of 10 months. Clinically, the disease is characterized by congenital microcephaly, mental retardation, and intractable seizures, usually in conjunction with megaloblastic anemia. Nystagmus is a frequently associated neurological sign. Treatment consists of supplementation of the absent amino acids, L-serine and glycine. Treatment usually results in significant reduction or total disappearance of seizure activity [376]. If treatment is started during infancy the head circumference may normalize. Psychomotor functions also improve.

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c Fig. 13.61a–c. Callosal abnormalities in nonketotic hyperglycinemia on sagittal T1-weighted spin-echo images. a Callosal agenesis in a 6-month-old male patient. b Callosal hypoplasia in a 9-month-old female patient. c Callosal hypotrophy in a 4month-old male patient

Imaging Findings

MRI findings consist of white matter abnormalities, suggestive of a combination of delayed and hypomyelination [377]. The delay in myelination can be very

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significant. There is also a diffuse volume loss of cerebral white matter, leading to prominent and predominantly supratentorial brain atrophy. As may be anticipated, appearance of the white matter changes is reminiscent of those observed in patients with disorders of folate metabolism. The corpus callosum is thin and short; this, together with the myelination abnormalities, may cause differential diagnostic problems with nonketotic hyperglycinemia on MRI in infancy, but both laboratory and 1H MRS allow for easy differentiation. After treatment, imaging findings show improvement. The volume of cerebral white matter increases, as shown by reduction of the size of the ventricles and decrease of the enlargement of the subarachnoid spaces. The corpus callosum becomes thicker. Myelination shows more or less progression too. Probably the best indicator of therapy-induced enhanced myelin synthesis is increase of the relative Cho concentrations in brain on 1H MRS, as indicated by increase of the Cho/Cr index.

13.4.3 Disorders of Carbohydrate Metabolism 13.4.3.1 Galactosemia

Galactose is derived from lactose through a hydrolytic process. Lactose is the major sugar constituent of breast milk. The hydrolysis takes place within the intestinal wall. The absorbed galactose then undergoes further metabolic steps to be eventually converted into either glycogen or glucose. The most frequent causes of galactosemia are galactokinase and galactose-1-phosphate uridyltransferase deficiency. Galactokinase deficiency is an insidiously developing metabolic disease related to the inability to convert absorbed galactose into galactose-1-phosphate through phosphorylation. Ingested galactose is, therefore, excreted unchanged or converted into galacticol. This substance is responsible for one of the earliest and most constant clinical manifestations of the disease, notably cataracts. Rarely, this may be further complicated by vitreous hemorrhages [378]. The disease does not have systemic or neurological manifestations, but pseudotumor cerebri-like episodes in affected patients may occur occasionally [379, 380]. In galactose-1-phosphate uridyltransferase deficiency, the second step of galactose metabolism after intestinal absorption is impaired. Galactose-1-phosphate is not further metabolized into uridine diphosphogalactose; therefore, due to the metabolic block,

galactose-1-phosphate, galactose, and its alternate catabolite, galacticol, accumulate. The disease has two clinical phenotypes. The classical form is related to complete enzyme deficiency. Affected neonates are normal at birth but a few days after breast feeding present refusal to feed, abdominal distension, vomiting, diarrhea, jaundice, and hypoglycemia. In fulminant cases, the disease may lead to death from liver or kidney failure or sepsis. As in galactokinase deficiency, cataracts may develop within a few weeks if the disease is not diagnosed and a lactose-free diet is not instituted promptly. Neurological complications include episodes of raised intracranial pressure (pseudotumor cerebri) and later, during the course of the disease, mental disability with ataxia, tremor, and dysarthria, occasionally even in patients under strict galactose-free diet [381, 382]. In the partial enzyme deficiency, affected patients are typically asymptomatic. The neurotoxicity in galactosemia and the development of cataracts (occasionally even in utero) are believed to be secondary to the adverse osmolar effects (increased osmotic pressure within the affected tissues, leading to water accumulation and swelling) of galacticol [383]. The synthesis of galactocerebrosides may also be impaired; this is believed to cause myelination abnormalities (dysmyelination), probably accounting for some of the late cognitive and neurological abnormalities [384]. Imaging Findings

In classical galactosemia in the acute postnatal stage, MRI shows diffuse vasogenic brain edema [383]. Later, signs of delayed and/or hypomyelination become conspicuous. Additionally, focal patchy white matter lesions have been described within the cerebral hemispheric white matter, predominantly in periventricular locations (Fig. 13.62). During the course of the disease, enlargement of the lateral ventricles and diffuse cerebral and cerebellar atrophy may also develop [381, 382, 385, 386]. 1 H MRS of a 6-day-old infant with galactose-1phosphate uridyltransferase deficiency demonstrated increased galacticol concentration within the brain parenchyma [383]. 13.4.3.2 Fructose Metabolism Abnormalities

Abnormalities of fructose metabolism include essential fructosuria, hereditary fructose intolerance, and fructose-1,6-biphosphatase deficiency. Essential fructosuria (fructokinase deficiency) is a nondisease, meaning that affected patients are

Metabolic Disorders

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Fig. 13.62a–d. MR imaging findings in galactosemia in twin sisters (both images at the age of 13 years). Axial T2-weighted fast spin-echo images. a, b Patchy white matter lesions in the peritrigonal areas and within the centrum semiovale. c, d Identical findings as in her sister

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healthy and symptom-free, despite the detectable biochemical abnormality. In hereditary fructose intolerance, in contrast to galactosemia, the first clinical signs and symptoms appear upon introduction of nonbreast milk-based nutrition formulas containing fructose or sucrose. Acute exposure to fructose leads to sudden clinical deterioration, including gastrointestinal tract dysfunction, hypoglycemia with convulsions, hepatic failure, coma and, if untreated, death. Under a fructose-free diet, clinical symptoms show rapid regression and patients develop normally. Although neurotoxic metabolites are not present in the disease, occasional episodes of hypoglycemia may have deleterious effect on the CNS. Fructose-1,6-biphosphatase is an enzyme of key importance in gluconeogenesis from lactate and amino acids in liver. Deficiency of this enzyme causes episodes of hypoglycemia and acidosis under conditions of increased glucose utilization or depletion of glucose and glycogen stores.

Imaging Findings

No abnormal imaging findings in the various forms of fructosuria have been reported. Theoretically, however, the CNS may be affected during the episodes of hypoglycemia; therefore, lesion patterns similar to those described in fatty acid oxidation disorders and persistent hyperinsulinemic hypoglycemia may be anticipated.

13.4.4 Disorders of Metal Metabolism 13.4.4.1 Copper Metabolism

Copper is a trace metal that is essential for the appropriate functioning of several enzyme complexes (cytochrome c oxidase, superoxide dismutase, lysyl oxidase, dopa-β-mono-oxygenase). Copper is

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absorbed from the intestines and then transported by plasma albumins to specific organs, notably to liver, brain, kidney, and eye. Two specific diseases related to impairment of copper transport are known: Menkes disease and Wilson disease.

connective tissue abnormalities include bladder diverticula, inguinal hernia, loose skin, and hyperflexible joints.

Menkes Disease

At birth, the brain appears to be normal on MRI. Occasionally, subtle signal abnormalities within the cerebral cortex may be seen, whose pathological significance is unclear [389, 390]. During the course of the disease, however, rapidly developing cerebral and cerebellar atrophy and prominent white matter disease (delay of myelination, perhaps with a component of demyelination) become obvious [391, 392]. The youngest patient in whom MRI already showed evidence of neurodegeneration (cerebellar atrophy and hypomyelination) was 5 weeks old [393]. Shrinkage of the brain can be so marked that spontaneous subdural fluid collections (hygroma, subdural hematoma) frequently develop [389, 394, 395] (Fig. 13.63). On T1-weighted images, the basal ganglia exhibit hypersignal similar to what is seen in chronic hepatic encephalopathies, including Wilson disease. The cerebral vessels are usually tortuous and elongated; this can be seen on conventional images but is better appreciated on MR angiography [390, 393, 395]. In a patient treated with copper histidinate from age 4 weeks, cerebral atrophy or white matter abnormalities did not develop; tortuosity of the cerebral arteries was, however, still conspicuous [396]. Ischemic stroke has also been reported as a complication of Menkes disease [106].

Menkes disease (kinky/steely hair disease, trichopoliodystrophy) is an X-linked metal metabolism disorder. The gene is located in Xq13.3. The disease is related to a defect of the transmembrane copper transport mechanism. One consequences is an impairment of normal intestinal absorption of copper, resulting in severe copper deficiency in blood (ceruloplasmin level is also low) and copper accumulation within the intestine (in fact, within the organelle-free cytosol of epithelial cells). In brain, which is one of the most severely affected organs in Menkes disease (besides liver), copper appears to be trapped within endothelial cells of the vessel walls and astrocytes, while neurons are in a state of copper deficiency [387]. The transport of copper is impaired at the cellular level too; therefore, copper cannot be delivered to copper-requiring enzymes, located within the cellular organelles, such as the mitochondria. The paradox of the disease is that, while a relatively high amount of copper is accumulated within the cytosol, intramitochondrial copper concentration is severely depleted. This also explains why oral or intravenous copper supplementation is ineffective. The most important enzymes which require copper as a cofactor are dopamine-β-hydroxylase (involved in catecholamine synthesis), cytochrome c oxidase (involved in oxidative phosphorylation), and lysyl oxidase (involved in elastin-collagen formation) [388]. Impairment of catecholamine (neurotransmitter) synthesis and oxidative phosphorylation explain the neurological manifestations (hypotonia, seizures) of the disease and progressive degeneration of the CNS. The elastin-collagen formation disorder possibly causes connective tissue abnormalities, including intimal fragility and the characteristically tortuous and elongated appearance of cerebral arteries. The onset of the disease is usually neonatal, but patients are typically normal during the first 2 or 3 months of life, after which neurological deterioration occurs, with loss of milestones, convulsions, hypotonia followed by spasticity and, eventually, lethargy. Most affected children die during the first years of life. Menkes disease is often referred to as “kinky hair” disease because of the peculiar appearance of the hair (pili torti); nevertheless, this may not be apparent in the newborn. Nonvascular

Imaging Findings

Wilson Disease

Wilson disease is of autosomal recessive inheritance. Multiple point mutations, all leading to the same disease, are known. The mutations are on chromosome 13. In contrast to Menkes disease (which is essentially an intracellular-transmembrane copper transport deficiency), Wilson disease develops due to an extracellular copper transport problem. A deficient transport protein prevents excretion of copper from the cells (in particular from hepatocytes) and incorporation of copper into ceruloplasmin. As a result, copper cannot be excreted into the bile either; hence, large amounts of copper are accumulated within liver and subsequently in other organs (brain, kidney, cornea), leading to degeneration of the involved tissues. This peculiar distribution explains the clinical manifestations of the disease, whose hallmarks are progressive hepatic insufficiency and behavioral, neurological, and ophthalmological abnormalities. Clinically, the disease usually manifests between 8 and 20 years of age, but earlier and later onset forms are also known.

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Fig. 13.63a–c. MR imaging findings in Menkes disease (courtesy of Dr. T. Huisman, Zurich, Switzerland). a Axial T2-weighted images at the age of 20 days. Essentially normal study. b, c Axial T1- and T2-weighted images of the follow-up examination at the age of 13 months. Prominent delay of myelination in conjunction with severe brain atrophy. Bilateral spontaneous subdural hematomas with fluid-fluid levels

Patients may have signs of either hepatic or CNS involvement or both at the time of initial clinical presentation. According to the dominant neurological abnormalities, several clinical forms of CNS disease may be identified. The classical form is characterized by extrapyramidal signs, notably dystonia and Parkinson-like features (pseudoparkinsonism). However, in other patients, cerebellar signs, such as ataxia and tremor (so-called wingbeating tremor) or bulbar signs (mainly swallowing difficulties and dysarthria) are present and may dominate the neurological picture. These functional abnormalities are related to involvement of basal ganglia, cerebellum, and brainstem. In patients presenting with CNS involvement, the so-called Kaiser-Fleischer ring in the cornea is almost invariably noted and greatly facilitates the clinical diagnosis. The diagnosis of Wilson disease is confirmed by laboratory studies, which reveal decreased serum ceruloplasmin and copper levels and high urinary excretion of copper. Without treatment, the disease relentlessly progresses and leads to death, usually due to liver failure or bleeding from esophageal varices. Treatment consists of penicillamine (binds free copper and facilitates excretion) and zinc (prevents intestinal absorption). In advanced stages of the disease, hepatic failure may require liver transplantation, after which the disease usually ceases to progress, but the already present damage to the CNS remains irreversible. Imaging Findings

CT is less sensitive in the detection of brain abnormalities than MRI. In advanced cases of Wilson

disease it may show hypodensities within the basal ganglia. MRI in clinically symptomatic Wilson disease is usually, but not always, abnormal. In up to 33% of the cases, asymptomatic patients may have subtle brain abnormalities (within putamina, claustra, frontal, temporal and parietal white matter, dorsal mesencephalon, cerebral and superior cerebellar peduncles), and conversely, normal MRI may be found in a small portion (27%) of patients with mild neurological manifestations [397]. The most significant changes are seen at the level of deep gray matter structures (putamina, globi pallidi, thalami, claustra), brainstem (mesencephalon and pons), cerebellum, and cerebral hemispheric white matter. None of the individual abnormalities is specific to the disease, but their combination usually constitutes a suggestive imaging pattern. At the level of deep cerebral gray matter structures, T2-weighted images may show ill-defined, bilateral symmetrical hyperintensities within the caudate nuclei, putamina, globi pallidi, thalami (lateral and intralaminar nuclei) and, sometimes, even within the claustra. The latter is an inconsistent (13%), but if present, a highly suggestive imaging finding and an important differential diagnostic clue in Wilson disease (Fig. 13.64). Hyperintense signal abnormalities within the striatum on T2-weighted images were found to show a good correlation with the presence of pseudoparkinsonian symptoms neurologically, whereas high signal on T2weighted images within the putamina alone is characteristically associated with dystonia [397]. Involvement of the claustra and thalami seems to mainly

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Fig. 13.64a–h. The full spectrum of gray matter lesions in Wilson disease on modular inversion recovery images in a 16-year-old male patient with Wilson disease. a–h Ill-defined hyperintensities are seen within the brainstem at the level of central tegmental tracts of pons and mesencephalon, pars compacta of substantia nigra, and thalami. More prominent signal changes are noted within the basal ganglia and claustra bilaterally. The caudate nuclei, putamina and globi pallidi are atrophic-necrotic too

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predispose to cerebellar signs. T2-weighted gradient echo images sometimes show prominent hyposignal within putamina, globi pallidi, substantia nigra, and red nuclei (Fig. 13.65). The exact nature of the magnetically susceptible substance in these structures is unclear, but may correspond to iron and/or copper [398]. In one case, the hyposignal on T2-weighted images progressed even under D-penicillamine therapy, suggesting that further iron deposition may occur in affected areas despite clinical improvement and effective copper removal from the plasma [399]. Conversely, T2 hyperintense basal ganglia lesions may be reversible after liver transplantation [400]. As in other hepatic encephalopathies, T1-weighted images may show faint and ill-defined hyperintensities within basal ganglia (mainly within the globi pallidi) and thalami, even in clinically well-controlled patients who do not have detectable abnormalities on

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T2-weighted images. This is believed to be secondary to abnormal accumulation of manganese (Fig. 13.66). In patients with Wilson disease, prominent enlargement of perivascular CSF spaces at the level of the basal ganglia was five times more frequent than in control individuals. Smaller or larger white matter lesions within cerebral hemispheres may also occur and are usually asymmetrical. As the disease progresses, atrophic diffuse brain atrophy develops. In the brainstem, ill-defined hyperintensities are often found at the level of the pons and the center of the mesencephalon; nevertheless, the most characteristic (although not pathognomonic) finding is the so-called giant panda face appearance of the upper mesencephalon. This consists of hypersignal within substantia nigra (mainly in the pars compacta) and tegmentum of the mesencephalon, in contrast with the hypointense appearance of red nuclei, cerebral peduncles, and

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Fig. 13.65a–d. MR imaging demonstration of magnetically susceptible substances within globi pallidi and substantia nigra in Wilson disease. a,b Axial T2weighted gradient-echo images. Prominent hypointensities are seen at the level of globi pallidi and pars reticulata of substantia nigra (arrowheads). c,d Axial diffusion-weighted echo-planar images (B = 1000s). Magnetic susceptibility artifacts (arrowheads) are further enhanced on these images

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deep cerebral gray matter structures. In the same study, MRS was found to be helpful in differentiating between portal-systemic encephalopathy and genuine neuronal damage in patients with Wilson disease. In patients with Wilson disease and portosystemic shunting, a significant decrease of the mI/Cr ratio was demonstrated with respect to patients without portosystemic shunting [403]. 13.4.4.2 Other Metals

Fig. 13.66. Signal abnormalities within the deep gray matter structures on the T1-weighted spin-echo images in Wilson disease. Ill-defined hyperintensities are seen within the globi pallidi bilaterally (arrowheads). Similar findings are not exclusive to Wilson disease and may also be seen in hepatic encephalopathies of other origin

tectum (Fig. 13.64). However, signal abnormalities may be present within the corticospinal tracts at the level of the cerebral peduncles (and posterior limbs of the internal capsule) in up to 24% of the patients. In the cerebellum, the dentate nuclei may or may not be involved and patchy lesions also are sometimes found in the cerebellar hemispheric white matter (Fig. 13.67). Lesions within the red nuclei, dorsal mesencephalic and pontine structures (dentatorubrothalamic and pontocerebellar tracts), and superior cerebellar peduncles are most frequently associated with cerebellar signs on neurological examination [397, 401] (Fig. 13.68). Rarely, lesions within the central and ventral parts of the pons may be found in patients with Wilson disease, and these are quite reminiscent of findings in central pontine myelinolysis [402]. Diffusion-weighted images may occasionally show hypersignal within some of the lesions, notably the mesencephalon and thalami. The paramagnetic substances within the deep gray matter structures (with or without hyposignal on T2-weighted, in particular gradient echo images) cause prominent hyposignal on diffusion-weighted images (Fig. 13.65). 1 H MRS in Wilson disease showed marginally decreased Cr, significantly decreased Cho, and normal NAA [69]. In another study, 1H MRS showed decreased NAA/Cr and Cho/Cr ratios within the

Several rare inherited diseases related to metal metabolism other than copper have been described. These include magnesium (primary hypomagnesemia, magnesium-loosing kidney), zinc (acrodermatitis enteropathica, hyperzincemia), manganese (prolidase deficiency), and molybdenum (combined or isolated deficiency of sulfite oxidase and xanthine oxidase).

13.4.5 Disorders of Mitochondrial Energy Metabolism 13.4.5.1 Disorders of Pyruvate Metabolism

Pyruvate can be formed from glucose, lactate, or alanine. Within the mitochondria, pyruvate is one of the primary sources of acetyl coenzyme A (alternatively, it may also be produced through fatty acid oxidation); the enzyme carrying out the process is the pyruvate dehydrogenase complex. Acetyl coenzyme A enters the tricarboxylic acid cycle, where through the synthesis of reduced nicotinamide and flavin adenine dinucleotides (NAD and FAD), it contributes to energy production (in the form of ATP) in the respiratory (electron transport) chain. Both pyruvate and acetyl coenzyme A may also be used in anabolic processes. Pyruvate is a potential source of gluconeogenesis, whose initial step is the conversion of pyruvate into oxaloacetate by the enzyme pyruvate carboxylase. At the same time, however, oxaloacetates may either enter the tricarboxylic acid cycle and contribute to energy production or are converted into aspartate, which is an essential substrate for the urea cycle. Acetyl coenzyme A may also be used for lipogenesis. Since pyruvate metabolism is a pivotal element in energy production and gluconeogenesis, it is obvious that all organs with high energy requirements, particularly the CNS, are vulnerable to any disorder in the process. The two most common abnormalities of pyruvate metabolism are deficiency of pyruvate

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b Fig. 13.67a, b. Cerebellar white matter lesions and diffuse brain atrophy in Wilson disease on coronal T2-weighted fast spin-echo images. a Enlargement of both extra- and intracerebral CSF spaces. Symmetrical, ill-defined hyperintensities within upper mesencephalic and diencephalic structures. Note the hypointense appearance of the red nuclei (arrows). b Ill-defined central cerebellar white matter lesions in conjunction with cerebellar atrophy

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Fig. 13.68a–d. MR imaging findings in a patient with Wilson disease presenting mainly with cerebellar manifestations. a–d Axial T2-weighted fast spin-echo images. Hypointensities are seen within the globi pallidi, red nuclei, and pars reticulata of the substantia nigra, but otherwise deep gray matter structures appear to be normal. Faint hypersignal is noted within the posterior limbs of internal capsules. The pars compacta of substantia nigra, the tegmental upper brainstem structures and more caudally, almost the entire cross-sectional area of brainstem (including pons, not shown here) exhibit abnormal hypersignal. Prominent cerebellar atrophy

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dehydrogenase complex and pyruvate carboxylase. Other enzyme defects in the tricarboxylic acid cycle are also known. Pyruvate Dehydrogenase Complex Deficiency

Pyruvate dehydrogenase is the most common cause of primary lactic acidosis. The enzyme has three subunits (E1, E2, and E3), all prone to mutations. Depending on the chromosomal location of the gene encoding the defective subunit, the inheritance may be autosomal (E1-β, E2, E3) or X-linked (E1-α subunit). Since the gene of the E1-α subunit on the X chromosome is by far the most frequent site of mutation, most cases of pyruvate dehydrogenase complex deficiency show an X-linked inheritance pattern. In case of deficiency of the pyruvate dehydrogenase enzyme, pyruvate is converted into lactate, which produces significantly less energy than complete oxidation. The disease is characterized by organ-specific and systemic abnormalities related to energy failure and lactic acidosis. The expression of the enzyme in different tissues is variable. In brain, the baseline activity of the enzyme is much higher than in liver or heart; therefore, the brain is particularly vulnerable and prone to damage, even in relatively minor enzyme deficiencies. The clinical presentations may be severe neonatal lactic acidosis (E1-α subunit deficiency, X-linked inheritance), milder forms of infantile or childhood lactic acidosis (E1-β, E2, or E3 subunit deficiency, autosomal recessive inheritance), as well as Leigh syndrome (autosomal recessive inheritance) or subacute-chronic progressive encephalopathy. Some degree of involvement of the CNS is always present in all forms. Affected infants with the neonatal form present with low birth weight, low Apgar scores, microcephaly and other dysmorphic features, poor feeding, hypotonia, and apnea, occasionally leading to sudden infant death. It is interesting that lactic acidosis appears to be more frequent in males in the neonatal form, whereas neurological manifestations are more common in females [404]. In the milder forms, episodic lactic acidosis, delayed development, hypotonia, seizures, and ataxia are typical clinical manifestations. In some cases the disease may resemble subacute necrotizing encephalopathy (Leigh disease), but only a small fraction of true Leigh disease cases are caused by pyruvate dehydrogenase complex deficiency. Neuropathological examination of the brain of an affected infant may show evidence of periventricular gray matter heterotopia, polymicrogyria, or agenesis of the corpus callosum [404, 405].

Imaging Findings

Dysgenesis of the corpus callosum has been documented by imaging studies [405, 406]. MRI evidence of cortical dysplasia or gray matter heterotopia has not been reported to date. Ventriculomegaly (colpocephaly) and diffuse brain atrophy are common. Atrophy of cerebellum can be particularly prominent. Deep gray matter structures (basal ganglia, thalami, upper brainstem) often show abnormalities, somewhat similar to the pattern seen in Leigh disease, although MRI findings may be also quite unremarkable in this respect. Documented white matter abnormalities include delayed myelination or more profound and extensive leukodystrophy-like changes, with relative sparing of subcortical U-fibers [407] (Fig. 13.69). In a 3.5-month-old infant, MRI showed obvious bilateral lentiform nucleus and subtle thalamic lesions with slight delay of myelination [408]. In an 8-month-old infant, only bilateral globus pallidus lesions and delayed myelination were described [21]. In another 11-month-old patient, delayed myelination and brain atrophy were found without evidence of deep gray matter abnormalities [409]. These observations well illustrate the spectrum of possible imaging phenotypic manifestations of the disease. 1 H MRS was found to be helpful in demonstrating abnormal lactate and monitoring therapeutic efficacy by showing progressive decrease and eventual normalization of lactate [406, 407, 409] (Fig. 13.70). Pyruvate Carboxylase Deficiency

The inheritance of pyruvate carboxylase deficiency is autosomal recessive. The gene is located on chromosome 11q. The disease has three clinical phenotypes: neonatal, infantile, and a so-called benign form. The neonatal form of the disease is always very severe and leads to death during the first couple of months of life [410]. It presents with hepatic dysfunction, lactic acidosis, hypoglycemia, seizures, spasticity, and in contrast to pyruvate dehydrogenase, usually macrocephaly. The infantile form is also severely disabling and has a poor prognosis with a fatal outcome. The clinical presentation of patients with the benign form of the disease is quite variable; typically, recurrent episodes of lactic acidosis are encountered with a wide range of associated systemic or CNS derangements. Patients with the mild form may live into adulthood without major disability [411]. Imaging Findings

Ventricular enlargement and cystic periventricular leukomalacia are common postnatal US findings in

Metabolic Disorders Fig. 13.69a–d. Conventional MR imaging findings in a 3-year-old male patient with pyruvate dehydrogenase deficiency. a Sagittal T1-weighted spin-echo image shows atrophy of cerebellar vermis and an incidental mega cisterna magna. b–d Axial T2-weighted fast spin-echo images. Prominent enlargement of the ventricular system. Subtle, patchy hyperintensities within the right putamen. Abnormal hyperintense appearance of the cerebral white matter, indicating demyelination and/or transependymal CSF permeation. Note partial sparing of subcortical U-fibers in the frontal regions

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b Fig. 13.70a, b. Proton MR spectroscopy of the brain in pyruvate dehydrogenase deficiency (same patient as in Fig. 13.69). a Single voxel proton MR spectrum (PRESS technique, TE: 135 ms, sample voxel 2x2x2 cm, positioned on basal ganglia on the right side). Prominent negative peak doublet at the 1.3 ppm level. b Single voxel proton MR spectrum (PRESS technique, TE: 270 ms, sample voxel 2x2x2 cm, positioned on basal ganglia on the right side). Prominent positive peak doublet at the 1.3 ppm level (J-coupling phenomenon), corresponding to lactate

the neonatal form of pyruvate carboxylase deficiency. In one report, this was demonstrated already in utero at 29 weeks of gestation [412]. CT examination of the brain in a 7-week-old infant with pyruvate carboxylase deficiency showed severe diffuse hypodensity of cerebral white matter (a pre-

vious CT examination, immediately after birth, was found to be normal) [410]. Published MRI data of confirmed cases are not available. In my personal experience with presumed pyruvate carboxylase deficiency, in the severe neonatal form MRI findings are rather unremarkable;

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sometimes, they show morphological signs of immaturity of the brain. MRS, however, is useful, since it shows abnormal amounts of lactate within the brain parenchyma (Fig. 13.71). 13.4.5.2 Defects of the Respiratory Chain

The so-called respiratory chain is a complex multiunit system within the inner membrane of mitochondria. It is responsible for electron transport during the end stage of oxidative phosphorylation. The respiratory chain consists of five different complexes (complex I-V), each with a specific role in the process of oxidative phosphorylation. Cytochrome c oxidase (COX), or complex IV, is the best known of the five enzyme complexes (Fig. 13.72). The respiratory chain enzymes are genetically encoded by both nuclear and mitochondrial DNA (except complex II, which is entirely encoded by mitochondrial DNA); this gives rise to an often complex inheritance pattern (Mendelian and maternal). Mitochondrial DNA mutations are particularly frea

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quent and include point mutations, deletions, insertions, and rearrangements [413]. Besides peculiarities of the inheritance of the defects of the respiratory chain, clinical manifestations of the disease in a given individual are further modulated by two peculiar additional phenomena, notably heteroplasmy and segregation. Heteroplasmy refers to the frequent presence of normal and mutant mitochondrial DNA within the same cell. During cellular proliferation, the normal and abnormal mitochondria segregate randomly; therefore, the concentration of mutant mitochondrial DNA changes from cell to cell and, since the same concept is also applicable to the early undifferentiated cells during embryogenesis, from organ to organ in the same individual as well. A critical percentage of abnormal mitochondria is required for abnormal energy metabolism within a given cell, and a critical number of abnormal cells is necessary for organ failure and the corresponding clinical disease manifestations. This explains the remarkable clinical heterogeneity of the disease entities in this group of pathologies.

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Fig. 13.71a–d. Conventional MR imaging and MR spectroscopic findings in a 7day-old male patient with primary lactic acidosis (presumed pyruvate carboxylase deficiency). a, b Axial T2-weighted fast spin-echo images. The cortical gyral pattern is somewhat rudimentary, and the extra and intracerebral CSF spaces are enlarged, but otherwise no definite structural abnormality is seen. c, d Single voxel proton MR spectra of the brain (PRESS technique, TE: 135 ms and 270 ms, sampling voxel: 2x2x2 cm, positioned on the basal ganglia on the right side), showing prominent peak doublets at the 1.3 ppm level, exhibiting the J-coupling phenomenon, consistent with abnormal lactate

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Fig. 13.72. The mitochondrial respiratory chain. There are five enzyme complexes, of which cytochrome c oxidase (COX) is the fourth. Both nuclear and mitochondrial DNA encode subunits to the various complexes in the chain

In respiratory chain deficiencies, practically any organ or tissue in any combination may be involved, although the most frequently affected organs are the CNS and the muscles (both skeletal and visceral). This is why respiratory chain defects are also referred to as mitochondrial encephalomyopathies. The spectrum of clinical manifestations of the mitochondrial respiratory chain defects is particularly broad [414]. Clinical signs and symptoms and laboratory data may indicate involvement of liver (hepatomegaly, hepatic failure), heart (cardiomyopathy), kidney (proximal tubulopathy), pancreas (exocrine pancreas dysfunction), intestines (diarrhea), skeletal muscle (myopathic features), bone marrow (pancytopenia), skin (pigmentation abnormalities), and CNS (hypotonia, various mitochondrial disease entities, such as Leigh disease, MELAS, MERRF, LHON, and more rare and less well-defined syndromes, such as lethal pontocerebellar hypoplasia) [415]. Since multisystem involvement is almost the rule in diseases related to defects of the respiratory chain, this can be an important clinical diagnostic clue. Additionally, systemic metabolic abnormalities, in particular episodes of ketoacidotic decompensation, are also common. There is some overlap between different disease entities with regards to both clinical and imaging manifestations. Similar mutations may present with different clinical phenotypes. Patients with the A3243G mitochondrial DNA mutation, which is typical for MELAS, may present with Leigh disease or MERRF-like clinical and imaging manifestations [416]. Furthermore, in patients with typical LHON mutations (3460 and 14484), Leigh disease-like clinical and imaging manifestations were described [417]. Sometimes, clinical features of two entities (MELAS and MERRF) may be present in the same patient [418]. Visual problems and optic atrophy are common in

MELAS and MERRF, although some of the associated abnormalities typical for LHON may be absent [419]. Conversely, myoclonus, which is the hallmark neurological abnormality in MERRF, may be found in patients with LHON or even in the other respiratory chain defect entities [420]. Histopathological findings in various mitochondrial encephalomyopathies may also show striking similarities (e.g., Leigh disease-like brainstem changes in MERRF) [421]. On histological examination of skeletal muscle biopsy specimens, ragged-red fibers may be found not only in MERRF, but also in most other mitochondrial encephalomyopathies (e.g., Leigh disease, Kearns-Sayre disease, MELAS) [419, 422, 423]. Leigh Disease

This disease is often referred to as subacute necrotizing encephalomyopathy. The inheritance can be autosomal (in some of the respiratory chain complex I and COX deficiencies), X-linked (pyruvate dehydrogenase E1-α deficiency), and maternal (mitochondrial point mutations) [424, 425]. In the majority of cases, Leigh disease is caused by enzyme (respiratory chain complex I, III, and IV, or pyruvate dehydrogenase) deficiencies, followed by mitochondrial DNA mutations [424, 426, 427]. The most frequent mitochondrial point mutations associated with Leigh syndrome are T8993G, T8933C, and A8344G. Recently, mitochondrial DNA depletion syndrome was found to be associated with Leigh syndrome clinically as well [428]. However, several other hereditary metabolic diseases, such as biotinidase and sulfite oxidase deficiency or Wernicke encephalopathy, have been reported to mimic, either clinically or histopathologically, Leigh disease [295, 429].

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Male patients are more frequently affected, and this preponderance is not explained by the existence of an X-linked variant among known genotypes. The disease typically appears during early infancy; the average is 6 months, but significant deviations exist, with much earlier (1 month) and later (10 years) onset. The disease presents with failure to thrive and progressive neurological deterioration, including developmental delay or loss of milestones, hypotonia, weakness, ataxia, dystonia, and seizures [426]. Respiratory problems and ocular abnormalities related to brainstem dysfunction (external ophthalmoplegia, nystagmus, and strabismus) are also frequently encountered [424, 427]. Laboratory tests reveal lactic acidosis and increased pyruvate concentrations both in blood and CSF. On histopathological examination, lesions (spongy degeneration) are found at the level of the deep gray matter structures, mammillary bodies, periaqueductal gray matter, oculomotor nuclei, substantia nigra, tegmentum and tectum of the mesencephalon, tegmentum of the pons, dorsomedial part of the medulla oblongata, subcortical white matter of the cerebral hemispheres, and deep cerebellar white matter. Imaging Findings

MRI findings in Leigh disease include abnormalities of deep cerebral gray matter structures, brainstem, deep cerebellar gray matter structures, and cerebral hemispheric white matter [423, 427, 430–433]. Basal ganglia changes are typical in Leigh disease; their magnitude and extent, however, is quite variable [144, 430, 434, 435]. The thalami are sometimes involved as well. At the level of the upper mesencephalon the pattern of signal changes sometimes resembles the “giant panda face” (hyperintensity within substantia nigra and central tegmental structures) [430]. Prominent signal changes are often present in the periaqueductal region and within the medulla oblongata; the latter may explain the frequent respiratory problems (episodes of apnea, sighing) of these patients [427, 428, 430, 436, 437]. The subthalamic nuclei are almost always involved; the detection of these lesions is, however, difficult [423, 432]. Involvement of the subthalamic nuclei in Leigh disease has been related to COX deficiency and, specifically, to mutations of SURF1, a nuclear gene encoding one of the ten n-DNA encoded COX subunits [433] (Fig. 13.73). The dentate nuclei frequently (but not always) show abnormalities [435]. Occasionally, medulla oblongata lesions extend caudally to the upper cervical spinal cord (Fig. 13.74).

Delayed and hypomyelination in Leigh disease are common findings on MRI. Additionally, white matter lesions within the cerebral hemispheres may also be present, which are usually patchy and predominantly subcortical, less frequently periventricular. White matter lesions are sometimes quite extensive and may also involve the cerebellar white matter [423, 437]. Sometimes these are remarkably symmetrical, mimicking leukodystrophy. Occasionally, lesions exhibit a stroke-like appearance, similar to what may be seen in MELAS [427, 436]. Rarely, cerebral hemispheric white matter lesions are the sole imaging manifestations of Leigh disease, reported in a case related to COX deficiency [438]. The central tegmental tracts are often abnormal on T2-weighted images and illdefined, faint hyperintensities may be present within the center of the pons (Fig. 13.75). Depending on the structure involvement and the progression pattern of the lesions, three subgroups have been identified in patients with Leigh disease [427]. In some patients, basal ganglia changes seem to precede brainstem abnormalities by several months or years. In another group, brainstem lesions appeared without basal ganglia or white matter involvement. In a third group, white matter lesions were found initially and were followed by brainstem lesions, but basal ganglia abnormalities never developed during the follow-up period. Fatal outcome of the disease due to respiratory failure was always associated with involvement of the medulla oblongata. As an uncommon imaging feature of Leigh disease, signal enhancement after intravenous gadolinium injection has also been described within some of the affected brain areas, including the periventricular white matter, periaqueductal and hypothalamic structures, and mammillary bodies [438, 439]. Overall, conventional MRI findings, especially when thalamic, tectal, and lower brainstem lesions are present, characterize a highly suggestive imaging pattern. The most important differential diagnoses are organic acidopathies or Wilson disease but, again, presence of the peculiar, structure-selective brainstem lesions in Leigh disease usually allows confident differentiation. Diffusion-weighted images may show hypersignal during acute metabolic attacks within the lesions in brainstem, basal ganglia, and dentate nuclei (Fig. 13.76). 1 H MRS is helpful by showing the presence of lactate in brain [69, 73], but obviously this is a nonspecific finding. The quantity of lactate appears to be remarkably high on the spectra if the sampling voxel is placed on the damaged basal ganglia, but abnormal lactate may also be demonstrated within appar-

Metabolic Disorders Fig. 13.73a–e. MRI in a 3-yearold boy with Leigh disease due to cytochrome c oxidase deficiency with SURF1 mutation (courtesy of Dr. A. Rossi, Genoa, Italy). a Coronal fast spin-echo T2-weighted image (4500/120) shows symmetric T2 prolongation involving the subthalamic nuclei (arrows). The substantia nigra (arrowheads), posteroinferior portion of the putamina (P), and medulla (M) are also involved. b–e Axial fast spinecho T2-weighted images show T2 prolongation involves the dentate nuclei (open arrows), central tegmental tract (arrowheads), and substantia nigra (arrows)

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ently normal brain areas [63, 73]. In visible lesions, the NAA peak is decreased and some decrease of the Cho peak is also suggested. In Leigh disease, regional variations of the NAA, Cho, and lactate levels have also been demonstrated, the most severe abnormalities being again shown at the level of the basal ganglia, suggesting that severity of respiratory deficiency may be a function of intensity of the baseline metabolic activity [73]. On successful therapy, the cerebral lactate peak may disappear, but in cases of metabolic deterioration it may reappear [440]. Kearns-Sayre Disease

Kearns-Sayre disease is a complex syndrome characterized by progressive external ophthalmoplegia and pigmentary retinal degeneration, associated with complete heart block, cerebellar ataxia, or elevated CSF protein level. The disease is usually of juvenile onset (but, by definition, the disease should start under

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20 years of age). The mitochondrial mutation usually affects complex I, III, or IV of the respiratory chain. Imaging Findings

In Kearns-Sayre disease, CT may show calcifications within the globi pallidi and caudate nuclei [441]. In one report, extensive subcortical calcifications were described in a patient with Kearns-Sayre disease associated with Down syndrome and multiple endocrinological abnormalities, including hypoparathyroidism [423]. On MRI, involvement of the deep gray matter structures is often but not always seen, with symmetrical abnormal hypersignal within the basal ganglia (predominantly within the globi pallidi, rarely within the caudate nuclei) and/or thalami on T2-weighted images [389, 423, 442, 443]. Interestingly, the putamina are always spared in Kearns-Sayre disease, which may be a differential diagnostic clue from an imaging

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Fig. 13.74a–h. Different conventional MR imaging patterns in Leigh disease on axial modular inversion recovery images. a–d 3year-old female patient. Abnormal signal intensities are seen within inferior olives, dentate nuclei, fasciculus longitudinalis medialis, central tegmental tracts, putamina and globus pallidus on the left side. e–h 2-year-old male patient. The pattern is very much similar to that of the previous patient, except that here the basal ganglia are normal. At the level of mesencephalon, the medial lemnisci and the substantia nigra are also involved

Fig. 13.75a–l. Different patterns of white matter involvement in Leigh disease on axial T2-weighted fast spin-echo images. a–d Delayed and hypomyelination in a 5-month-old female patient presenting with respiratory failure and hypotonia. Diffuse brain atrophy. Basal ganglia, substantia nigra and central tegmental tract lesions within the mesencephalon (the patient also had medulla oblongata lesions, not shown here). e–h Patchy white matters lesions within the cerebral hemispheres without involvement of cerebellar white matter. Note the basal ganglia lesions and signal abnormalities at the level of the vestibular nuclei in the brainstem. The splenium of the corpus callosum is also hyperintense. i–l Leukodystrophy-like appearance of the lesions involving both cerebral and cerebellar white matter. The inferior olives and basal ganglia are also abnormal

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standpoint with respect to Leigh disease, in which it is frequent [431]. Occasionally, the deep gray matter structures may exhibit hypersignal on T1-weighted images [431]. Within the upper brainstem, the substantia nigra and tegmental structures are typically abnormal, but lesions may also be present within the medulla oblongata [389, 431]. Ill-defined, rather diffuse white matter lesions within the cerebral hemispheres, predominantly subcortical in location, are also frequent [442]. In the cerebellum, white matter lesions also occur, typically centrally, but may also extend to the middle cerebellar peduncles [431, 443] (Fig. 13.77). Diffuse cerebral and cerebellar atrophy complete the list of imaging abnormalities. Diffusion-weighted images during the acute phase of the disease may show hypersignal within the lesion areas, consistent with isotropically restricted water diffusion (Fig. 13.77). 1 H MRS may or may not show abnormal lactate within brain parenchyma.

Fig. 13.76a–d. Diffusion-weighted imaging abnormalities in Leigh disease (axial diffusion-weighted echo-planar images, b = 1000s). a Increased signal within dentate nuclei and inferior olives (same patient as in Fig. 13.74e). b Signal abnormalities within central tegmental tracts of mesencephalon and putamina (same patient as in Fig. 13.74c). c Diffusion abnormalities within substantia nigra and basal ganglia (same patient as in Fig. 13.75b). d Restricted water diffusion within the white matter (same patient as in Fig. 13.76l)

Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS)

The acronym MELAS refers to mitochondrial myopathy and encephalopathy lactic acidosis with strokelike episodes [444]. This is probably the best known of the so-called mitochondrial diseases or mitochondrial encephalomyopathies. The disease is of maternal inheritance and the mutation occurs on mitochondrial DNA. In about 80% of cases, the site of the mutation is A3243G (socalled MELAS mutation of mitochondrial DNA), but several other rare mutations are also known [416, 419, 422]. As a result, complex I and IV respiratory chain enzymes usually become deficient [419, 422]. The clinical phenotypes (tissue involvement, age of onset, severity of the disease) show great variations. The age of onset is typically between 4–15 years, but early infantile and adult forms have also been reported [86, 416, 422, 445]. The disease sometimes becomes overt

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Fig. 13.77a–h. Conventional and diffusion-weighted MR imaging findings in patients with Kearns-Sayre disease. a–d Axial T2weighted fast spin-echo images in a 15-year-old female patient. Diffuse ill-defined white matter hyperintensities are seen within the cerebral hemispheres, and less prominently within the deep cerebellar white matter and middle cerebellar peduncles. At the level of mesencephalon, a giant panda face-like pattern is suggested. The globi pallidi are hypointense, otherwise no basal ganglia or thalamic abnormality is noted. Diffuse brain atrophy. e–h Axial diffusion-weighted echo-planar images (b = 1000s) in a 21-yearold female patient. An essentially similar lesion pattern is seen in this patient. The abnormal areas exhibit hypersignal, consistent with isotropically restricted water diffusion, probably related to myelin edema

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during a febrile illness (causing a mismatch between energy requirements and availability); nevertheless, developmental delay and learning disability may be noted before the initial clinical manifestation in some patients. The disease typically presents with sudden onset of headache, vomiting, convulsions, and myopathic signs, but focal neurological signs soon become obvious. On examination, optic atrophy and retinitis pigmentosa are frequently found, and diplopia and cortical blindness, as well as ataxia, generalized weakness (with proximal predominance), and sensorineural hearing loss may be found. Although CSF lactate is sometimes elevated, no systemic lactic acidosis is found. Systemic manifestations of the disease include cardiomyopathy and diabetes (both type 1 and 2). Imaging Findings

CT or MRI studies in MELAS typically show one or more stroke-like lesions within brain, typically involving the cerebral hemispheres. The most frequently affected areas are the parietal and occipital lobes, followed by the temporal and frontal regions [35]. The lesions involve both cortical and subcortical structures, and appear quite similar to infarctions. In the acute phase of the disease, they are associated with swelling, and postcontrast images may show enhancement [35, 446]. Careful analysis of the morphology and extent of lesions usually reveals a nonterritorial pattern, representing the most important differential diagnostic clue in this respect. If the lesions involve temporal lobes, imaging findings may mimic herpes encephalitis [445],

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while if located in temporo-occipital regions, venous infarctions related to thrombosis of transverse sinus may be considered, although MELAS lesions do not show a hemorrhagic character (Fig. 13.78). MR angiography fails to demonstrate evidence of occlusive arterial disease. In the chronic phase of the disease, decreased blood supply (due to decreased demand) may result in reduced vascular network in lesion areas, mimicking postocclusion vascular changes (Fig. 13.79). MR venography may be helpful in ruling out transverse sinus thrombosis in suspicious cases. CT examination in MELAS frequently reveals basal ganglia calcifications, which appear to be progressive on follow-up studies [35]. Hyperintense lesions within the basal ganglia (putamina, globi pallidi), thalami, and periaqueductal regions, somewhat similar to findings in Leigh disease or Kearns-Sayre syndrome, may be noted on T2-weighted MR images [35, 389, 419]. Cerebral and cerebellar atrophy are also common. The first sign of cerebellar atrophy may be represented by isolated enlargement of the fourth ventricle [35]. On diffusion-weighted images, stroke-like lesions usually exhibit a heterogeneous character, with hypo-, iso-, or hyperintense lesion components. The hyperintensities, if present, most probably correspond to T2 shine-through, rather than cytotoxic edema. Indeed, quantitative diffusion studies demonstrated normal or increased apparent diffusion coefficient within cortical-subcortical stroke-like lesions, indicative of vasogenic edema [447–449] (Fig. 13.79). In one study, a steep increase of the ADC was found during the first 2 days after the onset of the lesions,

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Fig. 13.78a–c. MR imaging findings in MELAS. Axial T2-weighted fast spin-echo images. a Initial MR imaging work-up in an 8-yearold male patient after the first stroke-like episode presenting with right hemiparesis. The left fronto-temporal lesion involves both cortical and subcortical structures and extends to the anterior and middle cerebral artery territories. b Follow-up examination at the age of 12 years, showing interval atrophic changes in the lesion. c The second follow-up study was performed a few months later, when the patient presented with initially right-sided hemianopsia shortly followed by total cortical blindness. New lesions are seen in both occipital lobes, but on the right side the lesion extends to the middle cerebral artery territory as well, in the posterior temporal lobe

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Fig. 13.79a–c. MR angiography and diffusion-weighted imaging in a 12-year-old male patient with MELAS, shortly after the onset of complete cortical blindness (same patient as in Fig. 13.78). a The MR angiographic image (3D time-of-flight technique) demonstrates a reduced vascular network in the left middle cerebral artery territory, interpreted as secondary to decreased demand. b Axial diffusionweighted echo-planar image (b = 1000s) showing hyposignal within the old left hemispheric fronto-temporal lesion area and signal inhomogeneities with faint hypo- and hypersignal within the fresh occipital lesion areas. c On the axial apparent diffusion coefficient map image, the new lesions are hyperintense, indicating increased water diffusion and suggesting vasogenic, rather than cytotoxic, edema

followed by a progressive decrease during the next 24 days [449]. Others advocated the importance of mitochondrial angiopathy-related changes in the lesion areas, notably rupture of the blood-brain barrier and hyperperfusion, as the possible cause of vasogenic edema [446]. These observations support the hypothesis that the lesions are actually not of ischemic origin, but rather secondary to metabolic crash (energetic failure). DWI data also suggest that some of the stroke-like brain lesions may be completely reversible [448]. 1 H MRS may be a useful complementary test, since a small lactate peak may be detected even in apparently normal brain areas, especially if they are associated with neurological abnormality [450]. This underlines the potential supportive role of MRS in the diagnosis of MELAS even in MR negative but clinically symptomatic cases. In an appropriate clinical setting, MRI, CT, and MRS findings provide a highly suggestive pattern and warrant further studies, in particular muscle biopsy, to confirm the diagnosis. Myoclonus Epilepsy and Ragged-Red Fibers (MERRF)

Historically, the presence of ragged-red fibers on histological specimens from skeletal muscles was an obligatory diagnostic criterion of the disease, but growing experience suggests that these may not be always present in all muscles in all patients with progressive myoclonus epilepsy due to mitochondrial

disease. On the other hand, myoclonus epilepsy is not exclusive to the syndrome, since many other metabolic or nonmetabolic diseases, characterized by progressive myoclonic epilepsy are also known, notably neuronal ceroid lipofuscinosis, nonketotic hyperglycinemia, Lafora body disease, sialidoses, UnverrichtLundborg disease, Ramsay-Hunt syndrome, and subacute sclerosing panencephalitis. The disease has either an autosomal recessive or maternal mitochondrial inheritance, or it is sporadic. The most frequently affected components of the respiratory chain are complex III and IV. The onset of the disease shows wide variations from 3 to 62 years, sometimes even within the same family. Myoclonus is usually the initial neurological manifestation, associated later with ataxia, dysarthria, optic atrophy, deafness, tonic-clonic seizures, proximal limb weakness, and dementia [421]. The disease course is also quite variable; in some cases, progression is rapid and affected patients die during childhood; in others, it is mild and very slowly progressive with a benign outcome. Histopathological workup of the brain mainly shows brainstem abnormalities, suggestive of some sort of system degeneration. The brainstem is usually diffusely atrophic and may show additional focal lesions, exhibiting a Leigh disease-like pattern. Although the cerebral cortex and white matter appear to be normal, metabolic studies of the brain suggest that the hallmark clinical features of the disease (myoclonus, seizures, dementia) are related to func-

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tional abnormalities due to the chronic depressed state of oxidative metabolism within the cortical gray matter [421]. Imaging Findings

Reports of imaging findings in MERRF are sparse [389, 451]. CT shows calcification in the globi pallidi. On MR images, calcified areas are hypointense on T2-weighted images. Otherwise, nonspecific cerebral hemispheric (subinsular and periventricular) white matter changes may be noted. Leber Hereditary Optic Neuropathy (LHON)

Leber hereditary optic neuroretinopathy (LHON) (see Chap. 31) is a maternally inherited disease; the most common mutation is at 11778 (affecting complex I of the respiratory chain); less frequently, the mutations are at 3460 or 14484 [452, 453]. In cases with G11778A mutation, the disease shows a clear male predominance (82%) and age of onset varies between 8 to 60 years, although in about 60% of the patients it is between 10 to 30 years [453, 454]. Onset of the disease below 10 and above 50 years of age is quite exceptional. Clinically, the disease presents with rapidly progressive bilateral visual loss, due to degeneration of optic nerves. The involvement of optic nerves is either simultaneous or there is a few months interval between the two sides. On ophthalmological examination, in addition to optic atrophy, telangiectatic microangiopathy, vascular tortuosity, and disk pseudoedema are frequent findings; the latter are believed to be distinct, albeit inconsistent, features of the disease, allowing differentiation from other mitochondrial encephalomyopathies (MELAS, MERRF), which may also present with visual disturbances and optic atrophy. Associated neurological abnormalities (LHONplus syndrome) may occur in up to 60% of patients, including tremor, polyneuropathy, and seizures. Thoracic kyphosis may be present in about 15% of cases [453]. No muscle or other systemic organ involvement has been described in the disease. The typical age of onset, the clinical features and, in a subset of patients, even imaging manifestations of the disease show strong similarities with multiple sclerosis (so-called LHON-MS), which is therefore the most important differential diagnostic consideration from the clinical standpoint [455]. Indeed, in patients who presented clinically with bilateral simultaneous optic neuropathy (and visual loss), about 17% were found to have LHON and 22% multiple sclerosis after complete workup [456].

Imaging Findings

Several reports of patients with LHON suggested that CT and MRI studies of the brain are typically normal [454,456]. However, if MRI study was performed with dedicated and high resolution imaging sequences, signal abnormalities within distal intraorbital optic nerves could be demonstrated in the chronic stage of the disease [457]. Since in the acute stage of the disease no abnormalities were noted, these findings (in conjunction with ophthalmological observations) may indicate that the primary site of mitochondrial dysfunction is intraocular, rather than retrobulbar. Furthermore, the optic nerve volumes in patients with LHON were found to be significantly lower than in healthy controls, suggesting that atrophy of optic nerves is a fairly constant abnormality (see Fig. 31.29, Chap. 31) [458]. There is, however, a growing number of reports which suggest that, occasionally, other lesions may also be detected in the brain in LHON. In at least two patients with the 11778 mutation, bilateral putaminal lesions were described [452, 453]. In one of these cases, it was associated with periventricular white matter lesions. In three other patients initially presenting with LHON (and found to have typical LHON mutations), Leigh disease-like syndrome developed later during the course of the disease, with corresponding imaging findings within the basal ganglia and brainstem structures [417]. In another case with the same mutation in a 44-year-old male patient, MRI study revealed bilateral, predominantly periventricular, white matter lesions in conjunction with abnormal signal within the intraorbital optic nerves [459]. Scattered white matter lesions are quite frequent MRI findings in clinically LHONMS patients with the 11778 mutation [455]. Even more disturbing was the finding of oligoclonal IgG bands within the CSF on two occasions; therefore, the disease was indistinguishable from multiple sclerosis [459]. A somewhat similar case was also described in another report [460]. 1 H MRS, as in many other “mitochondrial” diseases, may or may not show abnormal lactate within the brain parenchyma. 13.4.5.3 Fatty Acid Oxidation Disorders

Fatty acid oxidation disorders are probably more common metabolic disorders than previously believed [461]. Because of diverse clinical manifestations and diagnostic difficulties, disease entities belonging to this group are often underdiagnosed [462]. Metabolic fuels for the organism include glucose, lactate, fatty acids, and ketone bodies. The fatty acid

Metabolic Disorders

oxidation pathway is an important energy-producing mechanism and is involved in producing energy through β-oxidation of fatty acids and synthesis of ketone bodies. The fatty acid oxidation pathway is a particularly important alternate source of energy production during fasting, when availability of glucose is limited. In brain, glucose and ketone bodies are the most important energy providers, followed by lactate. This is in contrast to muscle (especially the myocardium), where fatty acids and ketone bodies are dominant sources of energy and glucose and lactate have only a complementary role. The oxidation of fatty acids is a complex process. Long-chain fatty acids are initially converted into fatty acyl-coenzyme A in the cytosol. This is followed by their transportation into the mitochondria, which requires carnitine. Medium- and short-chain fatty acids can enter the mitochondria freely, after which they are also converted into their fatty acyl-coenzyme A esters. The fatty acyl-coenzyme A molecules are then progressively broken down through the so-called β-oxidation cycle, whose end product is acetyl coenzyme A. During this stage, some energy is already provided for the respiratory chain (where ATP is synthesized) through the electron-transfer mechanism. Acetyl coenzyme A may then be used in two different ways. In liver, it is used for the synthesis of ketone bodies (acetoacetate and 3-hydroxybutyrate), which are then released and transported to the principal consumer organs (mainly to brain) where they provide alternative fat-derived fuel, especially during episodes of hypoglycemia (fasting etc.). In muscle (heart, skeletal muscle), acetyl coenzyme A enters the tricarboxylic acid (Krebs) cycle and contributes to ATP synthesis. Each of the aforementioned fatty acid oxidation steps may be deficient. Therefore, fatty acid oxidation disorders comprise carnitine cycle defects (carnitine transporter defect, carnitine-palmitoyl transferase deficiencies, and carnitine translocase deficiency), β-oxidation disorders (very long-, medium-, and short-chain acyl-coenzyme A dehydrogenase, as well as long- and short-chain 3-hydroxy-acyl-coenzyme A dehydrogenase deficiencies), electron transfer flavoprotein/electron transfer flavoprotein dehydrogenase deficiencies (multiple acyl-coenzyme A dehydrogenase deficiency, usually referred to as glutaric aciduria type 2), and ketone body synthesis (3-hydroxy3-methylglutaryl coenzyme A synthetase and lyase) defects. The mutant genes are located on chromosome 2q34-q35 in long-chain acyl-coenzyme A dehydrogenase, on chromosome 1p31 in medium-chain acylcoenzyme A dehydrogenase, and on 12q22-qter in short-chain acyl-coenzyme A dehydrogenase defi-

ciency. In glutaric aciduria type 2, the defective genes were mapped on chromosomes 15q23-q25, 19, and 4q32-qter. Because of the resultant impairment of aerobic energy metabolism at the mitochondrial level, fatty acid oxidation disorders are characterized by multiorgan (heart, skeletal muscle, liver) involvement [462]. The episodic metabolic decompensations (mild metabolic and lactic acidosis) may lead to secondary CNS manifestations, related to lack of metabolic fuels (hypoglycemia and hypoketosis). Brain involvement may present with signs of acute (Reye syndrome) or chronic encephalopathy (failure to thrive, developmental delay). Acute encephalopathy may be related to direct toxic effect of long- and medium-chain acyl-coenzyme A and acylcarnitines, but also to secondary metabolic derangements, such as prolonged hypoglycemia, lactic acidosis (due to inhibition of the tricarboxylic cycle), and hyperammonemia (due to the inhibition of the urea cycle). Peripheral neuropathy may also occur in fatty acid oxidation defects. Dysfunction of the mitochondria within the myocardium results in conduction problems initially, and global cardiac failure due to cardiomyopathy thereafter. One of the most severe systemic complications is exercise- or fasting-induced rhabdomyolysis, presenting clinically with myoglobinuria, skeletal myopathy, and acute heart failure. Fatty acid oxidation disorders are also increasingly recognized as possible causes of sudden infantile death, most probably due to cardiomyopathy [463]. Skeletal myopathy presents with weakness, hypotonia and muscle pain. Accumulation of noncatabolized fatty acids as triglycerides with resultant hepatic overload leads to chronic liver disease with steatosis and hepatomegaly. Factors which influence the clinical manifestations are biochemical and environmental. For example, long- and medium-chain fatty acid oxidation disorders usually, but not always, present with a more severe clinical phenotype than short-chain fatty acid oxidation disorders, but neurological manifestations tend to be more common in short-chain fatty acid oxidation defects. Very long-chain acyl coenzyme A dehydrogenase, long-chain 3-hydroxy-acyl coenzyme A dehydrogenase, and multiple coenzyme A dehydrogenase deficiencies are typically encountered in neonates or infants; the other disorders have neonatal, infantile, juvenile, and even adult onset forms. Environmental factors include fasting, physical exercise, and intercurrent illnesses, which are known potential triggering factors of metabolic decompensation. The aims of the treatment in fatty acid oxidation disorders are correction of carnitine deficiency (in defects of the carnitine cycle) and reduction of lipolysis to prevent fatty acid overload in liver. Appropri-

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ate dietary measures are essential, in order to prevent hypoglycemia and reduce fat intake. Carnitine Cycle Defects

Carnitine deficiencies generally present with cardiomyopathy, lipid storage myopathy, and metabolic encephalopathy. Carnitine transporter defect usually presents in infancy with mainly hepatic and cardiac problems [464]. Carnitine palmitoyl transferase 1 deficiency present with liver and kidney failure in infancy. It was also found to be associated with early postnatal death due to cardiac problems [465]. Carnitine palmitoyl transferase 2 deficiency has a severe neonatal and a mild adult onset form, both presenting with myopathic signs, including cardiomyopathy and hepatic disturbances; occasionally neurological manifestations (hepatic encephalopathy, infantile spasms, athetotic quadriplegia) may also be present [466]. Carnitine translocase deficiency is usually of neonatal onset and is characterized by severe muscle, heart, and liver disease. L-carnitine deficiency (without specifying the subtype) was found to be a potential metabolic cause of ischemic and hemorrhagic stroke in children [113].

Medium-chain acylcoenzyme A dehydrogenase is the most frequent form of fatty acid oxidation disorders. It presents with hepatic failure, usually during infancy. The resultant hypoglycemia and hypoketosis have a deleterious effect on the brain. Seizures, lethargy, and coma are typical signs of brain involvement; during episodes of metabolic decompensation, irreversible secondary brain damage may develop. Short-chain acylcoenzyme A dehydrogenase deficiency is usually associated with signs of chronic myopathy and encephalopathy (typically in the form of tone abnormalities and seizures) [192]. Long-chain 3-hydroxy-acyl-coenzyme A dehydrogenase deficiency usually presents in late infancy. Patients may have developmental delay, failure to thrive, acute encephalopathy, recurrent metabolic crises, hepatopathy, retinopathy, and peripheral neuropathy [468]. Medium-chain 3-hydroxy-acyl-coenzyme A dehydrogenase deficiency appears to have a neonatal onset and is incompatible with life. Short-chain 3-hydroxy-acyl-coenzyme A dehydrogenase deficiency seems to have a more benign course, but neurological complications (external ophthalmoplegia) may occur [469]. Imaging Findings

Imaging Findings

No imaging data of possible CNS involvement in L-carnitine deficiency are available. ␤-Oxidation Defects

Clinically, the most suggestive signs and symptoms of a defect in β-oxidation are cardiomyopathy, recurrent myoglobinuria, hyperuricemia, increased serum creatine kinase levels, peripheral neuropathy, hypoketotic hypoglycemia during fasting or stress, unexplained metabolic acidosis with or without hyperammonemia, Reye syndrome, unexplained coma, and sudden death during infancy or childhood, especially if these appear in combination with each other [467]. In different subtypes of β-oxidation defects the occurrence, age of onset, and severity of the different abnormalities may show variations. Very long-chain acylcoenzyme A dehydrogenase deficiency is often a neonatal disease presenting with episodes of lethargy, vomiting, and potentially lethal coma. Affected neonates present with hyperammonemia, hypoglycemia, hypoketosis, and lactic acidosis. The condition is usually untreatable and leads to death, except the Scandinavian phenotypes, which are compatible with life.

No systematic description of brain MRI findings in β-oxidation disorders is found in the literature. In my own experience, a case of long-chain acyl-coenzyme A dehydrogenase deficiency had bihemispheric, predominantly frontal, cortical dysplasia. In a patient with medium-chain acyl-coenzyme A dehydrogenase deficiency of neonatal onset, MRI showed delayed myelination and bilateral parieto-occipital abnormalities, compatible with the pattern typically seen after severe hypoglycemia (Fig. 13.80). In another patient, MRI was normal. It is probably reasonable to presume that in β-oxidation defects, if lesions are present within the brain, they may include malformations, delayed and hypomyelination, or sequelae of hypoglycemia and/or hypoxia, related to the metabolic crises. Electron Transfer Defects

Electron transfer defects are also referred to as multiple acyl-coenzyme A dehydrogenase deficiency or glutaric aciduria type 2. The disease is caused by deficiency of the electron transfer flavoprotein failing to transport electrons from intramitochondrial dehydrogenase enzymes (acyl-coenzyme A, branched-chain α-keto acid dehydrogenase, glutaryl-coenzyme-A

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Fig. 13.80a–d. MR imaging findings in a male patient with medium-chain acyl coenzyme A dehydrogenase deficiency (neonatal onset form). a,b Axial T1weighted inversion recovery images at the age of 1 year. Delayed and hypomyelination throughout the cerebral hemispheres. Bilateral symmetrical cortical-subcortical lesions exhibiting an atrophic character in the parieto-occipital regions. c, d Axial T2-weighted fast spin-echo images at the age of 2 years. There is some progression of the myelination, not fully accomplished though, but the parieto-occipital lesions are unchanged

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dehydrogenase). Hence, besides impairment of fatty acid oxidation (see above), catabolism of branchedchain amino acids (leucine, isoleucine, and valine, see in maple syrup urine disease) and glutaryl coenzyme A (a catabolic intermediate on the breakdown pathway of lysine, hydroxylysine and tryptophan, see in glutaric aciduria type 1) is also affected. Electron transfer defects represent a profound mitochondrial metabolic-energetic disorder. Glutaric aciduria type 2 has neonatal and later onset phenotypes. Both forms of glutaric aciduria type 2 are characterized by metabolic acidosis, organic (glutaric, 2-hydroxyglutaric, isovaleric, isobutyric, ethylmalonic) aciduria, hyperammonemia, and hypoglycemia without ketosis. The neonatal form may present with or without dysmorphic features. Described malformations in the neonatal form of the disease include facial dysmorphism, cerebral malformations, renal dysplasia, and abnormalities of external genitalia [49, 470]. The malformations are probably due to in utero energetic failure, rather than to direct toxic effect of abnormal accumulated metabolites. Those presenting with associated congenital anomalies usually expire within the

first few weeks of life. Patients with the other neonatal phenotype usually develop progressive cardiomyopathy and die by the age of 1 year [471]. The later onset type may present with occasional episodes of hypoglycemia at times of metabolic stress only. Imaging Findings

Imaging abnormalities of the brain in glutaric aciduria type 2 are probably the best described in the literature of all of the fatty acid oxidation defects. In the neonatal form, underdeveloped frontal and temporal lobes with enlarged Sylvian fissures (somewhat similar to glutaric aciduria type 1), delayed and hypomyelination, as well as agenesis of cerebellar vermis and hypoplasia of corpus callosum, have been described [72, 471, 472]. Parieto-occipital corticalsubcortical lesions, similar to those seen in mediumchain acyl-coenzyme A dehydrogenase deficiency (Fig. 13.80) may also be present. Although cortical dysplasia and gray matter heterotopia appear to be rather common autopsy findings, these have not been reported yet on neuroradiological studies. In the mild, late onset form, the MRI study may be normal.

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H MRS of brain in glutaric aciduria type 2 shows increased Cho/Cr ratio (suggesting demyelination) and elevated lactate (indicating abnormal energy metabolism); the latter, however, may be an inconsistent finding [72, 472]. Ketone Synthesis Defects

These include 3-hydroxy-3-methylglutaryl coenzyme A synthetase and lyase defects (see above in HMG coenzyme A lyase deficiency).

13.4.6 Lysosomal Disorders 13.4.6.1 Mucopolysaccharidoses

Mucopolysaccharidoses show autosomal recessive inheritance, except for Hunter disease, which is Xlinked recessive. The mutant genes are located on chromosome 4p16.3 in Hurler and Hurler-Scheie disease, on chromosomes 12q14 and 14 in Sanfilippo C disease, on chromosomes 16q24.3 and 3p21-p14.2 in Morquio A and B disease, on chromosome 5q11q13 in Maroteaux-Lamy disease, and on chromosome 7q21.11 in Sly disease. Mucopolysaccharidoses are multisystemic diseases with involvement of the skeletal system (dwarfism, bone and joint dysplasias, skull base abnormalities), eye (corneal opacities), liver, spleen (hepatosplenomegaly), heart (thickening of the valves), and CNS (primary and secondary involvement). Facial dysmorphias and skeletal dysplasias (dysostosis multiplex) are often characteristic of the disease and greatly facilitate the diagnosis, even on clinical grounds and plain X-ray skeletal survey. Laboratory tests provide further classification. In certain conditions, notably when neurological signs and symptoms suggest CNS involvement, MRI of the brain and spine may be indicated for further evaluation of the brain parenchyma, ventricular system, and cranio-cervical junction. CNS involvement in mucopolysaccharidoses may be direct or indirect. The most frequent imaging substrates of direct CNS involvement are enlarged perivascular spaces and white matter lesions, whereas indirect lesions include hydrocephalus and compression of the upper cervical spinal cord due to instability and narrowing of the cranio-cervical junction. Enlargement of perivascular spaces is related to abnormal mucopolysaccharide deposition in the leptomeninges, preventing normal outflow of interstitial fluid from the parenchyma.

Cerebral white matter lesions, which tend to be predominantly periventricular, may be due to delayed myelination and/or demyelination secondary to accumulation of macromolecules within neurons and oligodendrocytes, but transependymal CSF permeation (interstitial edema), in cases with prominent hydrocephalus, may also play a role. Hydrocephalus in mucopolysaccharidoses appears to be nonresorptive, most probably related to dysfunction of the pacchionian granulations, again due to meningeal mucopolysaccharide deposits [473]. Narrowing of the foramen magnum-upper cervical spinal canal area is due to combined effects of atlantoaxial instability (odontoid dysplasia in conjunction with ligament laxity) and mucopolysaccharide deposits within the synovial and dural structures. In Hurler (MPS-I-H) and Hunter (MPS-II) diseases the clinical picture is usually dominated by CNS involvement (mental retardation with progressive dementia, gait disturbances). Sanfilippo (MPSIII) disease presents with neurological abnormalities only, while hepatomegaly or dysostosis do not occur. Some degree of intellectual deficit may be present in Scheie (MPS-I-S) and Hurler-Scheie (MPS-I-HS) diseases. In Morquio (MPS-IV) and Maroteaux-Lamy (MPS-VI) disease no direct involvement of the CNS usually occurs, whereas progressive cranio-cervical junction abnormalities lead to stenosis of the upper cervical spinal canal with resultant cord compression and myelopathy, as well as corresponding neurological deficit (quadriparesis). Imaging Findings

The incidence and magnitude of the characteristic imaging abnormalities is variable in different forms of mucopolysaccharidoses. Enlarged perivascular spaces are most frequently encountered in Hurler and Hunter diseases, but may occasionally be seen in Sanfilippo disease as well (Fig. 13.81). These are sometimes very subtle and may be seen at the level of the corpus callosum only (Fig. 13.82). White matter changes are typical for Hunter, Hurler, Hurler-Scheie, Sanfilippo and Maroteaux-Lamy disease [474] (Fig. 13.83). Accumulated mucopolysaccharides (the resonance frequency was found to be around 3.7 ppm) were directly demonstrated within the abnormal appearing white matter in patients with Hurler, Hurler-Scheie, Hunter, and Sly diseases by 1H MRS. This was associated with increased Cho/Cr ratios [475]. Hydrocephalus is characteristic of Maroteaux-Lamy, Sanfilippo, and Hunter disease [474] (Fig. 13.84).

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Fig. 13.81a–d.Enlarged perivascular spaces in various forms of mucopolysaccharidosis on T1-weighted inversion recovery images. a, b 5-year-old female patient with Sanfilippo disease. c, d 2.5 year-old male patient with Hunter disease

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Fig. 13.82a, b. Enlarged perivascular spaces within corpus callosum in a 4-year-old female patient with mucopolysaccharidosis. a Sagittal T1-weighted spin-echo image. Enlarged callosal perivascular spaces (arrows). Note also the dysplastic odontoid process and the narrowing of the foramen magnum. b Sagittal T2-weighted fast spin-echo image. Similar findings

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Fig. 13.83a–c. White matter signal abnormalities in various forms of mucopolysaccharidosis on coronal FLAIR images. a 8-year-old female with Sanfilippo disease. Prominent enlargement of the extra- and intracerebral CSF spaces is conspicuous in conjunction with ill-defined, predominantly periventricular white matter signal abnormalities. b 6-year-old female patient with MaroteauxLamy disease. Ventricular enlargement without brain atrophy. The white matter lesions spare the subcortical U-fibers. c 10-year-old male patient with Hunter disease. Similar findings as in Figure 13.83a

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Fig. 13.84a.b. Communicating hydrocephalus in various forms of mucopolysaccharidosis. a 2-year-old female patient with Maroteaux-Lamy syndrome. Note the typical, abnormal configuration of sella and the characteristic deformity of the forehead associated with macrocephaly. b 10-year-old male patient with Hunter disease

Narrowing of the foramen magnum and upper cervical spinal canal is most prominent in Morquio syndrome, but is also frequently present in Hunter, Hurler-Scheie, and Maroteaux-Lamy disease [157, 476–478] (Fig. 13.85). 13.4.6.2 Metachromatic Leukodystrophy

Metachromatic leukodystrophy is caused by deficiency of cerebroside sulfatase enzyme. The enzyme has two components, notably the arylsulfatase A en-

zyme (ASA) and a sphingolipid activator protein, called saposin B. Arylsulfatase A is coded by a gene on chromosome 22q13.31-qter, while the gene of cerebroside sulfatase activator is located on chromosome 10q21-q22. Clinically, deficiency of either component may lead to metachromatic leukodystrophy, but arylsulfatase A deficiency is much more frequent. The impairment of the enzyme leads to accumulation of galactocerebroside sulfate (or sulfatide) within the oligodendrocytes and Schwann cells. Under normal conditions, cerebroside 3-sulphate accounts for about 3%–4% of myelin lipids, while in metachromatic leu-

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Fig. 13.85a–d. MR imaging of cranio-cervical abnormalities in various forms of mucopolysaccharidosis. a, b Sagittal T1-weighted spin-echo and T2-weighted fast spin-echo images in a 3-year-old male patient with Hurler disease. Dysplasia of odontoid process and diffuse stenosis of foramen magnum and cervical spinal canal, with mild compression of the spinal cord at the C1 level. c, d Sagittal T1-weighted spin-echo and T2-weighted fast spin-echo images in a 6-year-old female patient with Morquio disease. Dysplastic odontoid process, atlanto-axial dislocation, thickening of synovial and probably also of dural structures at the cranio-cervical junction. Severe stenosis of foramen magnum-upper cervical spinal canal, resulting in definite compression of the spinal cord

kodystrophy this may rise up to 30%. Thus, myelin within both the CNS and peripheral nerves becomes unstable and prone to abnormal breakdown. The disease, therefore, may be regarded as another example of dysmyelination-induced demyelination. At least three distinct types of arylsulfatase A deficiency have been identified, related to allelic heterogeneity of the arylsulfatase A locus. Depending on the type of mutation, inactive, unstable, or pseudodeficient enzymes may be encoded. The presence of the so-called pseudodeficiency allele (ASAp), coding an enzyme with decreased but sufficient residual activity, is a relatively frequent polymorphism, present in about 7%–15% of the normal population. Homozygosity for the pseudodeficiency allele (ASAp/ASAp) occurs in 0.5%–2.0% of the normal population and is not associated with clinically symptomatic disease, despite significantly reduced enzyme activity [479]. Patients with compound heterozygosity for a pseudodeficiency allele and an allele coding the inactive or unstable enzyme may be clinically asymptomatic too [141, 479, 480]. In patients with critically reduced (less than 10%) or absent arylsulfatase A activity, the disease is clinically manifest and has several clinical phenotypes. The most frequent is the late infantile one (onset between 1 to 3 years of age), accounting for 60%–70% of the cases. Early (3–6 years) and late (6–16 years) juvenile forms are encountered in about 25%, and the adult form in about 10%. A neonatal form also exists, but is very

rare. The different age-related clinical phenotypes are closely linked to known genotypic variations [140, 481, 482]. Mutation at the splice donor site prevents synthesis of arylsulfatase A, and affected patients have practically no arylsulfatase A activity. Homozygosity for this allele (allele I) leads to the severe, infantile onset form [141]. Another mutation results in synthesis of an active, but unstable, enzyme (“instability” actually means a shortened intralysosomal half-life of the enzyme within the oligodendrocytes) characterized by some residual activity which, however, is insufficient to prevent the disease. Homozygosity for this allele (allele A) was found to be associated with the adult onset form. Heterozygosity for allele I and allele A results in intermediate residual enzyme activity, hence the juvenile onset form of the disease. In cases of saposin B deficiency, patients have normal arylsulfatase A activity, which may be a misleading laboratory finding initially. Clinically, the resultant disease is indistinguishable from the phenotype caused by true arylsulfatase A deficiency. The infantile form of the disease presents with hypotonia, dysarthria, ataxia, gait disturbance, and progressive loss of motor skills, leading to para- and later to quadriplegia. Peripheral neuropathy and optic atrophy is always present. Death usually occurs 3–6 years from the onset of the disease after a decerebrated state. The juvenile form presents with spastic gait, ataxia, and progressive cognitive abnormalities. During the course of the disease severe spasticity develops. Pyra-

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midal signs, peripheral neuropathy, and ataxia are also typical neurological features of the adult onset form. The disease in the juvenile and adult forms shows a more protracted course than in the infantile form. However, the late juvenile and adult forms often present with misleading clinical manifestations. Epileptic seizures may precede or follow the appearance of neurological or cognitive abnormalities [483, 484]. Psychiatric disturbances (paranoid delusions, auditory, visual, and olfactory hallucinations), often misdiagnosed as a genuine psychotic syndrome (schizophrenia), movement disorders, and presenile dementia are also common [121, 141, 485]. Imaging Findings

In its classical infantile form, metachromatic leukodystrophy is a classical leukodystrophy with no apparent involvement of gray matter structures on MRI. The imaging abnormalities consist of a progressive centrifugal white matter disease, but an addi-

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tional postero-anterior gradient is also present. The corpus callosum (first the splenium, then more anterior components), internal capsules (initially only the posterior limbs, later also the anterior limbs), and deep hemispheric white matter are always involved. The subcortical U-fibers are typically spared during the initial stages of the disease. The external and extreme capsules are initially spared, but become abnormal later. In the early infantile form of the disease, a peculiar “tigroid” white matter lesion pattern may be seen within the centrum semiovale. This is due to initial relative sparing of perivascular myelin around transmedullary vessels, whose explanation is unclear. The tigroid pattern, if present, is a very suggestive element [486, 487] (Fig. 13.86). Signal changes may be present within the upper brainstem and along the corticospinal tracts; the latter may be due to Wallerian degeneration. Signal abnormalities within the cerebellar white matter are initially absent or rather subtle. During the disease course, progressive and eventually severe diffuse brain atrophy develops and

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Fig. 13.86a–e. MR imaging findings in infantile metachromatic leukodystrophy (2-year-old male patient with saposin B deficiency). a–d Axial T2-weighted fast spin-echo images. The so-called tigroid pattern is well appreciated. Note the faint signal abnormalities within the posterior limbs of the internal capsules and subinsular white matter, and the involvement of the corpus callosum, both posteriorly and anteriorly. e Axial T1-weighted inversion recovery image at level corresponding to c better demonstrate the sparing of the subcortical U-fibers

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cerebellar white matter involvement may become conspicuous [488]. The brain lesions do not show contrast enhancement. In the early juvenile form, the MRI findings may be quite similar to the infantile form. In the late juvenile form, diffuse involvement of cerebral white matter and sparing of cerebellar white matter were described in conjunction with signal changes within the cerebral peduncles, pons, and periaqueductal area, atrophy of the basal ganglia, and low signal intensity of the globi pallidi on T2-weighted images [484]. The tigroid pattern may also be present, especially in the early juvenile form [487] (Fig. 13.87). Diffusion-weighted images usually show signal abnormalities. Moderate hypersignal is sometimes seen in the presumed progression zone of the demyelinating process; in the late stage of the disease diffuse hyposignal is found, but this seems to mainly correspond to T2 shine-through artifact in most cases. However, the “tigroid” pattern is sometimes conspicuous on the diffusion-weighted images too (Fig. 13.87). 1 H MRS shows decreased NAA and elevated lactate peaks in the affected white matter in conjunction with an increased mI peak, a relatively distinct feature with respect to other leukodystrophies [489]. Decreased NAA is believed to be related to loss of integrity of neurons and of oligodendrocytes, whereas increased mI (a substance exclusively located in glial cells in normal brain) may reflect glial abnormalities and membrane instability (Fig. 13.88). Reports on MRI findings after bone marrow transplantation are somewhat controversial. In a case of a 2-year-old child with saposin-B deficiency, although peripheral neuropathy showed transient objective improvement after treatment, imaging findings showed unchanged white matter abnormalities and worsening

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brainstem and cerebellar atrophy [490]. In another report of two cases of metachromatic leukodystrophy, one patient with early juvenile onset improved, while the other with late juvenile onset stabilized after successful bone marrow transplantation [160]. In an adult onset case, follow-up MRI study after bone marrow transplantation demonstrated arrest of the disease process within brain, while electrophysiological studies (EEG, peripheral nerve conduction) and neuropsychological tests showed improvement [159]. 13.4.6.3 Multiple Sulfatase Deficiency

This is a rare, but very particular autosomal recessive disorder, since it combines the features of mucopolysaccharidoses and metachromatic leukodystrophy from both clinical and imaging standpoints [491]. As its name indicates, multiple sulfatase enzymes are deficient (i.e., those involved in metachromatic leukodystrophy and in various forms of mucopolysaccharidoses); however, residual enzyme activities vary considerably. The most frequent form is of early childhood onset; neonatal and juvenile forms also exist, but are rare. Clinically, facial dysmorphia, similar to that seen in mucopolysaccharidoses, hepatosplenomegaly, microcephaly (in the neonatal form macrocephaly), delayed development, progressive spasticity, blindness, and deafness are usually found. Imaging Findings

Imaging studies show a combination of the abnormalities that are detected in metachromatic leukodystrophy and mucopolysaccharidoses, notably

Fig. 13.87a, b. Diffusion weighted imaging findings in a 6-year-old male patient with arylsulfatase A-deficient metachromatic leukodystrophy. a Axial diffusion-weighted echo-planar image (b = 1000s). Extensive hyperintensities are seen within the centrum semiovale bilaterally. The deep periventricular white matter harbors hypointense areas which suggest tissue rarefaction. The tigroid pattern is recognizable. b Axial apparent diffusion coefficient (ADC) map image. Most areas showing hypersignal on diffusion-weighted images are hyperintense; therefore, these correspond to T2 shine-through. In the parietal areas, faint hypointensities are suggested which may correspond to water diffusion restriction

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Fig. 13.88a–c. Single voxel proton MR spectroscopic findings in metachromatic leukodystrophy (same patient as in Fig. 13.86). a PRESS technique, TE: 135 ms, sampling voxel, positioned on abnormal fronto-parietal white matter on the left side. Nonspecific findings. The NAA peak is decreased, the Cho peak is increased, and the peak doublet at the 1.3 ppm level represents lactate. b. PRESS technique, TE: 270 ms, sampling voxel, positioned on abnormal fronto-parietal white matter on the left side. Similar findings as in Fig. 13.88a, except that the lactate peak shows typical J-coupling phenomenon. c STEAM technique, TE: 20 ms, sampling voxel, positioned on abnormal fronto-parietal white matter on the left side. Note the very prominent mI peak on this spectrum at the 3.55 ppm level, which is hardly detectable on the longer echo time spectra

variable patterns of white matter disease (diffuse or multifocal), enlargement of ventricles and of extracerebral CSF spaces (characterizing diffuse brain atrophy), occasionally enlarged perivascular spaces, and cranio-cervical junction abnormalities with stenosis of the upper cervical spinal canal and possible cord compression [491]. 13.4.6.4 Krabbe Disease (Globoid Cell Leukodystrophy)

The underlying metabolic derangement in Krabbe disease (globoid cell leukodystrophy) is the defect of galactocerebroside β-galactosidase enzyme. The substrate of this enzyme is β-galactocerebroside. Nevertheless, deficiency of the enzyme results in accumulation of not only galactocerebroside, but more importantly, of its deacylated intermediate metabolite, galactosylsphingosine (or psychosine) within the cerebral white matter. Galactosylsphingosine is known to be toxic to oligodendrocytes; hence, myelin probably becomes unstable and prone to breakdown. It is, therefore, a disease affecting at the same time production and maintenance of myelin. Consequently, both the CNS and peripheral nerves are affected. Histopathological evaluation of affected white matter shows reduced number of oligodendrocytes, demyelination with secondary axonal degeneration, reactive astrocytic gliosis, and accumulation of globoid cells (multinuclear macrophages). The disease has an autosomal recessive inheritance. The gene is located on chromosome 14q31. Sev-

eral mutations have been identified, but no clear-cut genotype-phenotype correlation could be established [492]. In fact, different clinical phenotypes (infantile and adult) may occur within the same family [493]. The disease typically starts in early infancy (3– 8 months), but later onset forms, including adult, also occur. Initially the disease presents with irritability, tonic spasms, blindness, deafness, and pyramidal signs. As in many other demyelinating diseases, CSF protein is elevated. Electrophysiological studies reveal peripheral nerve conduction velocity abnormalities, consistent with peripheral neuropathy. Later, permanent hypertonia, hyperpyrexia, and seizures develop, followed by opisthotonos, loss of bulbar functions, and respiratory failure. The disease is rapidly progressive and death usually occurs between 12 to 18 months of age. In the later onset forms (onset of the disease after 21 months of age), the clinical presentation may be somewhat different and sometimes misleading. Vision loss, gait disturbance, progressive spastic paraparesis, dementia or, rarely, hemiparesis without peripheral nerve involvement may be the initial clinical symptoms in the late infantile, juvenile, and adult forms [494–496]. The disease, however, may also present with peripheral neuropathy only [497]. Similar to metachromatic leukodystrophy, the late onset forms of the disease show a more protracted course [498]. Allogenic hematopoietic stem-cell transplantation was found to be beneficial in the late onset form of Krabbe disease [161]. After the procedure, normal galactocerebrosidase level was restored within leuko-

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cytes. Reversal of CSF protein abnormalities was also achieved. In late-onset patients with neurological disability before the procedure, this was associated with clinical improvement. In a patient with family history of infantile onset disease who had no clinical manifestations before transplantation, the disease did not develop. Imaging Findings

CT studies in Krabbe disease describe subtle hyperdensities within the deep gray matter structures of the brain (Fig. 13.89) and, occasionally, also within the periventricular centrum semiovale [33]. This is in keeping with histopathological findings of calcifications in the same areas. MR examination of the brain often, but not always, shows hypointensities within basal ganglia and thalami on T2-weighted images, most probably related to the presence of calcifications. In the classical, early infantile form, the most prominent abnormalities are widespread white matter abnormalities, both infra- and supratentorially. Both the cerebral and cerebellar white matter are involved. In the cerebellum, the most central areas may exhibit a spongy, necrotic appearance. The dentate nuclei are spared. Within the brainstem, the pyramidal tracts are usually abnormal. The middle cerebellar peduncles and posterior parts of the pons also show hypersignal on T2-weighted images. Supratentorially, white matter abnormalities show a centrifugal pattern with an additional postero-anterior gradient [499]. This means that subcortical U fibers and frontal lobes may show sparing during early stages of the disease (Fig. 13.89). The posterior limbs of the internal capsules are involved earlier than the anterior limbs. The posterior-anterior gradient may also be conspicuous at the level of the callosal involvement. The external

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and extreme capsules are also relatively spared initially (Fig. 13.90). Additionally, enlargement of the prechiasmatic intracranial optic nerves was demonstrated by MRI (and on histopathology numerous globoid cells were found in affected areas) [500]. MRI of spine shows diffuse hypersignal within the spinal cord (Fig. 13.91). As a presumably unique feature of the disease, signal enhancement of cauda equina components after intravenous gadolinium injection was also described [41]. With progression of the disease, practically all white matter structures become abnormal, spongy changes appear in the periventricular regions, and diffuse brain atrophy develops (Fig. 13.92). The supratentorial white matter lesion pattern in the early stage of the disease may be quite similar to that of X-linked adrenoleukodystrophy, but significant differences also exist, both clinically and on imaging. In Krabbe disease, no intermediate zones are seen between the demyelinated and the “normal” white matter. Furthermore, although contrast enhancement has been also described in Krabbe disease, it is different from that seen in X-linked adrenoleukodystrophy (Fig. 13.14). In Krabbe disease, enhancement occurs either along the interface between the deep and the subcortical U fibers (along the presumed progression line of the demyelinating process) or in the deep parieto-occipital periventricular zones, whereas in X-linked adrenoleukodystrophy it is typically within the transitional, inflammatory zone between demyelinated and demyelinating areas. Finally, in X-linked adrenoleukodystrophy the cerebellar structures are not involved. In the burned-out phase, Krabbe disease may be difficult to differentiate from metachromatic leukodystrophy but, again, cerebellar involvement in the latter is either absent or less prominent.

Fig. 13.89a,b. CT and MRI findings in a 7-month-old girl with globoid cell leukodystrophy (Krabbe disease) (case courtesy of Dr. P. Tortori-Donati, Genoa, Italy). a Axial CT scan shows subtle hyperdensity of both thalami, consistent with calcification (arrowheads). b Axial fast spin-echo T2-weighted image shows hyperintense white matter within the centrum semiovale bilaterally. The U fibers appear to be spared in this early disease stage

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Fig. 13.90a–d. Conventional MR imaging findings in a 1-year-old boy with globoid cell leukodystrophy (Krabbe disease). a–c Axial T2-weighted fast spin-echo images. This study illustrates the imaging abnormalities in early stage of the disease. Only a small patchy hyperintense area is seen within the cerebellar white matter on the right side (arrow, a). The brainstem is spared, except the pyramidal tracts (arrowheads, a). Supratentorially, a postero-anterior gradient of white matter signal abnormalities is well appreciated. Only the posterior parts of posterior limbs of internal capsules are affected. The corpus callosum is abnormal both posteriorly and anteriorly. The subcortical U-fibers are lost in most areas. d Coronal FLAIR images. The centrifugal progression pattern of demyelination is well demonstrated. Within the deepest, periventricular white matter structures, spongy, markedly hypointense areas are seen

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Fig. 13.91a, b. Spinal cord involvement in globoid cell leukodystrophy (Krabbe disease). a, b Axial T2-weighted gradient-echo images of the cervical spine (same patient as in Fig. 13.90), showing obvious signal abnormalities within the spinal cord

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Fig. 13.92a–d. MR imaging findings in an 8-month-old male patient with globoid cell leukodystrophy (Krabbe disease). Clinically, the disease started at the age of 4 months with spasticity. By the time of the MRI study, the patient was in terminal stage, requiring assisted ventilation. a–d Axial T2-weighted fast spin-echo images. The brain is diffusely atrophic. Most cerebral white matter is abnormal; exceptions are the deep cerebellar white matter structures (around and within the hili of the dentate nuclei), brainstem tracts (except for the pyramidal tracts), and the anterior limbs of internal capsules. Note the markedly hypointense appearance of the deep gray matter structures of the cerebral hemispheres

Imaging findings in the early and late onset forms of Krabbe disease are different [501]. In the late onset forms white matter abnormalities are typically seen in the parietal, occipital and, less frequently, frontal periventricular regions; occasionally the disease may predominantly or exclusively involve the pyramidal tracts [494, 502, 503]. This peculiar “selective vulnerability” may be related to the fact that, although myelin turnover in adults is generally lower than in children, it is still relatively higher within the corticospinal tracts; therefore, the oligodendrocytes may be more vulnerable. Atrophy of corpus callosum is frequent. Conversely, cerebellar and basal ganglia

abnormalities are absent [501, 502]. In cases presenting with hemiparesis, cerebral white matter changes show significant asymmetry [495]. From an imaging standpoint, this may be misdiagnosed as a neoplastic pathology [504]. Diffusion-weighted images may show prominent hypersignal (isotropically restricted water diffusion) along the progression line of the demyelinating process in the early stage of the disease. On follow-up examinations, these changes may subside quite rapidly, and demyelinated areas turn into hyposignal (loss of physiological diffusion anisotropy), indicating fast and complete myelin loss,

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consistent with the usually also rapidly evolving clinical picture [505] (Fig. 13.19). The technique, especially when quantified and combined with diffusion tensor imaging, appears to be more sensitive to detect early changes within the white matter than conventional MRI techniques. Interestingly enough, in patients treated with bone marrow transplantation, some improvement in the diffusion properties of the cerebral white matter could also be demonstrated, indicating a beneficial effect on the disease process [505]. 1 H MRS shows significant regional metabolic differences, depending on the positioning of the sampling voxel. In the white matter, a prominent lactate peak is seen in conjunction with decreased NAA and slightly increased Cho peaks [506]. Conversely, a sampling voxel placed on the basal ganglia may yield a totally normal spectrum (Fig. 13.93). 13.4.6.5 GM Gangliosidoses

Diseases in this group of lysosomal disorders are characterized by abnormal visceral and neural accumulation of GM1 and GM2 gangliosides. The clinical pictures are, therefore, dominated by hepatosplenomegaly and encephalopathy. The presence of cherry-red spots at funduscopic examination is a characteristic, but nonspecific, finding in both gangliosidoses. GM1 Gangliosidosis

The deficient enzyme in this group is β-galactosidase. The gene is localized on chromosome 3p21.33. It catalyzes conversion of GM1 ganglioside into GM2 by removing terminal galactose. Deficiency of β-galac-

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tosidase results in accumulation of GM1 gangliosides in the brain and visceral organs. Three clinical phenotypes of GM1 gangliosidosis are known: infantile (type 1), juvenile (type 2), and adult (type 3). The infantile type usually leads to death in early infancy. Affected patients present with dysmorphic features and severe developmental delay, progressive spasticity, and tonic-clonic seizures, as well as hepatosplenomegaly. In type 2 and type 3 GM1 gangliosidoses, the diseases show a more protracted course, initially with gait and speech disturbances. Later, extrapyramidal signs (dystonia, choreoathetosis, parkinsonism) dominate the neurological picture [507, 508]. Imaging Findings

Data on MRI findings in the different forms of GM1 gangliosidosis are very sparse. Type 1 presents with delayed myelination and thalamic signal changes (hyposignal on T2-weighted images), and type 3 shows basal ganglia abnormalities (hyperintensity within the putamina) [508, 509]. The imaging patterns are nonspecific. No imaging data regarding type 2 GM1 gangliosidosis are available. GM2 Gangliosidosis

The deficient enzymes in this group are β-hexosaminidase A and/or B, or the so-called GM2 activator glycoprotein. In this group, besides GM2 gangliosides, GA2 gangliosides are also accumulated. According to the proportions between the two substances, O, B, and AB variants are distinguished. In the O variant, both A and B β-hexosaminidase enzymes are deficient, while in the B variant only the β-hexosaminidase A is deficient. The AB variant is related to deficiency of GM2

b Fig. 13.93a,b. Single voxel proton MR spectroscopic findings in globoid cell leukodystrophy (Krabbe disease) in the same patient as in Figure 13.90 (PRESS technique, TE: 135 ms, sampling voxel 2x2x3 cm). a This spectrum was obtained with the sampling voxel positioned on abnormal cerebral hemispheric white matter. It shows abnormal, but nonspecific pattern. All usual peaks, including NAA, Cr, and Cho, are decreased. The prominent negative peak doublet at the 1.3 ppm level corresponds to lactate. b When the sampling voxel is positioned on basal ganglia, the spectrum is normal

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activator protein. The defective genes are located on chromosome 15q23-q24 in the infantile type B variant, and on chromosome 5q13 in the O variant. The AB variant has only an infantile form. The O and B variants have infantile, juvenile, and adult forms. The best-known disease entities are Tay-Sachs disease (infantile type B) and Sandhoff disease (infantile type O). From the clinical standpoint, the two diseases are quite similar, except that in Sandhoff disease hepatosplenomegaly may be seen, whereas it is absent in Tay-Sachs disease. Patients have progressive macrocephaly and present with a progressive neurological disease already before 6 months of age, characterized by psychomotor deterioration, pyramidal, later extrapyramidal (choreoathetosis) signs, and generalized tonic-clonic seizures. The clinical presentation in the late onset forms is usually milder. Ataxia, supranuclear palsy, dystonia, and dementia are the most frequent neurological abnormalities. Imaging Findings

Imaging findings in Tay-Sachs and Sandhoff diseases are quite similar, and the lesion patterns are suggestive. CT shows hyperdensities within the basal ganglia and/or thalami [408, 510, 511]. This is probably due to calcifications. MRI, however, is particularly sensitive in demonstrating widespread white matter changes within the cerebral hemispheres. Practically all white matter structures are involved, except for the corpus callosum, anterior commissure, and posterior limbs of the internal capsules. The external and extreme capsules, as well as the medullary laminae between the pars medullaris and lateralis of the globi pallidi and the pars lateralis of globi pallidi and the putamina, are also abnormal. The white matter lesion pattern suggests centripetal demyelination. In the late stage of the disease, diffuse brain atrophy develops. The cerebral cortex shows atrophic changes quite early during the disease course. The putamina are always abnormal on T2-weighted images; subtle hyperintensities are also suggested at the level of the claustra. The caudate nuclei may be normal, but abnormalities similar to putaminal changes are typically present. Overall, the involved basal ganglia structures appear to be somewhat swollen, at least initially during the disease course [512]. The thalami are spared; actually, they seem to exhibit hyposignal on T2-weighted images. The cerebellar white matter often shows signal abnormalities on the T2-weighted images; hyperintensities are, however, less prominent than supraten-

torially. In the late-onset form of Sandhoff disease, cerebellar atrophy may be the sole imaging abnormality [513]. Typically, no abnormalities are seen within the brainstem and spinal cord. The overall lesion pattern in a macrocephalic infant can be highly suggestive of the disease [510] (Fig. 13.94). Diffusion-weighted images are usually quite unremarkable, suggesting a relatively slow demyelinating process. 1 H MRS shows nonspecific spectral alterations. The NAA peak is decreased, whereas the Cho peak is slightly increased. No lactate is identified within the brain. 13.4.6.6 Niemann-Pick Disease

Four types of the disease are known, all characterized by autosomal recessive inheritance. In types A and B, the disease is caused by deficiency of the sphingomyelinase enzyme, and the mutant gene is located on chromosome 11p15.1-p15.4. Niemann-Pick types C and D are biochemically and genetically different diseases, but the underlying metabolic derangement is not fully understood. In Niemann-Pick type C the gene is located on chromosome 18p. Niemann-Pick type A is an infantile onset disease. It is characterized by hepatosplenomegaly, but the brain is also involved. Neurological deterioration, initially in the form of hypotonia and then of spastic paraparesis, starts in early infancy. Type B disease has predominantly visceral manifestations (hepatosplenomegaly followed by cirrhosis, chronic pulmonary disease), while neurological manifestations are rare. In type C disease, infantile and juvenile onset forms are known. In the infantile form, the earliest clinical manifestation is hyperbilirubinemia, indicative of hepatic involvement, which may lead to early infantile death. Neurological signs and symptoms usually develop later in infancy and include hypotonia and loss of milestones, followed by spastic paraparesis, seizures, and gaze disturbances. In the juvenile form, learning difficulties, dementia, supranuclear ophthalmoplegia, cataplexy, ataxia, dystonia, and seizures (including gelastic seizures) occur [514]. The disease may be clinically mistaken for Wilson disease. Type D is a variant of the late-onset type C disease. Imaging Findings

The neurological abnormalities suggest predominant white matter and cerebellar involvement of the CNS. Indeed, brain atrophy, sometimes with cerebellar predominance and diffuse white matter disease

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Fig. 13.94a–h. MR imaging findings in GM2 gangliosidosis. a–d Axial T2weighted fast spin-echo images in a 20month-old macrocephalic male patient with GM2 gangliosidosis. This study was performed at a very early stage of the disease. The cerebral hemispheric white matter appears to be diffusely abnormal, indicating demyelination. The corpus callosum is totally, and the brainstem and cerebellar white matter are relatively, spared. Note the swelling of the basal ganglia and the hypointense appearance of the somewhat atrophic thalami. e–h Axial T2-weighted fast spinecho images in another patient (3-yearold male) with GM2 gangliosidosis, presenting with epileptic seizures and loss of milestones. The disease is at a more g h advanced stage, and the abnormalities are more prominent and extensive. The corpus callosum is almost totally involved, and signal abnormalities are present within the cerebellar white matter and the brainstem. The basal ganglia are less swollen. The claustra are well outlined because of the abnormalities within the adjacent external and extreme capsules. Note the thinning of the cerebral cortex

Metabolic Disorders

(probably a combination of dys- and demyelination) are the most common MRI findings in NiemannPick disease (Fig. 13.95). In infants, however, delayed myelination is the most typical MRI abnormality. In a series of patients with type C disease (most of them adolescents or adults at the time of study), MRI of brain showed mild or moderate cerebral (50%) and cerebellar (40%) atrophy in conjunction with white matter hyperintensities (mild in 30%, and marked in 20%). In three patients (all of them younger than 20 years) no abnormality was found [515]. In one patient with the late onset form of type C disease, brain atrophy was found by MRI, while no abnormality were found in another case [514]. 1 H MRS in type C disease showed significantly decreased NAA/Cr ratio (loss of neuronal integrity) in the caudate nucleus and centrum semiovale, and increased Cho/Cr ratio (demyelination) within the centrum semiovale and frontal cortex [515]. These data are in keeping with the pathological features of the disease, notably diffuse involvement of both gray and white matter structures of the disease with abnormal storage material within neurons and axons. a

13.4.6.7 Gaucher Disease

Gaucher disease is the most common among lysosomal storage diseases. It is usually caused by deficiency of the glucocerebrosidase enzyme, catalyzing conversion of cerebroside into ceramide by removing a glucose molecule. As a result, excess glucocerebroside accumulates in visceral organs. The galactocerebrosidase gene is located on chromosome 1q21. Rarely, the disease is caused by deficiency of saponin C (sphingolipid activator protein-2), required to activate the glucocerebrosidase enzyme. Three types of the disease are known. Type 1 is the most frequent and presents with hepatosplenomegaly, pancytopenia, lung disease, and skeletal abnormalities (aseptic necrosis of femoral head, diffuse osteopenia, vertebra plana). The CNS is not directly affected in type 1 disease (nonneuronopathic Gaucher disease). Type 2 (neuronopathic Gaucher disease) is characterized by both visceral and CNS involvement. Hepatosplenomegaly is associated with brainstem signs (spastic quadriplegia, oculomotor

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Fig. 13.95a–c. Conventional MR imaging findings in a 7-year-old male patient with Niemann-Pick disease (pre-bone marrow transplantation workup). a Sagittal T1-weighted spin-echo image shows prominent atrophy of cerebellar vermis and corpus callosum. b Axial T2-weighted image shows enlargement of intra- and extracerebral CSF spaces in conjunction with diffuse white matter abnormalities, suggestive of demyelination. c Coronal FLAIR image. White matter abnormalities are more conspicuous and exhibit peripheral predominance

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and bulbar abnormalities). A possible involvement of the dural structures (glucocerebroside deposits) has also been advocated [516, 517]. The disease starts in early infancy and leads to death during childhood. The type 3 form of the disease is actually an intermediate variant, sharing features of type 1 and type 2 forms. This is further divided into type 3a and 3b subtypes. Type 3a is a late-onset disease presenting with a more severe and progressive CNS disease; type 3b is of earlier onset and characterized by predominantly systemic involvement and milder, static CNS abnormalities. Imaging Findings

In type 1 Gaucher disease, spinal manifestations may cause neurological complications. Vertebra plana and multiple platyspondyly were found to cause spinal cord compression [518]. Furthermore, development of epidural masses may also cause compression of the spinal cord [519]. In the type 2 variant of the disease, MRI findings may be normal [520, 521]. In a 6-month-old child with type 2 Gaucher disease, unilateral dural thickening over the left cerebral hemisphere extending to the tentorium, in conjunction with mild atrophy of the ipsilateral cerebral hemisphere, was described. The myelination pattern was normal [516]. In a case we observed, there was hyperintensity of the deep white matter of the centrum semiovale and periventricular regions on both T2-weighted and FLAIR images associated with hyperintensity of the globi pallidi, dentate nuclei, and pontine tegmentum (Fig. 13.96). In type 3 Gaucher disease, mild brain atrophy may be found on imaging studies. In a 3-year-old child, communicating hydrocephalus developed, requiring ventriculoperitoneal shunting. This may have been due to meningeal involvement resulting in impaired CSF resorption [517]. Possible spine abnormalities in Gaucher type 3b disease include vertebral fractures, resulting in prominent kyphotic and/or scoliotic deformities. The vertebral bone marrow shows decreased signal intensity on T1-weighted images, indicating depletion of the fatty bone marrow [522]. 1 H MRS of brain in Gaucher disease shows normal NAA but slightly elevated inositol compounds [63]. 13.4.6.8 Fucosidosis

Fucosidosis is a rare lysosomal storage disorder due to deficient α-l-fucosidase activity, leading to accumulation of fucose-containing glycolipids and glycoproteins in various tissues. The gene is mapped

to chromosome 1p34.1–36.1. Several mutations have been identified, all leading to total or almost total absence of enzyme activity [523]. The disease is characterized by progressive mental (95%) and motor (87%) deterioration, coarse, dysmorphic facies, somewhat similar to that seen in mucopolysaccharidoses (79%), growth retardation (78%), recurrent infections (78%), dysostosis multiplex (58%), angiokeratoma corporis diffusum (52%), visceromegaly (44%), and seizures (38%) [524]. In one case, progressive dystonic posturing, initially unilateral but later involving both lower limbs, were also reported [525]. Based on the clinical presentation, two phenotypes were initially identified; a severe, rapidly progressive form leading to early childhood death (type 1), and a less severe, slowly progressive form with possibility of survival into adolescence or even adulthood (type 2). However, there is now increasing clinical evidence to suggest that instead of two distinct clinical phenotypes, a wide, continuous clinical spectrum may exist [524, 526–528]. Because of the lack of clear-cut genotype-phenotype correlation, it is possible that as yet unknown environmental factors or “modifying genes” also play a role. Imaging Findings

In patients examined during infancy with severe clinical presentation (“type 1”), extensive confluent symmetrical hyperintensities are seen on T2weighted images within the cerebellar and cerebral white matter. Cerebral white matter changes involve the internal, external, and extreme capsules, as well as the medial and lateral medullary laminae at the level of the lentiform nuclei and the internal medullary laminae of thalami. The putamina and the hypothalamic structures are slightly hyperintense. The globi pallidi and substantia nigra show increased signal on T1-weighted, and decreased signal on T2weighted images (Fig. 13.97). This may be due to iron or manganese, or even oligosaccharide deposits [529]. Calcifications are an unlikely explanation, since on CT the globi pallidi show low attenuation [530, 531]. MRI of spine may show vertebral beaking [529]. In cases with the less severe clinical phenotype (“type 2”), MRI findings include extensive, predominantly periventricular white matter changes. The internal medullary laminae of the thalami also show faint hypersignal on T2-weighted images. The corpus callosum is relatively spared, especially anteriorly. Signal abnormalities are found at the level of the globi pallidi, substantia nigra, red nuclei, and even mammillary bodies. These may be faintly hyperintense on T1-, but are clearly hypointense on T2-weighted

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Fig. 13.96a–f. MR imaging findings in a 19-month-old girl with Gaucher disease type 2 (courtesy of Dr. P. Tortori-Donati, Genoa, Italy). a–c Axial T2-weighted fast spin-echo images; d–f. axial FLAIR images. There is a mild hyperintensity of the periventricular and deep central white matter that spares the subcortical U fibers (c). Notice that the globi pallidi are slightly hyperintense, whereas the capsules are spared (b). Also notice mild hyperintensity of the pontine tegmentum and dentate nuclei (a)

images [527, 530, 531]. Diffuse cerebral and cerebellar atrophy may also develop later during the course of the disease [532]. In a 3.5-year-old boy with an intermediate form of the disease, MRI showed extensive cerebral hemispheric white matter abnormalities, mild cortical atrophy, and typical globus pallidus changes [527]. Overall, the findings are somewhat reminiscent of the imaging abnormalities seen in GM2 gangliosidosis. Low intensities of globi pallidi on T2-weighted images and involvement of the medullary laminae of the thalami, as well as of the medial and lateral medullary laminae of the lentiform nuclei, are quite characteristic and provide a suggestive imaging pattern in fucosidosis.

13.4.6.9 Mucolipidoses

Mucolipidoses are characterized by storage of multiple abnormal substances, notably mucopolysaccharides and glycolipids and, hence, the clinical manifestations are often reminiscent of those seen in mucopolysaccharidoses and sphingolipidoses. Neurological signs (dementia, seizures) are often present. Mucolipidosis type 2 shares similarities with Hurler disease and is usually lethal in early infancy. Mucolipidosis type 3 is less severe; it is characterized by skeletal abnormalities and mental retardation. Mucolipidosis type 4 presents with ophthalmological problems (corneal clouding, retinal degeneration), spastic paraparesis, and mental retarda-

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Fig. 13.97a–f. Conventional MR imaging findings in two female siblings with fucosidosis (courtesy of Dr. P. Tortori-Donati, Genoa, Italy). a–c Axial T1- and T2-weighted spin-echo images in a 5-year-old female patient. The globi pallidi exhibit a spontaneously hyperintense appearance on T1-weighted image (arrowheads, a). The globi pallidi and thalami show decreased signal on T2weighted images (b, c). Diffuse paucity of myelin within the cerebral hemispheres (c). d–f Axial (d, e) and coronal (f) T2-weighted spin-echo images in the 2-year-old sister. Abnormalities are more prominent and reminiscent of GM2 gangliosidosis. The cerebral hemispheric white matter is extensively abnormal. The abnormalities involve the external and extreme capsules (d), as well as the medial and lateral medullary laminae (f). An antero-posterior gradient is suggested. The basal ganglia exhibit increased signal, but the thalami are hypointense

tion in early childhood, but hepatosplenomegaly, dysmorphic features or skeletal abnormalities, which are common in other forms of mucolipidosis, are absent. Imaging Findings

Rather consistent MRI findings have been described in mucolipidosis type 4, including hypo- or dysplasia of corpus callosum (similar to that seen in nonketotic hyperglycinemia), cerebellar atrophy, periventricular and subcortical white matter, as well as markedly hypointense appearance of basal ganglia and thalami on T2-weighted images due to iron depositions [52] (Fig. 13.98).

13.4.6.10 Salla Disease

Salla disease is an autosomal recessive lysosomal storage disorder affecting lysosomal transmembrane transport of sialic acids. The encoding gene of the deficient transport protein, sialin, is located on chromosome 6q14-q15. The disease is quite frequent in Finland, where most reported cases were identified. The clinical phenotypes of the disease include severe, intermediate, and mild forms. The main feature of the disease in all forms is psychomotor retardation. In the severe form, spasticity, choreoathetosis, and dementia occur; patients are wheel-chair bound. In the inter-

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Fig. 13.98a–c. Conventional MR imaging findings in type IV mucolipidosis in a 3-year-old male patient. a Sagittal T1-weighted spin-echo image shows hypotrophy or hypoplasia of corpus callosum. b Axial T1-weighted inversion recovery image. Poor myelination throughout both cerebral hemispheres; peripherally, practically no myelin is seen. c Axial T2-weighted fast spin-echo image. Extensive white matter signal abnormalities, probably representing combination of delayed and hypomyelination

mediate form, ataxia and less severe psychomotor retardation are found. In the mild form, patients have mild ataxia and gait disturbances. The disease usually starts in infancy, shows a very protracted course, and life expectancy is almost normal. Approximately 20% of patients have epilepsy. Electrophysiological data (based on nerve conduction, visual, brainstem and somatosensory evoked potential studies) suggest that, similar to metachromatic leukodystrophy and Krabbe disease, the disease involves both the central and peripheral nervous system [533].

while they may be more prominent at the level of cerebellum. Quantitative 1H MRS in Salla disease revealed an interesting phenomenon. In contrast to most neurometabolic disorders (with the exception of Canavan disease), the overall NAA signal was found to be increased in the cerebral white matter (and not within the basal ganglia), probably due to a contribution from accumulated free N-acetylneuraminic acid (sialic acid) deposits within the lysosomes. Otherwise, increase of Cr and decrease of Cho content was demonstrated [536].

Imaging Findings

Typical MRI abnormalities in Salla disease are hypoplasia of corpus callosum, brain atrophy, and extensive white matter disease [533, 534] (Fig. 13.99). In the infantile age, severely delayed myelination is seen on MR images. The process of myelination may show some progression later, but remains abnormal. White matter abnormalities, which are seen mainly within cerebral hemispheres, may also be present within the brainstem and cerebellum [53, 535]. In some cases, progression of white matter abnormalities may be detected on follow-up studies. As in many other lysosomal storage disorders, these are believed to represent a combination of dys- and demyelination [53]. However, severity of these changes is usually in good correlation with severity of clinical phenotype and age of the patients. In milder clinical forms, for example, the internal capsules and immediate periventricular white matter structures may be relatively spared. The atrophic changes are usually mild supratentorially and minimal at the level of brainstem,

13.4.6.11 Chédiak-Higashi Disease

Chédiak-Higashi syndrome is a special autosomal recessive lysosomal disorder, because it is not due to a specific enzyme deficiency but to a fusion defect of primary lysosomes. Clinically, patients present in early infancy with oculocutaneous albinism, immunodeficiency (with frequent intercurrent pyogenic infections), and later with pancytopenia, splenomegaly, lymphadenopathy, and increased incidence of malignancies. All nucleated cells (including neuronal cells) and platelets contain giant lysosomal cytoplasmic inclusion granules. On histopathological examination, lymphocytic infiltration is seen at the level of leptomeninges, choroid plexuses, perivascular spaces, and peripheral nerves. From the neurological standpoint, peripheral neuropathy and progressive neurological deterioration, sometimes resembling olivopontocerebellar degeneration, are the most characteristic features of

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the disease, but affected patients are also prone to intracranial hemorrhagic complications. Imaging Findings

Reported imaging studies are sparse. The most common findings are atrophy and ill-defined, predominantly periventricular white matter disease [16] (Fig. 13.100).

13.4.7 Peroxisomal Disorders The peroxisomes are ubiquitous cellular organelles. Peroxisomal enzymes are involved in multiple metabolic pathways, including lipid metabolism. Peroxisomes are particularly abundant in the oligodendrocytes in neonates and infants. Their functional integrity is, therefore, indispensable in normal myelination and myelin maintenance pro-

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cess; hence, peroxisomal diseases typically present with CNS involvement with predilection of white matter (hypo-, dys-, and demyelination). The remarkable heterogeneity of peroxisomal disorders is explained by the complexity of the underlying biochemical derangements [537]. Schematically, two types of peroxisomal disorders are known: the so-called peroxisome biogenesis or assembly disorders and single protein defects [538]. Peroxisome assembly deficiencies (generalized peroxisomal disorders) are complex enzymatic deficiencies caused by dysfunction of practically all or several peroxisomal enzymes. Recent studies suggest that the underlying defect is at the level of transport of peroxisomal enzymes from cytosol (where they are synthesized) into peroxisomes (where they actually carry out their functions). Enzyme markers are recognized by peroxisomal membrane receptors, whose lack or deficiency prevents the migration of the enzymes into the peroxisomes; hence, these remain in the cytosol

Metabolic Disorders Fig. 13.100a–d. MR imaging findings in a 5-month-old male patient with ChédiakHigashi syndrome. a–d Axial T2-weighted fast spin-echo images. The overall pattern is quite similar to that seen in GM2 gangliosidosis. Extensive, diffuse white matter disease (probably a combination of hypomyelination and demyelination), showing an antero-posterior gradient. Note involvement of the extreme and external capsules and lateral and medial medullary laminae. The corpus callosum and the posterior limbs of internal capsules are relatively spared. The deep cerebral gray matter structures are abnormal; the most prominent signal abnormalities are seen within the putamina. Conversely, the brainstem and cerebellum are normal

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and subsequently disintegrate. In such cases, the peroxisomes are poorly developed and are not or hardly visible under the microscope. Peroxisome assembly deficiencies result in severe, often lethal polymalformative disorders, which are also characterized by early, often neonatal onset. The CNS, including sensory organs, and liver are almost always involved; occasionally, especially in the most severe forms, the kidneys, adrenal glands, and bones are also affected [539]. Infants present with hypotonia, difficulty in sucking and swallowing requiring gavage feeding, myoclonic seizures, abnormal vision (cataracts, retinopathy), and abnormal facies. Disease entities in this group include Zellweger syndrome (and Zellweger-like syndrome), neonatal adrenoleukodystrophy, infantile Refsum disease (and its variants pseudo-infantile Refsum disease, atypical Refsum disease), and probably hyperpipecolic acidemia. A clear-cut genotypic-phenotypic correlation in these initially clinically defined entities, however, is not established [57, 540, 541].

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The other group of peroxisomal disorders comprises single protein (enzyme) deficiencies, which may also be explained by failure of peroxisomal membrane transport (only one type of receptor may be missing); however, deficiency of specific enzymes may also occur. The peroxisomes appear microscopically normal, enlarged, or underdeveloped in this group. The resultant diseases are usually of later onset and the disease course may be more protracted and sometimes more benign, although lethal forms also exist. The best known diseases in this group are pseudoneonatal adrenoleukodystrophy (acyl coenzyme A oxidase deficiency), X-linked adrenoleukodystrophy, adrenomyeloneuropathy, classical Refsum disease, pseudo-Zellweger syndrome (peroxisomal thiolase deficiency), mevalonic aciduria, hyperoxaluria type 1, bifunctional protein deficiency, and glutaric aciduria type 3. Rhizomelic chondrodysplasia punctata is an intermediate form between generalized and single protein peroxisomal disorders, in which the peroxisomes

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are present but several peroxisomal functions are impaired. Peroxisomal disorders show remarkable clinical phenotypic heterogeneity. However, dysmorphic features, neurological abnormalities, and hepatointestinal dysfunction are characteristic for many of them. Indeed, peroxisomal diseases should always be suspected in a neonate presenting with a polymalformative syndrome associated with severe neurological disturbances. Biochemically, the majority of peroxisomal disorders is characterized by accumulation of very long-chain fatty acids, thereby providing a good screening opportunity. Imaging abnormalities also span over a wide spectrum of patterns, the most characteristic being neuronal migration disorders with hypo-, dys- and demyelination (e.g., Zellweger syndrome, neonatal adrenoleukodystrophy) and symmetrical demyelination with involvement of supra and/or infratentorial, typically posterior white matter structures (e.g., pseudoneonatal adrenoleukodystrophy, X-linked adrenoleukodystrophy-adrenomyeloneuropathy complex) [537]. Recently, MRI evidence of dramatic improvement of the myelination status in generalized peroxisomal disorders (Zellweger syndrome and infantile Refsum disease) was reported in patients treated with docosahexanoic acid [149]. 13.4.7.1 Zellweger Syndrome

Zellweger syndrome is the most severe, prototype form among peroxisomal assembly deficiencies. In this disease, practically all peroxisomal functions are absent. This autosomal recessive disease is of neonatal onset and is also called cerebrohepatorenal syndrome, referring to its typical multiorgan involvement. While in normal individuals liver and kidney cells are particularly rich in peroxisomes (consistent with their significant metabolic activity), in Zellweger disease there is a total absence of peroxisomes within the liver. This obviously has serious systemic consequences. Affected children present with facial dysmorphia (micrognathia, shallow orbital ridges, low/broad nasal bridge, high forehead, external ear deformity), severe neurological abnormalities (hypotonia, hypo- or areflexia, psychomotor retardation, visual and hearing deficit, seizures), and hepatodigestive problems (hepatomegaly, prolonged jaundice or even gallstones), but do not have adrenocortical insufficiency [542, 543]. Ophthalmological abnormalities (congenital glaucoma and cataracts, corneal clouding, pigmentary retinopathy) are also frequent. Laboratory abnormalities include high plasma levels of phytanic acid, pipecolic acid, bile acid intermediates, and saturated and unsaturated very long-chain fatty acids.

Infants with Zellweger disease fail to thrive and usually die during early infancy (before the age of 1 year). Histopathological workup of brain shows cortical dysplasia (pachygyria, polymicrogyria, parietal clefts), neuronal migration disorders, and dysplastic dentate and inferior olivary nuclei. There is evidence of both dys- and demyelination [544]. Imaging Findings

In keeping with the aforementioned pathological observations, the MRI hallmarks of Zellweger disease are markedly delayed (sometimes almost arrested) myelination, brain atrophy, periventricular germinolytic cysts, bilateral, symmetrical, predominantly perisylvian cortical dysplasia (polymicrogyria), and additional gray matter heterotopias [28, 545, 546]. Combination of the above features defines a practically pathognomonic imaging pattern. Diffuse, markedly delayed myelination is easily appreciated in both the inversion recovery and T2weighted images (Fig. 13.101). Analysis of the cortical ribbon in the temporo-parietal regions always reveals polymicrogyria-like changes. It is likely that the entire cerebral cortex is abnormal in these patients, but the nature and extent of abnormalities show regional and individual variations [546]. Cortical gyral abnormalities are often easier to identify on T2- than on T1weighted images (Fig. 13.4). The use of high resolution matrix significantly enhances their conspicuity. Subependymal, so-called germinolytic, cysts are occasionally present along the frontal horns of the lateral ventricles [28, 546] (Fig. 13.102). Incomplete opercularization, verticalization of the Sylvian fissures, colpocephaly [547], cerebellar cortical dysplasia, and hypo- or dysplasia of inferior olives have been also described [547]. I have seen one case with partial callosal dysgenesis. The presence of both white and gray matter abnormalities as well as the dysmorphic-dysplastic changes of the brain are in keeping with a profound metabolic abnormality of early intrauterine onset. Additional imaging workup shows calcification within the patella and acetabulum (plain X-rays) and cysts within the kidneys (US, CT) [548]. 1 H MRS may show marked NAA decrease in the white and gray matter, thalamus and cerebellum, in conjunction with an increase in Cho and cerebral glutamate and glutamine. Furthermore, decrease of mI in the gray matter probably reflects the concomitant effect of the disease on hepatic function. Increased mobile lipids in white matter (related to demyelination or abnormal storage of neutral fat within astrocytes and phagocytes) and an increase in lactate levels may also be detected [549, 550]. These findings are

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Fig. 13.101a–h. MR imaging findings on axial T1-weighted inversion recovery images in Zellweger disease. a–d 3month-old female patient. The myelination on these images is just a little more advanced than the neonatal pattern. e–h 5-month-old female patient. The myelination is somewhat more advanced but poor myelination within the optic radiations and splenium of the corpus callosum indicate that it is clearly delayed

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Fig. 13.102a–c. Germinolytic cysts in Zellweger disease. a Sagittal T1weighted spin-echo image in a 10-month-old male patient. b, c. Coronal T2-weighted fast-spin-echo (b) and gradient-echo image (c ) in a 6-monthold female patient. Subependymal germinolytic cysts (arrows) are present along the lateral walls of frontal horns on both sides. These are easier to depict on gradient echo image in this case, but the best imaging modality is FLAIR technique (see Fig. 13.52)

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not specific but provide insight into the pathological effects (neuronal and axonal degeneration, demyelination) of profound peroxisomal dysfunction on the developing brain (Fig. 13.103). From an imaging standpoint, the only theoretical differential diagnosis of Zellweger disease is fumaric aciduria, an extremely rare organic aciduria. This disease usually presents in early infancy with developmental delay, hypotonia, and seizures. It is associated with dysmorphic facial features. Most infants have polycythemia at birth. The MRI workup of the patients shows bilateral perisylvian polymicrogyria, open opercula, small brainstem, ventriculomegaly, and delayed myelination [48]. 13.4.7.2 Neonatal Adrenoleukodystrophy

This is an autosomal recessive disorder of neonatal onset. Although the disease shares many features

with Zellweger syndrome, dysmorphic features are less prominent and skeletal abnormalities are absent in neonatal adrenoleukodystrophy. Involvement of the CNS is always suggested already at birth by the presence of severe hypotonia, hearing loss, retinal degeneration, and seizures. Hepatomegaly and impairment of adrenocortical function are also hallmarks of the disease. The overall clinical presentation and the course of the disease are milder than in Zellweger disease. Affected patients usually die during late infancy, but occasionally may survive into childhood. Typical laboratory findings (increased plasma phytanic acid, saturated very-long-chain fatty acids and frequently, but not always, high pipecolic acid levels) lead to the correct diagnosis. Increased plasma ACTH level indicates abnormal adrenal function. On autopsy, neuronal migration defects are less severe than in Zellweger syndrome or even absent, but there is evidence of demyelination within the cerebrum, cerebellum and, rarely, within the tegmentum of brainstem [544, 551].

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Fig. 13.103a,b. Single-voxel proton MR spectroscopic findings in a 4-month-old female patient with Zellweger disease (PRESS technique, sampling voxel 2x2x2 cm, positioned on the subinsular region, including both gray and white matter structures). a On the spectrum at 135 ms echo time, NAA is markedly decreased and Cho is increased compared to age-matched normal controls (compare with Fig. 13.20c), indicating immaturity of the brain with increased myelin turnover, probably corresponding to demyelination in this case. A small, but clearly abnormal negative peak doublet is seen at the 1.3 ppm level. b On the spectrum at 270 ms echo time, the peak doublet at the 1.3 ppm level shows the J-coupling phenomenon, confirming that it corresponds to lactate

Imaging Findings

CT and MRI findings are compatible with dys- and/ or demyelination within the cerebellar and cerebral white matter [551]. Neuronal migration disorders (polymicrogyria, gray matter heterotopia) may also be conspicuous. The presence of contrast uptake in involved areas described on CT images suggests an active, perhaps inflammatory process, similar to that seen within the active inflammation zone in X-linked adrenoleukodystrophy [552].

cal examination shows malformation of the cerebral hemispheres. At the level of the cerebellum, atrophy or hypoplasia with cortical abnormalities (hypoplasia of cerebellar granular layer and ectopic location of Purkinje cells in the molecular layer) is found. There is mild volume reduction of the cerebral white matter (hypomyelination) but no evidence of active demyelination. The main autopsy findings are liver cirrhosis and hypoplastic adrenals [544, 554]. Imaging Findings

13.4.7.3 Infantile Refsum Disease

This is the least severe of the classical triad (Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease) of peroxisomal assembly deficits. The onset of the disease is later, and the development of affected infants may be normal up to the age of 6 months. The course of the disease is more protracted and death usually occurs during childhood or adolescence [553]. Although facial dysmorphia, growth retardation, retinitis pigmentosa, deafness, and other signs of encephalopathy are always present in this disease, the clinical picture is often dominated by hepatic-digestive problems. In contrast to Zellweger disease, chondrodysplasia and renal abnormalities are absent. Plasma levels of very-long-chain fatty acids, phytanic acid, pipecolic acid, and bile acid intermediates are elevated. Histopathologi-

In two siblings with infantile Refsum disease, one patient did not have detectable abnormalities by MRI. The other, a female patient, was found to have bilateral dentate nucleus signal abnormalities only [553]. In a subset of late onset peroxisomal assembly deficiencies (clinically exhibiting some, but not all, features of neonatal adrenoleukodystrophy or infantile Refsum disease) cerebral (mainly posterior with sparing of subcortical U-fibers) and cerebellar white matter disease, consistent with demyelination, was found [555]. 13.4.7.4 Hyperpipecolic Acidemia

Increased plasma pipecolic acid levels are present in other peroxisomal disorders; therefore, true hyperpipecolic acidemia refers to a disease in which high plasma and urinary levels of pipecolic acid are the only detectable biochemical abnormality.

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Imaging Findings

No reports on the imaging findings in hyperpipecolic acidemia are available to date. In three siblings with true hyperpipecolic acidemia, the association of Joubert syndrome has been described. 13.4.7.5 Rhizomelic Chondrodysplasia Punctata

In this rare autosomal recessive metabolic disease, multiple (phospholipid synthesis, oxidation of phytanic acid, and thiolase processing), but not all peroxisomal functions are absent. There is no accumulation of very-long-chain fatty acids. Dysmorphic features are evident at birth. Shortening of the proximal parts of the extremities (rhizomelic dwarfism) is the most characteristic physical examination finding. Severe psychomotor delay, failure to thrive, ichthyosis, and cataract complete the clinical syndrome. Phytanic acid levels are increased, but very-long-chain fatty acids are normal. The disease usually leads to death during the first year of life. Conradi-Hünermann syndrome is an autosomal dominant variety of rhizomelic chondrodysplasia punctata, characterized by less severe shortening of the limbs, lower prevalence of cataracts and psychomotor retardation, and a more protracted clinical course. Imaging Findings

Besides the straightforward abnormalities of the extremities, plain X-ray examination reveals more profound skeletal abnormalities, including calcifications within the epiphyseal cartilage, metaphyseal cupping, stippling of the epiphyses, and coronal clefts in the vertebral bodies. Brain MRI findings are dominated by white matter abnormalities, mainly involving the posterior cerebral areas. In a neonate, MRI revealed ill-defined signal abnormalities within the subcortical white matter in the frontal and parietal regions. There was no malformation or myelination abnormality [556]. In another patient, parieto-occipital white matter lesions were found at age 2.5 and 8.5 months in conjunction with progressive brain atrophy [557]. MRI findings in a 3-year-old male patient suggested a combination of delayed and dysmyelination, mainly in the occipital white matter [537]. In a 6-month-old female patient, severe cervical spinal canal stenosis with compression of spinal cord was found by both conventional X-ray and, later, MRI studies [558].

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H MRS in a neonate (the same patient referred to above) showed increased mobile lipids and mI in conjunction with reduced Cho and abnormal acetate [556]. The presence of mobile lipids and acetate was attributed to consequences of the underlying metabolic abnormality affecting phospholipid synthesis, notably accumulation of long chain acyl-coenzyme A (due to deficiency of dihydroxyacetonephosphate acyltransferase) and secondary inhibition of acetylcoenzyme A carboxylase, leading to in situ acetate synthesis within the brain. 13.4.7.6 Pseudoneonatal Adrenoleukodystrophy

Patients with pseudoneonatal adrenoleukodystrophy usually do not have dysmorphic features; clinical presentation of the disease is, however, quite similar to neonatal adrenoleukodystrophy. In contrast to that, however, in pseudoneonatal adrenoleukodystrophy, liver peroxisomes are present and actually enlarged. The underlying enzyme defect in this disease was found to be a deficiency of peroxisomal acyl-coenzyme A oxidase, resulting in impaired peroxisomal β-oxidation system. Affected patients present with psychomotor retardation and seizures. Imaging Findings

Initially, only delayed myelination is observed. In one patient, follow-up MRI study at the age of 3 years showed symmetrical signal abnormalities within the optic radiation, periventricular centrum semiovale, posterior limbs of internal capsules, pyramidal tracts at the level of the brainstem, and cerebellar white matter [537]. In another report, a 16-month-old female infant showed a markedly thin corpus callosum and underdeveloped cerebellum in conjunction with diffuse white matter abnormalities, suggestive of severely delayed myelination or demyelination. There was also evidence of foramen magnum stenosis and underdevelopment of the skull base [54]. 1 H MRS in a 10-month-old patient with a follow-up at the age of 13 months showed an absolute decrease of all metabolites, although NAA was more markedly decreased than Cho or Cr. The latter was interpreted to indicate diminished cell populations [550]. 13.4.7.7 X-Linked Adrenoleukodystrophy

This is the best known and most frequent among peroxisomal disorders. This entity belongs to the single enzyme (very-long-chain fatty acid-coenzyme A syn-

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thetase) deficiencies. In fact, either the enzyme itself is defective or, more likely, its peroxisomal membrane transport is impaired. The inheritance is X-linked recessive (the only such disease among peroxisomal diseases), but female carriers are not always entirely asymptomatic. The gene is mapped to Xq28. X-linked adrenoleukodystrophy has several clinical phenotypes [559]. The classical form is the childhood-onset cerebral phenotype. It seems, however, that the most common phenotype may actually be the adrenomyeloneuropathy form, which is discussed later. Atypical forms have also been described (adolescent- and adult-onset cerebral forms, self-limiting late-onset form, isolated adrenal insufficiency, asymptomatic phenotype, and heterozygote female phenotype). The age of onset in the classical childhood onset cerebral phenotype is usually between 4 and 8 years, but signs of adrenal insufficiency (hyperpigmentation, frequent intercurrent infections) may appear earlier. Neurological manifestations are slowly progressive, although acute onset has also been reported [560, 561]. The first manifestations of the disease are behavioral disorder, poor concentration and school performance, gait disturbances, visual and hearing problems, or seizures. Visual problems include decreased visual acuity, diplopia, and progressive loss of vision leading to cortical blindness. Transient visual symptoms after an acute illness (hypoglycemia and head trauma) have also been reported as the initial clinical manifestations of X-linked adrenoleukodystrophy [97]. Typically, the disease shows a relentlessly progressive character with dementia, spastic quadriplegia, total deafness, and decorticate state before death. Imaging Findings

X-linked adrenoleukodystrophy is a true leukodystrophy, with no involvement of gray matter structures. MRI findings are very characteristic, in most cases actually pathognomonic. It is noteworthy that MR abnormalities may precede the first clinical manifestations [562]. White matter abnormalities typically (80%) appear to be localized to the occipital region initially. The subcortical U fibers are spared for quite a long time. The splenium of the corpus callosum, posterior parts of the posterior limbs of the internal capsules, geniculate bodies, and pyramidal tracts within the brainstem are involved early in the disease course [563] (Fig. 13.104). Involvement of the external capsules and infero-lateral parts of thalami has also been described [537]. MRI data can be compiled into

a scoring system and this, together with the age of onset, was found to have prognostic value [564, 565]. The progression pattern of white matter abnormalities is centrifugal and postero-anterior [537]. This results in the most characteristic imaging (and histopathological) feature of the disease [544]. Three distinct zones (Schaumberg zones) are identified within hemispheric white matter lesion areas. The center of the lesion area, which presents with prominent hyposignal on T1-, and hypersignal on T2-weighted images, corresponds to the fully demyelinated, inactive burned-out zone. Dystrophic calcifications may be detected within this zone on CT (Fig. 13.105). Histologically, this area is characterized by irreversible axonal and myelin destruction, astrogliosis and absence of oligodendrocytes and inflammatory cells. Around this area, an intermediate zone is seen, which is best visualized anteriorly. It is only faintly hyperintense on T2-weighted images and often faintly hyperintense on T1-weighted images (Fig. 13.106). After intravenous contrast injection, signal enhancement is frequently but not always seen in this zone; if this is present at the time of the initial MR examination, it may have a positive predictive value for disease progression [566] (Figs. 13.14, 107). Histopathologically, this corresponds to the inflammatory zone, presenting perivascular lymphocytic infiltrates and myelin damage. Peripherally, another zone is identified, which is only faintly hypointense on T1-weighted images; on T2-weighted images, signal intensity in this zone is between those in the burned out and the inflammatory zones. This is a zone of active demyelination, but axons are preserved. Separation between this zone and, more anteriorly, the apparently normal, yet not affected, white matter is ill-defined. Rarely, the disease starts in the frontal lobes (15%), in which case the progression pattern is antero-posterior (with involvement of the rostrum of the corpus callosum and anterior limbs of internal capsules) [567]. Exceptionally, white matter changes are asymmetrical; this may cause differential diagnostic problems (infiltrative tumor, viral encephalitis) [95]. The cerebellar white matter is spared in some cases and involved in others, and perhaps these lesions appear in a more advanced stage of the disease. The middle cerebellar peduncles may also show signal abnormalities. When the cerebellar white matter and middle cerebellar peduncles are involved simultaneously with the occipital white matter, the pattern may be reminiscent of Krabbe disease. In the terminal stage of the disease, all supratentorial and cerebellar white matter structures are involved, including the subcortical U-fibers and the internal and external capsules [537].

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Fig. 13.104a–c. Involvement of corticospinal tracts within brainstem in Xlinked adrenoleukodystrophy in an 11-year-old male patient. a–c Axial T2weighted fast spin-echo images. Abnormal hypersignal is seen along the entire brainstem course of the corticospinal tracts bilaterally (arrows), notably at the level of cerebral peduncles (c), pons (b) and medulla oblongata (a)

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Fig. 13.105a,b. Calcifications in a 10-year-old male patient with X-linked adrenoleukodystrophy (courtesy of Dr. P. Tortori-Donati, Genoa, Italy). a, b Axial CT scans show calcifications within the hypodense cerebral white matter lesions bilaterally

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Fig. 13.106a–d. Conventional MR imaging findings in a 12-year-old male patient with X-linked adrenoleukodystrophy. a, b Axial T2-weighted fast spin-echo images. Symmetrical bilateral white matter lesions involving the parieto-occipital regions exhibiting a centrifugal progression pattern. The signal abnormalities extend to the posterior parts of internal, external, and extreme capsules, as well as the splenium of corpus callosum and postero-lateral parts of the thalami. This pattern indicates an additional posteroanterior gradient. c, d Axial T1-weighted inversion recovery images. The subcortical U-fibers are still spared in some, and already involved in other areas around the lesions

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Fig. 13.107a–c. Diffusion-weighted and gadolinium-enhanced T1-weighted imaging findings in an 11-year-old male patient with X-linked adrenoleukodystrophy (same patient as in Fig. 13.104). a Axial diffusion-weighted echo-planar image (b = 1000s). The central (burned-out) zones of the parieto-occipital lesions are markedly hypointense, the intermediate (inflammatory) zone is markedly hyperintense, and the peripheral (demyelinating) zone is faintly hyperintense. b Axial apparent diffusion coefficient (ADC) map image. This image suggests that the central burned-out zone is characterized by isotropically increased water diffusion and the inflammatory zone by relatively restricted water diffusion. In the most peripheral demyelinating zone, the hypersignal on diffusion-weighted image is most probably due to T2 shine-through artifact. c Gd-enhanced axial T1-weighted spin-echo image. The contrast enhancement is confined to the inflammatory zone

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In heterozygote female carriers, conventional MRI usually does not show abnormalities; rarely, subtle occipital and/or frontal periventricular signal changes may be present on T2-weighted images. MRI of spinal cord in both symptomatic and asymptomatic patients revealed atrophy in the thoracic region only or in the cervical and thoracic regions [568]. On diffusion-weighted images, the three distinctly different lesion zones in the cerebral hemispheric white matter lesions are also conspicuous. The burned-out zone is hypointense (total loss of diffusional anisotropy due to loss of tissue matrix), the intermediate inflammatory zone is moderately hyperintense, and the most peripheral demyelinating zone is very faintly hyperintense (Fig. 13.107). Diffusion tensor imaging may offer higher sensitivity than conventional MRI or DWI in the detection of early demyelination by demonstrating increased isotropic diffusion and decreased fractional anisotropy in normal-appearing white matter structures [569]. X-linked adrenoleukodystrophy has been extensively investigated by 1H MRS over the past years. 1 H MRS seems to be a sensitive indicator of brain involvement and disease progression. The detected metabolic abnormalities are, however, nonspecific. At the beginning of the disease, increased lactate, decreased NAA, and increased Cho peaks were found within the lesion areas [63, 75, 570]. Cr may also be elevated initially. Later, all metabolites decrease except mI, which appears to be relatively stable. More detailed examinations revealed regional differences depending on the sampling area (burnedout zone, active inflammation-demyelination, and apparently normal area). Indeed, a clear-cut gradient of metabolic abnormalities can be demonstrated by multivoxel 1H MRS, showing a severe decrease of NAA in the maximally affected area and progressive increase towards the “normal” regions. The lactate concentrations show a similar pattern. These findings were associated with an opposite tendency of the Cho peaks [571] (Fig. 13.108). In the burned-out zone, all peaks, but particularly NAA, are markedly decreased, consistent with global tissue disintegration. In the inflammatory and demyelinating zones, the NAA peak is decreased and the Cho peak is somewhat increased. Decreased NAA indicates loss of neuroaxonal integrity secondary to myelin breakdown; the latter is demonstrated by increased Cho. mI is normal or slightly increased. Lactate is present in all zones. Accumulation of lactate in active demyelination-inflammation zones is attributed to lymphocytes and to tissue necrosis in the burned-out zone.

In both clinically and radiologically asymptomatic and symptomatic patients (including heterozygote female carriers), 1H MRS may also demonstrate early metabolic changes in white matter areas which are apparently normal on conventional MR images. The increase of the Cho peak (and of the Cho/Cr ratio) in normal-appearing white matter probably reflects increased myelin turnover or low-grade demyelination [75, 570, 572–575]. On the other hand, no elevation of Cho may be demonstrated in definite lesion areas if these are stable on follow-up studies [571]. Response to therapy and, in particular, to bone marrow transplantation, may also be successfully monitored by 1H MRS [576]. 1 H MRS also confirmed a distinct metabolic character in a possible subset of adrenoleukodystrophy presenting with relatively late onset and showing spontaneous arrest of the disease process both clinically and on imaging. The 1H MRS pattern differs from those of classical X-adrenoleukodystrophy and adrenomyeloneuropathy in that, in these patients, no lactate is demonstrated, NAA is moderately decreased, Cho is normal or reduced, and mI is normal or moderately increased [577]. 13.4.7.8 Adrenomyeloneuropathy

Adrenomyeloneuropathy is not an independent disease entity; it is actually one of the clinical phenotypes of X-linked adrenoleukodystrophy, perhaps the most common but underrecognized one [559, 578]. The age of onset is usually between 20 and 30 years (therefore, it is usually not encountered in the pediatric patient population), but since both clinical and imaging findings are quite different from those in X-linked adrenoleukodystrophy, it is probably appropriate to discuss the disease separately. Although usually signs and symptoms of cerebellar, spinal cord, and peripheral nerve involvement (notably ataxia, paraparesis, and peripheral neuropathy) dominate the neurological presentation, mild cognitive disorder is often present. Adrenal insufficiency is a frequently associated clinical finding. Imaging Findings

The lesion pattern in MRI is in keeping with the neurological picture [579]. The most frequently involved structures are the posterior limbs of the internal capsules, brainstem, and cerebellar white matter (Fig. 13.109). Signal abnormalities within the brainstem can be quite prominent, but tegmental structures are relatively spared. The cerebellar white matter is

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Fig. 13.108a–c. Regional single-voxel proton MR spectroscopic (PRESS technique, TE: 135 ms, sampling voxel: 2x2x2 cm) findings in a 12-year-old male patient with X-linked adrenoleukodystrophy (same patient as in Fig. 13.106). a The sampling voxel was positioned on the burned-out zone. Significant decrease of all normal brain metabolites and abnormal lactate at the 1.3 ppm level. b The sampling voxel was positioned on the inflammatory-demyelinating zone. Decreased NAA and slightly decreased Cr and increased Cho peaks. A small lactate peak is again present. c The sampling voxel was positioned on the normal-appearing white matter in frontal lobe. Normal NAA and Cr peaks and no lactate. The Cho peak is slightly increased

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Fig. 13.109a–d. MR imaging findings in adrenomyeloneuropathy. a–d Axial T2weighted fast spin-echo images. Atrophy of brainstem and cerebellum in conjunction with abnormal signal intensities involving the white matter (note relative sparing of tegmental structures at the level of brainstem) and extending to posterior limbs of internal capsules bilaterally

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diffusely abnormal. The brainstem and cerebellum are usually atrophic. Involvement of supratentorial white matter is limited mainly to the posterior limbs of internal capsules and, sometimes, the splenium of the corpus callosum [408]. Involvement of the posterior limbs of the internal capsules is sometimes the first detectable imaging abnormality. Occasionally, lesions may be seen within the hemispheric white matter, especially in the advanced stage of the disease [559]. Enhancement may also occur within the lesions after intravenous contrast injection. MRI studies may be initially normal in patients with definite disease; characteristic lesions may appear on repeated followups only [537]. Diffusion-weighted images are unremarkable; no apparent diffusion abnormality is detected on visual evaluation. 1 H MRS of cerebellar white matter lesions shows significantly decreased NAA peak with grossly normal Cr and Cho peaks and a small amount of lactate. If cerebral lesions are present, NAA decrease and Cho increase may be demonstrated [571]. Similar but subtle metabolic changes may be detected in the normal appearing white matter.

13.4.8 Unclassified Leukodystrophies A large number of inherited leukodystrophies have been identified in the past few decades and their number is constantly growing. The underlying genetic and metabolic abnormality has been elucidated in some and, conversely, it is not yet known in many others. These diseases cannot be classified in any of the previously described categories. Some fall into the category of so-called macrocephalic leukodystrophies, notably Canavan disease, van der Knaap disease, vanishing white matter disease, and Alexander disease. Other diseases, notably AicardiGoutières disease, Cockayne disease, and PelizaeusMerzbacher disease, usually present with progressive microcephaly. 13.4.8.1 Canavan Disease

Canavan disease is an autosomal recessive metabolic disease and the gene was mapped on chromosome 17. The underlying biochemical abnormality is derangement of the metabolism of N-acetyl-aspartate (NAA). NAA is a “brain-specific” substance, meaning that the brain is the only organ where NAA is synthesized. Its role is, however, unknown. NAA is synthesized from

acetyl-coenzyme A and aspartate and is metabolized into acetate and aspartate by aspartoacylase enzyme. Deficiency of aspartoacylase enzyme causes marked brain accumulation of NAA, which subsequently enters the blood pool and is eventually eliminated through urine as N-acetylaspartic acid. Hence, in the wide sense of the term, Canavan disease is actually an organic acidemia and aciduria. The laboratory diagnosis of Canavan disease is based on demonstration of increased urinary excretion of N-acetylaspartic acid by gas chromatography/ mass spectrometry. Aspartoacylase activity can also be measured in cultured skin fibroblasts and this can be used for carrier testing, since in asymptomatic carriers of Canavan disease the enzyme activity is about half of normal [580]. Histological examination of brain parenchyma in Canavan disease shows spongy degeneration of the white matter in conjunction with myelin edema (without axonal damage) and swelling of astrocytes. The exact pathomechanism of the damage is not fully understood, but there is increasing evidence to suggest that it may be related to a profound impairment of brain water homeostasis, resulting in fluid imbalance between intracellular (axon-glial) and extracellular (interlamellar) spaces within the myelinated white matter. In the brain, NAA is synthesized within the neurons, and is one of the most abundant low molecular-weight cellular metabolites in brain tissue. Its exact biochemical-physiological function was unknown for a long time; lately, however, it was suggested that NAA has a role in the molecular efflux water pump system. It is hypothesized that NAA functions as a water transporter. Since the synthesis of NAA remains intact in Canavan disease, “overproduction” of NAA within neurons leads to increased water migration from the axon into the periaxonal space. Normally, hydrolysis of NAA by myelin-associated aspartoacylase takes place in this space. If NAA is not catabolized, excess water builds up in the space between axons and oligodendrocytes, leading to increased osmolar pressure and probably causing rupture of the sealed interlamellar spaces and, hence, intramyelinic edema, which eventually leads to demyelination and loss of glial cells [581]. Although rare, neonatal and juvenile forms are also known. The disease is typically characterized by an early infantile onset. After the first few months of life, patients present with macrocephaly, head lag, loss of milestones, hypotonia, irritability, and visual loss. Later, spasticity of limbs develops; choreoathetoid movement disorder and seizures may also appear. The disease rapidly leads to severe neurological crippling and a vegetative state. Death occurs

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after a few years, but longer survivals, over 10 years, also exist [582, 583]. The clinical phenotype of the disease may be modulated by residual aspartoacylase activity, explaining variations in age of onset, course, and length of survival [142]. Imaging Findings

Imaging findings are pathognomonic in the fullblown stage of Canavan disease. In the burned-out phase, however, they may be nonspecific. Practically all white matter structures of brain are involved, and this is easily appreciated on CT studies [582]. The relative sparing of the internal capsules and corpus callosum during the early stage of the disease suggests a centripetal progression pattern. However, the spongiform changes and imaging abnormalities are

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not limited to white matter structures only. In keeping with histological observations, MRI clearly shows abnormalities within the thalami and globi pallidi (but, histologically, also the deep layers of cortex and dentate nuclei show vacuolation). The caudate nuclei, putamina, and claustra are spared (Fig. 13.110). In the burned-out phase, the brain is atrophic. DWI shows rather uniform hypersignal within the abnormal white matter structures, consistent with isotropically restricted water diffusion, compatible with intramyelinic edema [584]. In the burned-out phase of the disease this significantly decreases, and in some areas totally disappears (Fig. 13.111). Although the diagnosis of Canavan disease is easily made by urine tests, a specific diagnosis may also be made by 1H MRS [276, 568, 585, 586]. There is usually a relative or absolute increase of the NAA

Fig. 13.110a–d. Conventional MR imaging findings in a 1-year-old male patient with Canavan disease. a–d Axial T2-weighted fast spin-echo images. The white matter disease is already quite extensive, but in a few areas myelin is relatively spared. These include the ventral brainstem structures, lateral aspects of middle cerebellar peduncles, internal capsules, and corpus callosum. The latter suggest a centripetal progression pattern. Note involvement of the thalami and globi pallidi

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Fig. 13.111a–d. Diffusion-weighted MR imaging findings in Canavan disease. a–b Axial diffusion-weighted echo-planar images in a 1-year-old male patient with Canavan disease (same patient as in Fig. 13.110). During the acute stage of the disease, the cerebral hemispheric white matter exhibits a diffusely and quite homogeneously hyperintense appearance in most areas, suggesting isotropically restricted water diffusion. In the frontal and parietal-occipital periventricular areas, markedly hypointense zones are seen, most probably corresponding to tissue necrosis. c, d Axial diffusion-weighted echo-planar images in a 6-year-old male with Canavan disease. In the chronic stage of the disease, the abnormal white matter shows mild hypersignal in the frontal regions and faint hyposignal in the parietal lobes. An area of tissue necrosis is again seen in the right frontal periventricular region (d)

peak in patients with Canavan disease, in conjunction with decrease of Cho and Cr (Fig. 13.22). mI may also be increased and abnormal lactate is commonly demonstrated. To date, increase of the NAA peak has been described only in Canavan disease; therefore, it is considered to be pathognomonic of the disease. 13.4.8.2 Megalencephalic Leukoencephalopathy with Subcortical Cysts (van der Knaap Disease)

bances and, in later stages of the disease, mental deterioration and seizures develop. No peripheral neuropathy is detected. Laboratory tests fail to demonstrate any specific metabolic abnormality. Histologically, the findings are consistent with vacuolating myelinopathy [589]. Although most described cases are in infants or children, the disease has also been identified in adults. The clinical history and the neurological findings are similar. Imaging Findings

This is one of the most recently identified leukodystrophies; it was initially called infantile-onset spongiform leukoencephalopathy with a discrepantly mild clinical course [104]. The disease has an autosomal recessive inheritance; the gene was mapped on chromosome 22qtel. The disease appears to be panethnic [587, 588]. The initial motor and mental development of patients is either normal or slightly delayed. Onset of the disease is usually during the first year of life. Patients present with macrocephaly. Clinically, the disease is characterized by a slowly progressive course; in particular, ataxia, spasticity, gait distur-

MRI findings are pathognomonic (Fig. 13.112). The brain is diffusely swollen during the early stage of the disease; later, sulcal and ventricular enlargement may be present. White matter disease is always severe at the time of the initial workup and shows a clear centripetal progression pattern. The peripheral white matter structures of the cerebral hemispheres are the most severely involved, including widespread disappearance of subcortical U fibers and presence of large subcortical cyst formations in the fronto-parietal and temporal regions, best shown by FLAIR images [590] (Fig. 13.113). These changes, as well as the initial slight

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c Fig. 13.112a–e. Conventional MR imaging findings in a 19-month-old male patient with van der Knaap disease. a–d Axial T2-weighted fast spin-echo images. On the highest cut, the cerebral white matter is diffusely abnormal; the cortex is somewhat atrophic (d). Supratentorially, the corpus callosum, anterior commissures, internal capsules (not entirely) and central corticospinal tracts are spared (b, c). Note involvement of the extreme and external capsules, as well as of the medial and lateral medullary laminae (b). Subtle signal abnormalities are also seen within cerebellar white matter and brainstem (a). e Axial T1-weighted inversion recovery image at level corresponding to b shows subcortical cysts within the anterior portions of the temporal lobes bilaterally

Fig. 13.113. Subcortical cysts in van der Knaap disease (same patient as in Fig. 13.112). a, b Coronal FLAIR images. The subcortical cysts within the superior temporal gyri, which are hardly conspicuous on T2- and T1-weighted images, are clearly demonstrated with this technique

sparing of the periventricular and subcortical white matter in the occipital regions, suggest an additional antero-posterior gradient. The deep white matter structures, notably the corpus callosum and internal capsules, are spared, but the external and extreme capsules are involved. The cerebellar white matter is also

involved, although much less markedly than supratentorial white matter structures. Subtle signal changes may be present within the brainstem, especially along the pyramidal tracts. The deep gray matter structures are normal; the cerebral cortex appears to be somewhat atrophic in most cases. No abnormal signal enhance-

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ment is seen within the brain parenchyma after intravenous contrast injection. In adults with the disease, atrophy is present instead of brain swelling, with enlargement of both extra- and intracerebral CSF spaces [480, 588]. In the sibling of an affected patient, macrocephaly and delayed myelination were found in infancy without further progression to manifest disease [591]. DWI shows prominent hyposignal within the subcortical cysts and somewhat decreased signal within the affected white matter. The ADC is, however, increased [590]. This suggests diffuse loss of white matter anisotropy and increased diffusivity. No definite hypersignal is seen within the unaffected white matter structures or along the interface between normal and abnormal areas (Fig. 13.114). 1 H MRS findings in affected white matter are nonspecific. The NAA/Cr ratio is usually reduced, whereas the Cho/Cr ratio is increased [104, 592]. The severity of these changes is variable, probably reflecting the magnitude of tissue disintegration. No abnormal metabolites are demonstrated. In an adult, decrease of absolute quantities of NAA (damage of neuroaxonal units), Cr and Cho (loss of oligodendrocytes) was found, while mI was normal (proliferation of astrocytes). The metabolic changes within the cortex were less prominent. No abnormality was found within the basal ganglia [480]. 13.4.8.3 Vanishing White Matter Disease

Vanishing white matter (VWM) disease, also referred to as childhood ataxia with central hypomyelination

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(CACH) or myelinopathia centralis diffusa, is also one of the recently identified distinct clinical-radiological entities [98, 593]. The disease has an autosomal recessive inheritance. The gene was mapped on chromosomes 3q27 and 14q24 [594]. In fact, the disease is caused by abnormalities affecting the so-called eukaryotic translation initiation factor (eIF2B), which has five subunits. Mutations of any of the subunits cause the same disease [595–598]. The translation initiation factor is needed for initiation of translation of RNA into proteins under various conditions, including stress. This is probably the explanation of the known stress (i.e., trauma, febrile illness)-triggered commencement and subsequent episodic deteriorations of the disease. Clinical presentation of the disease is quite characteristic [98]. Initially, psychomotor development of patients is normal. The disease is typically of late infantile or early childhood onset, but later onset (late juvenile and adult) cases with milder disease course are also known [138, 599, 600]. The first clinical manifestations of the disease seem to be preceded by minor head trauma or infections. The same factors are also responsible for episodes of deterioration, sometimes leading to coma in infantile and early juvenile onset forms. The disease has an otherwise chronic progressive course. Affected patients present with ataxia, dysarthria, spasticity, gait disturbance, but only mildly impaired mental capacities. In a case with late adultonset form, however, the initial clinical manifestation of the disease was dementia [599]. During the later stages of the disease optic atrophy and mild epilepsy may develop. The disease is always progressive but the disease course varies. The severe forms may lead to

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Fig. 13.114a–c. Diffusion-weighted imaging findings in van der Knaap disease (same patient as in Fig. 13.112). a–c Axial diffusionweighted echo-planar images (b = 1000s). The demyelinated white matter exhibits a hypointense appearance, suggestive of fully accomplished demyelinating process. The temporal subcortical cysts are well appreciated as well

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death at relatively young age (2–6 years), but patients with more moderate clinical phenotypes, living into young adulthood, have also been described. As a peculiar biochemical feature of the disease, laboratory workup of the CSF of affected patients shows marked elevation of glycine [601]. Imaging Findings

The MRI pattern of VWM disease is highly suggestive [98]. The brain appears to be slightly swollen and the gyri are somewhat broadened. The lateral ventricles show no, mild, or moderate dilatation. Cerebral hemispheric white matter changes are very prominent; signal properties of affected myelin are practically identical to those of CSF both on T1- and T2-weighted images. On proton density-weighted and FLAIR images, markedly hypointense areas are seen within deeper white matter regions, most probably corresponding to cavitations [598]. These may be absent during the early stage of the disease. The subcortical U fibers are usually involved, but may be

Fig. 13.115a–c. MR imaging findings in an 18-year-old female patient with vanishing white matter disease (courtesy of Dr. M. van der Knaap, Amsterdam, The Netherlands). a–c Sagittal T1-weighted spin echo (a), axial T2-weighted fast spin-echo (b) and axial FLAIR (c) images. Extensive white matter disease with involvement of the subcortical U-fibers. The signal properties of the involved white matter are almost identical to those of the CSF on all images. Note the relative sparing of the cerebellar white matter

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partially spared during the early stages of the disease. The posterior limbs of the internal capsules are often involved, whereas the anterior limbs are spared. The external and extreme capsules are always abnormal. The corpus callosum is also involved, except for its outer rim. The cerebellum is usually atrophic with vermian predominance. The cerebellar white matter is also abnormal, including the hili of the dentate nuclei. In the brainstem, central tegmental and pyramidal tracts also show abnormal hypersignal on T2weighted images. The gray matter structures, including the cerebral cortex and basal ganglia, appear to be normal. Incidentally, persistent cavum septi pellucidi and Vergae are quite frequently found, but the significance of this is unclear. On follow-up studies, the extent of white matter abnormalities and, in particular, of cavitations increases and atrophic changes also progress (Fig. 13.115). DWI findings of VWM disease have not been reported yet. 1 H MRS of gray matter shows decreased NAA, normal or slightly increased Cho, rather prominent

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lactate and glucose (at 3.43 and 3.80 ppm, respectively) peaks. When the sampling voxel is placed on affected white matter, very small, practically undetectable NAA, Cr, Cho, and mI peaks are obtained. Small amounts of glucose and lactate may, however, still be discernible [98]. In late onset forms, MRS abnormalities are similar, but less pronounced [138]. 13.4.8.4 Alexander Disease

This is a rare, sporadic “macrocephalic” leukodystrophy without clear inheritance pattern. It is perhaps autosomal dominant and the underlying abnormality may be an overexpression of the gene of so-called glial fibrillary acidic protein (GFAP), located on chromosome 11q13. The disease has neonatal, infantile, juvenile, and adult forms. The most frequent form is the infantile form, presenting delayed psychomotor development, failure to thrive, hypotonia, swallowing difficulties, and seizures, rapidly leading to death usually before the end of the first year of life. In the infantile onset form, macrocephaly is very characteristic; in late onset forms (juvenile and adult) it is not apparent. The adult form, which only very rarely has been described in children, is prevailingly characterized by bulbar signs [602]. Neuropathological findings in Alexander disease are characterized by abundance of so-called Rosenthal fibers (eosinophilic deposits within fibrillary astrocytes, which are probably composed mainly of aggregated GFAP) and widespread myelin loss. Imaging Findings

The imaging findings of the infantile form are concordant with the histological abnormalities. Supratentorially, extensive white matter disease is seen, showing a centripetal progression pattern with an additional antero-posterior gradient. Indeed, the periventricular white matter, posterior limbs of internal capsules, and splenium of corpus callosum may be relatively spared or normal initially. Large cystic lesions are typically seen in the frontal and temporal regions. The cortex appears to be normal, but basal ganglia abnormalities are common [603]. In the early stages of the disease, the basal ganglia may be swollen; later, they are atrophic (Fig. 13.116). The cerebellum also shows abnormalities, notably involvement of the hemispheric white matter and hilus of dentate nuclei and atrophy. On postcontrast T1-weighted images, signal enhancement along the ependymal lining of the lateral ventricles, sometimes extending to more remote areas of the frontal lobes and within the deep cerebral gray matter

structures is a frequent finding; occasionally, it may be seen at the level of dentate nuclei, midbrain, optic chiasm and fornix (Fig. 13.14). If stringent evaluation criteria are applied, the MRI lesion pattern is considered to be pathognomonic [46]. The imaging features that were found to be crucial in MRI-based diagnosis are extensive cerebral white matter disease with frontal predominance, sparing of periventricular structures, deep gray matter abnormalities, involvement of mesencephalon and medulla oblongata, and contrast enhancement. Presence of four of the five criteria allows correct diagnosis, hence obviating invasive diagnostic brain biopsy. 1 H MRS evaluation of obvious frontal white matter abnormalities showed markedly decreased NAA and abnormal lactate. In relatively preserved occipital regions, only slight decrease of the NAA peak was found, without an abnormal lactate peak [276]. These findings are consistent with the typical antero-posterior progression pattern of the disease. It is noteworthy that the adult form of Alexander disease differs from the infantile form not only clinically, but also on imaging. The prevalence of bulbar signs finds a correspondence on the MRI picture, which is characterized in younger patients by T2 signal abnormalities in the medulla compatible with areas of demyelination, while in older patients atrophy of the medulla is found [602]. Moreover, in a juvenile case we observed, lesions were restricted to the dorsal medulla, middle cerebral peduncles, and dentate nuclei, and enhanced with intravenous gadolinium administration (Fig. 13.117). 13.4.8.5 Leukodystrophy with Brainstem and Spinal Cord Involvement and High Lactate

This is the most recent of the newly identified leukodystrophies [43]. The underlying genetic and biochemical abnormalities are unknown to date; however, the disease seems to have an autosomal recessive inheritance. The first clinical manifestations of the disease typically appear in childhood, more rarely in adolescence. The patients present with progressive gait (spasticity and ataxia) and sensory (position and vibration sense) disturbances, dysarthria, and sometimes learning difficulties. Imaging Findings

Based on initial observations, conventional imaging findings are highly specific, perhaps pathognomonic. The pattern consists of extensive, predominantly

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Fig. 13.116a, b. MR imaging findings in a 3-year-old female patient with the infantile form of Alexander disease (courtesy of Dr. K. Chong, London, United Kingdom). a Axial T2-weightes spin-echo image. Extensive supratentorial white matter abnormalities. The subcortical U-fibers are involved in the frontal regions and spared in the occipital lobes. The basal ganglia are also abnormal. b Sagittal T1-weighted spin-echo image. The antero-posterior gradient of the white matter disease is well appreciated

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Fig. 13.117a–f. MR imaging findings in a 16-year-old male patient with the juvenile form of Alexander disease (courtesy of Dr. P. Tortori-Donati, Genoa, Italy). a, b Axial T2-weighted images; c, d axial FLAIR images; e, f Gd-enhanced axial T1-weighted images. There are abnormal T2 and FLAIR hyperintensities (a–d) within the posterior medulla, middle cerebellar peduncles, and dentate nuclei, with mild swelling of the affected areas. Notice moderate degree of enhancement after gadolinium administration (e, f). There were neither macrocephaly, nor other lesions, notably in the supratentorial compartment

periventricular white matter changes within the cerebral hemispheres, with relative sparing of the anterior corpus callosum, temporal lobes, and subcortical U-fibers. The deepest white matter shows signs of rarefaction on FLAIR images. The cerebellar white matter may also be involved during the advanced stages of the disease. The most characteristic abnor-

malities are found at the level of brainstem and spinal cord. Within the brainstem, the pyramidal tracts, medial lemnisci, anterior spinocerebellar tracts, and intraparenchymal trajectories of trigeminal nerves are involved. The superior and inferior cerebellar peduncles are affected early during the course of the disease; the middle cerebellar peduncles become

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abnormal later (Fig. 13.118). Spinal cord abnormalities consist of lesions within the lateral corticospinal tracts and dorsal columns (Fig. 13.119). None of the aforementioned lesions seem to show signal enhancement on postcontrast images. On available follow-up studies no evidence of progression was found but, as mentioned before, in the advanced stage of the disease the pattern appears to be more complete. Overall, the findings suggest a low-grade demyelinating process, but because of the peculiar tract involvement, a primarily axonal degeneration process is suspected. DWI and measurement of mean diffusivity and fractional anisotropy also suggest damage to the white matter matrix.

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H MRS shows nonspecific changes, including normal or slightly decreased Cho (low-grade demyelination, gliosis), decreased NAA (axonal damage), increased mI (gliosis), and increased lactate (impaired energy metabolism, tissue necrosis) (Fig. 13.119). 13.4.8.6 Aicardi-Goutières Syndrome

This rare, probably autosomal recessive, microcephalic disease is also called leukodystrophy with chronic CSF lymphocytosis and calcifications of the basal ganglia. Clinically, the disease appears in the neonate or in early infancy, but presence of intracerebral calci-

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Fig. 13.118a–f. Brain MR imaging findings in a 3.5-year-old female patient with leukodystrophy with brainstem and spinal cord involvement and high lactate on axial T2-weighted fast spin-echo images (courtesy Dr. M. van der Knaap, Amsterdam, The Netherlands). a–f Extensive white matter disease supratentorially (e, f), but the cerebellar white matter is also involved (a, b). Note sparing of the subcortical U-fibers. The posterior limbs of the internal capsules are abnormal (d). At the level of the brainstem (a, b) the signal abnormalities are confined to the pyramidal tracts, medial lemnisci, and intraparenchymal trajectories of the trigeminal nerves

Metabolic Disorders Fig. 13.119a,b. Spinal cord MR imaging and brain MR spectroscopic findings in leukodystrophy with brainstem and spinal cord involvement and high lactate on axial T2-weighted fast spin-echo images (same patient as in Fig. 13.118, courtesy Dr. M. van der Knaap, Amsterdam, The Netherlands). a Axial T2-weighted fast spin-echo image of the spinal cord. Lesions are seen within the lateral corticospinal tracts and the dorsal columns. b Single-voxel proton MR spectroscopy (PRESS technique, TE: 270 ms) of the brain; the sampling voxel was positioned on the cerebral hemispheric white matter lesion area. Significant decrease of the NAA peak, prominent mI peak at the 3.55 ppm level in conjunction with abnormal lactate at the 1.3 ppm level

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fications suggests that the underlying pathological process starts antenatally. It is a rapidly progressive, devastating disease, characterized by feeding difficulties, delayed and later practically arrested psychomotor development, progressive microcephaly, irritability, truncal hypotonia with limb spasticity and dystonic ocular and buccolingual movements, convulsions, opisthotonic posturing, and blindness leading to death in a few months or years. Persistent CSF pleocytosis is a key diagnostic feature of the disease. In about 50% of cases, intrathecal interferon-α synthesis was also demonstrated [604]. Imaging Findings

CT is an essential diagnostic modality in this disease, since it almost always demonstrates progressive calcifications within the basal ganglia, thalami, periventricular white matter of cerebral hemispheres, and cerebellum (Fig. 13.120). The presence and extent of

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calcifications is not correlated with the severity of the disease, and calcifications may be absent initially. On MRI, the disease presents with an essentially supratentorial and very extensive white matter disease with possible cystic lesions in the temporal and parietal lobes. The internal capsules are somewhat less affected, but are abnormal too. The pyramidal tracts within the medulla oblongata have been found to be also involved [605]. The cerebellar structures are spared. On T2-weighted images, calcifications are usually conspicuous due to their hyposignal within the abnormal, markedly hyperintense white matter. There is usually moderate to marked dilatation of the ventricular system, especially supratentorially, and progressive enlargement of extracerebral CSF spaces (Fig. 13.121). Occasionally, atrophic changes do not show progression on follow-up studies [606]. Overall, the clinical and imaging abnormalities suggest that Aicardi-Goutières syndrome is a primarily dysmyelinating process of undetermined etiology

Fig. 13.120a,b. CT imaging findings in Aicardi-Goutières syndrome (courtesy of Dr. P. Tortori-Donati, Genoa, Italy). a Axial nonenhanced CT image in a 1-yearold male patient. Calcifications are seen within the basal ganglia and the white matter, the latter predominantly in subcortical location. b Axial nonenhanced CT image in a 2-year-old male patient. Scattered punctate calcifications are seen within the cerebral hemispheric white matter. Extensive white matter density changes within the centrum semiovale. Mild atrophic changes

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with subsequent arrest of myelination and demyelination, triggering an increase in the number of white cells within the CSF and eventually leading to diffuse brain atrophy and calcifications. The most important differential diagnostic considerations are the neonatal form of Cockayne disease, intrauterine TORCH infections (especially cytomegalovirus), mitochondrial encephalopathies, biotinidase deficiency, and carbonic anhydrase II deficiency.

an important differential diagnostic clue, since it is seen in only a limited number of leukodystrophies (metachromatic leukodystrophy, Krabbe disease). The disease is characterized by progressive microcephaly, i.e., affected patients are normocephalic at birth, but develop relative microcephaly later during the disease course. One of the hallmark clinical features of the disease is hypopigmentation of the skin associated with photosensitivity.

13.4.8.7 Cockayne Disease

Imaging Findings

Cockayne disease is a rare autosomal recessive “microcephalic” leukodystrophy, usually of infantile onset (type 1). A congenital form (type 2) has also been described. The disease is believed to be the result of a defect in DNA repair mechanisms. It is a slowly progressive leukodystrophy, presenting initially with cachexia, progeric features and delayed development, and later with peripheral neuropathy. The latter is

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CT is a useful imaging tool, as it shows nonspecific calcifications, typically within the basal ganglia, dentate nuclei and, occasionally, subcortical white matter [607,608]. MRI shows cerebellar and brainstem atrophy (Fig. 13.122). Cerebral atrophy is also present, but it is usually less prominent. Supratentorially, extensive white matter disease is found; it is perhaps less severe than in most other leukodystrophies (Fig. 13.122). The

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Fig. 13.121a–d. MR imaging findings in Aicardi-Goutières syndrome (courtesy of Dr. P. Tortori-Donati, Genoa, Italy). a, b. Axial FLAIR and T2-weighted fast spinecho images in a 1-year-old patient (same as shown in Fig. 13.120a). The images show delayed myelination with early signs of demyelination. The corpus callosum is spared at this stage of disease. c, d Axial T1-weighted spin-echo and T2-weighted fast spin-echo images in a 2-year-old patient (same as shown in Fig. 13.120b). The extensive demyelination within the cerebral hemispheres is better appreciated on the T2-weighted image

Metabolic Disorders Fig. 13.122a–c. MR imaging findings in Cockayne disease in a 7-year-old male patient (courtesy of Dr. P. Tortori-Donati, Genoa, Italy). a Sagittal T1-weighted spin-echo image. Very prominent atrophy of cerebellum and brainstem. Note the characteristic facial profile of the patient. b Axial T2weighted fast spin-echo image. Marked enlargement of extra- and intracerebral CSF spaces supratentorially. Extensive white matter disease with some sparing of central corticospinal tracts. c Axial T1-weighted spinecho image. The hyperintensities at the level of putamina correspond to calcifications. Some myelin is still seen within the markedly atrophic splenium of the corpus callosum

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subcortical U-fibers are involved. There is sometimes a relative sparing of occipital white matter [608]. The corpus callosum and deeper white matter structures, including the internal capsules, may be somewhat less affected, suggesting a centripetal progression pattern [609]. Areas of calcification seen on CT images may present with hypersignal on T1-weighted and hyposignal on T2-weighted images (Fig. 13.122). On 1H MRS, increased lactate was found in the brain parenchyma [276]. 13.4.8.8 Pelizaeus-Merzbacher Disease

Three forms of Pelizaeus-Merzbacher disease are known: the classical, infantile type has an X-linked inheritance, the connatal type has both X-linked and autosomal forms, whereas the transitional form is sporadic or autosomal recessive. The disease is most probably due to a defect of the so-called proteolipid protein (PLP), a major constituent of normal myelin. The gene encoding PLP is on chromosome Xq22.

Depending on the severity of the functional defect of PLP, it results in impairment of myelin formation (absence of myelin or dysmyelination with subsequent demyelination). In the connatal form, little or no myelin is seen within the brain parenchyma. Clinically, both the connatal and the classical, infantile forms present with severe failure to thrive and developmental delay, nystagmus, extrapyramidal signs, seizures, and spasticity. Both forms are relentlessly progressive; in the connatal form death occurs during the first decade of life, whereas in the infantile form during the second or third decade. The transitional form is between the two aforementioned forms in severity. Recently, two additional entities have been added to the Pelizaeus-Merzbacher disease spectrum, i.e., the complicated and the pure type 2 spastic paraplegias. Imaging Findings

The typical MRI finding in Pelizaeus-Merzbacher disease is either almost total absence of myelin within

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brain (connatal type) or arrested myelination (classical form). In the connatal form the brainstem and cerebellum may be markedly atrophic. In the classical form, the pattern of myelination may be appropriate for a given stage of the myelination process (birth or early postnatal stage), but not for the actual chronologic age of the patient. Usually deeper and caudal structures (cerebellum, brainstem, diencephalon, and internal capsules) show signs of myelination [19, 610] (Fig. 13.123). A similar pattern, however, may develop in other pathological conditions, notably after early postnatal hypoxic-ischemic brain damage or severe CNS infections or systemic diseases, which constitute the most important differential diagnoses from an imaging standpoint. A peculiar MRI characteristic of the disease is the somewhat discrepant appearance of small amounts of myelin on T1- and T2-weighted images. While T1weighted images may show some hypersignal in myelinated areas (preserved “normal” gray-white matter con-

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trast), the same areas may not show any hyposignal on T2-weighted images (“reversed” gray-white matter contrast). This, again, probably indicates abnormal composition of myelin in apparently myelinated areas (dysmyelination). Occasionally, in the classical form a “tigroid” pattern of cerebral hemispheric white matter may also be observed; this probably corresponds to some sparing of perivascular myelin and suggests that a demyelinating component may also be present in the disease process [610]. The brain is diffusely atrophic. On DWI, Pelizaeus-Merzbacher disease was found to be characterized by preserved diffusion anisotropy, further supporting the hypothesis of a predominantly dysmyelinating pathomechanism [609]. In the early onset form of the disease, 1H MRS may reveal markedly decreased NAA and elevated Cho peaks, although in the later onset form normal NAA peak with markedly decreased Cho peak has also been described [276].

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Fig. 13.123a–d. MR imaging findings in a 4-year-old male patient with PelizaeusMerzbacher disease (courtesy of Dr. P. Tortori-Donati). a–d Axial T2-weighted fast spin-echo images. Some myelin is suggested within the brainstem, but within the cerebellum and supratentorially all white matter structures are completely unmyelinated

Metabolic Disorders

13.4.9 Miscellaneous Metabolic Diseases 13.4.9.1 Carbonic Anhydrase II Deficiency

Carbonic anhydrase II deficiency is an autosomal recessive metabolic disorder; the encoding gene of the enzyme is located on chromosome 8q 22. Heterozygotes are clinically asymptomatic, but have about 50% reduction of enzyme activity. The disease shows a clear preponderance, but is not exclusive, in Arab communities. Five different subtypes of the carbonic anhydrase enzymes are known. Carbonic anhydrase I is mainly found in erythrocytes, carbonic anhydrase III in muscle, carbonic anhydrase IV in lung, and carbonic anhydrase V in liver. Carbonic anhydrase II is present in most tissues of the body, notably in brain, kidney, liver, lung, and skeletal muscle. Carbonic anhydrase II is a metalloenzyme (requires zinc as a cofactor) and is responsible for reversible hydration of carbon dioxide. Deficiency of carbonic anhydrase II represents a complex clinical entity. The syndrome includes osteopetrosis, renal tubular acidosis, and intracerebral calcifications. The disease is usually recognized and diagnosed in childhood. Patients have short stature, growth retardation, mental retardation, poor dentition, and visual impairment. Dysmorphic facial features (thin nose, long upper lip, micrognathia, high forehead) are sometimes present. Some patients present with mild or severe anemia.

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Renal tubular acidosis is a result of a mixed defect, with a proximal component causing lowered transport for bicarbonate and a distal component causing inability to acidify urine. Consequently, metabolic acidosis with hyperchloremia and urinary alkalosis develop. Nephrocalcinosis may occur in a small percentage of patients. Imaging Findings

Intracerebral calcifications are always present in patients with carbonic anhydrase II deficiency, although not necessarily at the time of the first imaging workup. The calcifications, which affect both gray and white matter structures, are best demonstrated by CT. Calcified gray matter structures of brain include the caudate nuclei, putamina, globi pallidi, thalami, and dentate nuclei. Calcifications involving white matter structures are usually seen along the cortical-subcortical interface within the cerebral hemispheres and central white matter of cerebellum (Fig. 13.124). Skeletal abnormalities involve the skull, spine, and long bones. The skull base and calvarium are usually dense and thick, and cranial nerve foramina are narrow. In particular, stenosis of the optic canal may lead to visual problems, requiring surgical decompression. At the level of the spine, platyspondyly of variable severity is quite common. The long bones exhibit increased density and undertubulation. Paradoxically, at the same time, both long bones and neural arches of the vertebrae are somewhat fragile and prone to fractures. Dental abnormalities com-

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Fig. 13.124a, b. CT findings in carbonic anhydrase II deficiency. a, b Nonenhanced axial CT images. Dense calcifications within the cerebral hemispheres involving the subcortical white matter and the deep gray matter structures

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prise malocclusion, malformed teeth, retained primary teeth, and enamel defects with frequent caries. 13.4.9.2 Persistent Hyperinsulinemic Hypoglycemia (Nesidioblastosis)

Persistent hyperinsulinemic hypoglycemia is a potentially life-threatening condition. The underlying pathomechanism is inappropriate oversecretion of insulin, leading to severe hypoglycemia without ketosis. Two histopathological forms of the disease are known, which are clinically indistinguishable. The focal variant (nesidioblastosis) is related to a nodular somatic islet-cell hyperplasia, usually less than 1 cm in diameter, nested within an otherwise normal pancreas. Conversely, the diffuse form of the disease is a generalized functional abnormality of the Langerhans cells of the pancreas. The focal variant should not be confused with Langerhans cell adenoma, which has a totally different histological and clinical (late onset of hypoglycemia) presentation. Genetically, the focal variant is related to a mutation on chromosome 11p15. The diffuse variant follows a more complex, multifactorial inheritance and pathomechanism, with several genes and enzymes (glucokinase, glutamate dehydrogenase) involved. Persistent hyperinsulinemic hypoglycemia is probably the most frequent cause of neonatal hypoglycemia. Other etiological categories of neonatal hypoglycemia include early transitional-adaptive hypoglycemia (hyperinsulinism in erythroblastosis, or in infants of diabetic mothers), secondary-associated hypoglycemia (increased glucose utilization and glycogen depletion due to associated postnatal infectious, cardiorespiratory illnesses, etc.) and the classic transient neonatal hypoglycemia (intrauterine malnutrition and growth retardation causing diminished glycogen and lipid stores prenatally and increased glucose consumption after birth) [397]. Most cases with persistent hyperinsulinemic hypoglycemia present within the first few days of life with severe hypoglycemia, usually revealed by seizures. The infant is hypotonic, hypothermic, and often also cyanotic. Aggressive treatment with intravenous glucose and glucagon is required to prevent hypoglycemic brain injury (psychomotor retardation, epilepsy etc.), which is the most feared complication of the disease. The definitive treatment of the disease is partial (in the focal form) or subtotal (in the diffuse form) resection of the pancreas. In the focal form this may lead to a total cure; in the diffuse form, however, repeated hypoglycemic attacks may still occur. Other patients may develop insulin-dependent diabetes mellitus later in life.

Imaging Findings

In well-controlled cases of persistent hyperinsulinemic hypoglycemia, no imaging abnormalities are found. Otherwise, the disease may present with signs of hypoglycemic brain injury, similar to imaging findings in other common neonatal hypoglycemic conditions (see above) or metabolic diseases (carbohydrate metabolism abnormalities, aminoacidopathies and fatty acid oxidation disorders), which are also frequently associated with severe, symptomatic hypoglycemia (Fig. 13.80). Furthermore, there seems to be a clinical, histopathological, and imaging overlap between anoxic-ischemic encephalopathy (the two pathological conditions are frequently coinciding with each other), further complicating delineation of hypoglycemic brain injury syndrome as a distinct imaging entity. Hypoxia and/or asphyxia certainly potentiate the deleterious effects of hypoglycemia on the neonatal brain, and vice versa. Although it is not uncommon to find a fairly normal or unremarkable MRI study in infants after a severe episode of “pure” hypoglycemia (i.e., without associated, clinically overt anoxic-ischemic complications), it is still quite conceivable that hypoglycemic and anoxic-ischemic encephalopathies in the term neonate may share similar imaging features. The duration of the hypoglycemic episode also appears to be a decisive factor in the development of brain damage. Clinical and pathological observations suggest that severe hypoglycemia, if transient, is unlikely to cause permanent brain injury. This may be related to relative tolerance of the neonate to hypoglycemia compared to older children or adults. During or immediately after the acute episode of prolonged hypoglycemia, diffuse brain edema may be seen. Focal parenchymal lesions, if present, are found in the parietal-occipital regions, usually but not always symmetrically (Fig. 13.80). The lesions involve mainly the cortex, but subcortical structures may also suffer leading to decreased or absent gray-white matter differentiation. Neuropathological observations suggest that in hypoglycemia-induced cortical injury, the most superficial layers of the cortex are primarily involved. This appears to be in contrast with cortical lesions in posthypoxemia, which are predominantly seen within the intermediate and deep layers. This may have a potential differential diagnostic value, but currently available spatial resolution of MRI does not allow imaging differentiation of these histopathological changes. Occasionally, the deep gray matter structures (putamen, caudate nucleus) may be involved as well. After repeated episodes of hypoglycemia, diffuse brain atrophy develops in conjunction with secondary microcephaly. If focal parenchymal abnormali-

Metabolic Disorders

ties were present initially, these may develop into laminar cortical necrosis and/or encephalomalacialike lesions. 13.4.9.3 Creatine Deficiency

This disease has been identified recently and is related to deficiency of guanidinoacetate-methyltransferase, an enzyme found in liver and pancreas. Guanidinoacetatemethyltransferase catalyzes the conversion of guanidinoacetate to creatine. Creatine is then phosphorylated by creatine kinase, producing creatine phosphate. This reaction takes place within organs of energy utilization, notably brain and muscle, where creatine phosphate constitutes a permanent phosphate supply pool for ATP synthesis during energy utilization. Creatine and creatine phosphate are catabolized into creatinine, which is then excreted from the body through urine. Dysfunction of the enzyme leads to increased guanidinoacetate and depleted creatine, creatine phosphate, and creatinine levels. The normal dietary supply of creatine is not sufficient to compensate for lack of endogenous biosynthesis; therefore, chronic energy failure develops in sites of high energy requirements. Clinically, two phenotypes may be present [612, 613]. In some patients the disease develops in early infancy (5–6 months of age). Since the enzyme deficiency is certainly already present at birth, apparent delay in the onset of the clinical manifestations in this group is believed to be related to progressive depletion of maternally provided creatine reserves. Typical clinical signs include retarded psychomotor delay, followed by developmental arrest and even loss of acquired milestones. Severe hypotonia, swallowing problems, and extrapyramidal movement disorders develop. The other clinical phenotype is characterized by a late infantile onset (2–3 years of age). The clinical presentation is milder in this group, and is dominated by mental retardation and behavioral problems. Seizures, often triggered by febrile episodes, are present in both early and late infantile onset forms. Treatment of creatine deficiency consists of oral substitution of creatine in the form of creatine monohydrate, which results in improvement of both mental and motor functions, although full recovery does not occur. Recently, new variants of creatine deficiency syndrome have been identified. One is an autosomal recessive disorder, attributed to deficiency of arginine: glycine amidinotransferase [614]. In the other, elevated serum and urine creatine and normal guanidinoacetate levels were found, and the disease is believed to correspond to a defect of the creatine transport mechanism [615].

Imaging Findings

MRI of brain may be normal or show delayed myelination only [612;613]. In a patient with extrapyramidal movement disorder, bilateral globus pallidus lesions were found [612]. MRS findings are particularly relevant in this disease [616]. The disease was actually identified through the absence of the Cr peak on short echo (STEAM) 1H MRS within both gray and white matter structures of the brain (Fig. 13.125). One of the initial therapeutic considerations was to administer L-arginine, the precursor of guanidinoacetate, to supplement endogenous creatine synthesis; this practice led to the emergence of a peak at the 3.68 ppm level, which was identified as guanidinoacetate. This finding suggested that the enzymatic defect was at the next level of creatine biosynthesis, from guanidinoacetate to creatine. After several weeks of oral creatine monohydrate administration and withdrawal of L-arginine, creatine slowly reappears on the MR spectrum, reaching up to 50% of normal values, while guanidinoacetate disappears, confirming the aforementioned hypothesis. On 31P MRS, absence of phosphocreatine is demonstrated in both brain and skeletal muscle [617]. During administration of L-arginine, increased guanidinoacetate-phosphate but no creatine phosphate is detected within the brain parenchyma. After creatine monohydrate substitution, the former disappears, while the creatine phosphate peak becomes apparent. 13.4.9.4 Leukoencephalopathy Associated with Polyol Metabolism Abnormality

So far, only one patient with this disease has been described [618]. Nevertheless, since clinical mani-

Fig. 13.125. Single-voxel proton MR spectroscopic (PRESS technique, TE: 135 ms) findings in a 16-month-old male patient with guanidinoacetate-methyltransferase deficiency shows absent Cr peak and normal NAA and Cho peaks (courtesy of Dr. A. J. Barkovich, San Francisco)

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festations are quite nonspecific, clinical evolution is insidious, and routine metabolic screening tests usually do not include the assessment of polyols, the disease may actually be underrecognized. The underlying enzymatic abnormality has not been identified yet. Polyols (polyhydric alcohols) are metabolites of sugar and are probably produced in particularly large quantities in the brain. Biochemically, the disease is characterized by increased amounts of D-arabitol and ribitol in CSF, which suggests a defect on the catabolic pathway of these compounds within the brain parenchyma. Locally produced polyols may have a direct toxic and/or adverse osmolar effect on myelin. This hypothesis is supported by observations suggesting that polyols may have a role in the pathogenesis of peripheral neuropathy in diabetes mellitus and galactosemia. The index patient presented with slow and increasingly delayed development through childhood. He had epilepsy starting at age of 4 years, followed by visual and speech disorders, ataxia, and severe progressive mental retardation [618]. More recently, a new polyol (pentose) metabolism disorder (transaldolase deficiency) has been described. The disease presents with liver cirrhosis and hepatosplenomegaly in early infancy, but without CNS manifestations [619]. Imaging Findings

MRI findings show extensive white matter abnormalities, including an essentially centripetal progression pattern with involvement of subcortical U-fibers but sparing of internal capsules, corpus callosum, brainstem, and cerebellar white matter structures. The gray matter structures are normal. The brain is slightly swollen. A 3-year follow-up study showed no detectable interval changes. The whole MRI picture is somewhat reminiscent of L-2-hydoxyglutaric aciduria, except for lack of striatal and dentate nucleus lesions. 1 H MRS of brain revealed abnormal metabolites in the 3.5–4.0 ppm range, exhibiting the J-coupling phenomenon. These substances were identified as Darabitol and ribitol. At the same time, significantly decreased NAA, Cr, and Cho peaks were also found. A small amount of lactate was present. Unlike in many other leukodystrophies, mI was decreased. 13.4.9.5 Biotin-Responsive Encephalopathies

Classical biotin-responsive encephalopathies include multiple carboxylase deficiencies (biotinidase and holocarboxylase synthetase deficiency) [620].

Recently, however, novel entities characterized by biotin dependency without biotinidase or holocarboxylase synthetase deficiency have been described [621, 622]. These conditions are presumably related to a genetic defect in biotin transport mechanism, perhaps at the level of neurons or across the bloodbrain barrier. The most accurate description of the disease defines it as a subacute encephalopathy presenting with confusion, dysarthria, dysphagia, occasional supranuclear facial palsy, external ophthalmoplegia, rigidity, dystonia, and quadriparesis. The disease onset is usually in infancy or childhood. If the disease is diagnosed early and treated with oral supplementation of biotin, symptoms may be regressive, but reappear again upon withdrawal of biotin, characterizing a true biotin dependency state. Imaging Findings

The most characteristic imaging presentation of the disease is bilateral, symmetrical basal ganglia disease, with involvement of the caudate nuclei and putamina (biotin-responsive basal ganglia disease). These structures are initially swollen, while later they may become necrotic and atrophic (Fig. 13.126). These abnormalities are nonspecific and quite similar to those observed in some organic acidopathies (3-methylglutaconic acidemia, propionic acidemia). Lesions within the dentate nuclei have also been found in biotin-responsive basal ganglia disease, occasionally preceding basal ganglia changes (Fig. 13.127). The combination of dentate nucleus and basal ganglia lesions may also occur in organic acidopathies, but usually in a context of acute metabolic crisis and simultaneously. Conversely, in biotin-responsive basal ganglia disease the disease course is more protracted and there may be a time gap between the appearance of dentate nucleus and basal ganglia lesions, consistent with a subacute encephalopathy. Rarely, patchy white matter lesions may also be present within the centrum semiovale. DWI may show increased signal within the involved gray matter structures during the acute phase of the lesions. 13.4.9.6 Cerebrotendinous Xanthomatosis

Cerebrotendinous xanthomatosis (van BogaertScherer-Epstein disease) is an autosomal recessive lipid storage disease; the defective gene is localized on chromosome 2q33-qter. At least 37 mutations have been identified to date, without an obvious genotypephenotype correlation [623].

Metabolic Disorders

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Fig. 13.126a–d. The MRI appearance of basal ganglia lesions in biotin-responsive basal ganglia disease on axial T2-weighted fast spin-echo images. a 3-year-old female patient. Very subtle signal changes are seen within the head of the right caudate nucleus and within the left putamen anteriorly. b 4-year-old female patient. More prominent and symmetrical lesions within putamina and caudate nuclei. c 5year-old female patient. More extensive involvement of basal ganglia with marked swelling of the heads of caudate nuclei. d 16-year-old female patient. Very marked signal changes and swelling of the basal ganglia, also involving the adjacent external capsules

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Fig. 13.127a, b. The MR imaging appearance of dentate nucleus lesions in biotin-responsive basal ganglia disease. a Coronal FLAIR image in a 17-month-old female patient. The dentate nuclei lesions are in the subacute phase. These exhibit prominent hypersignal without swelling (arrowheads). b Coronal T2-weighted fast spin-echo image in a 5-year-old female patient (same patient as in Fig.13.126c). In this case, the dentate nucleus lesions are in chronic, atrophic phase already. The abnormal hypersignal is faint but still conspicuous (arrowheads)

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The underlying biochemical abnormality is deficiency of the hepatic mitochondrial enzyme, sterol 27-hydroxylase, which converts C27 sterol into C24 bile acid. As a result, synthesis of bile acids is markedly decreased and bile acid precursors accumulate. As a secondary effect, biosynthesis of bile alcohols and cholestanol increases through lack of normal feedback inhibition of cholesterol 7-alfa-hydroxylase (converting excess bile acid precursors into cholestanol) by the missing bile acids. Excess cholestanol (and cholesterol) is then released from liver and deposited in various tissues, notably the lens, CNS (brain and spinal cord), vessel walls, and muscle tendons. Age of onset of the disease is usually juvenile or adult. Cataracts are almost invariably present in patients with cerebrotendinous xanthomatosis, and usually appear early during the disease course. A history of chronic diarrhea is common. Later, neurological abnormalities ensue in conjunction with the appearance of tendon xanthomas; the latter is a rather inconsistent feature of the disease. On neurological examination, signs of cerebellar (cerebellar dysarthria), pyramidal and spinal cord (spastic paraparesis) involvement, and peripheral neuropathy are found. In a subset of patients, spinal cord manifestations may precede by several years both cerebellar and cerebral manifestations [624]. The patients are usually mentally challenged; mental retardation may be the first manifestation of the disease in childhood. Interestingly enough, the disease is usually misdiagnosed both clinically and on imaging. From the clinical point of view, neurological abnormalities are often misinterpreted as multiple sclerosis, neurodegenerative disease (Friedreich ataxia, hereditary spastic paraparesis), or presenile dementia. The neurological abnormalities show good correlation with histopathological findings, which demonstrate xanthomatous and hemosiderin deposits, spindle-shaped lipid crystal clefts, severe neuronal loss, demyelination, reactive astrocytosis, and calcifications within the involved structures, mainly the deep gray matter structures of cerebellum and cerebrum and in the immediate surrounding white matter. Supplementation of chenodeoxycholic acid arrests or reverses some manifestations of the disease process. Laboratory abnormalities (plasma cholestanol) improve and further xanthomatous depositions are probably prevented; therefore, early diagnosis and treatment are of great importance. Imaging Findings

MRI findings reflect the pattern of neurological and histopathological abnormalities [625]. The most prominent abnormalities are seen at the level of dentate

nuclei [626]. Additional gray matter structures which may also show signal changes are the pars reticulata of substantia nigra, globi pallidi, inferior olives, and periaqueductal nuclei. These lesions are typically hyperintense on T2-weighted images. At the level of dentate nuclei, however, hypointense lesion components may occasionally be identified, most probably corresponding to calcifications, iron, or hemosiderin deposits. On CT, however, no gross calcifications are seen in the majority of cases. As the disease progresses (in older patients), the white matter adjacent to the aforementioned deep gray matter structures also becomes involved; signal abnormalities are then present within the deep cerebellar white matter, cerebral peduncles, and posterior limbs of the internal capsules. Xanthomas may be seen occasionally within the choroid plexuses of the lateral ventricles at the level of the trigones [627]. The aforementioned lesions are typically symmetrical (Fig. 13.128). Nonspecific, ill-defined periventricular white matter lesions, in conjunction with cerebral and cerebellar atrophy and enlargement of the perivascular spaces, are also common [626]. When patients clinically present with spinal cord disease, MRI shows signal abnormalities within the lateral and dorsal white matter columns [624]. None of the lesions show hypersignal on T1-weighted images; this is believed to be due to the fact that lipid deposits contain sterols rather than fatty acids. Tendinous xanthomas may also be demonstrated by MRI, the most frequent and prominent lesions being seen at the level of the Achilles tendons. MR manifestations of the disease do not show improvement on treatment. 1 H MRS of the brain in patients with cerebrotendinous xanthomatosis showed decreased NAA and increased lactate. The decrease of NAA, a presumed indicator of extensive axonal damage, correlated with the patients’ disability [626]. 13.4.9.7 Sjögren-Larsson Syndrome

Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disease characterized by a triad of ichthyosis, spastic diplegia or tetraplegia, and mental retardation. SLS is due to deficiency of the fatty aldehyde dehydrogenase enzyme (whose gene was mapped to 17p11.2), a component of the fatty alcohol NAD+ oxidoreductase complex that is necessary for oxidation of fatty alcohol into fatty acid [628]. This deficiency results in tissue accumulation of long chain alcohols. The latter have been shown to partition into artificial lipid bilayers and synaptic vesicles. In the skin, this could affect the integrity of the epidermal water barrier, resulting in

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c

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Fig. 13.128a–d. MR imaging findings in cerebrotendinous xanthomatosis (courtesy of Dr. F. Barkhof, Amsterdam, The Netherlands). a–d Axial T2-weigted spin-echo images. At the level of dentate nuclei prominent hypointensities are seen (arrowheads, a) but the adjacent cerebellar white matter is also abnormal. Signal changes are present within the substantia nigra (arrows, b) and posterior limbs of the internal capsules (arrowheads, c), and faint hyperintensities are also suggested within the centrum semiovale (d)

d

increased water loss and resultant ichthyosis. In the CNS, myelin membrane integrity could be affected, resulting to myelin disruption and loss. Ichthyosis is congenital and tends to worsen with time. Spasticity can present as early as 4 months of age but usually appears within 3 years of age and also is progressive, with many patients being never able to walk or becoming wheelchair bound. Mental retardation is moderate to severe. Speech disorder is thought to result from a combination of mental deficiency and pseudobulbar palsy. Fundoscopy may reveal glistening white dots in the macular regions of the retina, a pathognomonic feature of the disease. The diagnosis is confirmed by testing enzyme activity in cultured fibroblasts. Cultured amniocytes and fetal skin biopsy allow prenatal diagnosis. Pathologically, the brain in SLS shows myelin loss in the hemispheric white matter as the most prominent feature. Myelin sheaths are ballooned. Lipid-laden macrophages, histiocytes, axonal loss and degenera-

tion, and astrocytosis are seen histologically. There is histological involvement of the descending brainstem tracts. The cerebellum is normal. Imaging Findings

The imaging characteristics of SLS [629–631] basically include confluent areas of low density attenuation on CT, and T2 hypersignal on MRI, in the involved cerebral hemispheric white matter. The abnormalities involve the deep white matter of the centrum semiovale, while the subcortical U fibers are spared. In our experience with three cases of SLS, there was hyperintensity on long TR sequences in the deep white matter of the frontal lobes with sparing of the subcortical U fibers, in one case extending posteriorly to the parieto-occipital areas; therefore, an antero-posterior gradient can be hypothesized to exist. One case had involvement of the callosal genu and fornix minor fibers (Fig. 13.129), adjoining the white matter abnormalities in the frontal

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Fig. 13.129a–c. MR imaging findings in a 7-year-old boy with SjögrenLarsson syndrome (courtesy of Dr. P. Tortori-Donati, Genoa, Italy). a, b. Axial FLAIR images. There is prominent, symmetrical hyperintensity of the deep white matter of both frontal lobes. The genu of the corpus callosum is also hyperintense (arrowheads). c Sagittal T2-weighted fast spin-echo image. There is hyperintensity at level of the genu of the corpus callosum (arrowhead). Also, faint hyperintensity is suggested within the tegmentum of the midbrain and pons (arrows)

lobes. There was no contrast enhancement in either case. Pontine tracts were found to be abnormal in one case, while the cerebellum was consistently normal. 1 H-MRS of the periventricular white matter lesions has revealed a high lipid peak at 1.3 ppm [631, 632]. The peak may be visible in the periventricular regions of affected patients even before dysmyelination becomes visible on conventional MRI [633].

A special credit must go to the technicians in the Department of Radiology of the King Faisal Specialist Hospital and Research Center for their devoted work and passion for high quality MRI.

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Acknowledgments The author wishes to thank Dr. Pinar T. Ozand and Dr. Enrique Chaves-Carballo for their help, advice and guidance during the preparation of the manuscript and for stimulating discussions through many years of clinical collaboration, Dr. Roberta Biancheri for her last-minute advice, and Dr. Jehad Al-Watban for making it all possible.

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609. Dabbagh O, Swaiman KF. Cockayne syndrome: MRI correlates of hypomyelination. Pediatr Neurol 1988; 4:113–116. 610. van der Knaap MS, Valk J. The reflection of histology in MR imaging of Pelizaeus-Merzbacher disease. AJNR Am J Neuroradiol 1989; 10:99–103. 611. Ono J, Harada K, Mano T, Sakurai K, Okada S. Differentiation of dys- and demyelination using diffusional anisotropy. Pediatr Neurol 1997; 16:63–66. 612. Schulze A, Hess T, Wevers R, Mayatepek E, Bachert P, Marescau B, Knopp MV, De Deyn PP, Bremer HJ, Rating D. Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism. J Pediatr 1997; 131:626–631. 613. van der Knaap MS, Verhoeven NM, Maaswinkel-Mooij P, Pouwels PJW, Onkenhout W, Peeters WAJ, Stockler-Ipsiroglu S, Jakobs C. Mental retardation and behavioral problems as presenting signs of a creatine synthesis defect. Ann Neurol 2000; 47:540–543. 614. Battini R, Leuzzi V, Carducci C, Tosetti M, Bianchi MC, Item CB, Stockler-Ipsiroglu S, Cioni G. Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree. Mol Genet Metab 2002; 77:326–331. 615. Cecil KM, Salomons GS, Ball WS Jr, Wong B, Chuck G, Verhoeven NM, Jakobs C, DeGrauw TJ. Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect? Ann Neurol 2001; 49:401–404. 616. Stöckler S, Holzbach U, Hanefeld F, Marquardt I, Helms G, Requart M, Hanicke W, Frahm J. Creatine deficiency in the brain: a new, treatable inborn error of metabolism. Pediatr Res 1994; 36:409–413. 617. Schulze A, Bachert P, Schlemmer H, Harting I, Polster T, Salomons GS, Verhoeven NM, Jakobs C, Fowler B, Hoffmann GF, Mayatepek E. Lack of creatine in muscle and brain in an adult with GAMT deficiency. Ann Neurol 2003; 53:248–251. 618. van der Knaap MS, Wevers RA, Struys EA, Verhoeven NM, Pouwels PJ, Engelke UF, Feikema W, Valk J, Jakobs C. Leukoencephalopathy associated with a disturbance in the metabolism of polyols. Ann Neurol 1999; 46:925–928. 619. Verhoeven NM, Huck JH, Roos B, Struys EA, Salomons GS, Douwes AC, van der Knaap MS, Jakobs C. Transaldolase deficiency: liver cirrhosis associated with a new inborn error in the pentose phosphate pathway. Am J Hum Genet 2001; 68:1086–1092. 620. Dabbagh O, Brismar J, Gascon GG, Ozand PT. The clinical spectrum of biotin-treatbale encephalopathies in Saudi Arabia. Brain Dev 1994; 16 Suppl:72–80. 621. Ozand PT, Gascon GG, Al-Essa M, Joshi S, Al Jishi E, Bakheet S, Al Watban J, Al Kawi MZ, Dabbagh O. Biotin-responsive basal ganglia disease: a novel entity. Brain 1998; 121:1267–1279. 622. Mardach R, Zempleni J, Wolf B, Cannon MJ, Jennings ML, Cress S, Boylan J, Roth S, Cederbaum S, Mock DM. Biotin dependency due to a defect in biotin transport. J Clin Invest 2002; 109:1617–1623. 623. Verrips A, Hoefsloot LH, Steenbergen GCH, Theelen JP, Wevers RA, Gabreels FJM, van Engelen BGM, van der Heuvel PWJ. Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain 2000; 123:908–919. 624. Verrips A, Nijeholt L, Barkhof F, an Engelen BGM, Wesseling P, Luyten JAFM, Wevers R, Stam J, Wokke JHJ, van der Heuvel LPWJ, Keyser A, Gabreels FJM. Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis. Brain 1999; 122:1589–1595.

Metabolic Disorders 625. Barkhof F, Verrips A, Wesseling P, Der Knaap MS, van Engelen BG, Gabreels FJ, Keyser A, Wevers RA, Valk J. Cerebrotendinous xanthomatosis: the spectrum of imaging findings and the correlation with neuropathologic findings. Radiology 2000; 217:869–876.

626. De Stefano N, Dotti MT, Mortilla M, Federico A. Magnetic resonance imaging and spectroscopic changes in brains of patients with cerebrotendinous xanthomatosis. Brain 2001; 124:121–131. 627. Vanrietvelde F, Lemmerling M, Mespreuve M, Crevits L, De Reuck J, Kunnen M. MRI of the brain in cerebrotendinous xanthomatosis (van Bogaert-Scherer-Epstein disease). Eur Radiol 2000; 10:576–578. 628. Rizzo WB, Craft DA. Sjögren-Larsson syndrom. Deficient activity of the fatty aldehyde dehydrogenase component of fatty alcohol: NAD+ oxidoreductase in cultured fibroblasts. J Clin Invest 1991; 88:1643–1648. 629. Di Rocco M, Filocamo M, Tortori-Donati P, Veneselli E, Borrone C, Rizzo WB. Sjogren-Larsson syndrome:

nuclear magnetic resonance imaging of the brain in a 4-year-old boy. J Inherit Metab Dis 1994; 17:112–114. 630. Van Mieghem F, Van Goethem JW, Parizel PM, van den Hauwe L, Cras P, De Meirleire J, De Schepper AM. MR of the brain in Sjogren-Larsson syndrome. AJNR Am J Neuroradiol 1997; 18:1561–1563. 631. Miyanomae Y, Ochi M, Yoshioka H, Takaya K, Kizaki Z, Inoue F, Furuya S, Naruse S. Cerebral MRI and spectroscopy in Sjogren-Larsson syndrome: case report. Neuroradiology. 1995; 37:225–228. 632. Mano T, Ono J, Kaminaga T, Imai K, Sakurai K, Harada K, Nagai T, Rizzo WB, Okada S. Proton MR spectroscopy of Sjogren-Larsson’s syndrome. AJNR Am J Neuroradiol 1999; 20:1671–1673. 633. van Domburg PH, Willemsen MA, Rotteveel JJ, de Jong JG, Thijssen HO, Heerschap A, Cruysberg JR, Wanders RJ, Gabreels FJ, Steijlen PM. Sjogren-Larsson syndrome: clinical and MRI/MRS findings in FALDH-deficient patients. Neurology 1999; 52:1345–1352.

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14 Neurodegenerative Disorders Ludovico D’incerti, Laura Farina, and Paolo Tortori-Donati

14.1 Generalized Brain Atrophy

CONTENTS 14.1

Generalized Brain Atrophy

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14.1.1 14.1.1.1 14.1.1.2 14.1.2 14.1.2.1

Neuronal Ceroid Lipofuscinosis Imaging Features 723 Classification 724 Alpers Disease 726 Imaging Findings 726

14.2

Extrapyramidal Neurodegenerations 727

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14.2.1

Pantothenate Kinase-Associated Neurodegeneration (Hallervorden-Spatz Syndrome) 727 14.2.1.1 Imaging Findings 728 14.2.2 Huntington’s Disease 729 14.2.2.1 Imaging Findings 730 14.3

Cerebellar Atrophy

14.3.1 14.3.1.1 14.3.1.2 14.3.2 14.3.2.1

730

Infantile Neuroaxonal Dystrophy 730 Imaging Findings 731 Differential Diagnosis 732 Inherited Ataxia 733 Autosomal Dominant Cerebellar Ataxia (ADCA) 733 14.3.2.2 Autosomal Recessive Ataxia 736 14.3.3 Pontocerebellar Hypoplasia 738 References

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14.1.1 Neuronal Ceroid Lipofuscinosis Neuronal ceroid lipofuscinosis (NCL) is a group of diseases that collectively represent the most common inherited neurodegenerative diseases in childhood. Their incidence in the United States is estimated at 1:12,500. The different forms are diffuse worldwide, although most are mainly observed in Finland [1]. NCL is inherited as an autosomal recessive trait. Patient age at presentation varies from early infancy to adulthood. Most childhood forms are characterized by progressive mental and motor deterioration, blindness, epileptic seizures, and premature death. 14.1.1.1 Imaging Features

Neuroradiologic features, as demonstrated by magnetic resonance imaging (MRI) studies of the brain, correspond to the neuropathological findings shared by all forms of NCL, i.e., progressive cerebral and cerebellar atrophy due to progressive and selective neuronal loss, wallerian degeneration, and gliosis of the white matter [2]. Cerebral and cerebellar atrophy is not constant and may be not obvious, especially in early MRI studies. When present, it is easily demonstrated both on CT and MRI studies. Cortical thinning is caused by loss of cortical neurons. This feature requires careful search and high resolution MRI techniques [3]. However, volumetric or quantitative measurements of cortical atrophy in NCL patients have not been carried out in the literature. Mild hyperintensity on T2-weighted images first affects the posterior periventricular area, then extends to the whole lobar white matter. Severe reduction of the hemispheric white matter is observed in the late stage of the disease, when cerebral atrophy is more prominent [3]. Signal changes correspond to wallerian degeneration and white matter gliosis.

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Signal hypointensity on T2-weighted images in the thalami and basal ganglia has been described in a number of patients. No definite explanation of this feature is available at present [4]. The association of cortical thinning and signal abnormalities involving the white matter and thalami provides a neuroradiologic picture (Fig. 14.1) that, albeit nonspecific, may be helpful to narrow the differential diagnosis of neurodegenerative disorders in infancy, or even to suggest the diagnosis. 14.1.1.2 Classification

In the past, NCL was classified on the basis of the age of onset into four groups: infantile (INCL), late infantile (LINCL), juvenile (JNCL), and adult NCL. Recent molecular genetic and biochemical studies have provided the basis for a new genetic classification. As a consequence, NCL is now classified on the basis of the abnormal gene. The genes involved are termed CLN 1 to 8. Different mutations in a single gene may result in different phenotypes, which may involve variations of age at onset [2]. CLN1

The CLN1 gene is mapped to chromosome 1p32. Mutations of the CLN1 gene produce four main phenotypes, characterized by varying age of onset: infantile NCL (INCL, Haltia-Santavuori disease), and variant forms with late infantile, juvenile, or adult onset. The infantile form is the most common form of NCL, and is most frequently observed in the Finnish population. Affected children apparently develop normally until 1 year; however, microcephaly may become evident by age 5 months. Development begins to slow during the second year of life. Hand hyperkinesia, myoclonic jerks, and seizures appear, together with progressive loss of motor abilities, truncal ataxia, and visual failure due to retinal degeneration and optic atrophy. The electroencephalogram (EEG) becomes flat, and the electroretinogram (ERG) is extinguished by the age of 3 years. Active movements and visual contact with the environment are usually lost by 3 years. Death occurs between age 8 and 13 years [4]. Neuropathologic features are progressive neuronal loss, infiltration of the cortex by macrophages, and astrocytic hyperplasia leading to severe thinning of the cortex. By age 3 years, almost all cortical neurons are lost. At autopsy, the brain is strikingly atrophic, and no clear demarcation can be found between the

cortex and white matter. Severe gliosis is found in the centrum semiovale, and the white matter is almost devoid of axons and myelin sheaths [2]. MRI and MR spectroscopy (MRS) studies performed before the age of 6 months are usually normal. Between 7 and 11 months, even before onset of the clinical symptoms, mild hyperintensity on T2-weighted images involves the deep white matter. Decreased signal intensity on T2-weighted images in the thalami is also observed. Cerebral and cerebellar atrophy may be found after 13 months, and increases after 3–4 years. MRI becomes abnormal before clinical signs appear, and allows differentiation from Rett syndrome, whose early clinical features are very similar to those of INCL, although MRI is normal [5, 6]. CLN2

CLN2 is mapped to chromosome 11p15. Mutations of the CLN2 gene cause almost all cases of classic late infantile NCL (cLINCL, Jansky-Bielschowsky disease). cLINCL seems to be more common in northern Europe. Epilepsy is the main and the earlier clinical feature of cLINCL; partial or generalized tonic-clonic seizures occur between age 2 and 4 years. They are usually followed by myoclonus, motor deterioration, and ataxia. Patients become unable to walk and sit unsupported. Later on, developmental regression becomes more evident, with gradual loss of speech. Gradual decline of vision, corresponding to progressive retinal atrophy, leads to blindness by 5 or 6 years of age. Affected children usually die in middle childhood. Neurophysiological findings are characteristic; the EEG shows occipital photosensitive response, while the ERG is diminished or extinguished. The visual and somatosensory evoked potentials (VEPs, SEPs) are grossly enhanced [7]. Severe cerebellar atrophy is the main neuropathological feature of cLINCL. Atrophy of the cerebral hemispheres is also found, together with severe loss of cortical neurons and loss of axons and of myelin in the white matter. Cerebellar atrophy may be observed in the MRI studies performed in the early stages of the diseases (Fig. 14.1). Abnormal signal intensity from the white matter and thalami are not described in the early phase of cLINCL. These features, together with cerebral atrophy, become more evident later in the course of the disease (Fig. 14.1). Therefore, early MRI findings are nonspecific, whereas neurophysiological features are more relevant for the diagnosis [5].

Neurodegenerative Disorders

a

b

c

d Fig. 14.1a–d. Late infantile neuronal ceroid lipofuscinosis. a, b Sagittal T1-weighted image (a) and axial proton-density-weighted image (b) at age 6 years. Very mild cerebellar atrophy. The corpus callosum is normal. The deep white matter of the centrum semiovale is mildly hyperintense (b). The lateral ventricles and sulci are normal. c, d Follow-up sagittal IR T1-weighted image (c) and axial T2-weighted image (d) at age 17 years. There is worsening of cerebellar atrophy and severe thinning of the corpus callosum (c). Axial T2-weighted image shows severe brain atrophy with marked thinning of the cerebral convolutions and almost complete disappearance of the cortical ribbon. Signal abnormalities are now extended to the subcortical white matter

CLN3

CLN3 is mapped to chromosome 16p12.1. Defects in the CLN3 gene cause juvenile NCL (JNCL, BattenSpielmayer-Vogt disease), which is the most common form of NCL worldwide. The incidence varies in different countries, being greater in Scandinavia (7:100,000 live births) [8]. The initial symptom is visual failure, presenting between 4 to 7 years of age and leading to blindness within 2 to 10 years. Impairment of cognitive functions with progressive deterioration of short-term memory usually starts by 8 or 9 years of age. Later on, after age 15 years, speech becomes dysarthric. Generalized

tonic-clonic or complex partial seizures appear in most patients between 7 and 18 years of age. Moreover, many patients may show signs of parkinsonism. Demise usually occurs in the third or fourth decade [9]. Severe ERG changes are present even in early stages. Vacuolated lymphocytes can be regularly demonstrated on peripheral blood films, a unique finding in NCL [9]. In JCNL, the brain is moderately atrophic and the cortex is slightly reduced in thickness [2]. The entire neuroretina is usually largely destroyed and replaced by scar tissue. Brain MRI and MRS are usually normal in the early stage of the disease. Progressive brain atrophy, mainly affecting the cerebral hemispheres, appears

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after the onset of clinical symptoms, usually around age 10 years. Thinning of the cortex, together with T2 hyperintensity involving the posterior periventricular white matter and the posterior limbs of the internal capsules, may be observed in this phase. T2 hypointensity of the thalami has also been reported [5, 6]. CLN4

The CLN4 locus corresponds to the hypothetic gene implicated in the adult onset NCL (ANCL, Kufs-Parry disease) [2]. CLN5

The CLN5 gene is located on chromosome 13q22; four different mutations are known. These mutations result in the Finnish variant LINCL, almost exclusively found in Finland so far. This variant is clinically and neuropathologically distinct from classic LINCL [2]. Clinical onset is between age 4.5 and 6 years, with slight motor clumsiness and muscular hypotonia followed by learning problems, mental retardation, and visual impairment. Later on, by the age of 7–8 years, patients develop epilepsy with generalized seizures, followed by ataxia and myoclonia between 7 and 10 years of age. Patients may survive into the fourth decade. Severe generalized brain atrophy is found at autopsy. Atrophic changes are more severe in the cerebellum. Purkinje and granular cells are almost completely destroyed, while relatively moderate neuronal loss is found in subcortical structures, associated with cortical astrocytosis and more severe loss of myelin in the white matter [2]. MRI demonstrates cerebellar atrophy in the early phase, and later severe cerebral and cerebellar atrophy [2, 5]. CLN6

The CLN6 gene is located on chromosome 15q21–23. Defects result in a variant form of LINCL, also called early juvenile NCL (Lake-Cavenagh disease). Most patients are from Southern Europe, Portugal, Romania, and the Czech Republic [10]. Clinical features resemble those of classical LINCL; some patients may have a slightly later onset and a more protracted course, with seizures, ataxia, and myoclonus as the leading symptoms. Even the neurophysiological findings resemble those observed in classical LINCL. Neuroimaging findings are considered nonspecific [11]. CLN7 and CLN8

A defect of the CLN8 gene is related to Northern epilepsy, also known as progressive epilepsy with mental

retardation. This is the most protracted form of NCL and, to date, has only been described in Finland [2]. Clinical onset occurs by age 5–10 years with generalized tonic-clonic seizures. The frequency of seizures increases towards puberty, but decreases spontaneously afterwards. Mental retardation becomes evident 2–5 years after the onset of epilepsy, and progresses slowly. Cerebellar symptoms become manifest after age 30 years. Diminished visual acuity is inconstantly observed. EEG shows slowing of the background activity. No consistent VEP abnormalities have been reported. On MRI, cortical atrophy has been observed in all patients over 40 years of age, while it is rare before 30 years [3].

14.1.2 Alpers Disease Alpers disease is a rare autosomal recessive disorder that was described in 1931 by Alpers as a “diffuse progressive degeneration of the gray matter of the cerebrum” [12]. The alternative term Alpers-Huttenlocher syndrome is used as well [13]. It is usually characterized by the clinical triad of psychomotor developmental delay, intractable epilepsy, and liver failure occurring in infants or young children [14]. It has been suggested that a mitochondrial dysfunction may represent the underlying cause of the disorder. Mitochondrial respiratory chain abnormalities [15, 16] and mtDNA depletion with deficiency of mitochondrial DNA polymerase-gamma (POLG) activity have been reported [17, 18]. The onset of Alpers syndrome is typically in infancy, after normal birth and neonatal period. The first sign of the disorder is usually characterized by intractable seizures. Status epilepticus may occur. Other neurologic features include hypotonia, spasticity, myoclonus, and dementia. The disease is rapidly progressive, with death by age 3 years. Neurologic deterioration is associated with liver failure. Neuronal loss, spongiosis, and astrocytosis are the main neuropathological abnormalities [19]. Liver biopsy shows microvesicular steatosis, cirrhosis, and abnormal bile duct architecture [14]. 14.1.2.1 Imaging Findings

Reports on imaging studies in Alpers disease are sparse. Focal hypodensities in both gray and white matter, followed by diffuse atrophy, have been reported by CT scan [19].

Neurodegenerative Disorders

On MRI, the predominant gray matter involvement is better seen on T2-weighted images [20]. Spongiform cortical atrophy prevails in the occipital region and may be associated with atrophy of the basal ganglia, notably in the thalami and globi pallidi. Delayed myelination and cortical thinning have been described [19] (Fig. 14.2). High signal intensities not restricted to any vascular territory, possibly reflecting cytotoxic edema, has been reported by diffusion-weighted images (DWI) [21]. MRS has revealed a lactate peak in cortical regions that appear abnormal on DWI, possibly representing respiratory deficiency with anaerobic metabolism. A reduced NAA/creatine ratio was found in both the abnormal and the normal appearing cortex, indicating widespread neuronal damage [22].

a

b

c

d

14.2 Extrapyramidal Neurodegenerations 14.2.1 Pantothenate Kinase-Associated Neurodegeneration (Hallervorden-Spatz Syndrome) Hallervorden-Spatz syndrome, recently renamed pantothenate kinase-associated neurodegeneration (PKAN) [23], is a rare neurologic disorder, inherited as an autosomal recessive trait, which usually presents in late childhood or early adolescence. Dystonia with oromandibular involvement, mental deterioration, pyramidal signs, and retinal degeneration are the main clinical features [24]. Demise usually occurs about 10 years after the onset, but a more protracted course may be observed. No biologic markers have been found.

Fig. 14.2a–d. Alpers disease. a Sagittal T1-weighted image and b axial T2-weighted image at age 8 months. There is a small cerebellum and evidence of enlargement of the subarachnoid spaces, although no clear-cut signal abnormality is present. c Sagittal T2-weighted image and d axial T2-weighted image at age 24 months. There is now diffuse cerebral and cerebellar atrophy. The basal ganglia also appear atrophic. Myelination is severely impaired

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Unlike other neuroaxonal dystrophies, axonal dystrophy with “spheroid bodies” (i.e., larger axonal swellings) is only present in the CNS, and not outside the brain. Therefore, skin or conjunctival biopsy is not helpful for the diagnosis [25], which is nevertheless suggested by MRI and clinical data. The denomination PKAN is today preferred both for ethical reasons [26] and because the responsible gene (PANK2) has been mapped to chromosome 20p13–p12 [27]. PANK2 encodes for pantothenate kinase, the key regulator enzyme in the synthesis of coenzyme A from pantothenate, playing an essential role in fatty acid synthesis and energy metabolism [23]. Defective membrane biosynthesis may result in cysteine increase, which may account for the accumulation of iron in the basal ganglia [23]. Hayflick et al. [28] recently demonstrated that all patients with classic PKAN (characterized by early onset with rapid progression) and one third of those with atypical disease (i.e., slow onset and slow progression) had PANK2 mutation and the characteristic MRI pattern with the “eye-of-the-tiger” sign. PANK2 mutation analysis may definitively confirm the diagnosis, and may be used for prenatal diagnosis in the affected families [27, 29]. 14.2.1.1 Imaging Findings

of the pallidum. This finding, called the “eye-of-thetiger” sign by Sethi et al. [30], is characteristic of the disease (Fig. 14.3). A corresponding hyperintensity of the globi pallidi may be detected on T1-weighted images (Fig. 14.4). Savoiardo et al. [31] gave the explanation for the topographical distribution of MRI signal abnormalities within the pallidum. These authors, in agreement with prior pathological investigations [32], demonstrated histologically that the pallidum was not uniformly involved in the disease. Its most medial-anterior part shows a rather “loose” tissue organization with vacuolization and very small amounts of iron, corresponding to T2 hyperintense that are consistent with increased water content, as shown both by lowand high-field intensity MRI. Conversely, the remainder of the pallidum is more “dense” and compact with abundant iron deposits, producing marked hypointensity on high-field intensity MRI due to magnetic susceptibility effects [31]. The same phenomena can account for the corresponding hyperintensity seen on unenhanced T1-weighted images. It is noteworthy that identical MRI abnormalities may be present in the HARP syndrome (hypopre-β-lipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) which is, however, part of the PKAN spectrum [33]. Moreover, the “eye-of-the-tiger” sign has been recently described in two asymptomatic siblings of

To understand the MRI abnormalities of PKAN, it is necessary to correlate the signal changes with the known pathological findings. Abnormally increased iron deposits within the globus pallidus, resulting in a rusty brown discoloration and neuroaxonal swelling, are the characteristic neuropathologic findings of the disease. Iron is absent from the CNS at birth, but continuous deposition occurs during life in healthy individuals. In children or adolescents with PKAN, iron deposition is extraordinarily marked for age. Iron deposits occur either in the form of granules in the vessels walls or as free tissue accumulations. These deposits are remarkable in the pallidum, but may also be found in lesser amounts in the substantia nigra and red nuclei. Dystrophic axons and reactive astrocytes have a similar distribution, but may also be found in other parts of the basal ganglia [30]. Since iron can be detected with high field intensity magnets, MRI is a very important tool for the diagnosis of PKAN in vivo. MRI findings differ according to magnet field strength. However, both at 0.5 and 1.5 T abnormalities are confined to the pallidum. At 0.5 T, there is uniformly high T2 signal intensity, whereas at 1.5 T there is markedly low T2 signal intensity with a small hyperintense area in the anterior medial part

Fig. 14.3. Pantothenate kinase-associated neurodegeneration (Hallervorden-Spatz syndrome). Axial T2-weighted image at 1.5 T shows the typical “eye-of-the-tiger” sign: marked hypointensity of the globi pallidi (arrows) with a small hyperintense area in the anterior-medial part of the nuclei (arrowheads)

Neurodegenerative Disorders

a

b

c

d

Fig. 14.4a–d. Pantothenate kinase-associated neurodegeneration (Hallervorden-Spatz syndrome). a, b Axial T2-weighted (a) and T1-weighted (b) images in a 7-year-old patient. T2-weighted image shows the “eye-of-the-tiger” sign (a). Unenhanced T1-weighted image shows hyperintensity of the globi pallidi (arrows, b) grossly corresponding to the regions of T2 hyposignal. c, d Axial T2weighted (c) and T1-weighted (d) images in a 21-year-old patient show similar findings

children genetically affected by PKAN. These data indicate that iron may accumulate in the pallidum before clinical symptoms and signs appear, and that MRI may reveal such abnormal accumulations [34]. Although genetic confirmation is presently required to establish the diagnosis, in our experience MRI remains the best diagnostic tool for a first provisional diagnosis. In a few cases, the diagnosis was suggested on the basis of the MRI findings, even before the clinical suspicion was proposed.

14.2.2 Huntington’s Disease Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder due to an expanded and

unstable expansion of the cytosine-adenine-guanine (CAG) trinucleotide repeat in the coding region of the IT-15 gene on the short arm of chromosome 4 [35]. The IT-15 gene encodes the huntingtin protein. Although on a cellular level mutant huntingtin is widely expressed in both neural and nonneural tissue, there is regional-specific neuronal loss in the neurons in the caudate and putamen. The inverse relationship between the CAG repeat size (at greater or equal to 40 repeats) and age of onset is unequivocal, and larger repeat numbers are associated with a younger age at onset [36]. The classic form of HD has a midlife onset characterized by choreic movements and cognitive decline, often accompanied by psychiatric changes. Juvenile-onset HD, occurring in about 5% of affected patients, is a rapidly progressive variant present-

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ing with rigidity, spasticity, and intellectual decline before the age of 20 years. Cerebellar symptoms and seizures may be present in a large percentage of affected children. The clinical diagnosis of juvenile HD may be elusive in the first stages of the disease due to the lack of choreic movements that characterize classic HD. Positive motor features characterized by excessive movement, such as chorea and dystonia, and negative motor signs including bradykinesia and apraxia may coexist in individuals with HD [37]. These symptoms result from the selective loss of neurons, most notably in the caudate nucleus and putamen. The neuropathological hallmark is a progressive degeneration of the basal ganglia. There is a medialto-lateral progression of neuronal loss in the caudate nucleus and a dorsal-to-ventral progression in the putamen. Atrophy of the basal ganglia is associated with loss of volume of the cerebral cortex, thalamus, and the white matter. Histologically, striatal pathology is characterized by loss of neurons and astrocytosis. In addition to basal ganglia involvement, pathologic changes in cortical regions of the brain including occipital, parietal, temporal, primary motor, cingulate, and prefrontal cortices have been reported in postmortem studies [38, 39]. Morphometric studies in vivo suggest an early loss of frontal lobe volumes [40]. 14.2.2.1 Imaging Findings

Atrophy of the caudate nucleus, with corresponding ex-vacuo enlargement of the frontal horns, is the main imaging feature, visible on both CT and MRI (Fig. 14.5). Quantification of atrophy can be made by the use of ratios comparing the intercaudate distance to the frontal horn width and calvarial inner table width. The use of frontal horn distance/intercaudate distance and bicaudate ratios has been shown to be helpful to confirm the diagnosis of HD in pediatric patients [41]. Additional features of juvenile HD are increased proton density- and T2-weighted signal in the atrophic caudate nuclei and putamina [41] (Fig. 14.5). A significant volume reduction in almost all brain structures, including total cerebrum, total white matter, cerebral cortex, caudate, putamen, globus pallidus, amygdala, hippocampus, brainstem, and cerebellum has been showed using high-resolution MRI [42]. Caudate atrophy and abnormal T2 prolongation in the putamina associated with MRS findings consistent with dense gliosis, i.e., elevated myo-inositol and diminished N-acetyl aspartate, creatine, and phos-

phocreatine, have been reported as helpful indicators of juvenile HD [43]. The elevated Glx/Cr ratio in spectra localized to the striatum may support the theory of glutamate excitotoxicity in HD [44].

14.3 Cerebellar Atrophy The differential diagnosis of cerebellar atrophy includes a very heterogeneous group of conditions. The ultimate diagnosis may, however, remain obscure in a significant proportion of cases (i.e., idiopathic cerebellar atrophy). Differentiation of cerebellar atrophy from cerebellar hypoplasia may be a matter of semantics, and can be difficult on imaging. The concept of “atrophy” implies a degenerative disorder in which there is a normal number of thin folia, so that the cerebellum has a shrunken appearance; on the contrary, “hypoplasia” implies a malformation characterized by marked reduction in size with a reduced number of folia, so that the cerebellum has a more rudimentary appearance. However, the use of these terms has not been uniform in the literature and remarkably, pontocerebellar hypoplasia is considered by many to be a neurodegenerative disorder. On MRI, atrophy of the cerebellum is characterized by a shrunken appearance of the cerebellum with corresponding enlargement of the fourth ventricle and subarachnoid spaces. The MRI picture can be progressive and is often aspecific, not allowing for an etiologic diagnosis in most instances (Fig. 14.6). However, signal abnormalities or involvement of other structures (brainstem, optic chiasm, supratentorial brain) can sometimes narrow the differential diagnosis. What follows is a description of some of the most common entities characterized by cerebellar atrophy as their main neuropathologic and imaging feature.

14.3.1 Infantile Neuroaxonal Dystrophy Infantile neuroaxonal dystrophy (INAD) is a rare neurodegenerative disorder inherited as an autosomal recessive trait, with onset in the first or second year of life. The clinical picture is characterized by psychomotor regression and hypotonia, progressing to spastic tetraplegia, visual impairment and dementia [45]. The course of the disease is usually slowly progressive; death is generally due to intercurrent disease, and occurs before age 10 years [46].

Neurodegenerative Disorders

a

b

Fig. 14.5a,b. Juvenile Huntington’s disease in a 8-year-old boy. a, b Axial T2-weighted images. There is atrophy of the heads of both caudate nuclei (arrows), which also are hyperintense. This results in a very characteristic isolated enlargement of the frontal horns. Notice that the putamina are also atrophic and hyperintense (arrowheads)

a

b

Fig. 14.6a,b. Idiopathic progressive cerebellar atrophy. a Sagittal T1-weighted image at age 6 months is normal. b Sagittal T1weighted image at age 5 years shows a shrunken cerebellar vermis with corresponding ex-vacuo enlargement of the fourth ventricle and cisterna magna. Note that the individual folia are present but are abnormally thin. Note also that the corpus callosum has enlarged and that the brainstem is normal. There were no associated abnormalities in this patient. The etiology of cerebellar atrophy remained unexplained

The basic metabolic defect is unknown. A failure of the neuroaxonal transport system has been suggested by Itoh et al. [47]. The diagnosis in vivo can be made by biopsy of skin, nerve, conjunctiva, or muscle. Axonal swelling and “spheroid bodies” throughout the central and the peripheral nervous systems are the pathologic hallmark of the disease [48]. However, spheroid bodies are also found in other conditions, and a definitive diagnosis of INAD depends on a combination of clinical and pathological features [45]. 14.3.1.1 Imaging Findings

The most frequent MRI findings are cerebellar atrophy [46, 49–56] and increased signal intensity in the

cerebellar cortex on long TR images [46, 50–53, 55– 58], corresponding to the neuropathological findings of neuronal loss, astrocytic gliosis, and shrinkage of the cerebellar cortex [58, 59] (Fig. 14.7). Cerebellar atrophy may be slightly more marked in the inferior part of the vermis and of the hemispheres and may be associated with enlargement of the cisterns surrounding the brain stem and with a large cisterna magna [56] (Fig. 14.8). MRI may detect cerebellar atrophy at a very early age [50, 56]. Progression of cerebellar atrophy may be observed, but the cerebellum may appear normal even in advanced stages of the disease [56, 60]. Other less constant MRI findings are slight hyperintensity in the dentate nuclei and in the posterior periventricular white matter on T2-weighted images

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a

b

c

d

Fig. 14.7a–d. Infantile neuroaxonal dystrophy. a Sagittal IR T1-weighted image; b, c coronal IR T1-weighted images; d coronal FLAIR image. Cerebellar atrophy involves both the vermis (a) and hemispheres (c). FLAIR image (d) reveals hyperintensity of the cerebellar cortex and dentate nuclei. Hyperintensity of the supratentorial periventricular white matter is also present. There is associated thinning of the optic chiasm (arrows, a, b)

(Fig. 14.7) and optic chiasm atrophy (Figs. 14.7, 8). These signs probably correspond to widespread neuroaxonal degeneration and dystrophic changes which also involve the optic pathways [48, 53, 56]. Marked T2 hypointensity in the globus pallidus has been described in three patients studied with 1.5 T MRI scanners [46, 51, 56], probably related to iron deposition. This finding, which is characteristic of PKAN, raised the doubt that INAD could actually be an intermediate form of PKAN. This hypothesis seems, however, unlikely, as the gene of PKAN, PANK2, has been mapped on chromosome 20 [27] and genetic association between these two conditions has not been demonstrated. Moreover, in PKAN, there are dystrophic axons in CNS but not in the peripheral nervous system. It has been suggested that the iron deposition may depend on a disturbance of iron protein function [61].

14.3.1.2 Differential Diagnosis

The differential diagnosis of INAD includes congenital ataxias, neuronal ceroid/lipofuscinosis, and ataxiatelangiectasia. However, these entities are characterized by a later onset and the clinical picture is different; furthermore, on MRI studies, increased T2 signal intensity in the cerebellar cortex is not present. In MELAS or other mitochondrial disorders, T2 hyperintensity in the cerebellar cortex may be observed. In these conditions, signal intensity is not diffusely and homogeneously increased as in INAD. Similar homogeneous high signal may be seen in cerebellitis, but the clinical history easily differentiates these diseases. High signal intensity may be seen in the dentate nuclei in Wilson disease, Leigh disease, L-2-OH-glu-

Neurodegenerative Disorders

a

b

Fig. 14.8a, b. Infantile neuroaxonal dystrophy. a Sagittal T1-weighted image; b coronal T2-weighted image. Sagittal image shows marked vermian shrinkage associated with a corresponding enlargement of both the fourth ventricle and cisterna magna. The optic chiasm is very thin (arrow, a). Coronal image shows the cortical atrophy involves both cerebellar hemispheres. Notice that the cerebellar cortex does not apparently show abnormal T2 signal intensity; however, this evaluation may be difficult due to the concurrent CSF hyperintensity (compare with Fig. 14.7d).

taric aciduria, and infantile Refsum disease; these disorders are, however, differentiated from INAD by their clinical and radiological pictures.

14.3.2 Inherited Ataxia Inherited ataxia is a heterogeneous group of neurodegenerative disorders in which a variable combination of signs of central and peripheral nervous system involvement is associated with progressive degeneration of cerebellum and of the spinocerebellar tracts in the spinal cord. On the basis of the mode of inheritance, hereditary ataxia is classified into autosomal dominant, autosomal recessive, and X-linked forms. 14.3.2.1 Autosomal Dominant Cerebellar Ataxia (ADCA)

ADCA have been classified on the basis of their clinical features [62]. More recently, the molecular and genetic approaches have provided the basis for genetic classification, which has had a significant impact on the diagnosis and treatment of the patients. ADCA are now classified in spinocerebellar ataxia (SCA) 1–25 according to the specific gene or chromosomal locus associated with the disease [63] (Table 14.1). In SCA, the molecular defect consists of expanded sequences of nucleotides repeats within the coding sequence, causing abnormalities in the corresponding protein. These mutated proteins are supposed to be involved in cell death and neurodegeneration [64, 65].

ADCA usually exhibit anticipation, a phenomenon consisting of earlier onset and more severe clinical expression in subsequent generations. Anticipation is particularly related to paternal transmission of longer abnormal sequences when compared to those harbored by the affected parents. Infantile or juvenile onset, as well as severity of symptoms, are therefore inversely related to the expansion size: the greater the number of nucleotides that repeat, the earlier the onset and the greater severity of the patient’s condition [66]. ADCA typically manifests in adulthood: a few cases of infantile onset in SCA 2 and SCA 7 are, however, reported. Moreover, an infantile form of dentatorubral-pallidoluysian atrophy (DRPLA) is recognized. SCA 2, SCA 7, and DRPLA are caused by expansion of the trinucleotide CAG in the chromosome 6p24– p23, 3p12–13, and 12p13.31, respectively. CAG repeats cause the synthesis of a polyglutamine tract in the corresponding proteins. These entities will now be briefly described. MRI findings in SCA are summarized in Table 14.2. SCA 2

Clinical features of SCA 2 are cerebellar ataxia, tremor, slow saccades, ophthalmoparesis, and hyporeflexia of the upper limbs. In SCA 2 patients, the MRI picture corresponds to that of olivopontocerebellar atrophy (OPCA), and may be identical to that of multiple-system atrophy with cerebellar ataxia (MSA-C). It includes widening of the cerebellar sulci, thinning of the pons with particular flattening of its ventral aspect, thinning of the middle cerebellar peduncles,

733

604432 15–40 yrs 604326 8–55 yrs

15q14–21.3 5q31–q33 Nystagmus

Nystagmus

Nystagmus

607136 6–50 yrs 15–25 yrs 607346 11–45 yrs

6q27 TATA-box binding protein 7q22–q32 1p21–q21

10–46 yrs

17 months Nystagmus to 39 yrs

2p15–p21

Pure cerebellar disorder

Dysphonia

Nystagmus

Nystagmus

Nystagmus, dysphagia

Nystagmus

Nystagmus

1p21–q23

7p21.3–p15.1 607454 6–30 yrs

19–64 yrs

606364 20–66 yrs

8q23–24.1

11

606658 10–50 yrs

19q13.3–q13.4 605259 Early Nystagmus childhood 19q13.4–qter 605361 10–59 yrs Nystagmus

603516 14–44 yrs

22q13

13q21

Nystagmus

Sensory neuropathy (mild), pyramidal signs

Clinical signs (other than ataxia and dysarthria) Supranuclear ophthalmo- Dystonia, spasticity, plegia, nystagmus, bulbar axonal polyneuropathy dysfunction Ophthalmoplegia, nystag- Myoclonus, sensory polyneuropathy mus, dysphagia Nystagmus, supranuclear Spasticity (onset 45 yrs) roptosis, facio-lingual fasciculations Polyneuropathy (sensory axonal), pyramidal No ophthalmoplegia signs Nystagmus, bulbar signs

Microcephaly

Dementia ( vermis) Cerebellar atrophy (> vermis) Cerebellar atrophy Cerebellar atrophy Generalized atrophy (some cases) Cerebellar atrophy Cerebellar atrophy Cerebral atrophy (some cases) Cerebellar atrophy Cerebellar atrophy Cerebellar atrophy Cerebellar atrophy

Spinocerebellar ataxia 3 (Machado-Joseph disease) Spinocerebellar ataxia 4 Spinocerebellar ataxia 5 Spinocerebellar ataxia 6 Spinocerebellar ataxia 7 Spinocerebellar ataxia 8 Spinocerebellar ataxia 10 Spinocerebellar ataxia 11 Spinocerebellar ataxia 12 Spinocerebellar ataxia 13 Spinocerebellar ataxia 14 Spinocerebellar ataxia 15 Spinocerebellar ataxia 16 Spinocerebellar ataxia 17 Spinocerebellar ataxia 18 Spinocerebellar ataxia 19 Spinocerebellar ataxia 20 Spinocerebellar ataxia 21 Spinocerebellar ataxia 22 Spinocerebellar ataxia 25

and mild T2 hyperintensity of the cerebellar cortex, middle cerebellar peduncles, and transverse pontine fibers. Signal abnormalities of these structures contrast with the normal signal intensity and thickness of the superior cerebellar peduncles and, within the brainstem, of the pyramidal fibers [67, 68] (Fig. 14.9). Brainstem and cerebellar atrophy have been confirmed by means of MRI-based volumetry, which also demonstrated that atrophic changes are more severe in SCA 2 than in SCA1 and SCA3 [69].

a

b

SCA 7

The clinical picture of SCA 7 is heterogeneous; the main feature is the association of cerebellar ataxia and progressive pigmentary macular dystrophy. SCA 7 presents a wide spectrum of clinical symptoms including visual loss, dementia, hypoacusia, severe hypotonia, and auditory hallucinations. Juvenile SCA 7 occurs on maternal and paternal transmission of the mutation, whereas the infantile form occurs only on paternal transmission and is associated with larger CAG expansion. MRI features consist of cerebellar atrophy and normal morphology of the brainstem; abnormal signal intensity is not described [70].

c Fig. 14.9a–c. Olivopontocerebellar atrophy in a 27-month-old child. a Sagittal T2-weighted image; b coronal IR T1-weighted image; c axial T2-weighted image. There is marked volume reduction of the cerebellum as a whole and of the brainstem, looking particularly marked at the level of the pons (a, b). Axial T2-weighted image shows abnormal signal along the transverse pontine fibers and midline (arrowheads, c) within a markedly atrophic pons, resulting in the typical “cross” sign

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Dentatorubral-Pallidoluysian Atrophy (DRPLA)

DRPLA has different modalities of presentation and a wide variety of clinical symptoms. The inheritance is autosomal dominant. The disease is rare outside of Japan, and few cases are described in Europe and in the United States. The clinical picture and the severity of the disease are related to the age of onset. Both early and late onset DPRLA patients have cerebellar ataxia, choreoathetosis, and dementia. Adult onset forms are differentiated from Huntington’s disease. Infantile onset DRPLA is characterized by progressive myoclonus epilepsy and mental retardation. The clinical course may be different within the forms and even within a single affected family. In juvenile cases, the epilepsy may change its characteristics as the disease progresses. Infantile cases with early onset of choreoathetosis, involuntary movement, and seizures without myoclonus are also described [71, 72]. The disease results from an instable expansion of the CAG trinucleotide localized on the chromosome 12p. The onset and the severity of the disease are related to the number of the expansions: early onset and severe clinical courses correspond to longer repeats. However, anticipation and expansion are significantly greater with paternal than with maternal transmission [73]. MRI findings in infantile DRPLA include mild sulcal and ventricular enlargement. T2 hyperintensity of the deep and peripheral white matter of the cerebral hemispheres are also reported. Hyperintensity on T2-weighted images in the pallidi has also been observed. Enlargement of the fourth ventricle and of the infratentorial subarachnoid spaces are related to cerebellar and brainstem atrophy. The tegmentum of the midbrain and of the superior pons are also involved. Cerebellar atrophy also involves the dentate nuclei [74, 75]. 14.3.2.2 Autosomal Recessive Ataxia

Autosomal recessive ataxia is characterized by progressive degeneration of the cerebellum and spinocerebellar tracts, resulting in early onset cerebellar ataxia associated with various neurologic, ophthalmologic, and systemic signs. While in ADCA mutated proteins are supposed to gain a toxic function, the pathogenesis of autosomal recessive ataxia is associated with a loss of function of specific cellular proteins involved in metabolic homeostasis, cell cycle, and DNA repair/protection processing [76].

The most common forms of recessive ataxia are Friedreich’s ataxia and ataxia-telangiectasia. More rare forms of recessive ataxia are infantile onset cerebellar ataxia, ataxia with oculomotor apraxia, and ataxia with vitamin E deficiency. Ataxia-telangiectasia can be considered a vascular phakomatosis, and is therefore described in Chap. 17. Friedreich’s Ataxia

Friedreich’s ataxia (FA) is the most common inherited cerebellar ataxia. The disease is inherited as autosomal recessive disorder; the onset is usually in childhood. Pathologically, FA is characterized by degeneration of the spinocerebellar tracts, posterior columns and, to a lesser extent, corticospinal tracts. Clinical manifestations include gait ataxia, pes cavus, speech impairment, lateral curvature of spine, rhythmic head tremor, kyphoscoliosis, and lower extremity weakness. Most of the patients have congestive heart failure secondary to a cardiomyopathy. About 25% of fatal cases of FA die of heart failure, and nearly three quarters have evidence of cardiac dysfunction in life [77]. The triad of hypoactive knee and ankle jerks, signs of progressive cerebellar dysfunction, and preadolescent onset is commonly regarded as sufficient for diagnosis. Motor nerve conduction velocities are usually normal or show a mild reduction; demonstration of abnormal sensory nerve conduction is useful in confirming the diagnosis [78]. Most forms of this condition are associated with a mutation in a gene on chromosome 9, at band q13, which codes for the mitochondrial protein frataxin (FRDA gene) [79]. GAA triplet expansion in the first intron of the FRDA gene is the cause of FA in 97% of patients [80]. Frataxin is involved in the regulation of mitochondrial iron content. Frataxin deficiency can cause intramitochondrial iron accumulation, which results in toxicity and cell death. Increased iron deposition has been demonstrated in myocardial biopsies from FA patients, and oxidative stress has been proven in cardiac muscle and cultured fibroblasts of FA patients. Therefore, FA should be regarded as a disorder of mitochondrial iron homeostasis [81]. Frataxin deficiency also plays an important role in the pathogenesis of cardiac hypertrophy [82]. The severity of FA correlates with the number of trinucleotide repeats: larger GAA expansions are associated with earlier age at onset and shorter times to loss of ambulation. The size of the GAA expansions has also been proved to be associated with the frequency of cardiomyopathy and loss of reflexes in the

Neurodegenerative Disorders

upper limbs [79]. Thus, the clinical spectrum of FA is considerably broad and the direct molecular test for the GAA expansion is useful for diagnosis, prognosis, and genetic counseling [83]. Due to the different modalities of clinical presentation, the frataxin trinucleotide expansion should be investigated in all sporadic ataxia patients with onset before age 40 years, even when the phenotype is atypical for FA [84]. Imaging Findings

MRI studies of the brain are almost always normal. Mild cerebellar atrophy is rarely observed, more prominent in the vermis, and no signal abnormality is usually found in cerebellum or in the cerebral hemispheres. Peculiar MRI abnormalities are found in the spinal cord; particularly, atrophy of the cervical cord with decrease of the anteroposterior diameter can be easily demonstrated in sagittal and axial sections. Axial T2-weighted images make it possible to demonstrate abnormal signal hyperintensity in the posterior or lateral columns of the spinal cord in the site of the nucleus gracilis, cuneatus, and accessory cuneatus (Fig. 14.10). These signal abnormalities are consistent with degeneration of posterior and lateral white matter tracts. Signal abnormalities with similar distribution are found in different pathological enti-

a

b

ties, and are thus nonspecific of FA [84]. However, their observation is useful for differential diagnosis in patients with progressive ataxia of uncertain clinical type [85]. Infantile Onset Spinocerebellar Ataxia (IOSCA)

The molecular defect of IOSCA is located on chromosome 10q24. The onset of the disease is between 1 and 2 years of age, in previously healthy infants. Slowly progressive ataxia, athetosis, and muscle hypotonia with loss of deep tendon reflexes may be the first presentation. Later on, ophthalmoplegia and hearing loss can be found, together with sensory neuropathy. Seizures may be present in the early phase or later in the course of the disease. MRI is normal in the early stages. Progressive cerebellar and pontine atrophy can be observed after 6 years of age [86]. Ataxia with Oculomotor Apraxia (AOA)

AOA is caused by mutation of the APTX gene on 9p13.3. It is clinically characterized by early onset cerebellar ataxia, oculomotor apraxia, areflexia, choreoathetosis, and by later appearance of peripheral neuropathy together with dystonia, scoliosis, and pes cavus. The onset is almost always in childhood or in adolescence. Telangiectasia and mental retardation are absent. The clinical phenotype is therefore similar to that of ataxia-telangiectasia, except for extraneurologic clinical and laboratory features [87, 88]. As the disease was first described by Aicardi in 1988 [87], the syndrome of ataxia with oculomotor apraxia is sometimes referred to as Aicardi syndrome; this runs the risk of confusion with the other Aicardi syndrome, which consists of agenesis of the corpus callosum with chorioretinal abnormalities.

Fig. 14.10a,b. Friedreich’s ataxia. a Sagittal T1-weighted image demonstrates thinning of the cervical cord. Mild atrophy of the cerebellar vermis is also seen. b Axial T2weighted section of the cervical cord demonstrates slight hyperintensity in the posterior and lateral columns of the cord.

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As well as in ataxia-telangiectasia, MRI demonstrates cerebellar atrophy without signal abnormalities. Ataxia with Vitamin E Deficiency (AVED)

AVED results from mutation in the gene encoding α-tocopherol transfer protein, mapped on 8q13.1– q13.3. AVED shows clinical features very similar, and in some cases identical, to those of Friedreich ataxia; cardiomyopathy is less frequently associated. The onset of the symptoms is between the ages of 6 and 18 years. Progressive development of ataxia and areflexia with a “dying back” degeneration of the peripheral nerves, along with spinocerebellar degeneration, are characteristic of AVED, with inconstant sign of fat malabsorption. MRI demonstration of cerebellar atrophy has been reported. The disease is differentiated from Friedreich’s ataxia by testing of vitamin E and by identification of the chromosomal abnormality [89, 90].

6.

7.

8.

9.

10.

11.

12. 13.

14.3.3 Pontocerebellar Hypoplasia

14.

The term pontocerebellar hypoplasia includes congenital disorders of brain morphogenesis with different etiologies, i.e., carbohydrate-deficient glycoprotein syndrome type 1, cerebromuscular dystrophies (Walker-Warburg syndrome, Fukuyama syndrome, muscle-eye-brain disease), and two types of autosomal recessive neurodegenerations known as pontocerebellar hypoplasia type I and II. These entities are described in further detail in Chap. 4.

15.

16.

17.

18.

References

19.

1.

20.

2. 3. 4.

5.

Zeman W, Donahue S, Dyken P, Green J. The neuronal ceroid lipofuscinoses (Batten-Vogt syndrome). In: Vinken PJ, Bruyn GW (eds) Handbook of Clinical Neurology, vol. 10. Amsterdam: North Holland, 1970:588-679. Haltia M. The neuronal ceroid-lipofuscinoses. J Neuropathol Exp Neurol 2003; 62:1-13. D‘Incerti L. MRI in neuronal ceroid lipofuscinosis. Neurol Sci 2000; 21(Suppl 3):S71-73. Santavuori P, Gottlob I, Haltia M, et al. CLN1. Infantile and other types of NCL with GROD. In: Goebel HH, Mole SE, Lake BD (eds) The Neuronal Ceroid Lipofuscinoses (Batten disease). Amsterdam: IOS Press, 1999:16-36. Vanhanen SL, Raininko R, Autti T, Santavuori P. MRI evaluation of the brain in infantile neuronal ceroid-lipofuscino-

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Acquired Inflammatory White Matter Diseases

15 Acquired Inflammatory White Matter Diseases Massimo Gallucci, Massimo Caulo, and Paolo Tortori-Donati

15.1 Introduction

CONTENTS 15.1

Introduction

15.2

Multiple Sclerosis 742

15.2.1 15.2.2

Epidemiology and Clinical Features Imaging Studies 744

15.3

Schilder’s Disease 746

15.3.1 15.3.2 15.3.3

Epidemiology and Clinical Features Neuropathological Findings 747 Imaging Studies 747

15.4

Devic’s Optic Neuromyelitis

15.4.1 15.4.2 15.4.3

Epidemiology and Clinical Features Neuropathological Findings 748 Imaging Studies 748

15.5

Balò’s Concentric Sclerosis 748

15.5.1 15.5.2 15.5.3

Epidemiology and Clinical Features Neuropathological Findings 748 Imaging Studies 749

15.6

Acute Disseminated Encephalomyelitis

15.6.1 15.6.2 15.6.3 15.6.3.1 15.6.3.2 15.6.3.3 15.6.4

Introduction 750 Clinical and Laboratory Findings 751 Imaging Studies 751 Conventional MRI Techniques 751 Variants of ADEM and Classification Issues Advanced MRI Techniques 757 Differential Diagnosis 759 References

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During the last decades, several different classifications were proposed to define white matter diseases. However, none proved to be completely satisfactory. Therefore, even now, some entities have clinical significance but no specific pathological, biochemical, or radiological support (i.e., Schilder’s myelinoclastic diffuse sclerosis), and the reverse is true with others. Furthermore, several diseases, although not primitively categorized as inflammatory white matter disorders, present mixed or poorly defined borders; such is the case of X-linked adrenoleukodystrophy, a genetically defined metabolic disorder which presents a constant and often dramatic white matter inflammatory component. White matter inflammation is also constant in some acquired metabolic diseases (i.e., Wernicke’s encephalopathy). Discussion is also progressing on review of single diseases which were apparently already well defined: are Devic’s neuromyelitis optica, Balò’s concentric sclerosis, and Schilder’s myelinoclastic diffuse sclerosis specific entities? Are they variants of multiple sclerosis (MS)? Or else, do they simply represent occasional combinations of some of the signs, symptoms, and findings that are common in pediatric MS? [1]. Considering the daily clinical experience with patients whose clinical onset, history, laboratory features, and MR findings are intermediate between acute disseminated encephalomyelitis (ADEM) and MS, are there definite borders between MS and ADEM? The main neuropathological features of demyelination are also controversial. Myelin destruction with no axonal involvement (myelin-axonal disconnection) was considered a pathological finding specific for demyelination until recently, when axonal involvement was demonstrated even in early stages of demyelination [2]. Apart from these preliminary questions, the didactic and practical need of categorizing demyelinating diseases remains, and the discussion can proceed only on the basis of the already established categories. Therefore, in this chapter we will consider inflamma-

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tory diseases to be part of the category of demyelinating ones, following the distinction proposed by Poser between demyelinating and dysmyelinating diseases. Among demyelinations, attention will be focused on inflammatory noninfectious diseases, i.e., MS, diffuse sclerosis (Schilder’s disease), neuromyelitis optica (Devic’s disease), concentric sclerosis (Balò’s disease), and ADEM and its variants (recurrent and necrotic-hemorrhagic forms). These definitions follow the criteria first proposed by Hallervorden, then revisited by Raine [3], and eventually completed by van der Knaap and Valk [4].

15.2 Multiple Sclerosis 15.2.1 Epidemiology and Clinical Features Multiple sclerosis (MS) is known to be a disease of adolescents and adults; however, this could be partly due to the fact that late-onset cases have attracted greater attention and are consequently better documented [5]. Epidemiological studies and the geographic distribution of MS have suggested that exposition to a transmissible agent (presumably a virus) can cause MS after a certain latency in genetically predisposed individuals. Considering the epidemic episode occurred in the Faeroe Islands [6], an interval of 6 years or longer is postulated between the exposure to the “MS agent” and the clinical onset. MS is the most disabling neurologic disorder affecting young adults in Europe and North America. Usually, the onset of MS occurs between ages 20 and 50 years; however, onset before puberty (12 years) and after age 60 years has also been documented [7]. The incidence of MS in childhood varies between 0.4% and 6%, with the highest incidence in patients with a history of neurologic symptoms between 10 and 15 years of age. In a population monitored by our group, infantile forms accounted for 3.2% [8]. In 1987, Duquette et al. [9] reported 125 patients out of 4,632 (2.7%) with onset of MS before age 16 years; only eight patients (0.2%) were younger than 11 years, with an incidence of 0.3%–0.4%. In our experience, always supported by magnetic resonance imaging (MRI), we found a 15% incidence during the first decade of life. Furthermore, very early onset has been documented to occur at 45 [10], 24 [11], and 10 [12] months after birth. In adult MS, the sex ratio is F:M = 2:1. This prevalence becomes more pronounced in childhood (F:

M = 3–5:1) [1, 8, 9, 12–14]; however, male predominance was reported in a group of patients younger than 10 years (F:M = 0.6:1) [15]. Clinical features in MS are extremely variable, thus making it difficult to define symptoms that can reliably lead to a correct diagnosis. Recurrent foci of demyelination are the main pathological evidence; a distinct propensity for involvement of certain white matter regions has been recognized, and the periventricular region, corpus callosum, optic nerves, and brainstem are most notably compromised. Focal neurologic symptoms consistently follow the demyelinating event, and persist for weeks or months until recovery, which often is complete. Most patients experience a relapsing-remitting course of exacerbation and remission of multifocal neurologic deficits, and fever is often reported; thus, clinical features can be similar to those of late-onset MS. However, several reports describe a more aggressive and atypical collection of symptoms. In a series of 56 cases reviewed by Menkes [1], the main symptoms at presentation were ataxia (31 cases), vision disturbances (19 cases), numbness or paresthesias (19 cases), headache and vomiting (10 cases), and seizures (one case). Optic neuritis is a common finding in childhood, and when it occurs at presentation the risk of MS ranges from 15% to a mean value of 30% [16, 17], the risk being lower (16%) if the initial brain MRI is normal [17] or in cases of bilateral optic nerve involvement. Usually, the patient or a relative will be able to exactly specify the date and the moment of the first neurologic symptom. Nevertheless, clinical onset is sometimes progressive during a period of weeks or months. Furthermore, it is well known that recurrences in functionally silent areas will not result in clinical manifestations. As in previous reports, in our experience with 24 cases [13] we found weakness and ataxia to be the most frequent presenting symptoms in the pediatric age group. Somatosensory disturbances are frequent during progression of the disease, whereas they are less common at presentation [18]. Other typical features of pediatric MS include vomiting and headache (three cases), lethargy (one case), and seizures (two cases). Moreover, MS in childhood often shows a more acute onset than adult forms. This more severe clinical evidence is related to the more aggressive pathologic features of demyelinating plaques, such as larger size, diffuse edema, and frequent necrotizing evolution. Also paraclinical and laboratory features differentiate pediatric MS from typical adult forms. For instance, cerebrospinal fluid (CSF) oligoclonal bands are present in 98% of adult patients, whereas they are found in 82% of pediatric cases [1, 12] due to a

Acquired Inflammatory White Matter Diseases

presumed delayed immune reaction in children and young adults. Clinical factors also play an important prognostic role, as demonstrated by Simone et al. [15] in a retrospective study based on a large group of 83 patients with clinical onset before age 16 years. They reported a slower rate of disease progression in young patients with MS, suggesting greater plasticity for recovery in the developing CNS. A secondary progressive course and a short interval between the first and second attacks were unfavorable factors associated with higher risk of developing severe clinical disability. The adverse prognostic role of a large number of relapses during the first two years of disease was also demonstrated. To summarize, the diagnosis of MS in the pediatric age group can be difficult, and criteria other than the classical ones postulated for the adult form should be evaluated. Nevertheless, specific diagnostic criteria have not yet been postulated, and the same criteria used for adult forms are also usually employed to categorize pediatric MS. Recently revised diagnostic

a

d

b

criteria by the International Panel on MS Diagnosis [19] focus on the objective demonstration of dissemination of lesions in both time and space. Compared with prior criteria, the new ones facilitate the diagnosis of MS especially in patients with atypical clinical presentations, including monosymptomatic disease and disease with insidious progression, without clear attacks and remissions. These criteria also seem to offer a wider possibility in pediatric forms, atypical by definition, even though specific validation is still lacking. Moreover, previously used terms such as “clinically definite” and “probable” MS are no longer recommended. The outcome of a diagnostic evaluation is MS, possible MS (for those at risk of MS, but in whom diagnostic evaluation is equivocal), or not MS. Finally, because the Panel confined diagnostic requirements to demonstration of lesion dissemination in space and time, MRI plays a major role, at least as great as clinical diagnostic methods or even greater, when one considers that its sensitivity is ten times higher than that of clinical examination.

c

Fig. 15.1a-d. Multiple sclerosis: different imaging features. a,b Axial T2-weighted image; c axial FLAIR image; d Gd-enhanced sagittal T1weighted image. a Typical appearance of deep white matter plaques, mostly ovoid in shape. General features are similar to those of the adult form of MS in this case. b Lumpy-bumpy (“bull’s eye”) appearance of acute plaque (arrow). c Ovoid sign (arrowhead) and corpus callosum involvement (arrow). d Different kinds of enhancement: oblong (arrowhead) and ring-like (arrow).

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15.2.2 Imaging Studies Conventional MRI Techniques

The neuroradiological features of pediatric MS basically reflect those of adult disease (Fig. 15.1). Following the recommendations from the International Panel on MS diagnosis, MRI criteria should derive from those enunciated by Barkhof et al. [20] and Tintoré et al. [21], which require evidence of at least three of the following four criteria: 1) one gadolinium-enhancing lesion, or nine T2 hyperintense lesions if gadolinium-enhancing lesions are not present; 2) at least one infratentorial lesion; 3) at least one juxtacortical lesion (i.e., involving the subcortical U-fibers); 4) at least three periventricular lesions. According to the same criteria, one spinal cord lesion can be substituted for one brain lesion.

a

d

b

Lesions will ordinarily be larger than 3 mm in cross-section, usually appearing oblong (“ovoid sign”). Oblong lesions are typically located at the callososeptal interface; perivenular extensions in the deep white matter generate radially oriented periventricular plaques that are often termed Dawson’s fingers (Fig. 15.2). The internal capsule and corpus callosum are often involved. The distribution of demyelinating lesions does not respect the vascular territories, and plaques modify over time, showing a “lumpy bumpy” (also known as “bull’s eye”) appearance in the acute stage, which is due to the presence of a core of high-intensity signal on T2-weighted sequences and surrounding edema. In more severe cases, confluent periventricular lesions are common (Fig. 15.2). The presence of contrast enhancement indicates blood-brain barrier breakdown, and is seen during the active demyelinating stage. Although neuroradiological evidence of pediatric and later forms of MS is similar, lesions outside of the typical areas and showing unusual morphology and signal intensity are more commonly observed

c

Fig. 15.2a–d. Multiple sclerosis in a 16-year-old girl. a–c Axial FLAIR images; d Sagittal T2-weighted image. Diffuse plaques of demyelination are seen in the paraventricular regions and in the centrum semiovale bilaterally as hyperintense lesions in FLAIR images, with local confluent appearance (a–c). Sagittal image (d) shows the typical radial arrangement of the demyelinating plaques, called Dawson’s fingers. Plaques did not enhance (not shown)

Acquired Inflammatory White Matter Diseases

in pediatric MS. Cases of plaques mimicking brain tumor (i.e., tumefactive or pseudo-tumoral plaques) associated with mass effect and ring enhancement have been often reported [22], as have lesions with large pseudo-necrotic core and with bleeding [1, 4, 9, 13, 23]. Pseudo-tumoral lesions (Fig. 15.3) are large, involve an entire lobe or even an entire hemisphere, and show diffuse edema that can produce mass effect (see also Schilder’s disease). Plaques larger than 20 mm in diameter (so-called giant plaques) account for 55%–66% of pediatric lesions, and often eventu-

ally result in pseudo-cystic lesions due to loss of brain matter [1, 4, 8, 9, 13, 17]. In the case of single pseudo-tumoral or hemorrhagic plaque, the correct diagnosis of MS is often difficult, and can be supported by a careful study of the rest of the central nervous system (CNS), looking for further small demyelinating lesions with typical features (FLAIR sequences are suggested). However, differentiation of MS from other pathologies is not always easy and feasible by means of conventional MRI.

a

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f

Fig. 15.3a–f. Giant pseudo-tumoral plaque in a 6-year-old female with sudden onset of acute left hemiplegia and numbness. a CT scan. b Axial T2-weighted image. c Gd-enhanced axial T1-weighted image obtained at presentation. d Axial T2-weighted image and e Gd-enhanced axial T1-weighted image obtained 6 months later. f Axial proton-density weighted image obtained after 18 months. Initial CT scan shows hypodense left frontal lesion, larger than 6 cm, with sparing of the cortex and very mild mass effect. MRI confirms large pseudo-tumoral lesion that is hyperintense on T2-weighted image (b). Contrast material administration reveals “open ring” enhancement (arrows, c) and pseudo-necrotic core (asterisk, c). Initial diagnosis was Schilder’s disease. Six months later a new frontal contralateral giant lesion appeared, again showing T2 hyperintensity (d), “open ring” enhancement (arrows, e), and pseudo-necrotic core (asterisk, e). Notice shrinkage of left frontal plaque (arrowheads, d). Control exam after 18 months shows also right frontal lesion has shrunk (arrow, f). Left frontal lesion is unchanged (arrowhead, f), but a hyperintense third lesion in the right subcortical parietal region has appeared (open arrow, f)

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Advanced MRI Techniques

15.3 Schilder’s Disease

Magnetization Transfer Imaging

Calculation of the magnetization transfer ratio (MTR) has been proposed to support the differential diagnosis [24]. The MTR is thought to be abnormal even within the apparently normal white matter in people with MS, whereas it is normal in cases of vasculitis or other pathologies. MR Spectroscopy

Recently, magnetic resonance spectroscopy (MRS) has been used in the attempt to improve MRI specificity. Plaques show decrease of N-acetyl-aspartate (NAA), a marker of vital neuronal tissue, and increase of choline (Cho)-containing compounds and inositol, suggesting demyelinating and membranoproliferative processes. NAA peak reduction is much more evident in chronic, nonenhancing plaques that appear hypointense on conventional T1-weighted images (so-called “black holes”), thus suggesting that these features indicate plaques with greater axonal damage. Less markedly reduced NAA levels are also present in T1 isointense plaques, and even in the apparently normal white matter [25, 26]. No detectable amount of lactate and free lipids in the plaques has been reported. Furthermore, MRS reveals reduction of NAA in the gray matter adjacent to a plaque [5]. One crucial point in the pediatric age group is to evaluate the risk of developing MS after a single episode of clinical neurologic deficit (so-called CIS = Clinically Isolated Syndrome). Again, the pediatric population has not yet been specifically screened in scientific trials. However, one should consider that the general risk of developing MS is reported to range between 19%–88 % after 14 years from the first episode, depending on the results of MRI performed at that time: in cases of normal MRI the risk is 19%, whereas it is 88% in cases of lesion detection [27]. A recent paper also stressed the possibility of identifying NAA reduction with MRS during the very early stages of MS [28]. This could favor correct differential diagnosis and early identification of MS in childhood. Diffusion-Weighted Imaging

Diffusion-weighted imaging (DWI) shows higher mean diffusivity in lesions and in the entire brain of patients with mildly disabling relapsing/remitting MS [29]. Even in this case, correct re-evaluation in the pediatric age group should be made to assess the real efficacy of these findings in pediatric MS.

15.3.1 Epidemiology and Clinical Features Schilder’s disease (SD), or myelinoclastic diffuse sclerosis, is a rare demyelinating disorder first described in 1912 by Schilder [30], who reported large, clear-cut areas of demyelination in both cerebral hemispheres of a 14-year-old girl. Schilder regarded this condition as a childhood variant of acute MS, naming it “encephalitis periaxialis diffusa”. A few years later, Schilder thought to have discovered two additional forms of encephalitis periaxialis diffusa, later recognized more properly by Lumsden, Poser, and Van Bogaert as adrenoleukodystrophy and subacute sclerotizing panencephalitis, respectively. In the following years, the term “Schilder’s disease” was used to refer to several familial or sporadic inflammatory or metabolic diseases involving large regions of white matter. According to Poser [31], the eponymic designation should be restricted to well-documented cases of myelinoclastic diffuse sclerosis that correspond to the illness described by Schilder in 1912. The Schilder form of MS is a designation now restricted to acute, subacute, and chronic cases showing one or more large plaques, greater than 2 × 3 cm and involving the hemispheric white matter, with or without smaller typical MS plaques in the brain or spinal cord, together with histological features identical to those of MS, normal ratios of very long chain fatty acids, and no evidence of involvement of the peripheral nervous system. The term has also been applied, albeit less appropriately, to longstanding cases with extensive hemispheric demyelination and shrinkage resulting from confluence of normal-sized plaques [32]. SD is an extremely rare condition that affects both adults and children of both sexes; however, children are more frequently affected than adults, probably because of the greater vulnerability of the pediatric CNS to autoimmune injuries owing to the well-known delay in humoral immune response, accounting for both aggressiveness and progression. The diagnosis is mainly based on exclusion criteria, mostly relating to infections, metabolic disorders (i.e., X-linked adrenoleukodystrophy), following Poser’s criteria [31, 33] (Table 15.1). Clinically, SD may manifest with epileptic seizures, hemiplegia, cerebellar ataxia, pseudobulbar palsy, and intellectual impairment [4]; a clinical onset with unilateral optic neuritis has also been documented [34].

Acquired Inflammatory White Matter Diseases Table 15.1. Poser’s criteria for the diagnosis of Schilder’s disease ƒClinical symptoms and signs often atypical for MS (bilateral optic nerve involvement, headache and vomiting due to increased intracranial pressure, psychiatric manifestations, convulsions) ƒCSF normal or not MS correlated ƒ Bilateral large areas of demyelination of cerebral white matter ƒNo fever, viral infection, or vaccination before clinical onset ƒNormal serum concentration of very-long-chain fatty acids

15.3.2 Neuropathological Findings Grossly, the lesions are generally sharply contoured and occupy a large portion of each cerebral hemisphere, asymmetrically. Histopathologically, SD shows well-demarcated demyelination and gliosis with relative sparing of axons, although microcystic changes and even frank cavitations can occur [35].

15.3.3 Imaging Studies MRI of SD consists of giant areas of white matter involvement with spared gray matter. The main localization of plaques is fronto-parietal, and they are often roughly symmetric and cause mass effect (Fig. 15.3). Vasogenic edema surrounding the rimenhancing lesions has been described [34]. The final evolution is often necrotic-atrophic. A very specific pattern of contrast enhancement was recently reported to distinguish large demyelinating lesions from infections or neoplasm; demyelinating lesions usually show an incomplete or open ring enhancement, with the open portion of the ring abutting the gray matter of the cortex or of the basal ganglia (Fig. 15.3) [37]. Spectra observed using MRS show the same patterns of MS, typical of acute demyelinating plaques: marked increase of Cho and reduction of NAA concentrations. A recent review of 24 children with demyelinating diseases found no statistical differences among clinical, CSF, and MRI evaluations in two groups representing MS (22 cases) and SD (two cases) [13]. Cases with SD-like onset and MS-like evolution (i.e., relapsing-remitting) have also been reported in literature; moreover, monophasic SD can be indistinguishable from ADEM [38, 39]. In conclusion, there are data to support the possibility that SD is neither a nosologic entity nor a variant of MS, seeming rather to be an occasional coincidence of some of the usual clinical, laboratory, pathological, and radiological findings and signs that occur mostly in pediatric MS.

15.4 Devic’s Optic Neuromyelitis 15.4.1 Epidemiology and Clinical Features In 1894, Devic described a combination of optic neuritis and transverse myelitis that was subsequently called Devic’s disease, or optic neuromyelitis (ONM). As with Schilder’s disease, it has long been controversial whether ONM should be considered an autonomous entity, a topographic variant of a not welldefined inflammatory demyelinating disease, or even an atypical manifestation of MS. ONM is more frequent in Asian populations, affects men and women equally, and patient age ranges between 5 and 65 years, although young adults are most commonly affected. This prevalence is probably due to the already reported delay of humoral immunity response proper of young individuals. ONM may present with a monophasic or relapsing course. Features associated with a relapsing course are female sex, older age at presentation, and longer interval between events (optic neuritis and myelitis) [40]. Wingerchuk et al. reported that almost all relapsing patients presented with isolated optic neuritis or myelitis and experienced the other event after longer than 3 months [40]. In ONM, optic neuritis is more often bilateral than unilateral, and transverse myelitis mostly involves the thoracic spinal cord (see Chap. 41). Optic neuritis and transverse myelitis may either occur simultaneously at presentation, or be separated by an interval ranging between days and 2–8 weeks, usually with optic neuritis preceding myelitis; longer intervals have also been described [40]. In a minority of patients, viral illness has been reported to precede the onset of the disease. Clinically, patients experience visual impairment ranging from scotoma to blindness, and motor dysfunction ranging from hyperreflexia without weakness to tetraplegia; sensory and sphincter functions are involved more rarely. ONM differs from typical MS in that blindness and tetraplegia occur earlier in the course of the disease [4, 41–43]. CSF findings consist of neutrophilic pleocytosis, whereas oligoclonal bands are not common (1 cm) and with poorly defined margins; mass effect is usually slight or completely absent. In contrast, MS lesions have well-defined margins on T2-weighted images due to a more prominent edematous component, and consequently appear more “swollen” [64]. After contrast material injection lesions of ADEM usually do not enhance; when present, enhancement usually involves all lesions simultaneously (Fig. 15.7). Contrast enhancement is obvious and prolonged in larger ADEM lesions, whereas

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a

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Fig. 15.6a–d. ADEM in a 14-year-old girl. a Axial FLAIR image and b Gd-enhanced axial T1-weighted image of the brain. c Sagittal T2-weighted image and d Gd-enhanced sagittal T1-weighted image of the spine. In this case, lesions are well recognizable on FLAIR image (a) but do not show enhancement (b). These hyperintense areas involve preferentially the subcortical white matter, but the cortex is also regionally hyperintense (arrows, a). Diffuse areas of abnormal signal intensity (open arrows, c) involve the whole spinal cord that is swollen at cervical level. Following gadolinium administration, mild enhancement is seen in some portions (open arrows, d)

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Fig. 15.7a,b. ADEM: selective white-matter involvement. a Axial T2-weighted image. b Gd-enhanced axial T1-weighted image. Lesions appear hyperintense on T2weighted image (a) and are superficially located, whereas the periventricular white matter is spared. Following gadolinium administration, all lesions enhance (b)

Acquired Inflammatory White Matter Diseases

a

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a

b

c

Fig. 15.8a,b ADEM in a 10-year-old boy: selective gray matter involvement. a,b Axial FLAIR images. Typical lesions involving basal ganglia, insulae, and medial frontal cortex (arrows, b). Notice swelling of the caudate heads (asterisks, a), and involvement of the left claustrum (arrowhead, a). Notice also there is isolate, essentially symmetric gray matter involvement in this case, with sparing of the white matter throughout the brain

Fig. 15.9a–c ADEM in a 4-year-old boy. a,b Axial FLAIR images. c Coronal T2-weighted image. FLAIR images (a,b) show diffuse involvement of the cortex, striatum (open arrows, b), and pulvinar (thin arrows, a). Also notice hyperintensity of the claustrum bilaterally (arrowheads, b). Coronal section (c) shows swelling of the frontobasal and temporal cortex as well as of both lenticular nuclei

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a

b Fig. 15.10a,b. ADEM with selective striatal involvement. a Axial T2-weighted image. b MR spectroscopy. Marked hyperintense signal from both putamina and head of caudate nuclei (a.) MRS spectrum from right putamen (b) shows reduction of choline and NAA peaks

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Fig. 15.11a–e. ADEM in a 10-year-old boy. a,b Axial FLAIR images and c Sagittal T2-weighted images at presentation. d Axial FLAIR image and e Sagittal T2-weighted image after 2 months. Diffuse involvement of the nucleo-capsular regions and, regionally, of the cortex (a,c) associated with a massive enlargement of the brainstem, and especially of the pons (b,c), that prompted an initial diagnosis of brainstem glioma at an outside institution. Two months later, MRI is normal (d,e); notice enlargement of subarachnoid spaces as side effect of steroid treatment

Acquired Inflammatory White Matter Diseases Fig. 15.12a–c. ADEM in a 6-year-old girl. a,c Axial T2-weighted images. d Gd-enhanced coronal T1-weighted image. Gross area of abnormal signal intensity in the left cerebellar peduncle (a) that markedly enhances (b). The medial portions of the thalami are also involved (arrows, c)

a

b

small lesions rapidly recover their blood-brain barrier integrity and may therefore fail to enhance, also in the acute phase of the disease (Fig. 15.6). Although lesions have been generally described to appear simultaneously with clinical presentation and to disappear with clinical recovery, different behaviors have also, albeit rarely, been documented. In adults, delay of one month between clinical onset and positive MRI findings has been described, and the same could also apply to pediatric patients; this suggests that, in cases of clinical evidence very suggestive for ADEM, normal initial MRI does not rule out the disease. Therefore, strict follow-up by means of MRI is mandatory [65]. Generally, lesions gradually resolve completely after steroid therapy (Figs. 15.11, 15.13); evidence of disease may persist on MRI for a long time, as much as 18 months, and sometimes white matter damage may be permanent [7]. 15.6.3.2 Variants of ADEM and Classification Issues Acute Relapsing Disseminated Encephalomyelitis

Although the clinical course of ADEM is usually monophasic, relapsing-remitting forms (i.e., acute

c

relapsing disseminated encephalomyelitis: ARDEM) have been documented (Fig. 15.14). These cases add to the controversy concerning the often blurred border between ADEM and MS, suggesting that these entities could represent two extremes of the same pathophysiological process [53, 66, 67]. Recurrent episodes are presumed to happen within a period of few months, usually with similar clinical, laboratory, and radiological features (i.e., stereotypy). If one considers relapses to be components of the same monophasic process, the term multiphasic disseminated encephalomyelitis (MDEM) should be used. Instead, the definition of ARDEM should be reserved for more heterogeneous (i.e., not stereotypic) cases, more similar to typical relapsing-remitting MS, though characterized by a first episode clearly referable to viral episodes or vaccination. Finally, if relapses occur with dissemination in space and time, a diagnosis of MS should be entertained [59]. Additionally, Tenembaum et al. [60] recently introduced a new category, called biphasic demyelinating encephalomyelitis (BDEM). Those authors observed a biphasic disease characterized by one definite relapse in 10 patients out of a group of 83 cases of ADEM. The second attack was observed after a mean interval of 2.9 years from the first event. Because they saw

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Fig. 15.13a,b. ADEM in the acute stage and after 3 months. a,b Axial T2-weighted images. Both the posterior limbs of the internal capsule are involved (arrows, a). Three months later, MRI is normal (b)

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Fig. 15.14a–d. ARDEM in an 8-year-old girl. a Axial proton density-weighted image at presentation. b Axial proton density-weighted image after 15 days. c Axial T2-weighted image after 1 month. d Axial T2-weighted image after 3 months. A few days after an upper respiratory infection and the head of the left caudate nucleus and putamen is swollen and hyperintense (a). A second location is evident in the right frontal region (arrowhead, a). Fifteen days later, the left striatal lesion has only slightly modified and the right frontal lesion is no longer visible; however, a new lesion has appeared in the right nucleo-capsular region (open arrow, b). One month later, marked improvement is recognizable bilaterally (c). Complete regression is seen three months later (d)

Acquired Inflammatory White Matter Diseases

only one definite relapse during long-term follow-up, they proposed the term BDEM instead of MDEM or ARDEM. Obviously, differentiation of BDEM from MS is possible only after long-term follow-up. Acute Hemorrhagic Encephalomyelitis and Acute Necrotic Encephalomyelitis

Lesions of ADEM may be prevalently explained by a microvascular inflammatory pathological mechanism. When the degree of inflammation leads to a stage of necrotizing vasculitis, two dramatic forms of ADEM can occur, i.e., acute hemorrhagic encephalomyelitis (AHEM) (Fig. 15.15) and acute necrotic encephalomyelitis (ANEM) (Fig. 15.16), respectively characterized by prominent hemorrhagic and necrotic components that are well depicted by MRI [63]. ANEM seen in Western populations probably has some relationship with acute necrotizing encephalopathy, a rare devastating complication of

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influenza and other viral infections that prevails in Eastern Asia and has a bleak prognosis with elevated mortality. This entity has been related to intracranial cytokine storms causing blood-brain barrier damage that results in edema and necrosis, without signs of direct viral invasion or parainfectious demyelination [68]. MRI findings involve a very characteristic concentric pattern of signal abnormality in the thalami associated with diffuse supratentorial white matter and brainstem involvement (Fig. 15.17). 15.6.3.3 Advanced MRI Techniques Magnetization Transfer Imaging

MTI has been especially proposed for the early diagnosis of ADEM in patients with silent conventional MRI at presentation. MTI has recently been used in adult ADEM, but not in cases of silent conventional

b

Fig. 15.15a,b. Persumed necrotic-hemorrhagic ADEM (AHEM). a Axial T2weighted image. b Axial T1-weighted image. Diffuse, symmetric involvement of the frontal lobes and of both lenticular nuclei (a). T1-weighted image shows areas of spontaneous hyperintensity in the lenticular nuclei, consistent with hemorrhagic components (open arrows, b). (Case courtesy of Prof. A. Carcione, Palermo, Italy)

b

Fig. 15.16a,b. Necrotic ADEM (ANEM) in a 3-year-old boy. a. Contrastenhanced CT scan; b. Axial T1-weighted image. CT scan obtained 3 days after measles vaccination shows areas of abnormal density in the nucleo-capsular regions, predominately to the right but with enhancement involving also the head of the left caudate nucleus (arrows, a). One year later, MRI (b) shows diffuse tissue loss in the nucleocapsular regions bilaterally

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Fig. 15.17a–e. Acute necrotizing encephalopathy in a 3-year-old boy on the 2nd day of seizures after influenza. a Axial T1-weighted image. b Gdenhanced axial T1-weighted image. c Coronal T2-weighted image. d Axial diffusion-weighted image. e Axial ADC map. T1-weighted images before and after contrast medium show low-signal thalami with a concentric pattern and faint enhancement (a,b). Coronal T2-weighted image (c) shows swollen thalami associated with high signal in the supratentorial white matter and brainstem. The concentric pattern is visible also on DWI (d,e). (Case courtesy of Dr. H.-S. Wang, Taipei, Taiwan)

MRI. MTI has been demonstrated to be normal in the normal-appearing brain tissue in patients with ADEM, and to be similar to sex-matched healthy control subjects [69]. Evidence of early changes in the brain of patients with ADEM may obviously allow early treatment, thereby improving the chances of better outcome.

Diffusion-Weighted Imaging

To date, results of diffusion-weighted imaging (DWI) in pediatric ADEM have been described only in one paper [70]. The value of DWI in the early diagnosis of ADEM and in differentiation from MS and other entities requires assessment in large study cohorts.

Acquired Inflammatory White Matter Diseases

15.6.4 Differential Diagnosis

MR Spectroscopy (MRS)

MRS certainly plays a role in the diagnosis of ADEM and in the differentiation from other disorders affecting the white and gray matter. Bizzi et al. [71] studied a 4-year-old boy with ADEM by means of MRS, and found patterns differing from those described in MS and mitochondrial diseases. They found low NAA levels on initial MRS; the neurologic picture, brain MRI, and NAA levels all returned to normal at 4 months follow-up. The reversibility of the NAA deficit indicates that, in ADEM, NAA reduction is related to transient neuronal-axonal dysfunction rather than to irreversible neuronal-axonal loss. Another perhaps more significant MRS finding is the evidence of decreased Cho levels during the acute phase in areas corresponding to high-signal regions on T2-weighted images (Fig. 15.10). Cho levels are usually elevated during the acute stage of MS and various leukodystrophies, probably because of myelin breakdown products. Low Cho levels in ADEM could indicate that an abnormal MRI signal could be consistent with edema rather than with demyelination, thereby acquiring great prognostic value [71].

Disorders presenting with imaging findings similar to those of ADEM include MS, Lyme disease, vasculitis, viral encephalitis, collagen vascular disease, Whipple disease, and subacute sclerosing panencephalitis. As was abundantly stated previously, the differentiation of ADEM from MS may be challenging. It is useful to remember that, when enhancement is present, it usually involves all lesions simultaneously in ADEM following gadolinium administration (Fig. 15.7), whereas this does not occur in MS. The main clinical and imaging findings useful for differentiating ADEM from multiple sclerosis are summarized in Table 15.2. Although a definite diagnosis of ADEM may be difficult to establish, its possibility should be raised especially in cases of young patients with severe onset of neurological symptoms, MR evidence of isolated lesions of the brainstem and cerebellum or symmetrical involvement of basal ganglia and/or thalami, and recent clinical history of infectious disease or vaccination. Prompt administration of steroids can lead to full clinical recovery.

Table 15.2. Differential diagnosis between ADEM and multiple sclerosis Parameter

ADEM

Multiple sclerosis

Clinical picture

Widespread CNS dysfunction Fever, headache, seizures Common consciousness impairment Bilateral optic neuritis

Predominant unilateral involvement Motor deficit, cranial nerve palsies Rare consciousness impairment Unilateral optic neuritis

Precedent viral infection

Common

Uncommon

Course

Acute (monophasic disorder)

Chronic (polyphasic disorder)

CSF

Mild pleocytosis Rare intrathecal IgG production and oligoclonal bands

High and persistent pleocytosis Intrathecal IgG production (70%–90%) Oligoclonal bands (90%–95%)

MRI

Diffuse lesions Poorly marginated (partly due to edema) Uniform appearance Predominant subcortical/deep white matter involvement Corpus callosum usually not involved

Predominantly unilateral lesions Well marginated Variable appearance Predominant periventricular white-matter involvement Corpus callosum typically involved

Gray-matter involvement

Common

Uncommon

Contrast enhancement

Homogeneous in all lesions

Heterogeneous (related to different stage of evolution of the lesions)

Spinal cord

Transverse myelitis

Response to steroid treatment Decrease in number and size of lesions

Partial myelopathy No modifications of lesions

Follow-up MRI

Complete/partial resolution of lesions New lesions (residual gliosis and demyelination may occur) No new lesions

Sequelae

Uncommon

Common

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Acquired Inflammatory White Matter Diseases 40. Wingerchuk DM, Hogancamp WF, O’Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology 1999; 53:1107–1114. 41. Mandler RN, Davis LE et al. Devic’s neuromyelitis optica: a clinical-pathological study of 8 patients. Ann Neurol 1993; 34:162–168. 42. Tashiro K, Ito K, Maruo Y, Homma S, Yamada T, Fujiki N, Moriwaka F. MR imaging of spinal cord in Devic disease. J Comput Assist Tomogr 1987; 11:516–517. 43. Tortori-Donati P, Fondelli MP, Rossi A, Rolando S, Andreussi L, Brisigotti M. La neuromielite ottica. Una ulteriore sfida nella diagnosi differenziale con le neoplasie intramidollari. Rivista di Neuroradiologia 1993; 6:53–59. 44. Jeffery AR, Buncic JR. Pediatric Devic’s neromyelitis optica. J Pediatr Ophthalmol Strabismus 1996; 33:223–229. 45. Gold R, Linington C. Devic’s dysease: bridging the gap between laboratory and clinic (Editorial). Brain 2002, 125:1425–1427. 46. Filippi M, Rocca MA, Moiola M, Martinelli V, Ghezzi A, Capra R, Salvi F, Comi G. MRI and magnetization transfer imaging changes in the brain and cervical cord of patients with Devic’s neuromyelitis optica. Neurology 1999, 53:1705–1710. 47. Hainfellner JA, Schmidbauer M, Schmutzhard E, Maier H, Budka H. Devic’s neuromyelitis optica and Schilder’s myelinoclastic diffuse sclerosis. J Neurol Neurosurg Psychiatry 1992; 55:1194–1196. 48. Lucchinetti CF, Mandler RN, McGavern D, Bruck W, Gleich G, Ransohoff RM, Trebst C, Weinshenker B, Wingerchuk D, Parisi JE, Lassmann H. A role for humoral mechanism in the pathogenesis of Devic’s neuromyelitis optica. Brain 2002; 125:1450–1461. 49. Balò J. Encephalitis periaxialis concentrica. Arch Neurol Psychiatry 1928; 19:242–264. 50. Karaarslan E, Altintas A, Senol U, Yeni N, Dincer A, Bayindir C, Karaagac N, Siva A. Balo’s concentric sclerosis: clinical and radiologic features of five cases. AJNR Am J Neuroradiol 2001; 22:1362–1367. 51. Moore GR, Neumann PE, Suzuki K, Lijtmaer HN, Traugott U, Raine CS. Balo’s concentric sclerosis: new observation on lesion development. Ann Neurol 1985; 17:604–611. 52. Bolay H, Karabudak R, Tacal T, Onol B, Selekler K, Saribas O. Balo’s concentric sclerosis: report of two patients with MRI follow-up. J Neuroimaging 1996; 6:98–103. 53. Korte JH, Bom EP, Vos LD, Breuer TJ, Wondergem JH. Balo concentric sclerosis. MR diagnosis. AJNR Am J Neuroradiol 1994; 15:1284–1285. 54. de Seze J, Stojkovic T, Ferriby D, Gauvrit JY, Montagne C, Mounier-Vehier F, Verier A, Pruvo JP, Hache JC, Vermersch P. Devic’s neuromyelitis optica: clinical, laboratory, MRI and outcome profile. J Neurol Sci 2002; 197:57–61. 55. Andreula CF, Recchia Luciani ANM, Milella D. Magnetic Resonance Imaging in the diagnosis of acute disseminated encephalomyelitis (ADEM). Int J Neuroradiol 1997; 3:21–34. 56. Kamei A, Ichinohe S, Onuma R, Hiraga S, Fujiwara T. Acute disseminated demyelination due to primary human herpesvirus-6 infection. Eur J Pediatr 1997; 156:709–712.

57. Dubreuil F, Cabre P, Smadja D, Quist D, Arfi S. Acute disseminated encephalomyelitis preceding cutaneous lupus. Rev Med Interne 1998; 19:128–130. 58. Yamada M, Inaba A, Yamawaki M, Ishida K, Yokota T, Uchihara T, Eishi Y, Okeda R. Paraneoplastic encephalomyelo-ganglionitis: cellular binding sites of the antineuronal antibody. Acta Neuropathol 1994; 88:85–92. 59. Dale RC, de Sousa C, Chong WK, Cox TC, Harding B, Neville BG. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain 2000; 123:2407–2422. 60. Tenembaum S, Chamoles N, Fejerman N. Acute disseminated encephalomyelitis. A long-term follow-up study of 84 pediatric patients. Neurology 2002; 59:1224–1231. 61. Hynson JL, Kornberg AJ, Coleman LT, Shield L, Harvey AS, Kean MJ. Clinical and neuroradiological features of acute disseminated encephalomyelitis in children. Neurology 2001; 56:1308–1312. 62. Kesselring J, Miller DH, Robb SA, Kendall BE, Moseley IF, Kingsley D, du Boulay EP, McDonald WI. Acute disseminated encephalomyelitis. MRI findings and the distinction from multiple sclerosis. Brain 1990; 113:291– 302. 63. Gallucci M, Caulo M, Cerone G, Masciocchi C. Acquired inflammatory white matter diseases. Child’s Nerv Syst 2001; 17:202–210. 64. Catalucci A, Caulo M, Puglielli E, Splendiani A, Masciocchi C, Gallucci M. Different MR features of acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) in the pediatric age group. Eur Radiol 2002; 12 (suppl 1): B0491 (Abs.) 65. Honkaniemi J, Dastibar P, Kahara V, Haapasalo H. Delayed MR imaging changes in acute disseminated encephalomyelitis. AJNR Am J Neuroadiol 2001; 22:1117–1124. 66. Tsai ML, Hung KL. Multiphasic disseminated encephalomyelitis mimicking multiple sclerosis. Brain Dev 1996; 18:412–414. 67. Hasegawa H, Bitoh S, Koshino K, Obashi J, Iwaisako K, Fukushima Y. Acute relapsing disseminated encephalomyelitis (ARDEM) mimicking a temporal lobe tumor. No Shinkei Geka 1994; 22:185–188. 68. Wang HS. Concentric thalamic change on MR of acute necrotising encephalopathy of childhood. Neuroradiology 2003; 45:661–662. 69. Inglese M, Salvi F, Iannucci G, Mancardi GL, Mascalchi M, Filippi M. Magnetization transfer ad diffusion tensor MR imaging of acute disseminated encephalomyelitis. AJNR Am J Neuroradiol 2002; 23:267–272. 70. Harada M, Hisaoka S, Mori K, Yoneda K, Noda S, Nishitani H. Differences in water diffusion and lactate production in two different types of postinfectious encephalopathy. J Magn Reson Imaging 2000; 11:559–563. 71. Bizzi A, Ulug AM, Crawford TO, Passe T, Bugiani M, Bryan RN, Barker PB. Quantitative proton MR spectroscopic imaging in acute disseminated encephalomyelitis. AJNR Am J Neuroradiol 2001; 22:1125–1130.

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Phakomatoses

16 Phakomatoses Paolo Tortori-Donati, Andrea Rossi, Roberta Biancheri, and Cosma F. Andreula

CONTENTS 16.1

Neurofibromatosis Type 1

16.1.1 16.1.2 16.1.2.1 16.1.1 16.1.3.1

Background 764 Clinical Findings 764 Cutaneous manifestations 764 Intracranial Lesions 764 Nonneoplastic Intraparenchymal Abnormalities 765 Gliomas 767 Neurofibromas 772 Orbital and Ocular Manifestations 774 Spinal Manifestations 775 Nontumoral Conditions 775 Tumoral Conditions 776 Vascular Abnormalities 780 Diagnostic Evaluation of NF1 Patients 780 Disorders Associated with NF1 780

16.1.3.2 16.1.4 16.1.5 16.1.6 16.1.6.1 16.1.6.2 16.1.7 16.1.8 16.1.8.1

764

16.2

Neurofibromatosis Type 2

16.2.1 16.2.1 16.2.2.1 16.2.2.2 16.2.3 16.2.3.1 16.2.3.2 16.2.3.3 16.2.4

Background 780 Intracranial Manifestations 781 Vestibular Schwannoma 781 Meningiomas 781 Spinal Manifestations 782 Schwannoma 783 Meningioma 783 Ependymome 784 Diagnostic Evaluation of NF2 Patients 784

780

16.3

Tuberous Sclerosis 785

16.3.1 16.3.2 16.3.2.1 16.3.2.2 16.3.2.3 16.3.2.4 16.3.2.5 16.3.1 16.3.3.1 16.3.3.2 16.3.3.3 16.3.3.4 16.3.3.5 16.3.4.6 16.3.5 16.3.5.1

Background 785 Clinical Findings 786 Neurological Manifestations 786 Cutaneous Manifestations 786 Ocular Manifestations 786 Other Clinical Manifestations 786 Relationships with other Phakomatoses 786 Brain Lesions in TSC 787 Cortical Tubers 787 Subependymal Nodules 793 White Matter Abnormalities 795 Subependymal Giant Cell Astrocytoma 796 Vascular Abnormalities 799 Diagnostic Evaluation of TSC 799 Differential diagnosis 800 Periventricular Calcifications 800

16.3.5.2 Cortical Malformations 800 16.3.5.3 Neoplasms 800 16.4

Sturge-Weber Syndrome 800

16.4.1 16.4.2 16.4.3 16.4.4 16.4.5 16.4.5.1 16.4.5.2 16.4.6 16.4.6.1 16.4.6.2 16.4.6.3

Background 800 Clinical Findings 801 Pathogenesis 801 Neuropathological Findings 802 Imaging Studies 803 Brain Abnormalities 803 Ocular abnormalities 807 Differential diagnosis 807 Tumors 807 Wyburn-Mason syndrome 807 Bilateral Parieto-occipital Calcifications with Epilepsy and Celiac Disease 809

16.5

Von Hippel-Lindau Disease

16.5.1 16.5.2 16.5.2.1 16.5.2.2 16.5.3 16.5.4

Background 810 CNS manifestations 810 Cerebellar hemangioblastoma 810 Spinal Hemangioblastoma 812 Ocular Manifestations 812 Papillary Cystadenomas of the Endolymphatic Sac 813 References

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813

The phakomatoses, also called neurocutaneous syndromes, are a heterogeneous group of congenital disorders primarily involving structures derived from the embryological neuroectoderm. Only the most common entities (i.e., neurofibromatosis types 1 and 2, tuberous sclerosis, Sturge-Weber syndrome, and von Hippel-Lindau syndrome) will be discussed in this chapter. The rare phakomatoses are described in Chapter 17.

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16.1 Neurofibromatosis Type 1 16.1.1 Background Neurofibromatosis type 1 (NF1), also called von Recklinghausen disease and formerly known as “peripheral neurofibromatosis”, is an autosomal dominant disease characterized by multiple café-au-lait patches, central nervous system (CNS) tumors, and mesodermal dysplasia. The diagnostic criteria for NF1, proposed at the National Institutes of Health (NIH) conference in 1987, are summarized in Table 16.1 [1, 2]. Although these criteria are now established, one should be aware that most diagnostic clinical features are uncommon in infants, whereas they become more evident with age [3]. Moreover, the clinical picture is highly variable and the course of the disease in individual patients is largely unpredictable. The estimated incidence of NF1 is 1 in 3,000 live births [4, 5]. Approximately 50% of cases show de novo mutations. This high mutation rate may be due to the large size of the gene and/or its unusual internal structure, both predisposing to deletions and other mutations. The NF1 gene is located on 17q11.2, and is a tumor suppressor gene [2]. Its product, neurofibromin, is widely expressed in a variety of human tissues, and negatively regulates signals transduced by Ras proteins. Although the actual mechanisms of oncogenesis remain largely unknown, it has been suggested that neurofibromin acts as a negative regulator of neurotrophin-mediated signaling for survival of embryonic peripheral neurons, thus contributing to the development of tumors [6, 7].

16.1.2 Clinical Findings 16.1.2.1 Cutaneous manifestations

The most common skin lesions (Fig. 16.1), and the first ones to appear, are café-au-lait spots, i.e., sharply demarcated, macular areas of hyperpigmentation. Albeit present from an early age, they usually become more evident as the child grows, and may significantly increase in size during puberty [8]. Axillary and inguinal freckling appears later than café-au-lait spots (sometimes during adolescence), and is found in about 60% of cases. Cutaneous neurofibromas develop at puberty and increase throughout life.

Table 16.1. Diagnostic criteria for neurofibromatosis 1 The patient should have two or more of the following: Six or more café-au-lait spots 1.5 cm or larger in postpubertal individuals 0.5 cm or larger in prepubertal individuals Two or more neurofibromas of any type or 1 or more plexiform neurofibroma Freckling in the axillary or inguinal regions Optic glioma (tumor of the optic pathway) Two or more Lisch nodules (benign iris hamartomas) A distinctive bony lesion Dysplasia of the sphenoid bone Dysplasia or thinning of long bone cortex A first-degree relative with NF1 (From References #1and 2)

16.1.2.2 Ocular Manifestations

The most consistent ocular manifestations are Lisch nodules (iris hamartomas), best visible by slit-lamp examination. Their presence and number directly relate to patient age. Lisch nodules are found in about 30% of cases by 6 years of age, and in virtually all patients after 12 years [8]. 16.1.2.3 Skeletal Manifestations

Skeletal manifestations result from mesenchymal dysplasia and include kyphoscoliosis, overgrowth or undergrowth of bone, erosive defects due to neurofibromas, and pseudoarthrosis of the tibia. Typical skull lesions include macrocephaly, lambdoid suture defect, and dysplasia of the greater sphenoidal wing. 15.1.2.4 Neurological Manifestations

The main neurological manifestations are cognitive deficits and specific learning disabilities (30%– 45% of cases), whose relationship with magnetic resonance imaging (MRI) findings is discussed below.

16.1.3 Intracranial Lesions The incidence of CNS manifestations in patients with NF1 is 15%–20%. These patients face a fourfold increased risk of developing CNS neoplasms than the general population [5]. Macrocephaly, either symmetric or asymmetric, is a common feature of NF1 (about 50% of cases).

Phakomatoses

c

a

b

Fig. 16.1a-d Neurofibromatosis type 1: external manifestations. a Cafè-au-lait spots. b Axillary freckling. c Cutaneous neurofibromas. d Lisch nodules. Courtesy of Prof. M. Ruggieri, Catania, Italy.

It may be related to calvarial thickening or to brain abnormalities such as hydrocephalus, hemimegalencephaly, or megalencephaly [9]. Quantitative MRI morphometry studies showed that the whole brain size is significantly larger in NF1 patients than in controls [10]. A striking and easily recognizable MRI feature is diffuse thickening of the corpus callosum (Fig. 16.2) as compared with age- and gender-matched controls. This may be explained by increased size of axons, increased number of axons (possibly related to apoptotic defects), or abnormal crossing and recrossing of axons through the midline [11]. There is no clear-cut correlation between the clinical picture and the presence and degree of callosal thickening.

Fig. 16.2. Callosal thickening in neurofibromatosis type 1. Sagittal T1-weighted image. Marked thickening of the corpus callosum is a frequent finding in NF1. Notice that all portions of the corpus callosum are present

d

Enlargement of cerebral white-matter tracts and midline structures has been shown in NF1 children with macrocephaly [12]. Dysplastic and neoplastic lesions are typical of NF1. In general, glial (i.e., intra-axial) tumors are more common in NF1, whereas meningeal and nerve sheath (i.e., extra-axial) neoplasms typically occur in neurofibromatosis type 2 (NF2). Other rarer CNS tumors in patients with NF1 include ependymomas, meningiomas, and primitive neuroectodermal tumors [13]. 16.1.3.1 Nonneoplastic Intraparenchymal Abnormalities

The most common intracranial lesions, occurring in about two-thirds of children and young adults with NF1, are represented by high-signal-intensity foci seen on long-repetition-time MR images both supraand infratentorially [14–16]. These abnormalities have received numerous designations, among which are “histogenetic foci”, “unidentified bright objects” (UBOs), and “neurofibromatosis bright objects” (NBOs); the latter will be used here. These lesions typically appear around age 3 years, increase in number and size until 10–12 years, and then tend to decrease, or even disappear, spontaneously [5, 16, 17]. However, we have observed NBOs in a 12-month-old boy. Because these lesions appear to be pathognomonic of NF1, several authors proposed to include them among the diagnostic criteria as a specifically pediatric feature [3, 15, 18–20]. NBOs have been described in 60%–80% of cases, but the incidence rises to 90% in patients with concurrent optic glioma [17]. They are typically multiple, and most commonly involve the white matter and basal ganglia (especially

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the globi pallidi). Other common locations include the middle cerebellar peduncles, cerebellar hemispheres, brainstem, internal capsule, splenium of the corpus callosum, and hippocampi [5, 17]. The exact nature and significance of NBOs are still unknown. Although they have been related to dysplastic glial proliferation, hamartomatous changes, or heterotopia [15, 21, 22], no histological evidence has been found to support these hypotheses [17, 23]. Pathological studies, performed in three cases by DiPaolo et al. [24], showed spongiform myelinopathy or vacuolar changes of myelin without frank demyelination, thereby supporting abnormal myelination as a causal factor [4, 5, 24]. Myelin vacuolization might develop in regions of chemically abnormal myelin, and could explain the hyperintensity seen in T2-weighted MR images. Progressive disappearance of T2 signal abnormalities with age could reflect subsequent normalization of water content, related to replacement of abnormal myelin with more stable myelin [25–27]. It has been speculated that neurofibromin might have region-specific effects, possibly responsible for both region specificity and the transient nature of these lesions [18].

Although NBOs are traditionally considered to be transient and benign, proliferative changes (i.e., development of tumors from previously recognized NBOs) have been described in NF1 children in whom the number and volume of NBOs were larger than usual [28, 29]. Imaging Studies

On MRI (Fig. 16.3), NBOs are hyperintense on PDweighted, T2-weighted, and FLAIR images; they are iso- to mildly hypointense on T1-weighted images. Sometimes, they may be slightly hyperintense also on T1-weighted images (Fig. 16.3) [15, 27, 30]. T1 shortening is more common with pallidal NBOs, and has been related to the presence of ectopic Schwann cells and melanocytes, hypermyelination within hamartomatous or gliotic areas, repair of vacuolized regions [27], and microcalcifications [24]. Mass effect, vasogenic edema, and contrast enhancement are usually absent. However, mass effect occasionally may occur [5, 15, 16], and transient enhancement has also been reported in a few cases [23, 31, 32]. On unenhanced

a

b

c

d Fig. 16.3a–d. NBOs in neurofibromatosis type 1. a–c Axial T2-weighted images. d Axial T1-weighted image. T2-weighted images show multiple hyperintense foci in the pons (arrows, a) and cerebellar dentate nuclei (arrowheads, a), showing no mass effect. The hippocampi are thickened and slightly hyperintense (arrows, b). Bilateral involvement of the globi pallidi is a hallmark of NF1 (c). Spontaneous hyperintensity is seen in T1-weighted images (arrowheads, d)

Phakomatoses

MRI, low-grade neoplasms may be indistinguishable from NBOs [33]. Therefore, follow-up MRI studies are recommended, and contrast-enhanced MRI should be repeated at six months to one year after the initial study [17]. A neoplasm should be suspected in the presence of markedly hypointense lesions on T1weighted images that show enhancement following gadolinium administration. MR spectroscopy can also help to differentiate NBOs from gliomas. Relationship Between MRI Findings and Cognitive Impairment

Global cognitive deficit (usually reduction of total IQ with significantly better verbal than performance rating) and/or a more specific cognitive deficit or learning disability are reported in 40% of NF1 children [34, 35]. Whether learning disabilities correlate with the presence of NBOs is still controversial [10]. Although a statistically significant correlation between cognitive impairment and the presence of hyperintense foci was found by some authors [35–37], others failed to identify such a correlation [19, 38, 39]. It has been suggested that the anatomic location of NBOs is more important than their mere presence or number. Particularly, thalamic NBOs would be significantly associated with neuropsychological impairment; recent knowledge on the role of thalamus in human cognition might support this hypothesis [40]. In addition to learning disabilities, attention deficit-hyperactivity disorder (ADHD) is also observed more frequently in NF1 patients than in the general population [37, 41, 42]. A correlation between the size of the corpus callosum and idiopathic ADHD has been suggested [43–45]. However, quantitative morphological studies did not reveal statistically significant differences in callosal size among NF1 patients with and without associated ADHD [46]. 16.1.3.2 Gliomas

Most parenchymal CNS gliomas occurring in NF1 are astrocytomas, whereas CNS tumors developing in NF2 usually are ependymomas [22, 47]. Optic Pathway Glioma

Optic pathway glioma (OPG) (Fig. 16.4) is the most common CNS tumor in the NF1 population, and typically occurs in the first two decades of life, with a peak incidence around 4–5 years [48]. The reported incidence ranges from 5%–30% to 70% of cases [15, 49]; however, the incidence of symptomatic patients is lower [17].

OPG usually involves one (40%–50% of cases) or both optic nerves (20% of cases), with possible extension to the posterior optic pathways. OPG occurring in NF1 patients is considered a separate entity from isolated OPG, with different clinical findings, prognosis, and imaging features [50]. The clinical course is extremely variable. OPGs frequently are asymptomatic and nonprogressive (especially if limited to the optic nerves), but may enlarge rapidly, leading to visual impairment and exophthalmos [17,51]. Spontaneous regression is another possible behavior of these lesions [51], as will be detailed later. Only around 30% of NF1-related OPGs are symptomatic at presentation, whereas non-NF patients with OPG usually elicit medical attention because of either visual or nonvisual symptoms [50]. Smaller tumor size and relative sparing of the hypothalamus might account for the milder clinical picture [50]. Furthermore, visual disturbances may be hindered by young patient age. Involvement of the posterior optic pathways (i.e., optic tracts and radiations) is usually associated with more aggressive course and increased risk of hypothalamic dysfunction, precocious puberty related to hypothalamic compression [52], and hydrocephalus [29,51]. Long-term outcome of OPGs appears to be favorably influenced by an associated NF1 condition. OPGs occurring in NF1 patients remain stable in around 50% of cases, compared with only 5% of non-NF cases [50]. Neuropathological findings

Pathologically, most OPGs are benign, slow growing, low-grade pilocytic astrocytomas [4, 22]. Although these tumors are benign, vascularity may occasionally be prominent, with a slow tendency to infiltrate the adjacent nervous tissue along perivascular spaces. OPGs are usually fusiform, intradural masses that stretch, rather than disrupt, the overlying meninges [53]. One or both nerves may be involved. Macroscopically, it may be difficult to separate tumor from normal nerve at the margins of the lesion. Histologically, neoplastic glial cells may not be distinguishable from reactive gliosis in some areas [54]. Two architectural forms of OPG have been described, depending on whether subarachnoid spread is present [17]. The first type is characterized by a diffuse expansion of the optic nerve without subarachnoid tumor (Fig. 16.4). The second type, characterized by predominant infiltration of the subarachnoid space, is associated with extensive thickening of the perioptic meninges, called “arachnoidal hyperplasia” or “arachnoidal gliomatosis” (Fig. 16.5). It is still controversial whether arachnoidal hyperplasia is a specific diagnostic sign of NF1 [55].

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d

Fig. 16.4a–e. Neurofibromatosis type 1. Optic pathway glioma in a 2-yearold boy. a,d Gd-enhanced sagittal T1-weighted images. b Axial T1-weighted image. c,e Axial T2-weighted images. The lesion involves the chiasm (thick white arrow, a), right optic nerve (thin black arrows, b,c), and prechiasmatic segment of left optic nerve (thin white arrow, b,c). Following gadolinium administration, enhancement is marked both in the chiasm (thick white arrow, a) and in the right optic nerve, that is markedly enlarged and tortuous (thick white arrows, d). Associated NBOs are recognizable in the nucleo-capsular regions bilaterally (e)

e

Imaging studies

On CT scan, enlargement of the optic nerve is recognizable. Bone algorithm reveals enlargement of the optic canals. MRI (Fig. 16.4) is the best imaging modality for assessing both the intra- and extracranial portion of these lesions [17]. Signal intensity is variable on both T1- and T2-weighted images, as well as the degree of enhancement [56]. T1-weighted images show distortion of the normal morphology and enlargement of the affected optic nerves. In the presence of arachnoidal hyperplasia, the relative hypointensity of the orbital portion of OPGs may correlate with the pathological finding of

peritumoral arachnoidal hyperplasia and fibrocollagenous reactive changes in association with neoplastic tissue [53]. Contrast-enhanced MRI detects arachnoidal hyperplasia as a thick rim of meningeal enhancement surrounding an abnormally enlarged optic nerve (Fig. 16.5). Chiasmatic and retrochiasmatic involvement is usually associated with abrupt signal change to moderate or strong T2 hyperintensity (Fig. 16.6), variably considered the result of edema, demyelination, gliosis, Wallerian degeneration, atypical glial proliferation, and true neoplastic extension [53, 56]. In these cases, MR spectroscopy can be useful to discriminate the true extent of tumor from nontumoral signal changes. Contrast

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enhancement is also highly variable in this location. It has been reported in around 60% of cases [50], and may be striking when the lesion involves the posterior optic pathways [4] (Fig. 16.6). In cases of diffuse involvement of the optic pathways, both signal intensity and enhancement pattern may differ in individual cases, and even within different portions of the same tumor [57]. NF-related OPGs differ from isolated OPGs in many ways (Table 16.2) [50]. Generally, NF-related OPGs are small neoplasms that only rarely show cystic-necrotic components; they involve preferentially the optic nerve, with preservation of the original shape of the optic pathway. Conversely, isolated OPGs often involve primarily the hypothalamus and optic chiasm with possible extension to adjacent structures; they usually are larger masses showing necrotic-cystic components. Spontaneous regression of OPGs (i.e., decreased/disappeared enhancement and/or size decrease) (Fig. 16.7) has been reported in children with NF1 [51, 58–63], but also in non-NF1 cases [64]. However, since spontane-

ous involution occurs more frequently in NF1 cases, this behavior has been related to the NF1-gene activity as tumor suppressor [58]. Alternatively, it has been hypothesized that so-called OPGs in NF1 are dysplastic, rather than neoplastic, lesions [51]. Alternate periods of involution and progression have also been described [51]. Recommendations for the management of OPGs are summarized below (see “diagnostic evaluation of NF1 patients”. Brain Gliomas

NF-related brain gliomas usually are low-grade (i.e., pilocytic) astrocytomas that may occur in the mesencephalic tectum, brainstem (especially medulla), cerebellum, and cerebral hemispheres [4, 5, 29, 65]. They generally affect younger children and are more frequently multicentric, rather than isolated, gliomas [66]. MRI findings are not different from those of isolated glio-

a b

c

d Fig. 16.5a–d. Neurofibromatosis type 1. Arachnoidal hyperplasia in a 2-year-old girl with optic nerve glioma. a Axial T2-weighted image. b Gd-enhanced axial T1-weighted image. c Coronal T2-weighted image. d Gd-enhanced coronal T1-weighted image. There is marked enlargement of the left optic nerve that is isointense on T2-weighted images. The peripheral portion, corresponding to arachnoidal hyperplasia, is enlarged and hyperintense on T2-weighted images (arrowheads, a). Coronal T2-weighted image is especially valuable in differentiating the thickened, isointense nerve from surrounding arachnoid hyperplasia (arrowheads, c). Following gadolinium administration, only the peripheral component enhances (arrowheads, b,d)

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d Fig. 16.6a–d. Neurofibromatosis type 1. Chiasmatic glioma in a 6-year-old boy. a Gd-enhanced sagittal T1-weighted image. b,d Gdenhanced coronal T1-weighted images. c Axial FLAIR image. Marked increased volume of the chiasm without enhancement (thick white arrows, a,b). Diffuse signal changes are recognizable at the level of basal ganglia, internal capsule, and optic radiations (c). It is not possible to determine the exact nature of these lesions, that may be variable (see text). However, two small enhancing areas are identifiable (arrows, d), likely related to true neoplastic lesions

mas (Fig. 16.8); on occasion, focal enhancing masses that may progress, stabilize or even regress may be seen (Fig. 16.7). One of the most common location of NF-related brain gliomas is the brainstem (Fig. 16.9). The brainstem is also a common location of NBOs, which often cause mass effect and may be difficult to differentiate from tumor (Fig. 16.10). In these cases, follow-up MRI examinations are mandatory, as stated above (see “nonneoplastic intraparenchymal abnormalities”). Despite the identical MRI appearance, NF-related brainstem gliomas are considered a distinct clinical entity from isolated brainstem gliomas, mainly based on their different long-term outcome [13, 67]. The clinical course of NF-related brainstem gliomas is more frequently indolent, and prolonged survival has been reported [13]. Furthermore, diffuse intrinsic tumors, focal enhancing tumors, and hemorrhage are poor prognostic indicators in isolated gliomas, but not necessarily in NF-related gliomas [67, 68].

The appropriate management of gliomas (both of the optic pathways and of the brain) in NF1 patients is still under debate, mainly because the natural history of these lesions is poorly defined [68]. Owing to their usually indolent behavior, conservative management with serial follow-up MRI studies is currently preferred [2, 13, 22, 51, 68]. Advanced MR Imaging

Proton MR spectroscopy (MRS) can be used to differentiate between normal brain, NBOs, and gliomas [69–71]. On three-dimensional multivoxel proton MRS, NBOs have shown elevated choline (Cho) levels, possibly reflecting increased myelin turnover [72], reduced creatine (Cr), and normal N-acetylaspartate (NAA) level; instead, tumors show Cho:Cr >2, without NAA levels [71]. Differentiation between diffuse brainstem enlargement occurring in NF1 patients and pontine gliomas

Phakomatoses Table 16.2. Comparison between clinical and imaging findings of NF-related and isolated optic pathway gliomas

Symptoms at presentation (either visual or non visual)

NF-related OPG

Isolated OPG

Uncommon

Constant

Long-term outcome (before treatment)

Stable tumor dimension Enlarged tumor Reduction of tumor size

Common Rare Possible

Uncommon + Usually absent

Site of involvement

Orbital nerve Chiasm Hypothalamus Optic tracts Optic radiations

++ ++ + + rare

+ +++ +++ + ++

Imaging features

Optic nerve thickening Average diameter Cystic-necrotic components Encased vessels Enhancement

+++ 2.5 cm rare rare ++

+ 4.5 cm common ++ ++

(Modified from reference #50)

b a

c

d Fig. 16.7a–d. Neurofibromatosis type 1. Spontaneous regression of gliomas in two different cases. Case 1: a,b Gd-enhanced axial T1-weighted images. Case 2: c,d Gd-enhanced sagittal T1-weighted images. In case 1, MRI performed at presentation (a) shows enlarged optic nerves and chiasm with patchy enhancement. Tumor extends to the right optic tract (arrow, a). After three years (b), the lesion is strikingly reduced in size in the absence of treatment, and does not enhance. In case 2, MRI performed at presentation (c) shows mesencephalic enhancing tumor with central necrosis (thin arrows, c). There is concurrent thickened, unenhancing optic chiasm (thick arrow, c). After two years (d), the mesencephalic lesion is markedly reduced in size (thin arrow, d), whereas the chiasmatic one is unchanged (thick arrow, d)

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b Fig. 16.8a,b. Neurofibromatosis type 1. Coexisting tumoral and nontumoral lesions in a 3-year-old girl. a Axial T2-weighted image. b Gd-enhanced axial T1-weighted image. Typical nucleocapsular NBOs (a) and astrocytoma of the left middle cerebellar peduncle showing marked enhancement (arrows, b) Fig. 16.9a,b. Neurofibromatosis type 1. Diffuse brainstem glioma. a Sagittal T1-weighted image. b Axial T2-weighted image. There is a diffuse brainstem glioma (a) that extends to the right middle cerebellar peduncle and cerebellar hemisphere (b). There is sling of perifocal edema in the right cerebellar hemisphere (black arrows, b). The fourth ventricle is displaced and compressed (white arrow, b), resulting in hydrocephalus that was treated with a shunt (white arrow, a)

a

b

has also been investigated using MRS. Preservation of the NAA peak in nonneoplastic, NF-related brainstem enlargement probably reflects preservation of brainstem neurons; conversely, significant NAA decrease is found in pontine gliomas [73]. Unsolved MRS issues include spectra showing transitional features between nonneoplastic changes and gliomas [69], and the occurrence of abnormal spectra in regions that appear to be normal on conventional MRI. The latter observation suggests that the metabolic abnormality could be a generalized phenomenon that involves the whole brain, regardless of the presence of visible signal changes on MRI [71, 72, 74]. Diffusion-weighted imaging (DWI) shows higher brain apparent diffusion coefficient (ADC) values in both hyperintense lesions of the basal ganglia and in the normal-appearing areas in NF1 children. These data have been postulated to reflect myelin abnormality in these patients [75]. Slight increase of ADC values of NBOs over long-term periods has also been described [76].

16.1.4 Neurofibromas Neurofibromas are the typical peripheral nervous system neoplasms of NF1, whereas schwannomas are characteristic of NF2. Although both these tumors originate from Schwann cells, they differ in many ways. Basically, neurofibromas (WHO grade I) infiltrate the nerve, show maldefined margins, are characteristically fusiform due to their intrinsic development, are unencapsulated, and involve multiple Schwann cells [14]. Conversely, schwannomas are benign, slow-growing tumors, encapsulated and eccentrically located on the nerve, arising from the Schwann cell and encasing the axon [14]. Histologically, neurofibromas are formed by multiple Schwann cells surrounding multiple axons, associated with fibroblastic proliferation, more or less myelinated fibers, and a huge amount of connective tissue, especially collagen and elastin. Contrary to schwannomas, neurofibromas have a propensity for anaplastic transformation [77]. Although both neurofi-

Phakomatoses

a

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d c Fig. 16.10a–e. NBOs in neurofibromatosis type 1: two different cases. Case 1: a Sagittal T1-weighted image. b Proton density-weighted image. Case 2: c Sagittal T2-weighted image. d Axial T2-weighted image. e Gd-enhanced axial T1-weighted image. Case 1: There is homogeneous thickening of the brainstem (a), with slight irregularity of the floor of the fourth ventricle (arrows, a,b). Typical NBOs involve the pons and both cerebellar hemispheres (b). Case 2: The medulla is enlarged and shows diffuse hyperintensity (c). On axial views, the right half of the medulla, the right flocculus (arrow, c), and both dentate nuclei (arrowheads, c) are involved. Notice absence of enhancement (e). Interpretation of these lesions as NBOs rather than tumors is difficult, and requires close neuroradiological follow-up. MR spectroscopy may increase diagnostic confidence

bromas and schwannomas may be, and generally are, multiple, neurofibromas usually are relatively few (i.e., five or six), whereas it is not uncommon to discover more than ten schwannomas in patients with NF2 [17]. Cutaneous and plexiform neurofibromas are the two typical forms of neurofibromas in the NF1 population (Fig. 16.1). While cutaneous neurofibromas produce the typical skin nodules, plexiform neurofibromas may involve several locations, including the cranial and spinal nerves, ganglia and nerve roots, peripheral nerves of the neck, trunk and limbs, and the autonomic nervous system [57]. The fronto-temporoorbital region is one of the most common locations of

e

plexiform neurofibromas (Fig. 16.11) (see the section below entitled “orbital and ocular manifestations”). The term “plexiform” indicates the irregularly cylindrical enlargement of the affected nerve [78]. They are multiple, tortuous and large masses arising along the axis of a major nerve, that typically is infiltrated by the lesion. These tumors have a potential for malignant change into neurofibrosarcoma. They contain Schwann cells and perineural fibroblasts [29]. Severe forms involving the subcutaneous nerves may cause monstrous skin lesions in adulthood. Diffuse involvement of the peripheral nerves of one arm may result in elephantiasis (Fig. 16.12).

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Fig. 16.11. Neurofibromatosis type 1. Plexiform neurofibroma involving the right eyelid in a 4-year-old boy. (Permission to publish this photograph was obtained from the parents)

Fig. 16.12. Neurofibromatosis type 1. Plexiform neurofibroma of the right upper limb and thoracic wall resulting in elephantiasis. Coronal T1-weighted image. The huge lesion causes diffuse enlargement of the right arm, and involves the axillary region and the homolateral brachial plexus and paravertebral region. Scoliosis results

Malignant neurofibromas (neurofibrosarcomas) may either originate from malignant degeneration of a pre-existing neoplasm or develop de novo. Neurofibrosarcomas commonly are large, well-delimited masses that do not tend to invade adjacent structures. On imaging, they are difficult to differentiate from benign neurofibromas or schwannomas, since signal heterogeneity may also be found in benign tumors [17]. Contrast enhancement is heterogeneous. Spinal neurofibromas are described in the paragraph below on “spinal manifestations”.

16.1.5 Orbital and Ocular Manifestations Orbital and ocular manifestations of NF1, other than OPG, include enlarged optic canals, Lisch nodules, choroidal hamartomas, buphthalmos, plexiform neurofibromas, and pulsatile exophthalmos [29]. Monolateral dysplasia of the greater sphenoidal wing is characterized by hypoplasia or partial agenesis of the greater wing and, partially, of the smaller wing of the sphenoid (Fig. 16.13). The middle cranial fossa is wider than normal, and the temporal lobe bulges through the bony defect, possibly causing pulsatile exophthalmos [4, 5, 14, 57] that may worsen as the disease progresses. Sphenoidal wing dysplasia is often associated with plexiform neurofibromas of the orbit and periorbital region, with involvement of eyelid, periorbital soft tissues, conjunctiva, iris, choroid, and ciliary bodies [17]. Extension to the cavernous sinus with involvement of the third to sixth

Fig. 16.13. Neurofibromatosis type 1. Dysplasia of the sphenoid wing associated with plexiform neurofibroma. Contrastenhanced axial CT scan. There is partial agenesis of the left greater sphenoid wing (open arrow) associated with plexiform neurofibroma involving both the adjacent orbit and the extracranial soft tissues (asterisks). The middle cranial fossa is enlarged

cranial nerves is frequent. Orbital tumors also may extend to the nasopharynx and pterygomaxillary fissure [17]. Involvement of the sella turcica with downward dural ectasia may mimic an empty sella or meningoencephalocele. Buphthalmos (Fig. 16.14), or ox’s eye, refers to an enlarged ocular globe. It usually is unilateral. Buphthalmos results from congenital glaucoma, related to abnormal drainage pathways or, occasionally, to a neurofibroma of the ciliary body and choroid. Dural ectasia may cause sectorial enlargement of dural structures (Fig. 16.15).

Phakomatoses

Enhancement is, again, variable (Figs. 16.16–18). Serpiginous hypointensities, due to involvement of small nerve fibers of the subcutaneous plexus, may occasionally become evident on MRI [57] (Fig. 16.17).

16.1.6 Spinal Manifestations 16.1.6.1 Nontumoral Conditions Fig. 16.14. Neurofibromatosis type 1. Axial CT scan. Buphthalmos of the left ocular globe associated with periorbital neurofibroma (asterisks).

a

b Fig. 16.15a,b. Dural ectasia in neurofibromatosis type 1. a Axial T2-weighted image. b Coronal T2-weighted image. Enlargement of the right Meckel’s cave (arrow). Compare with the contralateral normal side (arrowhead)

Plexiform neurofibroma involving the orbital apex or the superior orbital fissure may cause exophthalmos and impaired ocular movements. On CT scan, it appears as an iso- to hypodense mass, showing variable enhancement [17]. On MRI, the mass is iso- to hypointense in T1-weighted images and heterogeneously hyperintense in T2-weigthed images [17].

Scoliosis, nontumoral enlargement of the neural foramina with or without associated lateral meningoceles, posterior scalloping of the vertebral bodies, and multiple arachnoid cysts are the main nontumoral spinal manifestations of NF1. Kyphoscoliosis. Kyphoscoliosis may result from dysplasia of the vertebral bodies, neurofibromas, or intrinsic spinal cord lesions. It occurs in about 50% of patients, and is more pronounced in the lower cervical and upper thoracic spine [14]. It is usually associated with hypoplasia of the pedicles as well as the transverse and spinous processes, scalloping of the vertebral bodies, and hyperplastic bone changes. It is usually mild in the first years of life but worsens as the child grows, especially during adolescence [57]. Neuroimaging of scoliosis in NF1 patients (Fig. 16.19) mainly aims to identify the underlying cause, clarifying whether scoliosis is secondary to bone dysplasia, intrinsic spinal cord lesions (tethered cord, syringomyelia, and tumors), or paravertebral neurofibromas [17]. In general, scoliosis likely results from bony dysplasia if no associated dysraphic states, intrinsic spinal cord lesions, or paravertebral mass can be identified, and the conus medullaris lies at the normal level (L2 or above). Lateral meningoceles. Lateral meningoceles are dural diverticula that extend laterally through widened neural foramina into the paravertebral regions. They sometimes are multiple, and are mainly located in the thoracolumbar spine [57]. They probably result from primary dysplasia of the meninges, causing dural weakness and focal stretching in response to CSF pulsations [17]. They may be difficult to recognize when scoliosis is associated (Fig. 16.20). Meningoceles are isointense with CSF in all MR sequences. Dural ectasia. Dural ectasia results from ineffective resistance to CSF pulsations, and may cause scalloping of the posterior vertebral bodies and enlargement of the neural foramina [14]. Although similar to meningoceles, dural outpouchings are completely intraspinal, i.e., there is no extension to the paravertebral space [57].

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Fig. 16.16a–c. Neurofibromatosis type 1. Neurofibroma of the left lacrimal gland. a Axial T1-weighted image. b Axial T2-weighted image. c Gd-enhanced, fat-suppressed axial T1-weighted image. T1-weighted images show a hypointense tumor involving the left lacrimal gland (arrows, a). The lesion is hyperintense in T2-weighted images (arrows, b), and enhances inhomogeneously (arrows, c). Typical NBOs are recognizable in the nucleo-capsular regions (arrowheads, b)

As with meningoceles, dural ectasia shows the same signal intensity as CSF, and is easily differentiated from neurofibromas. Posterior scalloping of the vertebral bodies. In the presence of this condition, other entities must be ruled out, including spinal tumors (ependymoma, dermoid, lipoma, neurofibroma), ankylosing spondylitis, achondroplasia, syringomyelia, mucopolysaccharidosis, Ehlers-Danlos and Marfan syndrome [14]. 16.1.6.2 Tumoral Conditions

Fig. 16.17. Neurofibromatosis type 1. Plexiform neurofibroma. Sagittal T1-weighted image. Notice the “worm-like” appearance of the lesion, involving extensively the orbital region and extending to the frontal soft tissues

Spinal cord and nerve sheath tumors become clinically symptomatic mostly in older NF1 patients. Affected children may harbor intramedullary tumors (commonly low-grade astrocytomas) (15% of cases) [4], intradural-extramedullary tumors, and nerve sheath tumors (such as neurofibromas, plexiform

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a

b Fig. 16.18a,b. Neurofibromatosis type 1. Plexiform neurofibroma. a Gd-enhanced, fat-suppressed axial T1-weighted image. b 2D TOF MRA, coronal MIP. Huge plexiform neurofibroma arising from the right mastoid, extending beneath the longus capitis muscle. The tumor infiltrates the occipital squama and the foramen lacerum, occluding the internal jugular vein and sigmoid sinus. MRA shows reduced flow within the transverse sinus and absent visualization of the right internal jugular vein and sigmoid sinus

neurofibromas, and malignant nerve sheaths tumors) [4, 79]. In recent years, the MRI diagnosis of slow-growing, asymptomatic, sometimes multiple spinal neoplasms has been made easier (Fig. 16.21). Intramedullary NBOs, similar to those described in the brain, have also been reported [80]. Although spinal NBOs typically are asymptomatic, cause no cord swelling, and do not enhance, their differentiation from initial tumor growth requires followup MRI studies. Intraspinal and/or paravertebral neurofibromas occur almost exclusively in NF1, and especially involve the brachial plexus, intercostal nerves, and lumbosacral plexus. They may be isolated or multiple, monolateral or bilateral; they may involve the intraspinal compartment, the paravertebral tissues, or both (so-called “dumbbell” tumors) (Fig. 16.22). Because these tumors frequently are multiple, recognition of one lesion requires that MRI of the whole spine be performed [79, 81]. When small, intraspinal neurofibromas appear as nodules located along the nerve roots of the cauda equina (Fig. 16.23), as they grow, they tend to involve the neural foramina to extend into the paravertebral space [17]. Bilateral neurofibromas at a single level may compress the cord from both sides [17]. On MRI, neurofibromas typically show slight hyperintensity to muscle in T1-weighted images. In large neurofibromas, T2-weighted images show the so-called “target sign” [82], i.e., increased signal intensity in the periphery (due to eosinophilic fibers with less cellular components) and low signal intensity

Fig. 16.19. Neurofibromatosis type 1. Thoracic scoliosis in a 12year-old girl. Gd-enhanced coronal T1-weighted image. Scoliosis is caused by bilateral paravertebral neurofibromas, of which the left one is huge

in the center of the tumor (related to tightly packed eosinophilic fibers with high cellular components or dense central core of collagen [17]). In our experience, small or medium-sized neurofibromas of the cauda equina have been consistently characterized by isointensity in both T1-weighted and T2-weighted images, with marked, homogeneous enhancement (Fig. 16.23). Structural inhomogeneity may sometimes be observed.

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P. Tortori-Donati, A. Rossi, R. Biancheri, and C. F. Andreula Fig. 16.20a–d. Neurofibromatosis type 1. Dural ectasia and meningocele. Two different cases. Case 1: a Sagittal T1weighted image. b Coronal T1-weighted image. c Axial T1weighted image. Case 2: d Sagittal T2-weighted image. Case 1: There is severe scoliosis. Note the huge meningoceles (M), one of which abuts the aorta anteriorly (c). Dural ectasia results in scalloped posterior vertebral walls (open arrows, a,c). The spinal cord is displaced (thick arrow, c). Case 2: Sacral dural ectasia produces scalloping of the posterior walls of S1-2 vertebral bodies (arrows, d)

a

c

b

d

Fig. 16.21. Neurofibromatosis type 1. Spinal neurofibromas. Coronal T2-weighted image. Multiple plexiform neurofibromas involve diffusely the extra-spinal portions of the lumbo-sacral nerve roots (asterisks). (Case courtesy of Prof. A. Carella, Bari, Italy)

Phakomatoses

a

b

c

d

Fig. 16.22a–d. Neurofibromatosis type 1. Dumb-bell neurofibrosarcoma. a,b Coronal T1-weighted images. c Gd-enhanced coronal T1-weighted image. d Axial T1-weighted image. Huge, prevailingly hemorrhagic mass in the left paravertebral region. The mass extends along numerous metameres, is associated with scoliosis, and infiltrates the L1-2 vertebral bodies. The lesion extends into the spinal canal and displaces the cord contralaterally (arrowheads, b–d)

a

b

c

Fig. 16.23a–c. Neurofibromatosis type 1. Bunch of neurofibromas of the cauda equina. a Sagittal T1-weighted image. b Sagittal T2weighted image. c Gd-enhanced sagittal T1-weighted image. Multiple nodular lesions of the cauda equina are isointense to nerve roots both in T1-weighted (arrows, a) and T2-weighted images (arrows, b). Enhancement is marked (arrows, c)

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16.1.7 Vascular Abnormalities Symptomatic vascular dysplasias occurring in NF1 are due to intimal proliferation causing arterial stenosis and occlusion. The common and internal carotid, proximal middle cerebral, and anterior cerebral arteries are involved more frequently. Aneurysms and arteriovenous malformations are less common [17]. Although commonly asymptomatic, vascular dysplasia may cause neurological symptoms, especially with stroke-like episodes. Vascular dysplasia is difficult to identify on MRI. Narrowing of the supraclinoid carotids and proximal middle and anterior cerebral arteries is more evident with MR angiography. The moya-moya phenomenon has also been reported as a result of bilateral, progressive supraclinoid stenosis of the internal carotid arteries [83]. Epidural arteriovenous malformations usually involve the cervical spine. However, a lumbar epidural arteriovenous malformation presenting with signs of spinal cord compression was reported in a 10year-old girl [84].

16.1.8 Diagnostic Evaluation of NF1 Patients MRI plays an important role in both the diagnosis and follow-up of NF1. It has been suggested that a baseline cranial MRI should be performed in every child with an established diagnosis of NF1 in the first years of life [29, 85]. The optimal frequency of follow-up examinations is still a controversial matter [16, 29]. Contrast material administration is recommended in both the baseline MRI study (to better detect and characterize tumors and differentiate between tumors and nonneoplastic lesions) and follow-up examinations (for documenting stability or progression of neoplastic and nonneoplastic lesions [86]). OPGs are managed according to the rules expressed by the “NF1 Optic Pathway Glioma Task Force” [87]. Screening MRI is not recommended for asymptomatic children as it has not been shown to improve clinical outcome, whereas serial ophthalmological examinations are mandatory. In children with symptomatic OPGs, contrastenhanced MRI is recommended for both detecting and defining the extent of the tumor. 16.1.8.1 Disorders Associated with NF1

The association between NF1 and tuberous sclerosis has been rarely reported [88, 89]. The family history

of the case reported by Lee et al. [88] suggests that one phakomatosis is inherited from one parent, while the other disorder represents a de novo mutation. The association between NF1 and gliomatosis cerebri has been rarely reported [90, 91]. Some cases showing NF1 and Chiari 1 malformation have been reported [92, 93].

16.2 Neurofibromatosis Type 2 16.2.1 Background Neurofibromatosis type 2 (NF2), formerly called “central neurofibromatosis with bilateral vestibular schwannomas”, is an autosomal dominant disease whose incidence is 1 in 50,000 in the general population. The acronym MISME (Multiple Inherited Schwannomas, Meningiomas, and Ependymomas) has been proposed to reflect the pathology of this phakomatosis [22]. NF2 is clinically and genetically distinct from NF1. The NF2 gene (22q12.2) is a tumor suppressor gene whose product is called merlin or schwannomin [94]. The protein encoded by the NF2 gene shows a close relationship to the family of ERM (ezrin-radixinmoesin) proteins, which are linkers of cytoskeleton to membrane proteins. This suggests that merlin may regulate cell-matrix attachment, and changes in cell adhesion caused by mutant protein expression may be an initial step in the pathogenesis of NF2 [95]. On the basis of clinical heterogeneity, a distinction has been proposed between a mild form, the Gardner type (late onset, slow deterioration of hearing, and few tumors), and a severe form, the Wishart type (early onset, rapid progression of hearing loss, and multiple tumors) [2, 96, 97]. The genotype/phenotype correlation is not clear. Intrafamilial phenotypic variability has been described, and patients with the same mutations may show different phenotypes [98]. A higher incidence of intramedullary and nerve sheath tumors has been found in patients with nonsense and frameshift mutations, compared to patients with other types of mutations [99]. Mutations of the NF2 gene have also been identified in cases of meningiomas and schwannomas not associated with NF2 [100]. The diagnostic criteria for NF2, defined by the NIH Consensus Conference [1], are listed in Table 16.3. Cutaneous neurofibromas are seen in around 65% of cases. Unlike NF1, they are usually few and small. They usually develop earlier than cranial nerve

Phakomatoses Table 16.3. Diagnostic criteria for neurofibromatosis 2 Individuals with the following clinical features have confirmed (definite) NF2: Bilateral vestibular schwannomas (VS) or Family history of NF2 (first-degree relatives) plus Unilateral VS < 30 y or Any 2 of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract Individuals with the following clinical features should be evaluated for NF2 (presumptive or probable NF2): Unilateral VS schwannomas

Schwannomas Meningiomas Cord tumors (ependymomas)

Cutaneous

Neurofibromas

Neurofibromas (rare)

schwannomas [17]. Early-onset cataract (posterior subcapsular or cortical) is the most frequent ocular abnormality, and may be present in childhood; retinal hamartomas, combined pigment epithelial and retinal hamartomas, optic nerve sheath meningiomas, and epiretinal membranes have also been described [101]. The distribution of neural tumors in NF1 and NF2 is summarized in Table 16.4. 16.2.2 Intracranial Manifestations Schwannomas of the eighth and, more rarely, other cranial nerves, and meningiomas are the characteristic intracranial lesions of NF2. 16.2.2.1 Vestibular Schwannoma

Bilateral vestibular schwannomas (VSs) (Figs. 16.24– 16.26) are the hallmark of NF2. Although widely used, the term “acoustic schwannoma” is improper, as these lesions involve the superior vestibular, rather than the cochlear, branch of the eighth cranial nerve. Whereas solitary VSs arise in the fifth decade, bilateral NF2-related VSs involve the second-third decade

of life [22]. The second most common location for schwannomas is the trigeminal nerve, whereas the other cranial nerves are seldom involved [4]. NF2related schwannomas alternate phases of apparent stability and rapid growth; their growth rate is greater than that of isolated schwannomas [96]. VSs usually are round, solid masses that arise from the intracanalicular portion of the nerve (where the myelin is formed by Schwann cells) [14]. They may then extend to the cerebellopontine angle cistern, resulting in a typical “ice cream cone” appearance. MRI findings of bilateral VSs are equivalent to those of unilateral tumors. The mass is hypo- to isointense on T1-weighted images and iso- to hyperintense on T2-weighted images. Enhancement is marked, and may be either heterogeneous or homogeneous depending on the presence of cystic-necrotic changes [4, 14]. Cystic changes tend to develop as the tumor increases in size. 16.2.2.2 Meningiomas

Meningiomas (Figs. 16.25, 16.27) are extra-axial, small, nodular masses, often multiple (multicentric meningiomas are a frequent finding in NF2) and calci-

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a Fig. 16.24a,b. Neurofibromatosis type 2. Bilateral schwannomas of the eighth cranial nerves. a Gd-enhanced T1-weighted image. b Gd-enhanced coronal T1-weighted image. Both masses grow prevailingly into the cerebellopontine cisterns, although both also involve the inner acoustic canals, which are enlarged (arrows, a). The brainstem is engulfed

a

b Fig. 16.25a,b. Neurofibromatosis type 2. Bilateral schwannomas of the eighth cranial nerves and multiple meningiomas. a Gdenhanced axial T1-weighted image shows markedly enhancing bilateral schwannomas of the eighth cranial nerves (S), causing enlargement of the inner acoustic canals (thin arrows). There also is a large meningioma of the sphenoid bone (M) showing moderate, homogeneous enhancement. b Gd-enhanced coronal T1-weighted image shows both vestibular schwannomas, as well as less markedly enhancing meningiomas at level of the great cerebral falx and right sylvian fissure (thick arrows). Notice marked hyperostotic thickening of the calvarium (asterisks), a reactive phenomenon to the underlying meningiomatosis

fied. Any meningioma presenting in childhood should alert the clinician to possible NF2. On MRI, they show equivalent location and signal features as those of NF2unrelated meningiomas (see Chap. 10). Albeit inconstant, hyperostotic thickening of the adjacent skull (Fig. 16.25) is an important diagnostic finding. Calcifications may occur, particularly in the psammomatous type [4]. However, not all calcified intracranial lesions are related to meningiomas. Benign calcification of the choroid plexus also is common (Fig. 16.28).

16.2.3 Spinal Manifestations Imaging of the entire spine should be performed when one symptomatic spinal tumor is detected, because of the high incidence of multiple, asymptomatic spinal lesions without preferential localization [102]. Spinal tumors found in patients with NF2 include schwannomas, meningiomas, and ependymomas.

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16.2.3.1 Schwannoma

16.2.3.2 Meningioma

Schwannomas (Figs. 16.26, 16.27) commonly are multiple (usually more than ten), and histologically different from neurofibromas (see neurofibromatosis type 1). They may show hemorrhagic or cystic changes, and mainly involve the posterior nerve roots with possible extension to the spinal cord. Spinal schwannomas are well-delimited masses showing the typical “dumbbell” morphology due the presence of both intra- and extradural components, associated with enlargement of the neural foramen and vertebral scalloping. Enlargement of the neural foramina results from the mechanical action of the tumor, unlike bone changes of NF1 that are due to mesodermal dysplasia. Cystic change may be found within large tumors, while hemorrhage is rare. On MRI, they are isointense on T1-weighted images and hyperintense on T2-weighted images, with homogeneous gadolinium enhancement [102, 103].

Spinal meningiomas, solitary or more often multiple, show equivalent signal features as solitary meningiomas (see Chap. 40). They are always extramedullary, either intra- or extradural, and most frequently are located in the thoracic region. These tumors are well delimited from the nervous tissue, pial vascular structures, and dura. Gadolinium enhancement is marked, and is often, albeit not necessarily, associated with a “dural tail” due to infiltration of the adjacent dura [102, 103]. Dural tails are especially prominent in NF-related meningiomas, and allow differentiation from schwannomas. Occurrence of multiple lesions, local aggressiveness, fast and ubiquitous growth, and coexistence with schwannomas are distinctive features of NF2-related meningiomas.

Fig. 16.26a–d. Neurofibromatosis type 2. Spinal and intracranial schwannomas in a 14-year-old girl. a Coronal T1-weighted image. b Sagittal T1-weighted image. c Axial T1-weighted image. d Gd-enhanced axial T1weighted image. Huge dumb-bell schwannoma with an intraspinal component extending from T11 to L1. Notice enlargement of the involved neural foramen (black arrowheads, a,c), scalloping of the vertebral bodies (open arrows, b), and marked compression of the spinal cord (thin white arrows, a,c) and cauda equina. A second, smaller intraspinal lesion is recognizable at level of L2–3 (thick black arrows, a,b). The same child has bilateral vestibular schwannomas (d)

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P. Tortori-Donati, A. Rossi, R. Biancheri, and C. F. Andreula Fig. 16.27a–d. Neurofibromatosis type 2. Multiple meningiomas. a Sagittal T1-weighted image. b Gd-enhanced T1-weighted image. c Axial T2weighted image. Multiple meningiomas arise from the cerebral falx, superior surface of the right petrous bone, and inferior aspect of the tentorium. These lesions are isointense to gray matter on both T1-weighted (a) and T2-weighted images (b), and homogeneously enhance following gadolinium administration (b). The dura of the convexity is diffusely involved, resulting in meningiomatosis

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silent. On MRI, they show equal signal features as solitary ependymomas (see Chap. 40) (Fig. 16.29). They arise centrally in the spinal cord from the ependyma and grow toward the outer surface, involving several metameres. Hematomyelia may be the initial sign of spinal cord ependymoma. The differential diagnosis of multiple spinal tumors includes NF2, familial meningioma, and schwannomatosis [102]. Metastases are easily ruled out by knowledge of the primitive tumor.

Fig. 16.28. Neurofibromatosis type 2. Calcified choroid plexus. Axial CT scan. Grossly calcified right choroid plexus (open arrow). Calcification of choroid plexuses is rather common in NF2. It usually is not related to intraventricular meningiomas

16.2.3.3 Ependymome

Ependymomas are intramedullary tumors, either solitary (involving the conus medullaris and filum terminale) or multiple [4, 17]. They may be clinically

16.2.4 Diagnostic Evaluation of NF2 Patients MRI evaluation of the whole brain and spine both before and after gadolinium administration is suggested for patients with a definite diagnosis of NF2 [2]. Follow-up MRI every 6–12 months has been recommended for patients with identified spinal tumors [2]. Imaging evaluation should also be performed in cases with presumptive diagnosis and in first-degree relatives of NF2 patients [100]. In childhood, evidence of meningiomas or schwannomas should incur the diagnostic suspicion

Phakomatoses

16.3 Tuberous Sclerosis 16.3.1 Background

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Fig. 16.29a,b. Neurofibromatosis type 2. Spinal ependymoma. a Sagittal T2-weighted image. b Gd-enhanced sagittal T1weighted image. Intramedullary tumor involves most of the cervical spinal cord (a). Enhancement is irregular and partly multinodular (b). One could question whether this is a single lesion or, rather, there are multiple tumors

of NF2, since they are unusual tumors in the pediatric age group [17]. Furthermore, contrast-enhanced brain MRI should be performed if spinal meningioma or schwannoma are identified in a child [17]. In childhood, a diagnosis of NF2 should be considered in the presence of the criteria summarized in Table 16.5 [101]. The occurrence of skin tumors and cataracts are considered important clues in the early detection of children with NF2 [17]. Early diagnosis of NF2 by imaging evaluation appears crucial due to the high incidence of occult and asymptomatic tumors (especially spinal), and considering that an improvement of outcome in terms of hearing preservation has been demonstrated to positively relate with early diagnosis and treatment [104].

Table 16.5.

Criteria for suspecting NF2 in childhood

Presence of: • Unilateral VS • Multiple CNS tumors • Juvenile cataract (not due to other obvious causes) and one CNS tumor or skin tumor • Multiple spinal tumors without Lisch nodules or café-au-lait spots • Multiple skin schwannomas (From Reference #101)

The tuberous sclerosis complex (TSC), or Bourneville’s disease, is an autosomal dominant disorder with a new mutation rate of up to 70%, characterized pathologically by the presence of hamartomas in multiple organ systems. TSC exhibits genetic heterogeneity. The genes responsible for the disorder are tumor suppressor genes: TSC1 (9q34) encodes for a protein called hamartin, whereas TSC2 (16p13) encodes for a protein called tuberin. A cortical distribution of hamartin, as well as an interaction between hamartin and tuberin that could be involved in the regulation of cell proliferation and differentiation, have been demonstrated [105]. Both somatic and germ-line mosaicism for TSC1 and TSC2 have been described in many patients. TSC2 mutations are more common than TSC1 mutations in both familial and sporadic cases [106]. Although the clinical phenotype associated with TSC1 and TSC2 mutations is very similar, TSC2 seems to be more severe than TSC1 [106]. This could be due to (1) minor frequency of second-hit events in TSC1, and (2) different effects related to complete loss of hamartin versus the loss of tuberin [106]. Based on genetic data, TSC could therefore be separated into two different categories, despite the similarity of clinical phenotypes and the absence of significant imaging differences. The overall prevalence is of 1 in 30,000, and the birth incidence is 1 in 6,000 [107]. Therefore, TSC is the second most common phakomatosis after NF1 [108]. The traditional diagnostic criteria [109] have been revised recently on the basis of new clinical and genetic information [110]. The diagnostic value of such clinical signs as focal cortical dysplasia and ungual fibromas, once regarded as pathognomonic for TSC, has been questioned, since they may occur in individuals without other evidence of TSC. The revised diagnostic criteria for TSC are shown in Table 16.6.

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P. Tortori-Donati, A. Rossi, R. Biancheri, and C. F. Andreula Table 16.6. Revised diagnostic criteria for tuberous sclerosis complex Major features 1. Facial angiofibromas or forehead plaque 2. Nontraumatic ungual or periungual fibroma 3. Hypomelanotic macules (three or more) 4. Shagreen patch (connective tissue nevus) 5. Multiple retinal nodular hamartomas 6. Cortical tubera 7. Subependymal nodule 8. Subependymal giant cell astrocytoma 9. Cardiac rhabdomyoma, single or multiple 10. Lymphangiomyomatosisb 11. Renal angiomyolipomab Minor features 1. 2. 3. 4. 5. 6. 7. 8. 9.

Multiple, randomly distributed pits in dental enamel Hamartomatous rectal polypsc Bone cystsd Cerebral white-matter radial migration linesade Gingival fibromas Nonrenal hamartomac Retinal achromic patch “Confetti” skin lesions Multiple renal cystsc

Definite TSC Probable TSC Possible TSC

Either two major features or one major feature plus two minor features One major plus one minor feature Either one major or two or more minor features

a

When cerebral cortical dysplasia and cerebral white matter migration tracts occur together, they should be counted as one, rather than two, features of TSC. b When both lymphangiomyomatosis and renal angiomyolipomas are present, other features of TSC should be present before a definite diagnosis is assigned. c Histological confirmation is suggested. d Radiographic confirmation is sufficient. e One Panel member (M.R. Gomez) felt strongly that three or more radial migration lines should constitute a major sign.

16.3.2 Clinical Findings 16.3.2.1 Neurological Manifestations

Neurological manifestations of TSC include epilepsy (up to 90% of cases), learning difficulties (38%–58% of cases), mental retardation (50% of cases), and behavioral problems that include autism or atypical autism (>50% of cases). Epilepsy often begins during the first months of life. At this age, the most

common seizures are infantile spasms and partial seizures; the latter may precede, coexist with, or evolve into infantile spasms. Later, most patients develop simple partial seizures, complex partial seizures, or apparently generalized seizures. The prognosis of epilepsy usually is poor, with increasing severity and frequency and often poor response to antiepileptic drugs [8]. 16.3.2.2 Cutaneous Manifestations

Hypomelanotic patches (so-called white ash leafshaped macules) often are evident at birth, and are best demonstrated by Wood’s light. Facial angiofibromas are rare before age 4 years, and become more apparent as the child grows. They initially are located in the nasolabial fold, with subsequent bimalar (so-called “butterfly”) distribution (Fig. 16.30). Shagreen patches and subungual fibromas may be found in 20%–35% of post-pubertal patients. 16.3.2.3 Ocular Manifestations

Retinal giant cell astrocytomas (50% of cases), corneal disease, glaucoma, and achromatic retinal patches are the main ocular manifestations of TSC. 16.3.2.4 Other Clinical Manifestations

Renal lesions, usually angiomyolipomas (Fig. 16.31, 16.32) but also polycystic renal disease and renal carcinoma can occur. Cardiac rhabdomyoma (Fig. 16.32), skeletal abnormalities, and precocious puberty are other common manifestations of TSC. All patients with a presumptive diagnosis of TSC should undergo abdominal and cardiac ultrasounds. The reverse also is true, since renal or cardiac tumors may be the presenting manifestation of the disease; therefore, the possibility of TSC should be entertained in all patients harboring these uncommon tumors. 16.3.2.5 Relationships with other Phakomatoses

The association between NF1 and TSC has been rarely reported [88, 89]. The family history of the case reported by Lee et al. [88] suggests the possibility that one disorder is inherited from one parent, while the other represents a de novo mutation.

Phakomatoses Fig. 16.30a,b. Tuberous sclerosis. Facial angiofibromas associated with a shagreen patch. (Permission to publish these photographs was obtained from the parents)

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Fig. 16.31. Tuberous sclerosis. Renal angiomyolipomas. Abdominal CT scan. Both kidneys are enlarged and deformed due to multiple lesions showing inhomogeneous density. Adipose tissue islets are hypodense (arrow)

16.3.3 Brain Lesions in TSC TSC is considered to be a developmental disorder of cell proliferation, migration, and differentiation [17, 111, 112]. Brain lesions are represented by cortical tubers, subependymal nodules, white-matter abnormalities, and subependymal giant cell astrocytomas. Not all these lesions are necessarily present in each individual patient. However, all are histologically characterized by so-called giant or balloon cells, i.e., abnormal, large cells showing a combination of both neuronal and astrocytic features [112–114]. Giant cells contain large volumes of cytoplasm that may stain for neuronal markers, glial markers, both, or neither [115] (see below). Giant cells are related to primordial dysgenetic events resulting in incomplete or aberrant astrocytic or neuronal proliferation, with a potential bidirec-

tional differentiation towards the astrocytic or neuronal line. It is noteworthy that identical histological findings are seen in Taylor’s focal cortical dysplasia, thereby indicating a common underlying disorder; in fact, Taylor’s focal cortical dysplasia is sometimes referred to as a forma frusta of TSC [17]. According to the recent classification system for malformations of cortical development [115], balloon cells are present in all nonneoplastic malformations due to abnormal proliferation with abnormal cell types. Although the origin of these cells is still uncertain, they are thought to represent cells that failed to differentiate at a very early stage; they may therefore represent markers of malformations due to stem cell maldifferentiation [115]. Histopathological studies of white matter abnormalities showed that clusters of giant cells are located along the normal pathways of neuronal migration, i.e., radially from the ependyma toward cortical tubers or normal cortex, suggesting abnormal migration of these dysgenetic cells. According to this hypothesis, subependymal nodules result from abnormal giant-cell populations, whose migration is completely arrested in the germinal matrix zone. Partial migration produces heterotopia in the form of cell bands in the subcortical white matter. Cortical tubers are formed by cells that reached the cortical plate but failed to organize properly, producing dysplastic aggregations [112, 114]. Table 16.7 summarizes imaging findings of typical brain TSC lesions in children. 16.3.3.1 Cortical Tubers

Cortical tubers are firm nodules projecting above the surface of the cortex, varying in size from millimeters to several centimeters. They are scattered randomly

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P. Tortori-Donati, A. Rossi, R. Biancheri, and C. F. Andreula Fig. 16.32a–e. Tuberous sclerosis. Left temporal focal megalencephaly versus large neonatal tuber. a Cardiac long axis FSE T1weighted image. b Abdominal ultrasound. c Axial T2-weighted image. d Coronal T2-weighted image. e Axial T2-weighted image. Cardiac MRI shows rhabdomyoma, appearing as an unfloating mass originating from the apex of the left ventricle (thick white arrow, a). Ultrasound detects a hyperechoic renal angiomyolipoma in the upper pole of the right kidney (calipers, b). Initial MR study of the brain at age 2 months (c,d) does not show typical TSC lesions. However, there is significant enlargement of the left temporal pole, where the cortex is markedly thickened and hypointense in T2-weighted images (white arrowheads, c,d). At age 25 months, two small subcortical tubers in the right cerebral hemisphere are detected (arrows, e).

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over the cortical surface. Pathologically, they may be wide and flat (Pellizzi type 1) or round and dimpled (Pellizzi type 2). They usually expand the gyri with a blurred gray-white matter junction, but may also be located in the depth of the sulci. The number of tubers in individual patients may range from one to 20–40 [17]. It is worthwhile to mention that the term “cortical” is something of a misnomer. In fact, the subcortical white matter also is consistently involved, albeit

to a varying degree. Moreover, MRI studies generally detect a band of apparently intact cortex overlying the tubers, that appear to preferentially involve the subcortical regions [17]. Histologically, there is disrupted cortical lamination with loss of demarcation between gray and white matter. Collections of bizarrely shaped giant cells with stout processes, peripheral vacuolization, prominent nucleoli, and sometimes multiple nuclei colonize the

Phakomatoses Table 16.7. Neuroimaging findings of typical brain TSC lesions in the pediatric age group Cortical tubers

Subependymal nodules

Subependymal giant White matter abnormalities cell astrocytoma Solid Cystic (SGCA)

CT

Hypodense (both neonates and children) Hyperdense (calcified)

Isodense (non calcified) Iso-hypodense, Not easily Same density Hyperdense (calcified) slightly hyperdense identified as CSF (often with calcifica- (hypodensity) tions)

MRI (T1weighted images)

Neonates: hyperintense Children: iso-hypointense

Neonates: hyperintense Children: isointense to WM (noncalcified)

Iso-hypointense

Not identified

Same signal intensity as CSF

MRI (T2weighted images)

Neonates: hypointense Children: hyperintense

Neonates: hypointense Children: hyperintense (noncalcified) hypointense (calcified)

Variable signal intensity

Hyperintense areas

Same signal intensity as CSF

Enhancement

Absent/variablea

Absent/variablea

Marked

Usually absent

Evolution

Hypodense, isodense/isointense on CT/T1 MRI, persistently hyperintense on T2 MRI. Number and morphology may be modified. New lesions may appear. Old lesions may regress or even completely disappear

Increase in number, calcifications Possible evolution into SGCA (foramen of Monro)

Increase of size, possible neoplastic degeneration

Similar to tubers

a

The variable percentage of lesions showing CE depends on the MR magnet field strength; WM: white matter

abnormal cortex. Atypical astrocytes or abnormal, maloriented neurons may also be demonstrated with conventional stains [116, 117]. The subcortical white matter shows deficient myelination and gliosis [108]. Clusters of abnormal cells may be also found in the deep white matter as well as in the macroscopically normal cortex. Cortical tubers may calcify, albeit less frequently than subependymal nodules, secondary to degeneration of the central portion of the tuber. This phenomenon increases with age [108], and calcified tubers are only occasionally found before age 2 years. Whether cortical tubers have a preferential lobar distribution still is controversial. Some believe that the frontal lobe is most commonly involved, followed by the parietal, occipital, and temporal lobes [108, 112, 118]. Others regard the temporal lobe as the most common location [114, 119].

Neonatal tubers

In neonates and infants under 3 months of age, cortical tubers are hyperintense on T1-weighted images and hypointense on T2-weighted images (Fig. 16.32, 16.33) [120, 121]. Several hypotheses have been advanced to explain this pattern. These include (1) the contrast between the solid lesion and the relatively high concentration of water in the immature brain [112, 121, 122], (2) calcifications within the proteinaceous component [123], and (3) high cellularity with elevated nuclear-to-cytoplasmic ratio [122]. On CT scan, neonatal tubers are hypodense. Therefore, they may be barely discernible against the overall hypodensity of the unmyelinated brain. The neonatal MR pattern persists only rarely beyond the third month of age. Tubers in children

Imaging Studies

The neuroradiological appearance of cortical tubers varies with age. Especially, there are relevant differences in the MRI features of cortical tubers in neonates as compared to older children and adults.

In children, tubers are characterized by marked signal changes in all sequences (Fig. 16.34) but prevailingly in T2-weighted, FLAIR, and short-time inversion recovery (STIR) images. Because the signal abnormality is located predominantly in the subcortical

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Fig. 16.33a–f. Tuberous sclerosis: evolution of a case. a–c: MRI at neonatal age: a and b Axial T1-weighted images. c Axial T2weighted image. d–f: MRI at age 2 years: d and e. Axial T1-weighted images. f Axial T2-weighted image. On the initial MRI examination, T1-weighted images show diffuse abnormal white matter hyperintensities, as well as spontaneously hyperintense subependymal nodules (arrowheads, a, b). In particular, two subependymal nodules are clearly visible at level of the foramina of Monro (open arrows, a). On T2-weighted images, white matter abnormalities are barely recognizable, and no cortical tubers are demonstrable; however, the hypointense subependymal nodules clearly stand out against CSF hyperintensity (arrowheads, c). At 2 years of age, the subependymal nodules are now isointense to white matter, and several cortical tubers are recognizable on both T1- and T2-weighted images. Furthermore, a large white-matter signal abnormality is now visible in the right paratrigonal region (white arrows, f).

portions of the tubers, the terms “gyral core” and “sulcal island” have been used to indicate different imaging appearances of cortical tubers [124]. Gyral core: The term “gyral core” refers to rounded areas of abnormal signal intensity on both T1- and T2-weighted images that occupy the inner core of an expanded gyrus, surrounded by apparent normal cortex (Fig. 16.34). Sulcal island: When the subcortical white matter of two adjacent gyri is abnormal, a ring-like zone of increased signal intensity is seen to partially or completely engulf an island of isointensity. This isointense island is actually formed by two layers of normal-appearing cortex with an interposed sulcus, surrounded by hyperintense subcortical white

matter [124]. This pattern is called “sulcal island” (Fig. 16.34). Albeit rarely, gyral cores and sulcal islands are only visible in T2-weighted and FLAIR images. More rarely, cortical involvement with blurring of the graywhite matter is seen (Fig. 16.35). High signal intensity is related to gliosis and hypomyelination of the adjacent subcortical white matter, and sometimes extends from one tuber to another as well as into the depth of the involved gyri [125]. In T1-weighted images, tubers show variable signal behavior, ranging from marked hypointensity to isointensity. Cortical tubers typically show no appreciable contrast enhancement. However, degenerated (i.e., calcified) cortical tubers may seldom enhance,

Phakomatoses

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Fig. 16.34a–f. Tuberous sclerosis in a 21-month-old girl. a Axial T1-weighted image. b Axial T2-weighted image. c Axial FLAIR image. d,e Axial STIR images. f Axial T2-weighted image. So-called “cortical” tubers are seen as diffuse hyperintense areas involving both cerebral hemispheres in T2-weighted, FLAIR, and STIR images, whereas they are less evident in T1-weighted images. Note that signal changes actually involve the subcortical regions, whereas the adjacent cortex is flattened and thickened. In the right frontal region, these lesions are confluent, and connect two adjacent tubers (thick black arrows, b,c). Cortical thickening is apparent also in T1-weighted and STIR images. Subependymal nodules are isointense to white matter in T1-weighted images (open white arrows, a) and hypointense in T2-weighted images (open white arrows, b). They are located along the thalamocaudate sulcus and project into the ventricular cavity. A “gyral core” (white arrowheads, e,f) and a “sulcal island” (thin white arrows, e; thin black arrows, f) are recognizable in the right parietal and left frontal regions, respectively

without any tumor implication [17] (Fig. 16.36). Calcification of tubers is not a consistent feature. When present, it usually is detected best by unenhanced CT scan (Fig. 16.36). Unusual gyriform calcifications, simulating those of Sturge-Weber syndrome, have been reported [126]. Usually, most tubers tend to become hypodense on CT scan and isointense on MRI with the unaffected gray matter as the child grows (Fig. 16.37). Aging often implies changes in their morphology and number, including regression and even complete disappearance. Pathologically, Pellizzi type 1 tubers

are predominant in children, whereas Pellizzi type 2 tubers are more common in the older population. However, type 2 tubers have also been described in very young patients [112]. On MR images, Pellizzi type 1 (Fig. 16.35) and type 2 tubers differ from one another in that type 2 tubers show a central depression or umbilication, probably related to atrophy and degeneration within the tuber itself [112, 118]. Unusual cyst-like appearances (i.e., hypointense on T1-weighted images and hyperintense on T2-weighted images) have also been reported in a small proportion of cases [118].

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Fig. 16.35a,b. Tuberous sclerosis in a 6month-old boy. a Axial and b coronal T2weighted images. Pellizzi type 1 cortical tubers in the left temporal and parietal regions show a flat surface. A large left parietal tuber shows blurred gray-white matter interface (arrowheads, b)

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Fig. 16.36a–d. Tuberous sclerosis in a 9-month-old boy. a Axial CT scan. b Axial T2weighted image. c Axial T1-weighted image. d Gd-enhanced axial T1-weighted image. CT shows a large, markedly calcified cortical tuber in the right frontal lobe (white arrow, a). The lesion is hypointense in T2-weighted images (white arrow, b) and slightly hyperintense in T1-weighted images (black arrow, c). Enhancement following gadolinium administration is mild (black arrow, d)

a

Cerebellar tubers

Cortical tubers have been described in the cerebellum in 6%–15% of patients [108, 112, 127, 128]. Cerebellar tubers (Fig. 16.38) are less frequent than cerebral ones and are consistently associated with supratentorial tubers. They usually occur in older children with a large total amount of tubers. Remarkably, TSC2 is

expressed at high level in the cerebellum, thus suggesting possible different genetic control with respect to cerebral lesions [129]. Cerebellar tubers may be solitary or multiple, and may extend into the white matter as wedge-shaped lesions pointing to the fourth ventricle [130]. Their MRI appearance is similar to that of cerebral tubers; however, they show a greater

Phakomatoses

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Fig. 16.37a–c. Tuberous sclerosis: evolution of a case. a,b Axial CT scans at age 8 months. c Axial CT scan at age 9 years. At presentation (a,b), diffuse cortico-subcortical hypodense tubers and subependymal nodules are recognizable. A calcified subependymal nodule is visible along the lateral wall of the right lateral ventricle (arrowhead, b). A hyperdense subependymal giant cell astrocytoma with a small central calcified focus involves the region of the right foramen of Monro (thick arrow, a). At age 9 years (c), the tumor has markedly enlarged and shows shell-like calcifications (thick arrows, c). A second tumor containing calcified spots has arisen contralaterally (open arrows, c). The ventricular system is enlarged due to obstruction at level of the foramina of Monro. There are now numerous calcified subependymal nodules (arrowheads, c)

tendency to calcify with respect to cortical tubers [125]. Relationship between Cortical Tubers and Epilepsy

The relationship between cortical tubers and epilepsy still is debated. Unfortunately, MRI does not differentiate between epileptogenic and nonepileptogenic cortical tubers. Improved detection of epileptogenic foci by using multimodality imaging, i.e., FLAIR images together with [11C] α-methyl-L-tryptophan (AMT) PET, has been demonstrated recently [131]. Increased uptake of [11C] AMT is related to epileptiform activity, and may individuate epileptogenic tubers that may be considered eligible for epilepsy surgery. Several studies have been carried out in order to correlate number, size, and location of cortical tubers with the severity of mental retardation, but the results have been equivocal [114, 119, 132]. Since mental disability always is associated with epilepsy, their reciprocal influences have been investigated. However, no significant conclusion has been obtained as to whether seizures themselves play a role in causing mental retardation or, rather, mental retardation and epilepsy are two different aspects of the same brain dysfunction [119].

a

b Fig. 16.38a,b. Tuberous sclerosis. Cerebellar tubers in two different cases. a Axial CT scan. b Axial FLAIR -weighted image. CT shows multiple calcified cerebellar tubers (arrows, a). In a different case, FLAIR image shows hyperintense tubers in both cerebellar hemispheres (arrows, b)

16.3.3.2 Subependymal Nodules

Subependymal nodules (SENs) are small ( 2 years of age)

CE

Enhancement of leptomeninges and of hyperplastic choroid plexus

Evolution

Progressive ↓ of leptomeningeal enhancement (due to progressive thrombosis of capillaries) → atrophy → calcifications

b

a Fig. 16.55a,b. Choroidal angiomatosis in an 8-year-old girl with Sturge-Weber syndrome. a Axial unenhanced CT scan. b Contrastenhanced axial CT scan. A crescentic hyperdense lesion involves the right ocular globe (arrowheads, a). Following contrast administration, the angiomatous portion enhances (arrows, b). The unenhancing portion (arrowheads, b) is due to retinal detachment

Phakomatoses

16.4.6.3 Bilateral Parieto-occipital Calcifications with Epilepsy and Celiac Disease

This recently described syndrome [187, 188], whose etiology is still unknown, is characterized by intracranial calcifications similar to those found in SWS. Affected patients show neither neurological deficits nor facial angiomas. The course of epileptic seizures may be either benign or poor. Pathological abnormalities, characterized by a cortical vascular abnormality with patchy pial angiomatosis, fibrosed veins, and large jagged microcalcifications, are similar, albeit not identical, to those found in SWS [189]. Celiac disease may be clinically silent, and usually is diagnosed after the onset of seizures. The relationship between celiac disease and cerebral calcifications is unclear. Although a possible role of folic acid deficiency has been proposed, a common genetic predisposition seems to be more convincing. It has been proposed that celiac disease should be ruled out in all cases of epilepsy and cerebral calcifications of unexplained origin [189–191], and that patients affected with infan-

tile celiac disease should undergo EEG, followed by a neuroradiological examination if the EEG pattern is found to be altered [191]. CT scan shows bilateral cortico-subcortical calcifications, most commonly in the parieto-occipital region, without atrophy or density changes in the adjacent parenchyma. However, calcifications involving the frontal lobes have also been described [190] (Fig. 16.56). Contrast enhancement is absent. Serial CT scan examinations show increase of calcifications, reaching their greatest extent at puberty [190]. Stabilization of calcification size has been demonstrated after institution of gluten-free diet [192]. On MRI, calcifications may not be recognizable, or may produce mild hyperintensity in T1-weighted images (Fig. 16.57). Gradient echo T2*-weighted sequences are more sensible to calcium-related susceptibility effects, and may better identify them [190]. In a case we observed, mild enhancement was detected after gadolinium administration [193]. Table 16.12 summarizes the clinical and imaging findings that allow differentiation of SWS from bilateral parieto-occipital calcifications with epilepsy and celiac disease. Fig. 16.56a,b. Bilateral parietooccipital calcifications with epilepsy and celiac disease syndrome in two different patients. a Contrast enhanced axial CT scan. b Axial CT scan. a Cortico-subcortical bilateral parieto-occipital calcifications. Neither enhancement nor cortical atrophy are present. b Bilateral parieto-occipital and left frontal calcifications. Cortical atrophy is absent

a

a

b

b Fig. 16.57a,b. Bilateral parieto-occipital calcifications with epilepsy and celiac disease syndrome in a 13-year-old girl. a Axial T1weighted image. b Axial T2-weighted image. Diffuse, prevailingly cortico-subcortical calcifications of the temporo-occipital lobes and, partially, of the parietal lobe, are clearly seen in T1-weighted images (arrows, a). Fast spin-echo T2-weighted images are insensitive to calcium-related susceptibility effects, and accordingly fail to detect even quite large calcified spots such as in the present case.

809

810

P. Tortori-Donati, A. Rossi, R. Biancheri, and C. F. Andreula Table 16.12. Differential diagnosis between bilateral parieto-occipital calcifications with epilepsy and celiac disease syndrome and Sturge-Weber syndrome Bilateral parieto-occipital calcifications with epilepsy and celiac disease syndrome

Sturge-Weber syndrome

No

Yes

No

Yes

Lobar or hemispheric atrophy

No

Yes

Calcifications

Almost always bilateral Mainly cortico-subcortical

Almost always unilateral Bilateral in 15%–20% of cases Mainly cortical

Clinical findings Facial angioma Neurological deficits Imaging findings

16.5 Von Hippel-Lindau Disease 16.5.1 Background The von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by retinal angiomas and hemangioblastomas of the cerebellum, brainstem, and spinal cord. Pheochromocytoma, liver hemangiomas, and multiple pancreatic and renal cysts also may occur. The condition is transmitted as a dominant trait with variable penetrance. The VHL gene (3p25-p26) is a tumor suppressor gene, whose normal function is to regulate cell growth [194]. Therefore, inactivation of both alleles of the gene is a significant contributor to the pathogenesis of the tumors seen in this disease. Although symptoms usually are delayed to the second to fourth decade of life, hemangioblastomas may be detected in childhood [195]. Ocular symptoms prominently include sudden intraocular hemorrhage, and commonly antedate cerebellar complaints. Increased intracranial pressure or cerebellar signs are the common types of neurological involvement seen in this disease.

16.5.2 CNS manifestations Among gene carriers, 46% have CNS hemangioblastomas. Most commonly (52% of cases), the neoplasm is located in the cerebellum. It can be found in the spinal cord in 44%, and in the brainstem in 18% of patients with CNS hemangioblastoma [195]. VHL may be differentiated by isolated hemangioblastomas on the basis of the following criteria: at least two CNS locations of hemangioblastomas, or one CNS loca-

tion and one visceral location of hemangioblastoma, or one single CNS hemangioblastoma, with known family history for VHL. 16.5.2.1 Cerebellar hemangioblastoma

Cerebellar hemangioblastoma is a pial hypervascular nodule, always easily identifiable on MRI after gadolinium administration, located along the wall of a large cyst that results from fluid production. Because of its pial origin, the nodule is consistently superficial [196, 197]. The cerebellar hemispheres are affected more commonly than the vermis. Histologically, solid, cystic, hemorrhagic, and mixed variants have been described [198]. Since the nodule is not capsulated, the solid component may infiltrate the nervous tissue, leading to hemorrhage. Subarachnoid hemorrhage may occur as a result of high pressure rates within the angioma. On MRI (Fig. 16.58, 16.59), cerebellar hemangioblastoma typically appear as large, rounded, sharply marginated cystic lesions that show prolongation of both T1 and T2 relaxation times [17]. Variable intracystic signal intensity may occur, depending on protein or hematic content. A solid nodule may be seen within the wall of the cyst [5, 17]. After gadolinium administration, the mural nodule enhances strongly, whereas the cyst wall does not [5,199]; furthermore, the nodule consistently abuts the cerebellar surface. These features usually allow differentiation from pilocytic astrocytomas, which represent a much more common etiology for posterior fossa cystic masses with solid mural nodule; other differential features include multiplicity and the typical angiographic pattern (see below). The rare solid hemangioblastomas appear as solid cerebellar masses, usually showing prolongation of both T1 and T2 relaxation times unless hemorrhage causes high signal intensity on T1-weighted images [17].

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Phakomatoses

b a

Fig. 16.58a–c. Von Hippel-Lindau syndrome. Cerebellar hemangioblastoma. a. Gd-enhanced axial T1-weighted image. b Gdenhanced coronal T1-weighted image. c Digital subtraction angiography of the vertebrobasilar circulation, laterolateral projection. Huge cystic lesion with mural nodule in the right cerebellar hemisphere and vermis. The mural nodule is located superficially along the superior aspect of the right cerebellar hemisphere, and abuts the tentorium (arrowheads, b). The cyst wall does not enhance. Angiography shows the classic feature of a “cherry attached to a stalk” (arrows, c)

c

b

a Fig. 16.59a,b. Von Hippel-Lindau syndrome. a Gd-enhanced axial T1-weighted image. b Sagittal T2-weighted image. There is a huge cystic lesion involving the left cerebellar hemisphere and vermis. A tiny enhancing mural nodule is located superficially (arrow, a). On T2-weighted image, the low-signal nodule (arrow, b) is barely discernible

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Large feeding and draining vessels may be demonstrable by MRI and MRA. However, digital angiography better shows tangles of tightly packed, wide vessels, opacified in the early arterial phase [17] (Figs. 16.58). Sometimes, the typical finding of a “cherry attached to its stalk” may be recognized. Angiography also is useful for differentiating between pilocytic astrocytoma and hemangioblastoma, because only the latter shows a typical blush. 16.5.2.2 Spinal Hemangioblastoma

Spinal hemangioblastomas may occur throughout the spinal cord, with a preferential location in the conus medullaris and craniocervical junction (Fig. 16.60). They may be intramedullary, partially intra- and extramedullary, or purely extramedullary [200]. They show equivalent imaging findings as cerebellar hemangioblastomas. Syringomyelia often is associated. In these cases, contrast material administra-

tion causes enhancement of the solid tumor nodule, thereby facilitating the differentiation from idiopathic syringomyelia [17]. Furthermore, evidence of serpiginous areas of flow void within and adjacent to the tumor, representing enlarged vessels, is a typical MRI sign of spinal cord hemangioblastomas. Rare locations of hemangioblastomas include the brainstem and, exceptionally, the cerebral hemispheres. MRI findings are equivalent to those previously described.

16.5.3 Ocular Manifestations Retinal angiomas are detected by indirect ophthalmoscopy and fluorescein angiography. Imaging studies may demonstrate secondary retinal detachment due to fluid extravasation or hemorrhage; the angioma commonly is small and may remain undetected on MRI [17].

a

Fig. 16.60a–d. Von Hippel-Lindau syndrome. Hemangioblastomas in a young adult. a,b Gd-enhanced axial T1-weighted images. c Gd-enhanced sagittal T1-weighted image. d Digital subtraction angiography of the vertebrobasilar circulation, latero-lateral projection. There are two distinct enhancing nodules. The first one involves the cervicomedullary junction to the right (arrows, a,c), and is associated with a multiloculated intramedullary cyst extending caudally to C5. The second lesion is located at the level of the obex (arrowheads, b,c). Selective angiography of the vertebrobasilar system shows two distinct blushes corresponding to the enhancing nodules (arrow and arrowhead, d). (Case courtesy of Dr. B. Bernardi, Bologna, Italy)

c

b

d

Phakomatoses

16.5.4 Papillary Cystadenomas of the Endolymphatic Sac Papillary cystadenomas of the endolymphatic sac occur in VHL more frequently than in the general population. Hearing loss is the common clinical presentation. These tumors lie within the dura of the posterior fossa, originating along the posterior margin of the petrous pyramid at the site of the vestibular aqueduct, and may grow into the cerebellum or cerebellopontine angles. On CT, scattered calcifications at the level of the vestibular aqueduct and bone destruction are detected. On MRI, they appear as heterogeneous masses, isointense with scattered hemorrhage-related hyperintense zones on T1-weighted images, and hyperintense with areas of hypointensity on T2-weighted images. Contrast enhancement may be homogeneous or heterogeneous [17].

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The Rare Phakomatoses

17 The Rare Phakomatoses Simon Edelstein, Thomas P. Naidich, and T. Hans Newton

17.1 Introduction

CONTENTS 17.1

Introduction 819

17.2

Vascular Phakomatoses 819

17.2.1 17.2.2 17.2.3 17.2.4 17.2.5 17.2.6

Ataxia Telangiectasia 819 Wyburn-Mason Syndrome 821 Hereditary Hemorrhagic Telangiectasia 822 Blue Rubber Bleb Nevus Syndrome 823 PHACE Syndrome 826 Meningioangiomatosis 828

17.3

Melanophakomatoses

17.3.1 17.3.2 17.3.3 17.3.4 17.3.5 17.3.6 17.3.7

Hypomelanosis of Ito 829 Incontinentia Pigmenti 831 Waardenburg Syndrome 832 Neurocutaneous Melanosis 835 Nevus of Ota 837 McCune-Albright Syndrome 839 Nelson Syndrome 841

17.4

Other Phakomatoses

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17.4.1 Basal Cell Nevus Syndrome 842 17.4.2 Organoid Nevus Syndrome 844 17.4.3 Cowden-Lhermitte-Duclos (COLD) Syndrome 846 17.5

The rare phakomatoses may be grouped broadly into vascular phakomatoses and melanophakomatoses. Other entities, such as basal cell nevus syndrome and organoid nevus syndrome, will also be discussed here. Finally, Cowden-Lhermitte-Duclos syndrome will be discussed at the end of this chapter.

17.2 Vascular Phakomatoses Vascular phakomatoses are characterized by predominant disorder of the cerebrovascular system, with secondary additional neuroectodermal changes. These include ataxia telangiectasia (AT), WyburnMason syndrome (WMS), hereditary hemorrhagic telangiectasia (HHT), blue rubber bleb nevus syndrome (BRBNS), PHACE syndrome, and meningioangiomatosis. While the latter is described in Chap. 10, the remainder will be discussed here.

Conclusion 847 References

848

17.2.1 Ataxia Telangiectasia Ataxia telangiectasia (AT), or Louis Bar syndrome, is an inherited, autosomal recessive multisystem disease of childhood characterized by progressive cerebellar degeneration and ataxia, oculocutaneous telangiectasias, genomic instability, and immunologic defects that increase susceptibility to infection and malignant neoplasms [1]. AT is rare, with an incidence of 1 per 40,000 to 1 per 100,000 individuals [2, 3]. Approximately 1% of the population may be heterozygous for the affected gene (designated ataxia telangiectasia mutated or ATM, mapped to chromosome 11q22–23) [2, 4, 5]. The ATM gene encodes a large 350-kDaprotein that belongs to a family of kinases, shown to function in DNA repair and cell cycle checkpoint control following DNA damage.

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The neuronal degeneration observed in AT may result from faulty repair of DNA damage [6] or from faulty neurogenesis, since ATM appears to be required during the early development of the cerebellum [7]. The ATM protein is abundant in dividing neural progenitor cells, but becomes markedly downregulated as cells differentiate. ATM expression is high in areas of Purkinje cell precursors [8]. 17.2.1.1 Clinical Findings

AT typically presents in childhood, but may develop later, even into the late second decade [9]. The diagnosis is rarely made in the absence of the characteristic telangiectasias, so AT is probably underdiagnosed [4, 10]. The mucocutaneous telangiectasias usually appear at 3–6 years of age, but may be absent until the mid teens. They manifest first on the bulbar conjunctiva (Fig. 17.1), then (often symmetrically) on the bridge of the nose, face, neck, palate, dorsum of the hands, antecubital fossa, and popliteal fossa [5, 10]. When coupled with ataxia, they are pathognomonic for AT. Progeric skin changes, such as premature thinning and graying of the hair, loss of skin elasticity, and loss of subcutaneous fat, may also be present. Cerebellar ataxia may appear first as postural truncal instability or manifest later as impaired walking. Ensuing neurologic deficits may include dystonic posturing, choreo-athetosis, oculomotor apraxia, hypotonia, dysarthria, generalized muscle weakness, and wasting [2]. Cognitive performance frequently declines. Patients with AT have a high propensity for developing neural tumors. The thymus is rudimentary or absent in AT, concurrent with impaired humoral and cell-mediated immunity. Most patients suffer recurrent sinopulmonary infections with secondary complications, such as bronchiectasis and pulmonary arteriovenous fistulas [5, 11]. Endocrine abnormalities are frequent, including hypogonadism and insulin-resistant diabetes mellitus [5]. All AT patients show remarkable sensitivity to ionizing radiation [4, 12–14], leading to a 100–1,200 times higher incidence of malignancy than agematched controls in the general population [5]. Lymphoreticular malignancy is most common, especially in younger AT patients [11, 14]. Approximately 10%– 15% of AT patients show lymphoid tumors by early adulthood [11]. Other associated neoplasms include tumors of the epithelium (basal cell carcinoma), gastrointestinal and hepatobiliary tracts, ovaries, and

brain (medulloblastoma and glioma) [2, 4]. Patients with AT nearly always show elevated levels of α-fetoprotein and carcinoembryonic antigen [5, 15]. 17.2.1.2 Neuropathological Findings

The cerebellum shows atrophy of all cortical layers (Fig. 17.1), severe Purkinje cell loss, granule cell loss, and atrophy of the dentate nuclei [2, 9]. Telangiectatic vessels are seen in the leptomeninges [2]. There is loss of neurons in the olivary nuclei, substantia nigra, and oculomotor nuclei, as well as spongy degeneration and abnormal vasculature in the cerebral cortex [9]. Nucleocytomegalic cells may be seen in the anterior pituitary gland. The spinal cord shows axonal neuropathy, degeneration of anterior horn and dorsal root ganglial cells, and demyelination in the dorsal columns [2, 16].

a

b Fig. 17.1a, b. Ataxia telangiectasia. a Eye of young child showing telangiectasias on the bulbar conjunctiva. b Sagittal T2-weighted image shows atrophy of the vermis with increased prominence of the folia and enlargement of the fourth ventricle. (Courtesy of Drs. A. Osborn and L. Becker, Salt Lake City, UT, USA)

The Rare Phakomatoses

17.2.1.3 Imaging Studies

17.2.2.1 Clinical Findings

Owing to abnormally increased radiation sensitivity, magnetic resonance imaging (MRI) should be preferred to computerized tomography (CT) scan in the neuroimaging workup of these patients. The major central nervous system (CNS) abnormality found in AT is atrophy of the cerebellar cortex, involving the vermis and/or the hemispheres [10]. This manifests as decreased size of the cerebellum, increased prominence of the cerebellar folia and fissures, and dilatation of the fourth ventricle (Fig. 17.1). Atrophy of AT is panvermian and progressive, and, for these reasons, can usually be distinguished from localized anterosuperior vermian atrophy associated with alcoholic cerebellar degeneration. In younger patients with AT, cerebral white matter typically shows no focal signal intensity changes. Absence of such cerebral changes is considered to exclude macroscopic brain telangiectasias [5]. Occasional older AT patients show high T2 signal foci in the cerebral white matter, possibly indicating degenerative changes of the progeric type [5]. The spectrum of paranasal sinus disease ranges in severity from simple mucosal thickening to desiccated secretions, sinus opacification, air-fluid levels, and chronic sclerotic bone changes. The presence of sinusitis in conjunction with cerebellar atrophy suggests a possible diagnosis of AT.

WMS usually presents in childhood, occasionally at birth. Specific symptoms and signs vary with location and size of the AVM. The facial nevi vary from faint discolorations to extensive angiomatous nevi. They are usually unilateral, infrequently bilateral, and may conform to the distribution of the trigeminal nerve [18, 20]. Ocular features of WMS include exophthalmos, orbital bruit, and decreased vision (Fig. 17.2). CNS signs include headache, subarachnoid hemorrhage, and stroke. Seizures are a prominent clinical feature but are not universal. Arteriovenous shunting and steal may cause progressive neurological deficits and optic nerve atrophy [17].

17.2.1.4 Differential Diagnosis

The main entities entering the differential diagnosis include Friedreich ataxia, olivopontocerebellar degeneration (in which cerebellar atrophy is more hemispheric than vermian), and cerebello-olivary degeneration.

17.2.2 Wyburn-Mason Syndrome Wyburn-Mason syndrome (WMS) is a neurocutaneous disorder characterized by concurrent, usually unilateral facial nevi, orbital arteriovenous malformations, and cerebral arteriovenous malformation (AVM) distributed along the optic apparatus [17, 18]. WMS is extremely rare with no predilections of age and gender, and with few angiographically documented cases in the literature. WMS is believed to stem from vascular dysgenesis in the early embryonic period [18, 19].

17.2.2.2 Neuropathological Findings

As initially described, WMS comprised a unilateral or bilateral hindbrain AVM, ipsilateral retinal AVM (Fig. 17.2), and ipsilateral cutaneous facial nevus. The expanded spectrum of WMS now includes variants with orbital AVMs that spare the retina [17], bilateral orbital [21] or retrolental [18] AVMs, and AVM of the cerebral hemispheres, basal ganglia, thalamus, optic nerves/chiasm, mandible, and maxilla [17, 21]. At present, therefore, unilateral and/or retinal AVM is not required for the diagnosis. No specific associations are described in the literature. One concurrent Dandy-Walker malformation was reported, but thought to be coincidental [18]. 17.2.2.3 Imaging Studies

The imaging findings reflect the primary vascular lesions and any secondary complications. Thus, CT, MRI, and angiography reveal AVMs within the orbits, retro-orbital region, cerebral hemispheres, and brainstem, any associated subarachnoid or intraparenchymal hemorrhage, and any optic nerve atrophy that results from direct compression or chronic ischemia. The retinal AVMs vary from tiny angiographically occult lesions to large, tortuous, and dilated vessels covering much of the retina [18]. Arterial supply to the AVMs arises from the internal carotid artery more often than from the vertebrobasilar arteries or the external carotid artery (Fig. 17.2). Venous drainage is primarily via the cavernous sinus or the vein of Galen [20].

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a

b

Fig. 17.2a–c. Wyburn-Mason syndrome. a The bulbar conjunctiva shows a vascular malformation. b Retinoscopy discloses enlarged tortuous vessels in the retina with arteriovenous shunts. c Right lateral internal carotid angiogram demonstrates a diffuse malformation of the optic apparatus with enlargement of the right optic nerve, intra- and peri-optic intraorbital malformation, malformation in the hypothalamus, and posterior extension of the malformation through the optic radiations.

c

17.2.3 Hereditary Hemorrhagic Telangiectasia Hereditary hemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal dominant vascular phakomatosis characterized by concurrent epistaxis, mucocutaneous and visceral telangiectasias, recurrent hemorrhage with chronic anemia, and visceral arteriovenous shunting. HHT is found throughout a wide geographic distribution among diverse ethnic and racial groups. The incidence has been reported to vary from approximately 1 per 3,000 individuals in certain island populations [22] to 1 per 100,000 individuals in the general population [23, 24]. Penetrance is as high as 97% by age 50 years [25]. Linkage studies have shown that HHT is a genetically heterogeneous disorder that affects the receptors for transforming growth factor (TGF). Thus far, three gene loci responsible for three separate types of TGF-β receptors have been identified [24, 26–28]. The gene HHT 1 (chromosome 9q33–34) codes for endoglin, a TGF-β type 3 receptor, and is associated with pulmonary AVMs [27, 29]. HHT 2 (chromosome 3p22) is associated with the TGF-β type 2 receptor [24]. HHT 3 (chromosome 12q13) relates to the ALK 1 (activin receptor like kinase 1) gene, a TGF-β type 1 receptor [28]. Multiple different muta-

tions have been found in HHT 1 and HHT 3 [27]. HHT mutations lead to dysregulation of the TGF-β signal transduction pathways [24]. As the proteins encoded by HHT 1 and HHT 3 are expressed exclusively in vascular endothelial cells, they affect angiogenesis, vasculogenesis, and the properties of the endothelial cells [27, 30], potentially altering vessel maturation. 17.2.3.1 Clinical Findings

The most common manifestation of HHT is epistaxis, resulting from spontaneous bleeding of nasal mucosal telangiectasias (up to 93% of patients) [31]. Skin telangiectasias typically present later than mucosal telangiectasias, and often appear after the initial episode of epistaxis. Neurologic symptoms are seen in 8%–27% of patients, and reflect both intrinsic telangiectasias of the brain and secondary consequences of arteriovenous shunting at other sites. These lesions include intraparenchymal and subarachnoid hemorrhage, transient ischemic attacks and stroke, brain abscess, and seizures (see Chap. 8) [22, 32]. Approximately two thirds of all neurological deficits are due to embolic complications of pulmonary AVMs, and one third to intracerebral hemorrhage [33], usually from cerebrovascular malformations. The overall

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risk of presenting with intracerebral hemorrhage from cerebral AVM is low, ranging from 0% [32] to 2% [23], as is the overall long-term risk of intracranial hemorrhage from cerebral AVM [23]. Patients with HHT may also present with hemoptysis or hemothorax (often massive) due to pulmonary AVMs. 17.2.3.2 Neuropathological Findings

Pathologically, the smallest, earliest-detectable telangiectatic lesions of HHT are focal dilatations of postcapillary venules. These continue to dilate, and eventually connect with dilated arteries through the capillaries. The capillary segments then disappear gradually, likely becoming arterioles due to the increased flow rates, thereby creating a direct arteriovenous communication. Mononuclear cells, primarily leukocytes, collect in the perivascular space throughout this process [22, 34]. Like telangiectasias, the AVMs of HHT also lack capillaries and consist of direct connections between arteries and veins, but the connections in the AVMs are much larger [22]. Cerebrovascular malformations are found in approximately 23% of HHT patients [32]. Many of these are of indeterminate type, but most are probably AVMs [32]. Cavernous malformations, dural AV fistulae, aneurysms [23], and carotid-cavernous fistulae [33] have also been reported in HHT patients. Vascular malformations of the spinal cord are seen in up to 8% of HHT cases with CNS involvement. These are usually confined to the dorsal portions of lower thoracic-lumbar cord, but occasionally involve the cervical portion [33].

17.2.3.3 Imaging Studies

In HHT, vascular lesions identified radiologically include telangiectasias (primarily in the skin and mucosal surfaces), cerebrovascular malformations (Fig. 17.3), aneurysms, and secondary cerebral infarctions or abscesses (Fig. 17.4) due to paradoxical thrombi, gas emboli, or septic emboli [32, 35] (see Chap. 8). The classic AVMs identified display a conspicuous vascular network, with flow voids and enlarged adjacent pial vessels on MRI. However, this appearance is seen in only 16% of cases [32]. Most cerebrovascular malformations found in HHT have an atypical appearance on MRI, with variable signal intensity, enhancement, and hemosiderin staining (76%). About 8% of lesions resemble the classic description of developmental venous anomalies (DVA, formerly known as venous angiomas) (see Chap. 9). These appear as a caput medusa of small veins, leading to a prominent collecting vessel that courses through normal brain parenchyma, and are best seen after contrast administration. MRI may well underestimate the prevalence of cerebrovascular malformations in HHT [32], implying that HHT patients should be evaluated with both MRI and angiography.

17.2.4 Blue Rubber Bleb Nevus Syndrome Blue rubber bleb nevus syndrome (BRBNS), also named Gascoyne’s syndrome or Bean syndrome, is a rare vascular phakomatosis characterized by multiple benign vascular malformations of the skin and

a

b Fig. 17.3a, b. Hereditary hemorrhagic telangiectasia. a Eversion of the lower lid discloses multiple small conjunctival telangiectasia. b Lateral internal carotid angiography demonstrates multiple small vascular malformations arising from distal middle cerebral artery branches (arrows).

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Fig. 17.4a–c. Hereditary hemorrhagic telangiectasia. a Gdenhanced axial T1-weighted image shows large brain abscess. b Gd-enhanced sagittal T1-weighted image shows additional enhancing focus in the medial surface of left frontal lobe (arrowhead). c Selective catheter angiography of left internal carotid artery shows arteriovenous malformation fed by the callosomarginal artery, corresponding to the enhancing focus shown by MRI. (Case courtesy of Dr. P. Tortori-Donati, Genoa, Italy)

b

intestines, with consequent gastrointestinal hemorrhage and anemia. Other organ systems, such as the CNS and the musculoskeletal system, are affected less commonly. BRBNS is rare, with approximately 200 cases reported in the literature to date. Both genders are affected equally [36, 37]. All races are affected [36, 37], but BRBNS has been reported less often in blacks [36, 38]. BRBNS most commonly presents sporadically [39–41]. A minority of pedigrees suggest possible autosomal dominant inheritance [39, 42–45]. Pathogenesis and molecular biology are not yet known. 17.2.4.1 Clinical Findings

The syndrome may manifest the characteristic skin lesions at or within a few years of birth. Most cases are diagnosed by age 20 years [46]. Occasionally, these patients are first recognized in late adulthood [47]. The natural history and overall prognosis of BRBNS are unknown. However, systemic complications

begin to appear after the age of 10–20 years [48], and sudden massive gastrointestinal hemorrhage remains the most frequent cause of death [37]. The characteristic skin lesions (Fig. 17.5) are multiple blister-like, blue-violet, soft, rubbery, compressible intracutaneous and subcutaneous vascular malformations that have been likened to the rubber nipple of a baby bottle. They tend to occur on the trunk, perineum, and upper extremities [36], and often involve the palms of the hands and the soles of the feet. The nevi of BRBNS do not affect the nail beds, however, distinguishing them from the telangiectasias of HHT [49]. The blue rubber bleb nevi vary in size from 0.1 to 10 cm, vary in number from one to several hundred, and typically increase in size and number with age [48, 50]. BRBNS may affect the brain, spinal cord, or orbital contents [46]. Clinical features vary in severity from focal deficits, such as extremity weakness [51], ataxia, blurred vision, ophthalmoplegia [52], and intermittent proptosis [53], to gradual [54] or acute [55] paraparesis, seizures [51], coma, and death [52].

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a b

c

d

f

e Fig. 17.5a–h. Blue rubber bleb nevus syndrome. a–c General manifestations; d, e Neuropathologic findings; f–h Imaging findings. General manifestations include engorged conjunctival vessels (a), bluish discoloration of the finger consistent with a subungual blue rubber bleb nevus (b), and multiple plantar nevi (c). d Axial section through the cerebellum shows dilated parenchymal vessels. e Section through the right parietal-occipital lobes shows multiple small and large thrombosed malformations on the cerebral surface and within sulci, and dilated vessels within the parenchyma. f Time of flight MR angiography, coronal MIP reconstruction demonstrates small vascular anomalies intracranially. g Sagittal T1weighted image and h Gd-enhanced coronal T1-weighted image centered on the suprasellar region show a hyperintense, enhancing lesion consistent with a cavernous malformation at the optic chiasm. (a–e, reproduced from ref. #46, with permission; g, h case courtesy Dr. S. Blaser, Toronto, Canada)

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Orthopedic complications are frequent in BRNS. Local effects include bone and limb hypertrophy due to hypervascularity, and bone deformity and fractures due to adjacent or intraosseous hemangiomas [36, 56]. 17.2.4.2 Pathological Findings

Pathologically, the blue rubber bleb nevi show irregular dilated blood-filled spaces lined with cuboidal or flat endothelial cells, and surrounded by fibrous stroma, typical of cavernous hemangiomas [48, 50]. The reported histologies of the vascular lesions seen in the BRBNS range from cavernous and venous hemangiomas to capillary telangiectasias and AVMs [57]. Small thrombosed vascular malformations of the cerebral surface and sulci, adjacent areas of cortical infarction, and dilated cerebral vessels may also be found (Fig. 17.5) [46, 58]. CNS lesions may include large intraparenchymal hemangiomas [52, 59], DVAs (see Chap. 9), and neurovascular anomalies such as aberrant venous sinuses [51], and vein of Galen/straight sinus dilatation [60]. Vertebral hemangiomas may extend into the spinal canal [54] to cause epidural hemorrhage [55]. Nerve root and leptomeningeal lesions also occur [61]. Orbital abnormalities include vascular lesions of the conjunctiva, iris, macula [62], retina [63], intraconic space, and the orbital apex [64]. 17.2.4.3 Imaging Studies

Imaging studies may display calcification within the caudate nucleus and posterior fossa. Flow voids and areas of moderate to marked contrast enhancement within the cerebellum, caudate nucleus, and cerebral cortex indicate angiomas of diverse size. These correlate angiographically with vascular malformations, but are not true AVMs, since they show no definite arteriovenous shunting (Fig. 17.5) [52]. In patients with BRBNS, MRI and MR angiography also display anomalous venous sinuses, thromboses of sinuses, and adjacent cerebral atrophy [51], presumably related to altered f low dynamics. One case of concurrent thrombosed vein of Galen malformation has been identified successfully by CT [58]. The vertebral bodies may show stippled “honeycomb” lesions characteristic of hemangioma and any associated epidural hemangioma within the spinal canal, as well as any concurrent epidural hematoma or spinal block [59, 65].

Contrast-enhancing lobulated intraconal orbital lesions consistent with hemangiomas are demonstrable by CT. Larger lesions of similar nature may be seen within the soft tissues of the neck, in association with partial thromboses and hyperdense phleboliths.

17.2.5 PHACE Syndrome The acronym PHACE describes a phakomatosis encompassing the features of Posterior fossa malformations, large facial Hemangiomas, Arterial anomalies, Coarctation of the aorta and cardiac defects, and Eye abnormalities [66]. When ventral developmental defects including clefts of the sternum and supraumbilical raphe are also present, the syndrome may be termed PHACES syndrome [66, 67]. In practice, PHACE syndrome represents a spectrum of anomalies, because most affected patients display only one extracutaneous manifestation [67]. PHACE syndrome is rare, with fewer than 150 cases reported [67]. The facial hemangioma generally presents at birth, or in the early postnatal period. The interval between birth and correct diagnosis of PHACE syndrome varies with the type and severity of the associated abnormalities. Cardiac anomalies may present on ultrasound prenatally or perinatally. Neurological sequelae may present only after several years. Approximately 90% of PHACE patients are female [66, 67]. The pathogenesis of PHACE syndrome is unknown. The condition may represent a spectrum of variably severe malformations caused by a common morphogenetic event in utero. The concurrent features suggest that such an error might be expressed between 6 and 8 weeks of gestation, possibly in relation to the ontogeny of the cerebral vasculature [68]. The known embryologic connections between the trigeminal nerve and cerebellum during the second month of gestation suggest similar timing [69]. The paralogous HOX genes, A1 and B1, that help to regulate hindbrain development, and the Eph (erythropoietin producing human hepatocellular carcinoma line) genes, proteins and receptors that are important in neurologic development, may also be implicated in the PHACE syndrome. The receptors related to Eph constitute the largest subfamily of receptor protein tyrosine kinases, and are heavily involved in the cell–cell interactions that help to pattern the nervous system.

The Rare Phakomatoses

17.2.5.1 Clinical Findings

The hallmark of PHACE syndrome is a large “plaquelike” facial hemangioma, often ulcerated (Fig. 17.6). These hemangiomas tend to involve one trigeminal nerve division predominantly, but are not strictly dermatomal in distribution. The V1 division is involved most commonly (75% of cases) [67]. About 25% of cases are bilateral [67]. Clefting of the sternum and/or the supraumbilical raphe is seen most often in PHACE patients with hemangiomas in the V3 distribution [67]. One third of PHACE patients show cutaneous hemangiomas in areas other than the head and neck. Extracutaneous hemangiomas also occur at diverse sites. Patients with cutaneous lesions involving the mandibular region have a particularly high risk of subglottic hemangiomatous lesions [66, 67]. Among PHACE patients with intracerebral anomalies (see below), approximately 90% eventually manifest neurologic sequelae, ranging from migraine headaches to seizures, developmental delay, mental retardation, and hemiparesis [67]. Arterial anomalies of the head and neck (Fig. 17.6) occur in at least one third of patients, especially arterial stenoses or occlusions, aneurysms, and anomalous branches of the internal carotid artery (i.e., persistent trigeminal artery) [67, 68, 70]. Proximal occlusions of the cerebral arteries with dilated basal collateral vessels (moyamoya) [70] reflect the potential for progressive neurovascular disease. Absence or hypoplasia of carotid and vertebral arteries [66, 68], intracranial AVMs [71],

a

b

and possibly intracranial cavernous hemangiomas [72] also occur. Frontal lobe calcifications, microcephaly, absent foramen lacerum, and transverse sinus thrombosis have been reported in the PHACE syndrome. Cardiac and aortic abnormalities are seen in more than one third of cases. Aortic coarctation is the most common defect. Aberrant vessel origins, aneurysms, and hypoplasias also occur. The most common cardiac anomalies are persistent ductus arteriosus, ventriculo-septal defects, arterial septal defects, and pulmonary stenosis [67]. A broad range of ophthalmologic abnormalities, including microphthalmos and anterior segment ocular defects, are found in about 20% [67] to 33% [69] of cases. These abnormalities tend to be ipsilateral to the facial hemangioma. Ventral developmental defects, including clefting of the sternum and the supraumbilical raphe occur in 20% or less of patients [66, 67], usually in association with a hemangioma in the V3 distribution. Other possible associations include congenital hypothyroidism [70], ectopic lingual thyroid [66], and auricular anomalies [67]. 17.2.5.2 Imaging Studies

The key neuroimaging findings of PHACE syndrome are the anomalies of the posterior fossa and neurovasculature. Dandy-Walker malformation is the most common finding (approximately one third of cases) [71, 73–75]. Less common CNS abnormalities reported include hypoplasia or agenesis of the cerebellum, vermis [71], and corpus callosum [67],

c

Fig. 17.6a–c. PHACE syndrome. a Cutaneous manifestations; b, c Catheter angiography. a This infant shows a large facial hemangioma that involves the territory of the second division of the left trigeminal nerve, predominantly. b Left subclavian angiogram shows aneurysms and stenoses of the thyrocervical artery. c Left internal carotid angiogram demonstrates fusiform aneurysmal dilatations and stenoses of the left internal carotid artery.

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Fig. 17.7a–d. PHACE syndrome. a, b Baseline MRI and c, d MR angiography of the head. a Axial T2-weighted image and b coronal STIR image show hypertrophy of the right flocculus (arrows, a) and extensive cerebellar cortical dysplasia involving homolateral cerebellar hemisphere (arrows, b). Notice large basilar trunk (arrowhead, b). c Axial partition and d Coronal MIP reconstruction from 3D TOF MR angiography show severe abnormality of the circle of Willis. There is agenesis of both internal carotid arteries, with the whole intracranial circulation supplied by the basilar trunk (arrowheads, d). CT (not shown) confirmed absence of both carotid canals in the petrous bones. (Case courtesy of Dr. A. Rossi, Genoa, Italy)

abnormalities of the septum pellucidum [67], and intracranial arachnoid cysts [75]. Cerebellar cortical dysgenesis has been reported in one case (Fig. 17.7) [68]. Ipsilateral microphthalmos, optic atrophy, and exophthalmos may also be identified in PHACE patients [68, 69]. MR angiography and catheter angiography may document neurovascular anomalies (including absence or hypoplasia of the internal carotid, external carotid, posterior cerebral, and posterior inferior cerebellar arteries) (Fig. 17.7), aneurysms, and moyamoya. Anomalies of the aortic arch and great vessels are also common. Thus, all patients with facial hemangiomas should undergo (1) brain imaging with particular attention to the posterior fossa, and (2) neurovascular imaging from the aortic arch and great vessels to the circle of Willis and its major branches.

17.2.5.3 Differential Diagnosis

PHACE syndrome may be distinguished from the Sturge-Weber syndrome because the cutaneous facial lesions differ, and because the Sturge-Weber syndrome is characterized by leptomeningeal vascular malformations and subjacent cortical calcifications, with progressive underlying brain atrophy. Furthermore, the posterior fossa, neurovascular, and ophthalmologic anomalies of PHACE syndrome are not typically part of the Sturge-Weber syndrome [66].

17.2.6 Meningioangiomatosis Meningioangiomatosis is described in Chap. 10.

The Rare Phakomatoses

17.3 Melanophakomatoses The melanophakomatoses are subdivided into hypomelanoses and hypermelanoses. The hypomelanoses include hypomelanosis of Ito (incontinentia pigmenti achromians), Bloch-Sulzberger syndrome (incontinentia pigmenti), and Waardenburg syndrome. The hypermelanoses include neurocutaneous melanosis, nevus of Ota, McCune-Albright syndrome, and Nelson syndrome.

17.3.1 Hypomelanosis of Ito Hypomelanosis of Ito (HI), also named incontinentia pigmenti achromians and pigmentary mosaicism of Ito type, is a neurocutaneous syndrome characterized by cutaneous hypopigmentation in a distinctive pattern of streaks, whorls, and patches along the lines of Blaschko (Fig. 17.8), associated with CNS features primarily of seizures and mental retardation, musculoskeletal abnormalities, and less common cardiac and genitourinary anomalies. Initially considered to be rare [76], HI is actually the third or fourth [77] most frequent neuroectodermal disease after neurofibromatosis type 1, tuberous sclerosis, and Sturge-

Fig. 17.8. The lines of Blaschko. The lines of Blaschko form characteristic bilateral, symmetrical patterns characterized by swirling whorls on the anterior surface of the chest, a prominent, deep, inferiorly-directed “V” in the midline of the back, and longitudinal extensions parallel to the extremities.

Weber syndrome. The incidence/prevalence rates are estimated variably as 1 per 10,000 new patients in a hospital population, as 1 per 1,000 patients in a pediatric neurology service, and as 1 per 8,000 births (and 1 per 82,000 individuals in the general population) [78]. The mode of inheritance of HI has been reported to be autosomal recessive, autosomal dominant, and X-linked, but no precise mechanism has been proven. At present, HI may best be regarded as a phenotype of chromosomal mosaicism, rather than as a single condition [78]. The recognition that chromosomal mosaicism is the pathogenetic basis of many cases of HI helps to explain the protean clinical manifestations of HI and their often asymmetric expression. 17.3.1.1 Clinical Findings

The skin lesions of HI (Fig. 17.9) are detected in the neonatal period in about 50% of patients, and in the first few months of life in 80% [78]. However, skin lesions may remain unrecognized until other symptoms appear, or until the child is exposed to the sun [78], particularly in fair-skinned individuals [79]. They manifest as hypopigmented lines that form a variable pattern of whorls, patches, zigzag- and S-shaped markings over the abdomen, and V-shaped markings over the midline of the back [78]. This pattern conforms to the lines of Blaschko [79]. The lesions are sharply demarcated, appear to increase in hyper- or hypopigmentation in childhood or adolescence, and then decrease in prominence later in life [78, 79]. They may be unilateral or bilateral. If unilateral, they typically respect the anterior and posterior midlines. The palms, soles, and mucous membranes are usually spared [78]. Other ectodermal findings include café-au-lait spots, angiomatous nevi, nevus of Ota, mongolian blue spots, alopecia, variations in hair color and texture, and dental abnormalities. The significance of cutaneous findings is uncertain [78]. There is no known correlation between the severity of skin involvement and the severity of the extracutaneous phenotype, particularly regarding the CNS [78, 79]. CNS pathology is reported in 40%–90% of cases. Mental retardation and/or developmental delay of variable severity are seen in 50%–60% of cases. An additional 10% show autistic features. Seizures are reported in 10%–50% of cases, and usually manifest as tonic-clonic, partial, or myoclonic seizures, or as infantile spasms. They usually appear within the first year of life, and are often refractory to treatment. Other reported findings include microcephaly, macrocephaly, facial and orbital asymmetry [79],

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Fig. 17.9a–f. Hypomelanosis of Ito. a, b External findings; c, d Neuropathologic findings; e–g Imaging findings. a Photograph of the back shows a whorled, curvilinear depigmented lesion of the skin conforming in pattern to the lines of Blaschko. b In another patient, there is characteristic anterior thoracic swirling pattern. In patients with darker skin coloration, the whorling hypomelanotic lesions are more conspicuous. c, d Gross morphology. Hematoxylin and eosin/ luxol fast blue stains of two specimens of cerebral cortex. Compare normal cortex (c) with abnormal cortex from a patient with hypomelanosis of Ito (d), showing variable thickness of the cortex, fused gyri, indistinct gray/white matter junction, and gray matter heterotopia (arrowhead, d) within the white matter. e Axial CT scan; f Axial T2-weighted image; g Sagittal T1-weighted image. Asymmetric calvarial volume, asymmetric volumes of the two occipital horns, and abnormally increased signal in the right parietooccipital lobes are shown. The corpus callosum is small, especially posteriorly (arrowheads, g). (a, b reprinted from ref. #79, with permission)

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orbital hypertelorism, low-set ears, inner epicanthal folds [78], neurosensory deafness, nystagmus, ataxia, muscular hypertonia or hypotonia, hyperkinesia, and spinal muscular atrophy. Concurrent musculoskeletal abnormalities, including short stature and/or delayed skeletal maturation [78], scoliosis, limb length discrepancies [78, 79], hemihypertrophy, pes and genu valgus [78], and digital anomalies [78], are common. Dental abnormalities [78] and ocular abnormalities, such as strabismus, myopia, and fundal hypopigmentation are also common. Tumors have been reported in patients with

g

hypomelanosis of Ito, but no definite link to neoplasia has been proven [78]. Congenital cardiac and genitourinary anomalies are found in less than 10% of cases [78]. Breast asymmetry has also been reported. 17.3.1.2 Neuropathological Findings

Patients with hypomelanosis of Ito show disordered neuronal migration, cortical lamination and sulcation, with laminar or band gray matter heterotopias, poorly defined gray/white junctions, pachy-

The Rare Phakomatoses

gyria, polymicrogyria, and/or hemimegalencephaly (Fig. 17.9). Other findings include abnormal neurons and astrocytes, hypoplasia of the brainstem, cerebellum, and corpus callosum [78, 79], hypomyelination, demyelinated corticospinal tracts, dilated VirchowRobin spaces [77, 78], periventricular cystic lesions [77], and gliosis. 17.3.1.3 Imaging Studies

There are no constant imaging findings in HI. Approximately one fourth to one third of patients display normal neuroimaging studies [76], or only show enlarged perivascular spaces. In the remainder, abnormalities may be grouped into white matter alterations and structural malformations. More than 50% of HI patients have MRI-demonstrable white matter abnormalities, thought to be pathologically related to dilated Virchow-Robin spaces and/or altered/delayed myelination [78]. These abnormalities appear as early as at a few months of age [78]. T2-weighted and FLAIR images show multifocal, symmetric high signal foci in the periventricular and subcortical white matter, particularly in the centrum semiovale [78]. CT shows these same features as multiple low density areas in the deep white matter of the hemisphere, or as a diffuse low density in the white matter (when large numbers of lesions are present). White matter lesions are static over time, and show no correlation between the extent of the lesions and patient age [77]. Neuroimaging reveals a broad range of structural brain anomalies (Fig. 17.9) in approximately 50% of HI patients, including hemispheric asymmetry (hemiatrophy and particularly hemimegalencephaly), dysplasia/hypoplasia of cerebellum and corpus callosum, gray matter heterotopia, blurred gray/white junctions, agyria, polymicrogyria, porencephaly, and periventricular cysts [77–79]. Neurovascular abnormalities including moyamoya [77, 78] and AVMs [78] have occasionally been identified in patients with HI.

17.3.2 Incontinentia Pigmenti Incontinentia pigmenti (IP), also named linear sebaceous nevus syndrome, melanosis cori degenerative, melanosis cutis linearis, or Bloch-Sulzberger syndrome, is a rare X-linked dominant genodermatosis affecting organs and tissues of ectodermal and mesodermal origin. It is characterized by swirled patterns of skin hyperpigmentation associated with

dental, nail, CNS, ocular, and skeletal abnormalities [80–82]. IP is rare, with an overall incidence quoted as one per 40,000 girls. The female-to-male ratio ranges from 37:1 [81] to 99:1 [80]. Although IP was initially considered to be lethal for males in utero, it does rarely occur in males, several of whom have been shown to have Klinefelter syndrome (47 XXY). IP affects Caucasians more than other ethnic groups [80]. Familial IP is caused by mutations in the NEMO gene (Xq28), and is here referred to as IP2, or “classical” IP. Sporadic IP, the so-called IP1, which maps to Xp11, is categorized as hypomelanosis of Ito (see above). The NEMO (NF-kappaβ essential modulator) gene encodes a critical regulatory component required for the activation of the NF-kappaβ signaling pathway, which plays a crucial role in inflammatory responses, cell proliferation, and apoptosis. 17.3.2.1 Clinical Findings

IP may present at birth with skin lesions (Fig. 17.10). These lesions assume their characteristic appearance from 3 to 24 months of age, and often disappear completely in the third decade of life [80]. Skin changes are present in 100% of IP patients. These appear to evolve through multiple stages: (1) initial changes, usually seen at birth, consist of skin erythema, watery vesicles, and pustules often in a linear distribution on the limbs; (2) within the first 3 months of life, linear verrucous clusters of papulonodules and areas of hyperpigmentation appear; (3) between 3 and 24 months, nearly pathognomonic gray/brown swirl-like zones of hyperpigmentation appear on the trunk, along the lines of Blaschko [83, 84]; and (4) from infancy to young adulthood, skin lesions show atrophic scarring and gradual resolution of skin hyperpigmentation, followed by skin pallor [80, 85–87]. Histologically, there is dislocation of melanin from the basal layer of the epidermis, which consequently becomes “incontinent” of pigment, giving the syndrome its name [88]. Other dermatologic changes include focal or generalized alopecia (70%) and onychodystrophy (60%) [80]. Approximately 40%–50% [80, 81] of IP patients have neurological abnormalities, most commonly mental retardation, spasticity, and microcephaly. Up to 13% show seizures, and structural abnormalities of the brain (see below). Ocular abnormalities are present in 35% [80] to 77% [89] of IP patients. Retinal pigment epitheliopathy is common in IP (35%), and may be pathogno-

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monic. Other ocular changes include arteriovenous anastomoses, peripheral regions of low perfusion, diverse abnormalities of the retinal vasculature [80], strabismus, optic nerve atrophy [86], and microphthalmia [81]. Fewer than 10% of cases with retinal epitheliopathy progress to exudative retinal detachment [80, 89]. Dental anomalies are seen in over 50% [86] of IP patients, and include anodontia, hypodontia, microdontia, delayed eruption of teeth, and malformations of the dental crown described as peg-shaped teeth [86]. Skeletal abnormalities include hip dysplasia and underdevelopment of one half of the body. Congenital cardiovascular anomalies are occasionally encountered [90]. Notably, IP shows a large clinical variability even within families [91]. 17.3.2.2 Imaging Studies

17.3.3 Waardenburg Syndrome

IP patients who are neurologically normal have normal neuroimaging studies. In the remainder, MRI displays both developmental and acquired lesions of the CNS, including hemimegalencephaly (Fig. 17.10), hypoplasia of the corpus callosum, gray matter heterotopia, gray matter thickening, polymicrogyria, focal neuronal necrosis, hemorrhagic necrosis, periventricular and subcortical white matter lesions which may be transient [92], and cerebral atrophy [81]. Neonates and infants may show foci of T1 and T2 shortening in the periventricular white matter, par-

a

ticularly the watershed regions, and sometimes show progressive white matter atrophy with an appearance similar to end-stage periventricular leukomalacia. The corpus callosum may also be thinned, presumably from damage to cortical neurons and their commissural transcallosal axons. Vascular occlusive phenomena may be similar to those seen in the retinae of IP patients; indeed, retinal changes may serve as a marker for CNS disease [88]. Radiologic studies of the ocular globes may show microphthalmia, evidence of retinal detachment, and hemorrhage. Dental imaging reveals a wide range of abnormalities in greater than 50% of those scanned, including anodontia, hypodontia, delayed eruption of teeth, impactions, and malformations of the crown leading to peg-shaped teeth [86].

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Waardenburg syndrome (WS) comprises four overlapping melanophakomatoses, designated WS types 1–4 [93]. WS 1 is characterized by widened distance between the inner canthi (telecanthus, dystopia canthorum) and variable associated findings of abnormal nasal root shape, abnormal eyebrows, hypopigmentation of neural crest derivatives (iris and head hair), and inner ear anomalies with sensorineural hearing loss [94]. WS 1 is an autosomal dominant trait, occurring

c

Fig. 17.10a–c. Incontinentia pigmenti: external findings. a, b External findings; c Imaging findings. Neonate with vesicular eruptions in a linear distribution that conforms to the lines of Blaschko along the trunk (a) and the limbs (b). c Axial T2-weighted image. There is left hemimegalencephaly with distortion of cortical thickness and lamination, and alteration in the signal of the white matter.

The Rare Phakomatoses

in approximately 1 per 35,000 individuals [95], characterized by both phenotypic and genotypic diversity [96]. The defect in WS 1 localizes to the PAX3 gene on the long arm of chromosome 2 (2q35–q37.3) [96, 97]. The human PAX3 gene plays a central role in neural development, and is expressed in developing somites, dorsal spinal cord, mesencephalon, and neural crest derivatives. Its role probably varies in different tissues, but does relate to cell surface properties in the neural tube and the somites [98]. PAX3 is also required for normal formation of the enteric ganglia. WS 2 resembles WS 1 almost completely, except that WS 2 patients do not show dystopia canthorum. However, WS 2 patients show no PAX3 linkage. The affected gene is microphthalmia (MITF), located on the short arm of chromosome 3 (3p). It is a “master gene” [99] in the development and subsequent function of melanocytes derived from neural crest. WS 2 is less common than WS1. WS 3, also named Klein-Waardenburg syndrome, is a severe variant of WS 1 with concurrent upper extremity/pectoral girdle involvement. WS 3 patients also exhibit mutations in the PAX3 gene [97]. WS 4, also called Waardenburg-Shah syndrome, is a variant of WS 1 with concurrent Hirschsprung’s disease, inherited as an autosomal recessive trait. Most cases of WS 4 result from mutations in the genes encoding: (1) the endothelin type B receptor (EDNRB) at chromosome 13q22 [100]; (2) its physiologic ligand endothelin 3 (EDN3); and (3) the transcription factor SOX 10 [101], which acts as a critical transactivator of tyrosinase-related protein-2 during melanoblast development and of MITF (microphthalmia transcription factor: see above) [99]. Both WS 3 and 4 are very uncommon [94]. 17.3.3.1 Clinical Findings

The diagnosis of WS is usually made by associating sensorineural hearing loss with hypomelanotic features, such as impaired pigmentation of the eyes or hair. Inner ear malformations are found in 25% [102, 103] to 67% [95] of patients with WS 1, and in 50% of patients with WS 2. WS 1 is the most common cause of congenital inherited sensorineural deafness [96], and accounts for 0.9%–3% of congenital deafness in institutionalized patients [95]. A significant minority (approximately 3%) of deaf children have WS [104]. Audiologic testing shows great variability in the laterality and severity of hearing impairment associated with WS [105]. Overall, approximately 80% suffer some degree of hearing loss [106], two thirds bilateral

and one third unilateral [95, 106]. Numerous abnormalities of the membranous labyrinth have been found, including absent organ of Corti, stria vascularis and spiral ganglia atrophy, collapse of Reissner’s membrane [95, 102, 107–109], and atrophy of all sensory epithelia of the inner ear [105, 110]. Ossicular hypoplasia has also been reported [95]. Patients may experience primarily vestibular symptoms without hearing loss [111]. Pigmentary changes (Fig. 17.11) manifest as vitiliginous skin patches in 55% of affected patients. Tufts of hair may be similarly affected, causing hypopigmented or depigmented patches of hair in the midline (i.e., the white forelock) (29%) [95]. These may be detected at birth, but continue into adulthood. Premature graying of facial and scalp hair is seen in 44% of patients, particularly in the midline. All four types of WS show pigmentary changes of the eyes (Fig. 17.11). In the iris, pigmentary deficiency leads to a blue “color.” If one iris is affected, the two eyes show different coloration (one blue), termed heterochromia iridis. If both irides lack pigment, both display a deep sapphire blue similar in “color” to the wings of the morpho butterflies, termed iris bicolor. WS 1 has a definite, inconstant relationship to myelomeningocele [112]. WS 1 is now a major “cause” of myelomeningocele, since treatment of women with folate has eliminated the vast majority of the myelomeningoceles formerly caused by folate deficiency [113, 114]. WS 3 appears to be a more severe variant of WS 1, with the additional features of upper extremity/pectoral girdle involvement. Additional abnormalities include muscle and bone hypoplasia, flexion contractures of the digits, and syndactyly or syncarpalism [95, 115–117]. Most, if not all, of these additional features are found in Poland’s syndrome [118]. Poland’s syndrome has also been described in association with other CNS/head and neck abnormalities, such as Moebius syndrome [119], mandibular deformity [120], cranio-fronto-nasal dysplasia[121], myelomeningocele [122], primary microcephaly [123], neurofibromatosis type 1 [124], coloboma of the optic disc [125], and facio-auriculo-vertebral dysplasia [126]. 17.3.3.2 Imaging Studies

Approximately half of those with audiological impairment have radiographically demonstrable abnormalities of the inner ear [127], whereas the other half do not [128]. Notably, however, abnormalities of the membranous labyrinth have been shown to exist in the absence of radiographic anomalies, including

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Fig. 17.11a–e. Waardenburg syndrome. a–d External features; e Imaging findings. a Young child with the characteristic focal hypopigmentation of the hair designated ”white forelock.” b Adolescent girl with heterochromia irides (right eye blue) and characteristic nasal tip. c Young child with bilateral hypoisochromia and characteristic “morpho butterfly blue” coloration of the irides. d Depigmented skin patches on the legs of a child. e Serial axial CT sections of the petrous pyramids in a 4-year-old boy show a slightly hypoplastic superior semicircular canal (black arrows), short stubby lateral semicircular canals (arrowhead), absent common crus and posterior semicircular canal, bulbous cystic vestibule (open black arrow), dysplastic cochlea containing implant, and obliteration of the oval window. (Reprinted from ref. #94, with permission)

The Rare Phakomatoses

absence of the organ of Corti, stria vascularis, and spiral ganglion. Overall, 17% display anomalies of the inner ear (Fig. 17.11) [129]. Approximately 25%–50% of those with radiologic findings have absent posterior semicircular canals, with or without concurrent dysplasia of the superior and lateral semicircular canals [127]. Abnormality of the lateral semicircular canal is more common, but far less specific, than absence of the posterior canal. Hence, absence of the posterior semicircular canals is suggestive of WS [127]. Other imaging abnormalities identified include a bulbous vestibule, and obliteration of the oval window [94]. Malformations of the internal acoustic canal are seen in 11% [129]. Cochlear hypoplasia is relatively uncommon (8%); therefore, many WS patients are suitable candidates for cochlear implantation [129].

17.3.4 Neurocutaneous Melanosis Neurocutaneous melanosis (NCM), or Touraine syndrome, is a rare sporadic neuroectodermal dysplasia, defined by large or multiple congenital cutaneous nevi in association with meningeal melanosis or melanoma [130, 131]. By definition: (1) large means >20 cm in an adult, >9 cm on the infant scalp, or >6 cm on the infant body; (2) multiple means greater than or equal to 3; (3) there must be no evidence of cutaneous malignant melanoma except when examined meningeal lesions are histologically benign [132]; and (4) there must be no evidence of malignant CNS melanoma, except where examined areas of the cutaneous lesions are histologically benign [133–135]. NCM is rare, with about 100 cases reported in the literature [135, 136]. Giant congenital melanocytic nevi (GCMN) occur in approximately 1 per 20,000 live births [137]. The percentage with cerebral melanosis is unknown. NCM appears to be more frequent in Caucasian populations [134, 138], but no population-based studies exist to document this. No genetic predisposition to NCM has been identified [134, 135, 138]. The pathogenesis is unknown. 17.3.4.1 Clinical Findings

By definition, all patients with NCM are born with congenital melanocytic nevi (Fig. 17.12). Approximately two thirds of the nevi are giant nevi, and one third numerous nevi without a predominant lesion [134]. All patients with NCM show satellite nevi [139]. There is a complex relationship between GCMN, NCM, and malignancy, depending in part on the

location of the giant nevi. Of patients with GCMN, approximately two thirds display a ”bathing trunk” nevus in the lumbosacral region, one-third a “capelike” nevus in the occipital area-upper back, and the remaining few nevi on the anterior trunk [134]. In more than two thirds of giant nevi, the main portion of the nevus spares the scalp and neck, though most of these patients have smaller lesions on the scalp, face, and neck [134]. Overall, the cumulative lifetime risk for malignant transformation of GCMN is about 12% [140]. The specific risk of NCM is unknown [141]. It must be noted that the amount of melanin in the GCMN and the black coloration may diminish markedly during the first months of life, or disappear completely [141]. Patients with NCM typically present with neurological manifestations early in life (median age 2 years) [142]. Occasional patients do not present until the second decade [134] or later [138, 143]. Ninety-two percent have died by the time of reporting [144]. The most frequent neurological problem is hydrocephalus (present in at least two thirds of patients) [145]. Patients who present near puberty may show signs and symptoms of focal intracranial masses and psychiatric disturbance, in addition to those of increased intracranial pressure [134, 137, 145]. Myelopathy may result from invasion of the cord by malignant leptomeningeal cells or from cord compression secondary to either melanotic masses or CSF collections resulting from nonbacterial melanotic arachnoiditis [142]. Even in the absence of malignant melanoma, symptomatic NCM has an extremely poor prognosis, with progressive deterioration and early death (median 3 years) [144] in the vast majority of patients. Since the interval between initial presentation and death ranges from a few days to 20 years, a small minority of patients may have a good medium term prognosis [142]. NCM has been found in association with other conditions, including Dandy-Walker malformations [137, 146–150], intraspinal melanotic arachnoid cysts and lipomas [151], intraspinal lipoma alone [152], and syringomyelia [142, 153]. Rarer associations include multiple hemispheric pial telangiectasias, coexistent Sturge-Weber syndrome [134, 135, 152], neurofibromatosis type 1 [135], subdural and intraparenchymal hemorrhages [153], and chronic psychosis [154]. 17.3.4.2 Neuropathological Findings

The characteristic CNS feature of NCM is an overpopulation of benign melanocytic cells in the leptomeninges, designated “melanosis” (Fig. 17.12) [137].

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Fig. 17.12a–g. Neurocutaneous melanosis. a, b Skin manifestations; c, d Neuropathologic findings; e–g Imaging findings. Infants with a “cape-like” (a) and “bathing-trunk” (b) giant melanocytic nevi. Postmortem specimens show gross pigmentation of meninges of the brain (c) and spine (d). e Sagittal T1-weighted image; f Axial T1-weighted image; g Coronal T1-weighted image. Marked signal elevation caused by melanin deposition in the pons (thick arrow, e), vermis (thin white arrows, e, f), and amygdala (black arrows, f, g).

This melanosis may be nodular or diffuse. Melanosis is particularly frequent in areas that normally have melanotic cells, such as the temporal lobes, amygdala [155], brainstem and cerebellar folia [137], cerebral convexities, basal pia-arachnoid [156], upper cervical spinal cord, and lumbosacral spinal canal [134, 135]. Therefore, it is the extent of melanocytic infiltration that is pathological, not its distribution [134]. In NCM, the leptomeninges may be moderately to markedly thickened with intense brown pigmentation. Parenchymal melanin deposits most frequently represent perivascular infiltrates of melanocytes within the Virchow-Robin spaces, especially of the amygdala [134, 135, 153], and not malignant infiltration. Melanin-laden macrophages, designated “melanophores,” may also contribute to the parenchymal pigmentation observed in the amygdala, basal ganglia, thalamus, pons, cerebellum, and dentate nuclei [142]. In two thirds of patients with NCM, there is

communicating hydrocephalus due to melanocytic cell accumulation at the basal subarachnoid cisterns. In the remaining third, hydrocephalus is noncommunicating due to aqueductal stenosis or outlet fourthventricular obstruction [134, 142]. Furthermore, it has been proposed that the Dandy-Walker malformation seen in association with NCM may be acquired, following obstruction to the exit foramina by leptomeningeal melanosis late in fetal life [155]. Histopathologically, melanotic cells of NCM show marked pleomorphism, may occur in nests and nodules, and extend into the parenchyma by infiltrating the Virchow-Robin spaces [137]. Thus, differentiation from true melanoma may be difficult. Pathological features helpful for diagnosing true melanoma include necrosis and hemorrhage, invasion of the basal laminae of blood vessels, cellular atypia, frequent mitoses [134], and nodular invasion of the parenchyma with destruction of the underlying brain [137]. Up

The Rare Phakomatoses

to half the cases of NCM ultimately develop primary malignant CNS melanoma [136]. Early distinction of NCM from melanoma has uncertain utility, since the prognosis of symptomatic NCM is almost universally poor, irrespective of the presence or absence of malignancy [134, 137]. 17.3.4.3 Imaging Studies

MRI shows signal abnormalities on both T1- and T2weighted images. Melanin deposits appear as zones of increased signal on T1-weighted images (Fig. 17.12) [135, 157, 158] and low signal on T2-weighted images [159]. Stable free radicals [142], such as the paramagnetic semiquinones and semiquinonimines within the melanin, cause T1 and T2 shortening, and are the likely source of signal alterations. However, the intensity of the signal change depends upon the number and maturation of the melanocytes [160]. Therefore, (1) NCM patients with amelanotic melanocytomas and amelanotic melanomas, or with amelanotic melanocytosis, may show no signal alteration [160]; and (2) patients with immature lesions may show no abnormal hyperintensity on T1-weighted series, despite marked leptomeningeal melanotic infiltration [160]. As a further complication, unusually high concentrations of paramagnetic species may exaggerate the T2 effect, thereby “paradoxically” diminishing T1 signal intensity. For the same reason, patients with marked melanin deposits who receive Gd-chelates for contrast enhancement may display paradoxical diminution of T1 signal intensity. Lastly, hemorrhage within melanomas adds to the intrinsic complexity due to the confounding effects of diverse hemoglobin breakdown products. T2-weighted images display the normal distribution of leptomeningeal melanin as zones of low signal intensity, especially along the ventral medulla oblongata [159]. In NCM, the leptomeninges show diffuse pigmented thickening that is especially marked along the base of brain and around the brainstem [161, 162]. The leptomeninges typically show intense contrast enhancement along the basal cisterns, tentorium, brainstem, inferior vermis, and the folia of the cerebellar hemispheres. Less frequently, enhancement is most prominent over the cerebral convexities and quadrigeminal plate cistern, and there is subtle enhancement at the cisterna magna, optic chiasm, inferior vermian cistern, and spinal cord surface [160]. Thus far, no MRI criteria have distinguished successfully between benign leptomeningeal melanosis and malignant melanoma [160]. Nevertheless, features more nearly suggestive of malignancy include focal nodular or plaque-like meningeal contrast

enhancement, growth of pre-existing lesions [142], and presence of edema around, or necrosis within, the melanotic deposits [135, 142]. Nonetheless, all of these features may still be absent in a true malignant melanoma [135]. Furthermore, prominent leptomeningeal enhancement also occurs with meningeal inflammations, such as tuberculosis, fungal infections, and sarcoid, and with tumors, such as leptomeningeal lymphoma, leptomeningeal metastases from extracranial tumors, and leptomeningeal spread of a wide variety of primary brain tumors [160]. It has been suggested that repeated MRI studies be used in patients with GCMN at risk of NCM, but no specific interval periods have been suggested. This may assist in determining the actual risk of NCM in GCMN patients, as well as in delineating the variability of MRI findings in NCM according to age or brain development [133].

17.3.5 Nevus of Ota Nevus of Ota (NO), also named oculodermal melanocytosis and nevus fusca-caeruleus ophthalmomaxillaris, is a hypermelanotic melanocytic phakomatosis, characterized by an area of non-hairy, macular hyperpigmentation over the distribution of the first and second divisions of the trigeminal nerve, commonly associated with ocular and intracranial involvement. NO is most common in Asian populations, especially the Japanese [163], and is rare in Caucasians [164]. The age of presentation has a bimodal distribution, with one peak at birth-infancy and a second in adolescence [165]. The characteristic cutaneous pigmentation is noted at birth or perinatally in approximately 50% of patients. In the other 50%, the dermal pigmentation becomes evident later, most frequently at puberty [163]. Women are more commonly affected than men, in a ratio ranging from 5:1 to 7:3 [166]. No specific genetic defect has yet been identified. Hyperpigmentation is believed to result from maldevelopment and abnormal migration of neural crest cells, particularly melanocytes. 17.3.5.1 Clinical Findings

The nevus of Ota is a macular or slightly raised discoloration involving the skin and mucous membranes at the forehead, temple, or eyelids, in the distribution of the ophthalmic and maxillary divisions of the trigeminal nerve (Fig. 17.13). It is typically unilateral (95%)

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b Fig. 17.13a–d. Nevus of Ota. a External findings; b

a

Imaging findings; c, d Surgical findings. a Hyperpigmentation of the skin in the territory of the ophthalmic division of the right trigeminal nerve. b Axial T1-weighted image shows high signal at the tentorial margin along the inferomedial right temporal lobe (arrowheads), consistent with a focal pigmented lesion. c Operative exposure. The temporalis fascia, pericranium, and dura all show dense black pigmentation. d The resected lesion is a 3-cm, densely black tumor nodule attached to the resected cuff of melanotic dura. Histologically, the lesion was a meningeal melanocytoma. (Case courtesy of G. Leung, reprinted from ref. #163, with permission)

c

and infrequently bilateral (5%) [167, 168]. The nevus is described variably as brown, black, purple [169], blue/black, or slate gray [163]. The nevus may fluctuate in extent and coloration, but does not undergo spontaneous regression [165]. Associated pigmentation of the mucous membranes may manifest as melanosis of the palate, pharynx, nasal mucosa, or tympanum [169]. Approximately half the patients with NO show ocular involvement, with melanosis of the conjunctiva, iris, fundus choroid, sclera, and optic disk [163, 169]. This phenotype is nearly always unilateral [170], so this subset may be designated oculodermal melanocytosis [163]. NO may also be associated with intracranial melanosis, involving the skull, periosteum, dura, cerebral hemisphere, Meckel’s cave, pineal gland, and optic chiasm. Although NO is more prevalent in Asian populations, malignant transformation appears to be much more common in Caucasians [166]. Melanomas may develop within the cutaneous nevus itself, or at a separate site. Associated CNS melanomas involve

d

the meninges primarily [171], but may be intraparenchymal in a significant number of cases. Masslike melanotic tumors range from highly aggressive malignant melanomas [169] to diffuse melanosis and benign melanocytoma (Fig. 17.13) [163]. Very rarely, the melanoma is contralateral to the NO, possibly as a result of cerebrospinal fluid spread from leptomeningeal melanosis [169] or from an area of NO-associated bilateral leptomeningeal melanosis [172]. NO may be associated with spinocerebellar degeneration [173], Klippel-Trenaunay-Weber syndrome [174, 175], and Sturge-Weber syndrome [176–178]. Up to 10% of NO patients may also suffer glaucoma [179]. 17.3.5.2 Imaging Studies

The inherent paramagnetic effects of melanin shorten the T1 and T2 relaxation times in NO, causing prominent signal increase on T1-weighted images and signal decrease on T2-weighted images. On noncontrast T1weighted images, the melanin-containing periosteum

The Rare Phakomatoses

and meninges are displayed as high signal structures juxtaposed to the dark border formed by the cortical bone of the adjacent inner table (Fig. 17.13) [163]. Since malignant melanomas commonly bleed, detection of hemorrhage within the lesion suggests a greater likelihood of malignant melanoma than of benign meningeal melanocytoma [180]. The specific signal characteristics necessarily vary with the age of any hemorrhage present [181]. Benign meningeal melanocytoma usually demonstrates homogeneous contrast enhancement on both CT and MRI [180, 182, 183]. Malignant melanoma may appear less homogeneous secondary to concurrent hemorrhage.

17.3.6 McCune-Albright Syndrome McCune-Albright syndrome (MAS) is a sporadic disease, classically defined as the triad of café-au-lait spots, polyostotic fibrous dysplasia, and endocrinopathy manifesting either as precocious puberty [184] or as other, usually hyperfunctional, endocrinopathies [185–187]. The presence of at least two of the three components of the triad is considered sufficient for diagnosis, since incomplete forms of the disease are known to exist [188]. MAS is rare, and accounts for approximately 5% of all cases of fibrous dysplasia. It results from point mutation of the GNAS 1 gene, situated at chromosome 20q13 and normally producing the α subunit of the signal transducing G protein (Gsα) [187, 189–191]. The specific point mutations result in constitutive overactivation of the cyclic adenosine monophosphate (cAMP) signaling pathway. Thus, cell function and proliferation in a wide variety of tissues may be involved, causing abnormal skin pigmentation, endocrinopathies, and fibrous dysplasia. The diversity of clinical phenotypes is best explained as a mosaic distribution of cells bearing the mutant allele, and is most consistent with the occurrence of a postzygotic mutation [192]. 17.3.6.1 Clinical Findings

MAS presents in different ways at different ages. Cutaneous pigmentary lesions are often present at birth, or appear in childhood [186]. Café-au-lait pigmentation usually appears as large, irregular, tan to brown macules on the trunk and extremities. The lesions are unilateral, do not cross the midline, and often terminate abruptly at the ventral midline [185]. They frequently follow the lines of Blaschko, suggest-

ing that they reflect an underlying cellular mosaicism [186]. They usually show predilection for the forehead, nuchal area, and intergluteal cleft [185, 186]. No abnormal pigmentation is found in 10%–20% of MAS patients [185]. Accelerated growth, precocious puberty, other endocrinopathies, and facial forms of fibrous dysplasia usually also present in childhood [185, 186]. In MAS, bony overgrowth frequently compromises the neural foramina, causing cranial nerve palsies [185]. Massive hyperostosis and expansion of the skull base may lead to blindness from compression of the optic nerve, deafness from overgrowth into, and obliteration of, the tympanic cavity, and recurrent infections of the middle ear and paranasal sinuses due to ostial obstructions [187]. Facial asymmetry with secondary orbital displacement [185] may be marked (Fig. 17.14). Theoretically, pituitary adenomas developing as part of the MAS endocrinopathy could also compromise cranial nerves in the suprasellar/parasellar regions, causing visual field defects and ophthalmoplegia. Primary parenchymal lesions of the brain and spinal cord do not form part of the MAS. MAS endocrinopathies are characterized by autonomous excessive hyperfunction of hormonally responsive cells, leading to sexual precocity in 66%, hyperparathyroidism in 33%, growth hormone excess in 25%, and Cushing’s syndrome in 9% [187]. Hyperprolactinemia is found in 50% of MAS patients with increased growth hormone levels. Primary hyperparathyroidism [187, 189], autonomous adrenal hyperplasia [186], and prepubertal testicular enlargement have also been described. 17.3.6.2 Imaging Studies

The neuroimaging and head and neck imaging findings of MAS primarily reflect the bony changes of polyostotic fibrous dysplasia. Craniofacial fibrous dysplasia is present in 100% of disseminated cases [193]. There is sometimes massive thickening of all affected bones, including any or all of the calvarium, skull base, facial bones, and mandible (Fig. 17.14). The involved bones show diffuse expansion and characteristic osteoid matrix. Multiple neural foramina show narrowing or obliteration, especially the optic canals. Bone changes involving the facial skeleton and mandible often involve, expand into, and obliterate the paranasal sinuses and nasal fossa [193, 194]. On MRI (Fig. 17.14), the expanded bone usually shows increased T2 signal and enhances dramatically and heterogeneously. MRI is also useful for identifying the extent of these lesions and for differentiating

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Fig. 17.14a–g. Fibrous dysplasia. a–c Chronological series, showing progressive asymmetrical expansion of the midface and jaw at age 4 years (a) and 8 years (b). At 10 years (c), surgical intervention has restored a nearly normal appearance. d Set of coronal and axial bone algorithm CT scans show maxillary and mandibular expansion, frontal and ethmoid thickening with intact cortex and typical groundglass appearance of the matrix, and narrowing of the basal neural foramina. e Histology of the resected bone. The specimen shows a haphazard arrangement of curvilinear trabeculae of woven bone surrounded by cellular fibrous proliferation. There is osteoblastic rimming of the bony trabeculae. f Lateral skull radiograph and g Sagittal T1-weighted image show skull base is expanded and sclerotic. The basal neural foramina are narrowed.

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The Rare Phakomatoses

fibrous from cartilaginous lesions [189]. On both T1and T2-weighted images, the fibrous lesions tend to be lower in signal than normal cartilage. In fibrous dysplasia, the bony cortex remains notably intact despite other marked bony changes. If cortical erosion is identified, sarcomatous degeneration should be considered. Overall, the risk of malignant degeneration of affected bone in MAS is 4% [185], and most commonly affects the craniofacial bones [185]. The three most frequent malignant lesions are osteosarcoma, fibrosarcoma, and chondrosarcoma. Thus, a high degree of suspicion is necessary when reviewing these cases. The importance of MRI of the pituitary fossa in MAS is apparent [189], with both micro- and macroadenomas encountered as a manifestation of the endocrinopathy (see fig. 18.27, chap. 18). Whole-body scintigraphy and SPECT imaging with 99m technetium MDP often show intense uptake in the involved craniofacial bones [189].

associated with elevated ACTH levels and hyperpigmentation in patients previously adrenalectomized for Cushing’s disease [195]. The incidence of NS following bilateral adrenalectomy is usually given as 10%–30% [196], although rates as low as 2.5% [197] and as high as 38% [198] and 47% [195] have been reported. The prevalence of NS is decreasing, as fewer patients are treated for Cushing’s syndrome by means of bilateral adrenalectomy [198, 199]. The interval between adrenalectomy and onset of NS may vary from 1 to 30 years [198–201]. The risk of developing NS may be greater in pediatric patients undergoing adrenalectomy than in adults [195], but this has not been established definitively [195, 200, 202]. Pituitary adenomas seen in Cushing’s disease and NS are associated with high circulating levels of ACTH and other peptides derived from the precursor molecule pro-opiomelanocortin (POMC). These have melanocyte stimulating hormone (MSH)-like activity that leads to the hyperpigmentation [203]. 17.3.7.1 Clinical Findings

17.3.7 Nelson Syndrome Nelson syndrome (NS) is defined by the appearance of an enlarging, usually aggressive, pituitary tumor

Patients with NS have cutaneous hyperpigmentation that may be most pronounced in scars and in areas exposed to sun (Fig. 17.15) [204].

Fig. 17.15a–c. Nelson syndrome. a, b Skin and nails of the hands in two patients; c Imaging findings. The nail beds show intense (a) and subtler (b) hyperpigmentation, which disappeared after treatment of the secondary pituitary lesion in both cases. c Gd-enhanced coronal T1-weighted image shows marked pituitary enlargement.

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Classically, the pituitary tumors seen in NS are large and locally invasive, are incompletely resectable, and show propensity to recur [198, 205]. These tumors show a more aggressive growth potential than those typically seen in Cushing’s disease [198, 205–207]. Rare tumors may progress to pituitary carcinoma, with craniospinal and/or systemic metastases [206, 207]. As with other pituitary tumors, clinical symptoms and signs may include local effects such as headache, loss of visual acuity and visual field defects, and diplopia due to cavernous sinus and cranial nerve involvement [207], and more generalized effects due to compromise of function of normal pituitary tissue leading to signs and symptoms of hypopituitarism [197], such as muscle weakness, amenorrhea, obesity, impotence, loss of libido, and hypertension [204]. 17.3.7.2 Imaging Studies

Neuroimaging features of NS essentially relate to demonstration of pituitary micro- or macroadenomas (Fig. 17.15), with or without extrasellar extension or local invasion. MRI is more effective than CT in demonstrating pituitary adenomas, particularly microadenomas, although CT does define bony expansion/ erosion of the sella/parasellar region more clearly. MRI can also define changes in the tumor itself, such as infarction [208], growth and recurrence, and local complications such as cavernous sinus involvement, dural invasion, and evidence of the relative invasiveness/aggressiveness characteristic of NS tumors [207]. As well as the intrasellar position of pituitary tumors, both CT and MRI can also define more unusual locations, such as enlarging tumor in the cavernous sinus in the setting of postpituitary surgery empty sella, and rare entities such as ectopic Nelson tumor in the sphenoid sinus [209].

17.4 Other Phakomatoses 17.4.1 Basal Cell Nevus Syndrome Basal cell nevus syndrome (BCNS), also named nevoid basal cell carcinoma syndrome or Gorlin-Goltz syndrome, is an autosomal dominant neurocutaneous syndrome of ectodermal and skeletal anomalies, classically consisting of multiple basal cell carcinomas of the skin, odontogenic keratocysts of the jaw, and

bifid ribs. Additional manifestations include calcified dural folds, diverse neoplasms, and hamartomas [210, 211]. BCNS is very uncommon, with prevalence estimates ranging from 1 per 57,000 to 1 per 164,000 individuals. Patients with BCNS most commonly present in childhood. BCNS shows autosomal dominant inheritance, variable expressivity, complete penetrance, and no gender predilection. Approximately 35%–50% of cases represent new mutations. The genetic defect underlying BCNS is a germ line mutation in the sonic hedgehog receptor gene PATCHED, that maps to chromosome 9q22.3–q31 [211–215]. PATCHED forms part of the hedgehog signaling pathway, which is critical in determining embryonic patterning and cell fate in multiple structures of the developing embryo [213, 216, 217]. PATCHED is also a tumor suppressor gene [211–213, 218]. 17.4.1.1 Clinical Findings

Increased mean height, macrocrania, macrosomia, and skeletal and dental abnormalities tend to present in childhood. Jaw cysts present in older children and adults. Most patients with BCNS develop basal cell carcinomas (75%–90%) (Fig. 17.16), typically presenting from puberty to about 35 years of age [212, 219, 220]. The number of lesions varies from a few to as many as thousands at one time. Other cutaneous features of BCNS include palmar and plantar pits (65%–80%) and small keratin-filled cysts known as milia (30%–50%). Occasionally, skin lesions are limited to one side or quadrant of the body [211, 212]. Multiple mandibular and maxillary odontogenic keratocysts are seen in up to 90% of patients (Fig. 17.16) [211, 212, 221]. Medulloblastomas are strongly associated with BCNS, and occur in 1%–5% of patients (Fig. 17.16) [211]. Boys are affected more often than girls [3:1]. The medulloblastomas associated with BCNS characteristically present early, i.e., during the first 2 years of life. Hence, BCNS should be excluded in all medulloblastoma patients younger than 5 years [219]. Since giving radiation therapy to patients with BCNS leads directly to large numbers of invasive basal cell carcinomas within the radiation field, this distinction must made at tumor diagnosis to choose appropriate treatment protocols [211, 219]. Calvarial and facial abnormalities other than odontogenic keratocysts are present in up to 70% of BCNS patients, including macrocrania, frontal bossing, and hyperpneumatized paranasal sinuses. Cleft palate is

The Rare Phakomatoses

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Fig. 17.16a–k. Basal cell nevus syndrome. a–c Clinical features; d, e Pathologic findings; f–h Odontologic features; i–k. Imaging findings. a Basal cell nevi on the back. b Absence of a prominent knuckle at the 4th ray indicates a short 4th metacarpal. c Characteristic palmar pits become more easily discernible with patient aging. d The basal cell epithelioma occupies the dermis with an irregular cell configuration at the interior (arrows). e The squamous epithelium-lined epidermal cyst (arrows) has ruptured and caused foreign body giant cell reaction (arrowheads). f Patient photograph shows fullness of the lower face. g The open mouth shows peg-shaped teeth, thinning of the gingiva and marked expansion of the mandible. h Panorex radiograph discloses the multiple odontogenic cysts. i Axial bone algorithm CT scan; j Axial CT scan; k Coronal T2-weighted image. There is a predominantly lucent lesion that expands the mandible, thins the cortex, and displaces the teeth (i). Noncontrast axial CT of the brain reveals dural calcification of the falx and tentorium (j). In a different patient, MRI reveals a medulloblastoma (k). (Reprinted from ref. #212, with permission)

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found in about 5%, and diverse ocular abnormalities in 25%–33% [211]. Musculoskeletal anomalies, including malformations of the ribs and vertebral anomalies, are seen in up to 75% of BCNS. Sprengel deformity, pectus excavatum, and marfanoid body habitus are also recognized. Hamartomatous osteolytic bone lesions may appear in the phalanges, carpus, tarsus, long bones, pelvis, and calvarium. Other associations include renal anomalies, cardiac and ovarian fibromas, mesenteric cysts, and, possibly, an increased risk of lymphoma [222, 223]. 17.4.1.2 Imaging Studies

The most frequent findings in BCNS are odontogenic keratocysts and calcifications of the intracranial dural surfaces (Fig. 17.16). Keratocysts involve both the mandibular and maxillary alveolus, and are usually multiple (average: 6; range: 1 to 30 lesions per patient) [211]. They appear as expansile, sharply marginated, cystic lesions, which cause thinning of the overlying cortex. In the early stages, they can be seen to have originated from the region of the tooth root, but later on, dramatic expansion of the lesion may obscure this relationship. The cyst content resembles water, with low attenuation on CT, low signal intensity on T1-weighted MR images, and high signal intensity on T2-weighted images. Dural calcifications of BCNS resemble all others, except for appearing at an unusually young age. Basal cell carcinomas may become quite invasive, and have a predilection for perineural spread. For that reason, MRI may demonstrate destruction of the underlying bone and/or contrast enhancement along the regional cranial nerves. Although not in the classic syndrome description, lamellar calcification of the falx is a prominent feature early in life, and is present in 90%–100% of adult patients with BCNS (Fig. 17.16) [211, 211]. Calcification of the tentorium cerebelli, petroclinoid ligaments, and the diaphragma sellae are seen in 60%–80% of patients. Since physiological calcification of the dura is uncommon in children, BCNS should be considered in any pediatric patients with such falx calcification [219]. Conversely, adult patients without CT evidence of falx calcification are unlikely to have the syndrome [212].

17.4.2 Organoid Nevus Syndrome Organoid nevus syndrome (ONS), also called epidermal nevus syndrome, Schimmelpenning-Feuerstein-

Mims syndrome, Solomon’s syndrome, and Jadassohn’s nevus phakomatosis, is a rare phakomatosis classically characterized by the triad of nevus sebaceous of Jadassohn, mental retardation, and seizures. This triad has gradually been expanded to include a broad and variable spectrum of other structural, neurological, ophthalmological, skeletal, urogenital, and cardiovascular anomalies. No specific incidence or prevalence rates have been reported for this rare syndrome. ONS typically occurs sporadically. Claims for occasional familial occurrence are debated [224–226]. No gene has yet been identified. The pathogenesis of ONS is unknown. Proposals generally suggest that alterations in early embryogenesis [227], such as anomalous development of neuroectoderm prior to the fourth week of gestation, could result in concurrent brain, skull, and ocular abnormalities [224]. The nevus sebaceous itself could reflect abnormal ectodermal development at a later stage of embryonic life [224]. 17.4.2.1 Clinical Findings

The clinical findings are usually present at birth, but may not be appreciated until later [224], even as late as 24 years [225]. The nevus sebaceous of Jadassohn (also designated the “organoid nevus”) is a requisite of the syndrome, but may not be clinically visible at birth [228]. It is composed of multiple tissue elements, including a variable mix of epidermal hyperplasia, sebaceous glands, apocrine glands, and hair follicles [224, 229]. Hence, clinical appearance can vary dramatically. Organoid nevi can appear anywhere on the body. However, patients with the concurrent neurological abnormalities of ONS usually display them on the face and scalp (Fig. 17.17), perhaps extending onto the neck and trunk [228, 229]. The two most common neurologic manifestations of ONS are seizures (67%) and mental retardation (67%) [225]. Structural abnormalities of the cerebrum and/or cranial vault are observed in 72% [225], the most characteristic being hemimegalencephaly ipsilateral to the organoid nevus (Fig. 17.17). Hemimegalencephaly is a hamartomatous condition described in Chap. 4. Arachnoid cysts are also seen frequently with ONS [230]. Rarely, brain tumors, usually gliomas, have been documented in patients with ONS. Ocular involvement is seen in approximately 50%–60% of patients with ONS [225, 227]. The most frequent lesion is a complex epibulbar choristoma, commonly found on the anterior surface of the globe [230]. These tend to be unilateral, and when extensive, may be accompanied by other ocular malformations,

The Rare Phakomatoses Fig. 17.17a–e. Organoid nevus syndrome. a, b external manifestations; c–e. Imaging findings. a, b The facial and scalp organoid nevi display a yellow/brown/orange, verrucous appearance, associated with waxy, well-demarcated plaques. The somewhat linear distribution follows the lines of Blaschko. c Axial CT scan; d Axial T1-weighted image; e Coronal T1-weighted image. There is marked asymmetric overgrowth of the facial soft tissue and bone (arrowheads, c–e) associated with homolateral hemimegalencephaly (arrows, e).

a

c

b

d

such as microphthalmia, corneal staphyloma, and malformations of the lens and iris [229]. Other ocular lesions associated with ONS include choroidal complex choristomas with intrascleral bone and cartilage [224, 229], colobomas of the eyelid, iris, choroid, and optic disk, oculomotor nerve palsy plus occasional microphthalmia and optic nerve atrophy [224]. In combination, the neurological and ocular abnormalities of ONS can manifest as one form of disseminated oculocerebral dysgenesis, with devastating visual consequences. In these patients, visual loss may result from intractable seizures, hypoplasia of the optic radiations associated with hemimegalencephaly, and/or anterior and fundal lesions of the ocular globe [229]. Inner ear malformations, such as widened internal acoustic canals and dysplastic lateral semicircular canals, as well as conductive hearing loss, may also be seen in ONS [231]. Other inconstant associations of ONS involve hypertrophy of the face and extremities, rib notching and congenital hip dislocation [225]. Cardiac anomalies include ventriculoseptal defect, coarctation of the aorta, patent ductus arteriosus, and aberrant coronary arteries [225]. Urinary system abnormalities

e

include double collecting system, horseshoe kidney and nephroblastomatosis [225]. 17.4.2.2 Pathological Findings

Macroscopically, organoid nevi are yellow/brown/ orange and verrucous, and are often associated with waxy, well-demarcated plaques [229]. They are usually at least partially linear in distribution [229], following the lines of Blaschko (Fig. 17.17) [225, 229, 232]. Organoid nevi display a three-phase natural history, with corresponding age-dependent macroscopic and histopathological findings. In infancy and childhood, the lesions are small and hairless, with underdeveloped sebaceous glands. During puberty, hormonal (androgenic) stimulation induces massive proliferation and maturation of sebaceous and apocrine glands, and papillomatous epidermal hyperplasia. Following puberty, secondary benign and malignant neoplasms may develop [225, 229]. Basal cell carcinoma will arise in up to 15%–20% of these lesions [225, 229]. For that reason, prophylactic excision may be performed at or before the onset of puberty.

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An interesting feature of the pathology of ONS is the sharp demarcation between the skin tumors and hemimegalencephaly, which are hamartomatous, and the most common ocular lesions which are choristomatous [229]. 17.4.2.3 Imaging Studies

The major imaging findings of ONS are those of hemimegalencephaly ipsilateral to the organoid nevus (Fig. 17.17), whose imaging findings are described in Chap. 4. Ultrasound, CT, and MRI can be valuable in detecting high-density scleral ossifications and epibulbar cartilage within the choristomas and the heterogeneous signal and density of fat, dermal elements, cartilage and ectopic lacrimal gland within the complex choristomas [230]. To the extent possible, care must be taken to avoid misdiagnosing calcified ocular lesions of ONS as retinoblastoma or choroidal osteoma, particularly when ONS has not yet been diagnosed [224].

17.4.3 Cowden-Lhermitte-Duclos (COLD) Syndrome Paolo Tortori-Donati, Andrea Rossi, and Roberta Biancheri

Lhermitte-Duclos disease (LDD) is a rare lesion characterized by overgrowth of the cerebellar cortex whose neoplastic, malformative or hamartomatous nature has been the subject of enduring debate since its first description in 1920 [233]. It is included among neuronal and mixed neuronal-glial tumors in the most recent WHO classification of tumors of the CNS [234]; however, it is also included in current classification schemes of cerebellar malformations [235]. Other names that have been used to describe this entity include diffuse cerebellar hypertrophy, gangliocytoma dysplasticum, dysplastic cerebellar gangliocytoma, granular cell hypertrophy, granule cell hypertrophy of the cerebellum, hamartoma of the cerebellum, and purkinjeoma [236]. The coexistence of LDD and Cowden syndrome was recognized in 1991 by Padberg et al. [237]. Cowden syndrome is an autosomal dominant condition with variable expression that results from a mutation in the PTEN tumor suppressor gene on chromosome arm 10q [238]. It is characterized by hamartomatous neoplasms of the skin and mucosa, gastrointestinal tract, bones, CNS, eyes, and genitourinary tract [239]. There is increased incidence of breast carcinoma in women and of thyroid carcinoma in both men and

women with this condition. Recent evidence [239– 242] supports the contention that LDD and Cowden syndrome are part of a single spectrum that should better be classified as a phakomatosis. The acronym COLD (Cowden-Lhermitte-Duclos) has been introduced [239] to denominate this new entity. Recognition of this association is important because it may lead to an early diagnosis of cancer [239]; therefore, all patients with LDD should receive a thorough dermatological and systemic screening [242]. 17.4.3.1 Clinical Findings

The main presenting signs in patients with LDD are headache, signs of increased intracranial pressure, and noncommunicating hydrocephalus [239, 240]. Cerebellar signs, such as movement disorders and tremor, are usually less prominent [243]. Patient age at presentation ranges from birth [244] to the sixth decade, although most affected patients are in their third or fourth decade of life [240]. The natural history of LLD is not well established. Most lesions are probably stable, but recurrence after surgery has been described [240, 243]. Surgical excision of the mass is advocated as the treatment of choice [240]. 17.4.3.2 Neuropathology

LDD is characterized by thickened, coarse cerebellar folia producing enlargement of a part of one cerebellar hemisphere with possible extension to the vermis or, rarely, to the contralateral hemisphere [245]. The affected folia contain large ganglion cells in the granular cell layer and prominent myelinated tracts in the outer molecular layer [245], while the underlying white matter is greatly reduced [240, 246]. Histologically, the severity of the lesion may vary from a recognizable granular cell layer containing occasional large dysplastic neuronal cell bodies, to an unrecognizable granular layer occupied by a population of large nerve cell bodies that are believed to be hypertrophied granule cells [240]. There is no widespread consensus as to whether LDD is a tumor or not. At present, objections to the view that LDD is of neoplastic nature are considered to be very serious and substantial [240]. 17.4.3.3 Imaging Studies

MRI detects a mass lesion within the cerebellar hemisphere displaying a highly characteristic gyriform,

The Rare Phakomatoses

striated structure that corresponds to the enlarged folia [240, 247]. The lesion is hypointense to normal gray matter on T1-weighted images and usually does not enhance with contrast material administration [247]. On T2-weighted images, the lesion presents with a well-circumscribed hyperintensity and a unique striated pattern with isointense bands within the area of hyperintensity, indicating the structure of widened gyri and displaced sulci of the cerebellar cortex (Fig. 17.18) [240]. The T1 hypointense and T2 hyperintense striation corresponds to the inner portion of the diseased folia, consisting of the deep molecular layer, the internal granular layer, and the white matter, whereas the outer molecular layer of the folia remains isointense in both sequences [243]. The characteristic striated pattern can also be visible on CT as an alternating hypodense-isodense layered formation [243, 246], although MRI remains the modality of choice. Scattered calcifications have been rarely reported [246], as has contrast enhancement. It is noteworthy that, when present, both calcification and contrast enhancement correlate with the isointense layer, consistent with microscopic descriptions of a proliferation of blood

a

c

vessels in the pia and adjacent molecular layer with concomitant calcium deposition [248]. The central white matter of the cerebellum can be hyperintense in long TR MRI sequences, possibly reflecting scant myelination (Fig. 17.18) [246]. In newborns, the lesion may not display the characteristic striated pattern, as a result of incomplete myelination [243, 246]. In one study, proton MR spectroscopy revealed increased levels of lactate and decreased levels of N-acetyl-aspartate, similar to low-grade tumors, but decreased levels of myo-inositol and choline, which is not suggestive for tumors. This behavior was felt to reflect the controversial histopathologic nature of this entity [249].

17.5 Conclusion The rare phakomatoses are a fascinating set of neuroectodermal conditions that illustrate how derangements in genetics, protein metabolism, and signaling pathways manifest clinically. They provide insight into the basic mechanisms of life.

b

Fig. 17.18a–c. Cowden-Lhermitte-Duclos syndrome. a, b Axial T2-weighted image; c Coronal T2-weighted image. There is hypertrophy and signal hyperintensity of the cortex of the superior aspect of the left cerebellar hemisphere, resulting in a striate pattern (a, b). Signal hyperintensity also involves the underlying hemispheric white matter, possibly related to scant myelination (c). This lesion has been stable for years without any treatment. (Case courtesy Dr. P. Tortori-Donati, Genoa, Italy)

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S. Edelstein, T. P. Naidich, and T. H. Newton KJ. Congenital Malformations of the Brain. Pathological, Embryological, Clinical, Radiological and Genetic Aspects. New York: Oxford University Press, 1995. 237. Padberg GW, Schot JD, Vielvoye GJ, Bots GT, de Beer FC. Lhermitte-Duclos disease and Cowden disease: a single phakomatosis. Ann Neurol 1991; 29:517–523. 238. Nelen MR, Padberg GW, Peeters EA, Lin AY, van den Helm B, Frants RR, Coulon V, Goldstein AM, van Reen MM, Easton DF, Eeles RA, Hodgsen S, Mulvihill JJ, Murday VA, Tucker MA, Mariman EC, Starink TM, Ponder BA, Ropers HH, Kremer H, Longy M, Eng C. Localization of the gene for Cowden disease to chromosome 10q22–23. Nat Genet 1996; 13:114–116. 239. Robinson S, Cohen AR. Cowden disease and LhermitteDuclos disease: characterization of a new phakomatosis. Neurosurgery 2000; 46:371–383. 240. Nowak DA, Trost HA. Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma): a malformation, hamartoma or neoplasm? Acta Neurol Scand 2002; 105:137–145. 241. Koch R, Scholz M, Nelen MR, Schwechheimer K, Epplen JT, Harders AG. Lhermitte-Duclos disease as a component of Cowden’s syndrome. Case report and review of the literature. J Neurosurg 1999; 90:776–779. 242. Vantomme N, Van Calenbergh F, Goffin J, Sciot R, Demaerel P, Plets C. Lhermitte-Duclos disease is a clinical manifesta-

tion of Cowden’s syndrome. Surg Neurol 2001; 56:201–204. 243. Kulkantrakorn K, Awwad EE, Levy B, Selhorst JB, Cole HO, Leake D, Gussler JR, Epstein AD, Malik MM. MRI in Lhermitte-Duclos disease. Neurology 1997; 48:725–731. 244. Roessmann U, Wongmongkolrit T. Dysplastic gangliocytoma of cerebellum in a newborn. Case report. J Neurosurg 1984; 60:845–847. 245. Friede RL. Developmental Neuropathology, 2nd edn. Berlin: Springer, 1989:347–386. 246. Vieco PT, del Carpio-O’Donovan R, Melanson D, Montes J, O’Gorman AM, Meagher-Villemure K. Dysplastic gangliocytoma (Lhermitte-Duclos disease): CT and MR imaging. Pediatr Radiol 1992; 22:366–369. 247. Meltzer CC, Smirniotopoulos JG, Jones RV.The striated cerebellum: an MR imaging sign in Lhermitte-Duclos disease (dysplastic gangliocytoma). Radiology 1995; 194:699–703. 248. Awwad EE, Levy E, Martin DS, Merenda GO. Atypical MR appearance of Lhermitte-Duclos disease with contrast enhancement. AJNR Am J Neuroradiol 1995; 16:1719– 1720. 249. Klisch J, Juengling F, Spreer J, Koch D, Thiel T, Buchert M, Arnold S, Feuerhake F, Schumacher M. Lhermitte-Duclos disease: assessment with MR imaging, positron emission tomography, single-photon emission CT, and MR spectroscopy. AJNR Am J Neuroradiol 2001; 22:824–830.

Sellar and Suprasellar Disorders

18 Sellar and Suprasellar Disorders Paolo Tortori-Donati, Andrea Rossi, and Roberta Biancheri

CONTENTS 18.1

Anatomy, Embryology, Normal Evolution, and Physiological Variations 855

18.1.1 18.1.1.1 18.1.1.2 18.1.2 18.1.3 18.1.4 18.1.4.1

Anatomy 855 The Pituitary Gland 855 The Neurosecretory Regions 856 Embryology 857 Normal Evolution and MRI Appearance 858 Normal Morphological Variations 858 Rathke’s Cleft Remnants or Cysts of the Pars Intermedia 858 18.1.4.2 Primary Empty Sella 859 18.1.4.3 Secondary Empty Sella 859 18.2

Congenital Disorders of the Pituitary Gland 863

18.2.1 18.2.2 18.2.3

Aplasia or Hypoplasia of the Pituitary Gland 863 Pituitary Dystopia 864 Duplication of the Pituitary Gland 864

18.3

Hypopituitarism (Pituitary Dwarfism)

18.3.1

Imaging Studies 865

18.4

Diabetes Insipidus 867

18.4.1

Imaging Studies 868

18.5

Precocious Puberty

18.6

Sellar and Suprasellar Mass Lesions

18.6.1 18.6.1.1 18.6.1.2 18.6.2 18.6.3 18.6.4 18.6.5 18.6.5.1 18.6.5.2 18.6.5.3 18.6.6 18.6.6.1 18.6.6.2 18.6.6.3 18.6.7 18.6.7.1 18.6.8

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Rathke’s Cleft Cysts 871 Imaging Findings 871 Differential Diagnosis 872 Pituitary Adenomas 872 Pituitary Hyperplasia 875 Langerhans Cell Histiocytosis 875 Chiasmatic-Hypothalamic Astrocytoma 876 Epidemiology and Clinical Picture 876 Biological Behavior and Neuropathology 877 Imaging Studies 877 Craniopharyngiomas 878 Epidemiology and Clinical Picture 878 Biological Behavior and Neuropathology 880 Imaging Studies 881 Suprasellar Germinoma 884 Imaging Studies 884 Hamartoma of the Tuber Cinereum (Hypothalamic Hamartoma) 886 18.6.9 Suprasellar Arachnoid Cysts 887 18.6.10 Lymphocytic Hypophysitis 887 References

889

18.1 Anatomy, Embryology, Normal Evolution, and Physiological Variations 18.1.1 Anatomy 18.1.1.1 The Pituitary Gland

The pituitary gland, or hypophysis, is an ovoid body that is continuous with the infundibulum, a hollow, conical, inferior process originating from the tuber cinereum. It lies within the sella turcica and is covered superiorly by a circular diaphragm of dura mater, pierced centrally by an aperture for the infundibulum [1]. The pituitary gland consists of two major parts (Fig. 18.1), differing in their origin, structure, and function: the neurohypophysis is a diencephalic downgrowth connected with the hypothalamus, whereas the adenohypophysis is an ectodermal derivative of the stomodeum (see below). Both portions include part of the infundibulum, which has a central infundibular stem, called pituitary stalk, and is continuous with the median eminence of the hypothalamus. Surrounding the infundibular stem is the pars tuberalis or infundibularis, a component of the adenohypophysis. The latter can be divided into the pars anterior or distalis and pars intermedia, separated from one another in fetal and early postnatal life by the socalled hypophyseal cleft, a vestige of the Rathke’s pouch from which the adenohypophysis develops. Usually obliterated in childhood, the hypophyseal cleft may sometimes persist as a variably sized cystic cavitation. In summary:  the neurohypophysis includes the pars posterior, the infundibulum or pituitary stalk, and the median eminence;  the adenohypophysis, which makes up about 75% of the gland, includes the pars anterior, pars intermedia, and pars tuberalis.

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Blood-brain barrier

Anterior lobe of pituitary gland* Posterior lobe of pituitary gland Pineal gland Tuber cinereum Median eminence Subcommissural organ* Subfornical organ Organ vasculosum of the lamina terminalis Area postrema in the medulla

Yes No No No No Yes No No No

* These regions show gadolinium enhancement due to high capillary density.

Fig. 18.1. Anatomy of the sellar and suprasellar region. 1 Column of the fornix; 2 Paraventricular nucleus; 3 lateral hypothalamic area; 4 posterior hypothalamic nucleus; 5 ventral tegmental area; 6 medial preoptic nucleus; 7 anterior hypothalamic nucleus; 8 dorsomedial nucleus; 9 ventromedial nucleus; 10 principal mammillary fascicle; 11 mammillary body; 12 lateral preoptic nucleus; 13 supraoptic nucleus; 14 suprachiasmatic nucleus; 15 infundibular nucleus; 16 right superior hypophyseal artery; 17 infundibulum; 18–20 anterior pituitary lobe (18 pars infundibularis; 19 pars distalis; 20 pars intermedia); 21 posterior pituitary lobe; 22 posterior intercavernous sinus; 23 anterior intercavernous sinus; 24 left inferior hypophyseal artery; 25 right inferior hypophyseal artery. (Reproduced from: R. Nieuwenhuis, J. Voogd, C. van Huijzen. Das Zentralnervensystem des Menschen, 1988; Copyright owned by Springer Verlag, Berlin Heidelberg)

The hypothalamus is a thin layer of tissue forming the floor and lateral walls of the third ventricle and separating the ventricular cavity from the suprasellar cistern. Its inferior surface, called tuber cinereum, is a ridge of gray matter extending from the optic chiasm anteriorly to the mammillary bodies posteriorly. The median eminence forms the floor of the third ventricle, where the infundibular stem attaches to the base of the brain. The subcommissural organ lies under the posterior commissure, at the junction between the third ventricle and the cerebral aqueduct. The subfornical organ is located by the inferior surface of the columns of the fornix. The organum vasculosum is located at the lamina terminalis before the optic chiasm, and may be

18.1.1.2 The Neurosecretory Regions

The pituitary gland is the largest of the circumventricular organs (Table 18.1) (Fig. 18.2), whose denomination derives from their location adjacent to the third and fourth ventricles. Circumventricular organs produce secretory substances, either true hormones or factors influencing the elaboration of hormones at other sites [2], and govern the hormones that control behavioral, physiologic, and endocrine responses to a variety of peripheral stimuli. Regulation of homeostatic functions, such as lactation, parturition, gestation, reproduction, metabolism, temporal rhythms, arousal, and cardiovascular dynamics, requires communication between the neurosecretory regions of the brain and the rest of the body. Because of their function, most of these structures lack a blood-brain barrier.

Fig. 18.2. Midline sagittal diagram of the brain showing the neurosecretory regions. Note that the hypothalamus on either side of the third ventricle is not shown in this midline section. (Modified from [2])

Sellar and Suprasellar Disorders

functionally considered a sort of accessory anterior pituitary lobe. The area postrema is a paired midline structure located on the dorsal surface of the medulla oblongata dorsally to the obex of the fourth ventricle.

[6]. In the same period, dorsally to the Rathke’s pouch, the infundibular process arises from the floor of the diencephalon and extends towards the buccal cavity. The primordia of the lateral lobes of the adenohypophysis, partially wrapped around the infundibulum, will differentiate into the pars tuberalis. The infundibulum will form the median eminence, the pituitary stalk, and the posterior pituitary lobe. Although this embryogenetic theory is widely accepted, a few points have been questioned. Recent studies suggest that the Rathke’s pouch may arise as an independent vesicle near, but unconnected to, the buccal cavity [7, 8]. Contrary to classical concepts, the anterior pituitary lobe could originate from the neuroectoderm and derive from the ventral neural ridge, rather than the stomodeum. Although studies on quail-chick chimera models seem to support this hypothesis, there is no conclusive evidence of a similar process in mammalian embryos [9]. Genes and correspondent pituitary transcription factors contributing to the embryologic development and definitive function of the anterior pituitary gland have been recently identified. They differ in their distribution, timing of appearance, and extinction. Some have global effects on pituitary development, whereas others have more limited influences. The entire cascade of pituitary transcription factors has been described in animal models. The murine Rpx (Rathke’s pouch homeobox) is expressed from the earliest developmental stages, initially throughout the prosencephalic plate and later only in the Rathke’s pouch. A phenotype of anterior pituitary agenesis is caused by the disruption of this gene. The pituitary OTX protein persists in

18.1.2 Embryology The two lobes of the pituitary gland develop from two completely different origins [3–5] (Fig. 18.3). The anterior lobe originates from an ectodermal outpocketing of the stomodeum in front of the buccopharyngeal membrane, known as Rathke’s pouch. The posterior lobe derives from a downward extension of the diencephalon, the infundibulum. At about 3 weeks of gestation, the Rathke’s pouch is an invagination of the stomodeum located immediately rostral to the notochord, that grows dorsally as the budding diencephalic infundibulum grows ventrally. At about 32 days of gestation the Rathke’s pouch disconnects from the oral cavity. Ten to twelve days later it is brought in contact with the diencephalon, thereby originating the anterior pituitary lobe. The anterior wall of the pouch will form the adenohypophysis, whereas the posterior wall will develop into the pars intermedia. The remainder of the Rathke’s pouch, called craniopharyngeal canal and extending from the floor of the sella turcica to the skull base, eventually disappears. However, nests of pituitary tissues can sometimes persist along its course, forming the so-called “ectopic pharyngeal hypophysis” and “ectopic intrasphenoid hypophysis.” Occasionally, adenomas develop from these remnants a

f

b

c

f

d a

c

b

g

d e

f p

m

h

q

i

t n r l

d

o

e

s

Fig. 18.3a–e. Embryology of the pituitary gland. a, b: Cephalic portion of a 22-day-old embryo (a) and of a 42-dayold embryo (b); c–e: 62-day-old fetus (c), 75-day-old fetus (d), and 90-day-old fetus (e). a: thickening of the epiblast of stomodeum; b: pharyngeal membrane; c: notochord; d: Rathke’s pouch; e: entoblast; f: infundibulum; g: pharyngo-hypophyseal peduncle; h: pars tuberalis; i: anterior lobe; l: pars intermedia; m: posterior lobe; n: cartilaginous portion of the sphenoid; o: wall of the stomodeum; p: optic chiasm; q: pituitary stalk; r: sella turcica; s: rhinopharyngeal mucosa; t: meningeal spaces. (Modified from [5])

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the mature animal and its disruption causes pituitary hypoplasia and complete hypopituitarism. The Prop-1 (Prophet of Pit-1) gene is necessary for the subsequent expression of Pit-1 in somatotrophs, lactotrophs, and thyrotrophs. Mutations in the human homologous Prop-1 and Pit-1 result in combined deficiency of multiple pituitary hormones and morphological abnormalities of the pituitary gland [10].

18.1.3 Normal Evolution and MRI Appearance The pituitary gland undergoes dynamic changes [11–14] in size and shape throughout life, reflecting the complex hormonal environment of the gland itself (Table 18.2). In newborns, the gland is typically convex, sometimes pear-shaped, with very high signal intensity on T1-weighted images (Fig. 18.4). This appearance persists for the first month and gradually changes during the second month (Fig. 18.4), until the adult appearance, with a flat superior surface and isointensity of the anterior lobe to the white matter on T1- and T2-weighted images, is achieved (Fig. 18.5). These changes correlate with the intense endocrine activity, lactotroph hyperplasia, and protein synthesis known to occur in the gland during the neonatal period [15]. At puberty, the pituitary gland undergoes dramatic changes [16] in size and shape, basically represented by marked enlargement. In girls, the gland may swell symmetrically to a height of 10 mm, appearing nearly spherical (Fig. 18.6), whereas in pubertal boys it may reach 7–8 mm. By the second month of life, the posterior neural lobe of the gland becomes progressively recognizable next to the dorsum sellae as the “bright spot,” because of its marked hyperintensity on T1-weighted images (Fig. 18.4). The explanation of this bright T1 signal is still controversial. It may be related to one or more of several factors, i.e., pituicyte neurosecretory granules, lipids, or phospholipid vesicles [11]. The vasopressin-associated carrier protein, neurophysin, is a very high molecular weight glycoprotein that complexes with vasopressin to form insoluble crystal aggregates. Neurophysin has

been recently identified in the anterior lobe of the fetus [17]. This is of interest because the fetal anterior lobe, like the posterior one at all ages, is also hyperintense on T1-weighted images. This leads to speculation that neurophysin causes high signal intensity, both in the neurohypophysis and in the neonatal adenohypophysis. Regardless of its chemical origin, the bright spot serves as an important marker of neurohypophyseal function and, when present, documents integrity of the hypothalamic-neurohypophyseal tract. However, it is important to know that (1) the bright spot is absent in most, albeit not all, cases of central diabetes insipidus (see below); (2) it may be absent in 10% of normal individuals; and (3) its absence has been noted in cases of nephrogenic diabetes insipidus [18]. Following gadolinium administration, marked enhancement of the adenohypophysis, due to its high capillary density, and of the infundibulo-tuberal region is well evident. The posterior lobe blends with the anterior lobe due to its spontaneous hyperintensity [2] (Fig. 18.5). The other neurosecretory structures can become visible only using very thin slice thickness. The normal pituitary stalk usually tapers smoothly along its course. It is approximately 3 mm in diameter near the optic chiasm and 2 mm where it inserts into the gland [19].

18.1.4 Normal Morphological Variations 18.1.4.1 Rathke’s Cleft Remnants or Cysts of the Pars Intermedia

Remnants of the anterior pituitary anlage are frequently encountered in the form of cleft-like spaces at the interface of the anterior and posterior lobes [9], characterized by hypointensity on T1-weighted images and hyperintensity on T2-weighted images (Fig. 18.7). In some cases, they are recognizable only following gadolinium administration (Fig. 18.7). Progressive accumulation of secretions within such space gives rise to the Rathke’s cleft cysts (see below).

Table 18.2. Changes in shape and size of the pituitary gland with age Age

Number of cases

0.1–1.5 wk 17 17 1.7 wk-1.5 mo 1.5- 7 mo 17 7 mo- 1 year 25 1 year- 2 years 25 From [14], modified wk = weeks; mo = months

Shape Convex

Hourglass

Flat

Concave

16 15 17 16 15

1 2 3 2 8

10 10 16 14 19

0 0 1 3 3

Measurement (mm) Mean Mean Mean anteroheight width posterior 4.12 18.41 6.79 3.94 18.65 6.76 3.94 19.38 7.44 3.48 19.92 7.84 3.72 10.08 8.16

Sellar and Suprasellar Disorders

a

b

d

c

Fig. 18.4a–d. Normal pituitary gland appearance at different ages of life in three different patients: neonate (a, b); 1-month-old boy (c); 2-year-old boy (d). a Sagittal T1-weighted image; b coronal T1-weighted image; c sagittal T1-weighted image; d sagittal T1-weighted image. Neonate (a, b): typical spontaneous hyperintensity and pear-shape appearance. At the end of the first month of life (c), the signal intensity of the anterior pituitary lobe decreases with respect to the posterior bright spot. At 2 months of age (d), the pituitary gland shows the typical adult pattern

18.1.4.2 Primary Empty Sella

Albeit infrequently, the pituitary gland may show a flattened surface caused by intrasellar herniation of the subarachnoid spaces through an incompetent diaphragm, as is more commonly found in elderly adults. Rhythmic CSF pulsations contribute to chronic compression of the pituitary gland, resulting in its flattening against the inferoposterior portion of the sellar floor, as well as stretching and lengthening of the pituitary stalk (Figs. 18.8, 18.9). Its frequency is about 5% of unselected autopsies in adult age [9, 11]. This anomaly is considered an anatomical variant except when specific signs and symptoms referable to the region, such as endocrine

dysfunction, CSF rhinorrhea, or visual field loss, are present [20–22]. 18.1.4.3 Secondary Empty Sella

A secondary form of empty sella more often occurs postoperatively or after radiation therapy, when the intracranial subarachnoid space extends into the sella to occupy a “dead space.” Secondary empty sella may also occur after spontaneous infarction or involution of a pituitary adenoma [9]. In case of hydrocephalus, herniation of the anterior portion of the third ventricle, particularly the infundibular recess, into the sella may be responsible for compression and flattening of the gland against the sellar floor (Fig. 18.10).

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a

b

c

d

Fig. 18.5a–d. Normal sellar region. a Sagittal T1-weighted image; b Gd-enhanced sagittal T1-weighted image; c coronal T2-weighted image; d Gd-enhanced coronal T1-weighted image. a The posterior pituitary bright spot (arrowhead), anterior pituitary lobe (arrow), pituitary stalk (PS), median eminence (ME), chiasm (c), lamina terminalis (LT), tuber cinereum (TC), and mammillary bodies (MB) are clearly visible. The chiasmatic and infundibular recesses of the third ventricle are recognizable (thin arrows). b Following gadolinium, the whole pituitary stalk (PS), median eminence (ME), and tuber cinereum (TC) enhance. Note that the hyperintensity of the posterior lobe blends with the enhancement of the anterior lobe. c On the coronal T2-weighted image, the pituitary gland (PG) is isointense with white matter. The stalk is barely recognizable (arrowhead). The cavernous sinuses (CS) and internal carotid arteries (ICA) are recognizable laterally. The optic chiasm (C) and anterior cerebral arteries (ACA) are also visible. d Following gadolinium injection, the pituitary gland (PG) and cavernous sinuses enhance. The pituitary stalk is clearly visible (arrowhead) in its midline position, generating a T-shape together with the overlying optic chiasm (C)

a

b

Fig. 18.6a, b. Pubertal pituitary gland in a 11-year-old girl. a Gd-enhanced coronal T1-weighted image; b Gd-enhanced sagittal T1-weighted image. Marked and symmetrical increase of size of the anterior pituitary lobe that appears nearly spherical. The height of the gland is about 10 mm

Sellar and Suprasellar Disorders

a

b

c

d

e

Fig. 18.7a–e. Cysts of the pituitary gland. Two different cases (First case: a–b; second case: c–e). a, b Case #1. a Sagittal T1-weighted image; b sagittal T2weighted image. There is a small cyst of the pars intermedia that is hypointense on the T1-weighted image (arrow, a) and hyperintense on the T2-weighted image (arrow, b). c-e Case #2. c Sagittal T1-weighted image; d Gd-enhanced sagittal T1-weighted image; e Gd-enhanced coronal T1-weighted image. A small, elongated cyst of the pars intermedia is recognizable only following gadolinium administration. (arrows, d, e)

a

b

c

Fig. 18.8a–c. Empty sella syndrome: schematic representation. a Normal relationships of the subarachnoid space and the sella and its contents; b primary empty sella: an arachnoidal diverticulum enters the sella to compress the gland posteroinferiorly; c secondary empty sella: the sellar contents undergo destruction to vacate the sella. (Modified from [9])

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a

b

Fig. 18.9a, b. Primary empty sella. a Sagittal T1-weighted image; b coronal T1-weighted image. There is a deep pituitary fossa containing an anterior pituitary lobe that appears as a thin layer (arrows, a, b). The posterior lobe is flattened against the dorsum sellae (arrowhead, a). The pituitary fossa is mainly filled with CSF. The pituitary stalk is thinned (open arrow, a). The median eminence (EM) is displaced downward at the level of the apex of the dorsum sellae

b

a

d Fig. 18.10a–d. Secondary empty sella: two different patients. a Case #1. Sagittal T1-weighted image. A huge cerebellar tumor with supratentorial hydrocephalus is evident. The anterior third ventricle causes erosion of the quadrigeminal plate and compression of the anterior (arrow) and posterior pituitary lobe (arrowhead). b-d Case #2. b Sagittal T1-weighted image; c coronal T1-weighted image; d axial c T1-weighted image. Aqueductal stenosis (arrowhead, b) and hydrocephalus with enlarged third ventricle are evident. The infundibular recess herniates into the sella (thin arrow, b). The pituitary gland is flattened onto the floor (open arrow, b). The posterior portion of the sella is occupied by a cystic formation (asterisk, b) whose nature is difficult to establish, due to the abnormal morphology of the region. However, it could be an arachnoidal diverticulum. The coronal image shows downward herniation of the third ventricle (arrow, c). The walls of the hypothalamus and the mammillary bodies (arrows, d) are splayed

Sellar and Suprasellar Disorders

With time, the basal hypothalamus may be transformed into a thin membrane, with loss of nuclear architecture and, occasionally, of neurons, and presence of gliosis [9].

18.2 Congenital Disorders of the Pituitary Gland The most common congenital disorders of the pituitary gland include hypoplasia and agenesis, pituitary dystopia, and duplication.

18.2.1 Aplasia or Hypoplasia of the Pituitary Gland It may either be isolated (Fig. 18.11) or as a part of complex syndromes, such as Kallmann syndrome, Pallister-Hall syndrome, CHARGE (Coloboma, Heart anomaly, Choanal Atresia, Retardation, Genital and Ear anomalies), and Coffin-Siris syndrome (Fig. 18.12). It may also be associated with other central nervous system (CNS) malformations, such as anencephaly, septo-optic dysplasia, holoprosencephaly, and corpus callosum agenesis [23] (Table 18.3). Hypoplasia of the pituitary gland may be clinically asymptomatic.

b

a Fig. 18.11a, b. Pituitary gland aplasia. a Gd-enhanced sagittal T1-weighted image; b Coronal T2-weighted image. Complete absence of the pituitary gland and infundibulum, that are not recognizable even following gadolinium administration (a). Both sagittal and coronal images show a flat pituitary fossa (a, b) in the absence of detectable gland remnants. An ectopic posterior lobe is visualized at the level of the median eminence (arrow, a). Notice abscene of the dorsum sellae (a)

a

b

Fig. 18.12a, b. Global pituitary hypoplasia in a 4-year-old boy with Coffin-Siris syndrome. a Sagittal T1-weighted image; b Gdenhanced sagittal T1-weighted image. In addition to pituitary hypoplasia, there is global hypoplasia of the corpus callosum

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P. Tortori-Donati, A. Rossi, and R. Biancheri Table 18.3. Pituitary hypoplasia Isolated Associated with CNS malformations Agenesis of corpus callosum Holoprosencephaly Septo-optic dysplasia Associated with complex syndromes Kallmann syndrome Pallister-Hall syndrome Coffin-Siris syndrome CHARGE

18.2.2 Pituitary Dystopia Pituitary dystopia is commonly found in pituitary dwarfism (see below).

18.2.3 Duplication of the Pituitary Gland Pituitary gland duplication is extremely rare. It is usually associated with facial anomalies (median cleft a

c

lip and median cleft face syndromes) and with other CNS abnormalities, such as corpus callosum agenesis, posterior fossa abnormalities, absence of the olfactory bulbs and tracts, absence of the anterior commissure, and abnormalities of the circle of Willis [8, 24, 25]. MRI studies have rarely been reported, due to early death occurring in most cases because of the severity of associated malformations [24]. MRI usually reveals paired infundibula extending inferiorly to two small pituitary glands, and a broad pituitary fossa with two lateral recesses where the two pituitary glands are located (Fig. 18.13). There also is a characteristic thickening of the floor of the third ventricle extending from the median eminence to the mammillary bodies, which is easily visible on midline sagittal MR images (Figs. 18.13, 18.14); the reason for this appearance remains unclear, although it might be related to duplication of the hypothalamic nuclei. Sometimes, persistence of the craniopharyngeal canal may be recognized (Fig. 18.14). Pituitary duplication has been considered to result from splitting of the notochord at an early embryonic stage [8]. However, this hypothesis is based on the unproven assumption that the pituitary gland develops from the neuroectoderm (see above). Thereb

d

Fig. 18.13a–d. Duplication of the pituitary gland in a 1-month-old boy with cleft lip and palate. a Sagittal T2-weighted image; b Gd-enhanced coronal T1weighted image; c and d sagittal T1-weighted images. On the midline sagittal plane, the floor of the third ventricle is thickened (arrow, a). Coronal image shows two pituitary stalks (arrows, b) converging into two small, separate pituitary fossae (arrowheads, b). The two different glands are shown in the paramedian sagittal images (arrowheads, c, d). The anterior and posterior lobes of one gland are also clearly recognizable in c

Sellar and Suprasellar Disorders

a

b

Fig. 18.14a, b. Duplication of the pituitary gland in a 6-month-old infant. a Gd-enhanced coronal T1-weighted image; b Gd-enhanced sagittal T1-weighted image. Two different pituitary stalks directed laterally to an enlarged pituitary fossa are well seen (thin arrows, a). A marked thickening of the floor of the third ventricle is recognizable both on coronal and on sagittal images (thick arrow, a, b). The corpus callosum is hypoplastic (white arrowheads, b). A persistent craniopharyngeal canal is visible (black arrowhead, b). (Case courtesy Drs. M. Hamon-Kérautret and J.P. Pruvo, Lille, France)

fore, the embryological causes of this malformation remain ultimately undefined.

18.3 Hypopituitarism (Pituitary Dwarfism) The growth hormone (GH) is released from the anterior lobe in response to stimulation from the hypothalamus mediated by growth hormone releasing hormone, which is transported by portal vessels in the pituitary stalk. GH deficiency (GHD) causes pituitary dwarfism, whose diagnosis is based on the following criteria: (1) short stature with normal body proportions; (2) low growth velocity; (3) delayed skeletal maturation; and (4) characteristic clinical appearance, including facial features (defective dentition) and underdeveloped genitalia in boys. Incidence is two- to threefold higher in males than in females. Two categories of GHD are defined: idiopathic (sporadic and genetically determined), which is the most common form, and secondary to lesions of hypothalamic-pituitary axis. Idiopathic GHD may be isolated (IGHD) or associated with multiple anterior pituitary hormone deficiencies (MPHD). Only idiopathic GHD will be considered in this chapter.

18.3.1 Imaging Studies The typical MRI appearance of pituitary dwarfism is characterized by pituitary dystopia, consisting of

failed conjunction between the anterior and the posterior lobe [9]. Morphologically, it is characterized by (Fig. 18.15): I. hypoplasia of the anterior pituitary lobe, which is housed within a small pituitary fossa. II. absence or marked thinning of pituitary stalk. The stalk is usually not identifiable on baseline MRI, although, when present, it may be seen after gadolinium administration (Fig. 18.16); III. ectopic posterior lobe (“ectopic bright spot”). The ectopic posterior lobe may be found anywhere along the infundibular axis (Fig. 18.17), although it is usually located at the level of the infundibular recess of the third ventricle (Fig. 18.15). The term “pituitary stalk interruption syndrome” (PSIS) is used when MRI shows this triad. However, only 40%–60% of patients with idiopathic GHD will display the full triad of MR findings [18, 26]. The remainder may have normal MRI or isolated anterior pituitary hypoplasia with a normal posterior lobe [27]. Although it is generally accepted that MR abnormalities are greater in children with MPHD than in those with isolated GHD [26, 28–31], it has been recently suggested that the lower the GH peak, the greater the severity of MR abnormalities and the likelihood of finding an ectopic posterior pituitary, irrespective of the number of associated anterior pituitary hormone deficiency [27]. Identification of PSIS can clarify the diagnosis of GHD in clinically and biochemically difficult cases, but caution is needed as there have been reports of ectopia of the posterior lobe in apparently normal individuals [32]. The pathogenesis of idiopathic GHD is still a controversial matter. Traditional explanations invoke

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a

b Fig. 18.15a, b. Pituitary stalk interruption syndrome. a Sagittal T1-weighted image; b coronal T1-weighted image. The hypoplastic anterior lobe is located into a small pituitary fossa (black arrow, a). The posterior lobe is ectopic and located at the level of the median eminence (white arrow, a, b). The infundibulum is not visible. A cystic pineal gland and a dysmorphic body of a hypoplastic corpus callosum are associated

a

b Fig. 18.16a, b. Pituitary dystopia in a 6-year-old boy. a Sagittal T1-weighted image; b Gd-enhanced sagittal T1-weighted image. The ectopic posterior lobe is located at the level of the median eminence (white arrow, a) and the hypoplastic anterior lobe is located into a small pituitary fossa (black arrow, a). Following gadolinium, a very thin pituitary stalk is seen (arrowhead, b)

a traumatic origin, based on the high incidence of breech deliveries among children with MPHD and severe GHD. However, the association with other structural CNS malformations, the occurrence of familial cases, and the recent genetic insights support an underlying developmental anomaly [27, 31, 33–35]. To further support this hypothesis, it has been suggested that a congenital anomaly of hypothalamic and pituitary development might in itself be the cause, rather than the consequence, of breech delivery [33]. Genetically determined GHD (5% of cases) may be inherited as autosomal dominant, autosomal recessive, or X-linked forms, or can occur as a part of complex syndromes, such as Russell-Silver syndrome, Prader-Willi syndrome, Cornelia de Lange syndrome,

Fanconi anemia, Turner syndrome, Williams syndrome, and Pallister-Hall syndrome. Morphological changes of the pituitary gland have been described in children with congenital combined pituitary hormones deficiency due to documented mutations of genes involved in the embryologic development and function of the pituitary gland (see Embryology). MR studies show normal stalk and orthotopic posterior pituitary in cases with Prop-1 and Pit-1 mutations [36, 37]; the anterior pituitary gland can be either normal or hypoplastic [36, 37]. Congenital hypoplasia of the anterior pituitary gland (sometimes with an “empty sella” appearance) is, however, the most common MRI finding in children with Prop-1 mutations [36]. It has been suggested that this variability could be partly explained by different gene mutations [36].

Sellar and Suprasellar Disorders

a

b

Fig. 18.17a, b. Pituitary dwarfism in a 14-year-old girl. a Sagittal T1-weighted image; b coronal T1-weighted image. The ectopic posterior lobe (arrowhead, a, b) is located immediately above an almost normal anterior lobe

The differential diagnosis of pituitary dystopia is both clinical and radiologic. From a clinical standpoint, it should be remembered that pituitary dystopia, either isolated or associated with other malformations (Fig. 18.18), may be observed in clinically asymptomatic patients [9]. Radiologically, dysontogenetic masses of the tuber cinereum (Fig. 18.19) must be differentiated from an ectopic posterior pituitary lobe. In these cases, the posterior lobe is found in its normal intrasellar location.

Hereditary CDI. Hereditary forms of CDI are rare. Arginine vasopressin gene mutations have been found in autosomal dominant cases. Wolfram’s syndrome is an autosomal recessive condition characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness (hence, the acronym “DIDMOAD”), mental retardation, seizures, urinary and hematologic abnormalities. The main neuropathological feature is a diffuse neurodegenerative process in the CNS. MRI studies show absence of the bright spot, shrinkage of the optic nerves, chiasm, and tracts, and, sometimes, atrophy of the hypothalamus, brainstem, cerebellum, and cerebral cortex [43–45] (Fig. 18.20).

18.4 Diabetes Insipidus Diabetes insipidus is characterized by excretion of abnormally large volumes of dilute urine. Normal production of vasopressin and structural and functional integrity of the pituitary stalk and posterior lobe are required for maintaining water balance [9]. Diabetes insipidus may be central (neurogenic or pituitary) or nephrogenic. Central diabetes insipidus (CDI) is caused by inadequate vasopressin secretion; it may be idiopathic, hereditary, or secondary to various lesions (Table 18.4). Idiopathic CDI. Approximately 30%–50% of CDI cases are considered idiopathic [9, 11, 38, 39]. However, it should be noted that CDI may be an early sign of hypothalamic disease, which only becomes apparent over time [9]. Therefore, serial brain MR imaging studies are essential when the first MRI is normal or shows isolated pituitary stalk thickening [40–42]. Since suprasellar mass lesions may be small and even undetectable on MRI, neuroimaging studies should be repeated at 6-month intervals for 5 years.

Fig. 18.18 Ectopia of the posterior pituitary lobe. Sagittal T1weighted image. The ectopic posterior lobe is located cranially to the anterior lobe (arrowhead). There are associated dysgenesis of the commissural plate and Chiari I malformation

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Secondary CDI. The main causes of secondary CDI are listed in Table 4.

18.4.1 Imaging Studies

Fig. 18.19. Dermoid of the tuber cinereum. Sagittal T1-weighted image. A small, spontaneously hyperintense mass is seen at the level of the tuber cinereum (arrow). It should not be misdiagnosed as an ectopic posterior lobe. The posterior lobe is in fact recognizable in its physiological site (arrowhead); the pituitary stalk is also clearly visible

Table 18.4. Causes of central diabetes insipidus Idiopathic Hereditary Autosomal dominant Wolfram’s syndrome Secondary Hypothalamic disease Trauma (surgery, head injury) Tumors (craniopharyngioma, glioma, germ cell tumor) Inflammatory/autoimmune diseases Infections (encephalitis or meningitis) Vascular diseases Systemic diseases (sarcoidosis, Langerhans cell histiocytosis)

a

Neuroradiological findings of idiopathic and hereditary CDI are identical. Absence of the pituitary bright spot is considered a nonspecific indicator of CDI [11, 38–41] (Fig. 18.21). However, persistent posterior lobe hyperintensity has been occasionally described in CDI (Table 18.5). Apart from posttraumatic transactions, the pituitary stalk may be either normal or thickened (entirely or proximally). A thickened infundibulum or pituitary stalk suggests germ cell tumors, lymphocytic hypophysitis, lymphoma, and granulomatous diseases (such as tuberculosis and sarcoidosis). However, it may also be present in idiopathic cases [38– 40]. Increase in the size of the stalk on follow-up studies supports the diagnosis of infiltrative/neoplastic disorders. Association of anterior pituitary hormone deficiency with MRI evidence of progressive reduction in size of the anterior pituitary is reported in a variable percentage of patients with CDI [38].

18.5 Precocious Puberty Precocious puberty is characterized by premature onset of secondary sexual characteristics before age 8 years in girls and 9 years in boys. Precocious puberty

b Fig. 18.20a, b. Wolfram’s syndrome (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness—DIDMOAD) in a 15-year-old girl. a Sagittal T1-weighted image; b Coronal T1-weighted image. The posterior bright spot is not visible. Atrophy of the chiasm is shown both on sagittal and coronal images (arrowhead, a, b)

Sellar and Suprasellar Disorders

is classified into: (1) gonadotropin-dependent, or central, due to premature activation of the hypothalamicpituitary axis; and (2) gonadotropin-independent, or peripheral, due to elevation of gonadal sex steroid levels from peripheral causes [46].

Causes of central precocious puberty (CPP) are manifold (Table 18.6). Hypothalamic pathology is demonstrable in fewer than 10% of cases [9]. Hamartomas of the tuber cinereum and other tumors causing CPP are described below. Intracranial tumors not

a

b Fig. 18.21a, b. Central diabetes insipidus. a Sagittal T1-weighted image; b Gd-enhanced sagittal T1-weighted image. The posterior bright spot is not visualized (arrow, a). Following gadolinium, both the anterior and the posterior lobes enhance Table 18.5. Rare conditions of CDI with persistent hyperintensity of the posterior pituitary lobe Familial autosomal dominant CDI Idiopathic or secondary CDI on initial MRI with subsequent disappearance of high signal during follow-up The normal residual tissue of the hypothalamic nuclei might explain this persistence, suggesting that MRI at the onset of disease might not be sensitive in these cases CDI associated with midline cerebral malformations, such as alobar holoprosencephaly or septooptic dysplasia A defect in hypothalamic function leading to failure of osmoreception, with normal synthesis and storage of vasopressin, has been suggested as mechanism of CDI in these cases

Table 18.6. Causes of central precocious puberty Idiopathic central precocious puberty CNS tumors Hamartoma of the tuber cinereum Hypothalamic and optic gliomas (often associated with neurofibromatosis 1) Other tumors (craniopharyngioma, pineal masses, suprasellar germinoma, astrocytoma, ependymoma, cerebral hemispheric and cerebellar tumors) Previous CNS injury Head trauma (associated with cerebral atrophy or focal encephalomalacia) Infections (meningitis, encephalitis, abscess) Cranial irradiation Hypoxic-ischemic encephalopathy Other CNS disorders Developmental abnormalities (especially those associated with seizures and mental retardation) Arachnoid cyst Hydrocephalus (even after shunting) Granuloma (tuberculous or sarcoid) Syndromes (neurofibromatosis 1, tuberous sclerosis, septo-optic dysplasia) Associated with GnRh-independent precocious puberty (long-standing congenital adrenal hyperplasia) From [46] modified.

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primarily located in the sellar or suprasellar region may deform or compress the hypothalamic-diencephalic structures, thus causing CPP. However, CPP may also occur in rare cases of cerebral hemispheric or cerebellar tumors not involving the hypothalamicdiencephalic structures [47]. Finally, we have seen a case of compensated tetraventricular hydrocephalus due to prior dural sinus thrombosis that presented with CPP, probably resulting from distortion of the hypothalamic region. Pituitary hyperplasia is generally reported to occur in CPP [11, 48]. Pituitary height is an index of hypothalamo-pituitary activation. It has been found to be in the pubertal range in girls with classical CPP, and normal for age in girls with only premature thelarche or mild forms of CPP [49]. On MRI, the anterior pituitary lobe is homogeneously enlarged and shows normal and homogeneous enhancement (Fig. 18.22).

a

Systematic studies of the size and shape of the pituitary gland in children with CPP compared with age-matched normal controls showed that change in pituitary grade is the most useful variable for the diagnosis of CPP [50]. Pituitary grade is defined by the concavity of the upper pituitary surface according to Elster’s grade (Fig. 18.23). However, the presence of a pituitary gland of normal size does not exclude CPP, since either normal or small glands have been described in cases of CPP with hypothalamic glioma [48]. In these cases, the smaller pituitary gland could be related to a functional effect of the hypothalamic tumor. We have observed a case of CPP in which MRI showed an intrasellar bony spur (Fig. 18.24). In another case, CPP was associated with a pituitary adenoma. When the initial MRI is negative, neuroimaging studies should be repeated after 6 months before a diagnosis of idiopathic CPP is made.

b

Fig. 18.22a, b. Pituitary hyperplasia in a 3-year-old girl. a Sagittal T1-weighted image; b Gd-enhanced coronal T1-weighted image. The anterior pituitary lobe is homogeneously enlarged and appears nearly spherical (arrowhead, a). Following gadolinium administration, it shows homogeneous enhancement (b)

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Fig. 18.23. Grading of the shape of the pituitary gland. Grade 1: a gland with a markedly concave superior surface; grade 2: minimal concavity of the gland (central depression less than 2 mm); grade 3: an essentially flat gland; grade 4: a minimal convexity (elevation less than 2 mm); and grade 5: a markedly convex round gland, appearing nearly spherical. (Modified from [16])

Sellar and Suprasellar Disorders

a

b

Fig. 18.24a, b. Central precocious puberty in a 7-year-old girl. a Sagittal T1-weighted image; b coronal T1-weighted image. Huge intrasellar osseous spur (arrows, a, b), originating from the quadrilateral plate and bulging into the pituitary fossa. The bright posterior pituitary lobe wraps around the spur, with a C-shape on the sagittal image (a) and a rounded shape on the coronal image (b)

18.6 Sellar and Suprasellar Mass Lesions The common clinical presentations of these disorders are summarized in Table 18.7.

images, about 50% are hyperintense, 25% isointense, and 25% hypointense [54]. Contrast enhancement is usually absent; when present, it is confined to a thin rim along the cyst wall, related to the compressed pituTable 18.7. Sellar and suprasellar disorders: common clinical presentations

18.6.1 Rathke’s Cleft Cysts Progressive accumulation of secretes within cysts of the pars intermedia gives rise to Rathke’s cleft cysts (RCC). RCC are congenital, intrasellar and/or suprasellar, benign epithelium-lined cysts containing mucoid material, accounting for fewer than 1% of all intracranial masses. They are rarely found in children. Over 50% of affected patients suffer from GH or prolactin deficiency, headaches, or visual impairment. Although RCC are commonly thought to arise from remnants of the Rathke’s pouch, which relates them to craniopharyngiomas, a possible origin from neuroepithelial tissue [51] or endoderm [52, 53] has been suggested. 18.6.1.1 Imaging Findings

CT density varies with cyst content; RCC are more commonly low density lesions, whereas mixed or high density is uncommon [54]. Calcifications are absent. On MRI (Fig. 18.25), they appear as rounded cysts whose signal behavior is highly variable both on T1- and T2weighted images. On T1-weighted images, about two thirds are hyperintense to brain and one third shows low signal intensity, similar to CSF. On T2-weighted

Hypopituitarism Craniopharyngioma Kallmann syndrome Septo-optic dysplasia Idiopathic Diabetes insipidus Langerhans cell histiocytosis Germ cell tumors Craniopharyngiomas Lymphocytic hypophysitis Tuberculosis Sarcoidosis Hypothalamic-pituitary malformations Precocious puberty Hamartoma of the tuber cinereum Hypothalamic glioma Choriocarcinoma Teratoma Pituitary adenoma Increased intracranial pressure Hydrocephalus Head trauma Hypoxic-ischemic brain injury Hypothalamic astrocytoma Langerhans cell histiocytosis Kallmann syndrome Nonfunctioning pituitary adenoma Delayed puberty Pituitary adenoma Rathke’s pouch cyst Amenorrhea From [73], modified.

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a

b

Fig. 18.25a–c. Rathke’s cleft cyst. a Sagittal T1-weighted image; b coronal T2weighted image; c Gd-enhanced coronal T1-weighted image. A huge cystic intrasellar lesion developing in the suprasellar region is shown. Signal intensity is slightly higher than that of CSF both on T1-weighted (a) and T2-weighted images (b). Following gadolinium, the right lateral aspect of the wall enhances due to residual adenohypophyseal tissue (arrow, c). Note stretched, elevated chiasm (arrowheads, a–c)

c

itary gland surrounding the cyst [54–56]. Knowledge of this enhancement pattern is of crucial importance in order to avoid surgical excision of normal pituitary tissue with consequent secondary hypopituitarism. 18.6.1.2 Differential Diagnosis

Differential diagnosis between craniopharyngioma and Rathke’s cleft cyst can be difficult on neuroimaging studies (Table 18.8). Other differential diagnoses include arachnoid cysts, cavitated pituitary adenomas, and inflammatory cysts.

18.6.2 Pituitary Adenomas Pituitary tumors are relatively uncommon in children, with only 2% of pituitary adenomas affecting the pediatric age group. They are more common in adolescents than in younger age groups [57, 58], and may occur in the setting of rare phakomatoses, such as the McCuneAlbright and Nelson syndromes (see chap. 17).

About 25% of pediatric adenomas are hormonally inactive. Nonfunctioning adenomas typically present with delayed puberty, short stature, or primary amenorrhea (in girls) [59]. Secreting adenomas generally produce prolactin, ACTH, or GH; therefore, they will produce a picture of delayed menarche, Cushing’s disease, or gigantism, respectively. Prepubertal children more frequently have ACTH-releasing adenomas, while pubertal and postpubertal patients are most likely to have prolactinomas [60]. The clinical presentation of prolactinoma varies with patient age and gender. Prepubertal children present with headache, visual disturbance, and growth failure; pubertal females present with symptoms of pubertal arrest and hypogonadism, possibly associated with galactorrhea; pubertal males may present with headache and visual impairment as well as pubertal arrest or growth failure. In our experience, pituitary adenoma has been associated with precocious puberty (see above). Pituitary apoplexy, characterized by sudden enlargement of a pituitary adenoma secondary to extensive tumor infarction or hemorrhage, seldom occurs in children and adolescents. Clinically, acute headache and visual loss are the main manifestations [61, 62].

Sellar and Suprasellar Disorders Table 18.8. Differential diagnosis between Rathke’s cleft cyst and craniopharyngioma

Type of lesion Size/common location Invasiveness Composition of walls Recurrence

Rathke’s cleft cyst

Craniopharyngioma

Retention cyst 8–30 mm/intrasellar No Single layer of columnar or cuboidal epithelium No

Tumor 0.5–10 cm/suprasellar Yes Thick layers of squamous or basal cells Yes

a

b

c

Fig. 18.26a–c. PRL-releasing microadenoma in an 18-year-old girl. a Coronal T1-weighted image; b coronal T2-weighted image; c Gd-enhanced coronal T1weighted image. The unenhanced coronal T1-weighted image shows indirect signs of microadenoma: rising of the pituitary diaphragm on the left and contralateral shift of the pituitary stalk; however, the lesion itself is isointense with the normal pituitary gland parenchyma, and is therefore not immediately visible. On the T2-weighted image, a rounded, markedly hypointense mass of about 9–10 mm of size is visible (arrows, b). Following gadolinium, the microadenoma is recognizable as a round hypointense area (arrows, c)

Imaging Studies

The imaging features of pituitary adenomas do not differ significantly from those of adults. Depending on size, they are categorized into microadenomas and macroadenomas. Microadenomas are smaller than 10 mm in diameter and lie entirely within the pituitary gland. They appear as small, hypointense masses on T1-weighted images. Some may only become apparent as nonenhancing spots within the gland on early postcontrast images (Fig. 18.26), whereas mild enhancement may be seen on delayed images [63]. Their appearance on T2-weighted images is variable. The pituitary stalk may or may not be displaced contralaterally, and the gland may show an upward convexity (Fig. 18.26). Thin coronal and sagittal sections both before and

after half-dose gadolinium injection must be obtained in order to minimize the risk of small lesions remaining undetected because of partial volume averaging. Macroadenomas are larger than 10 mm in diameter (Fig. 18.27). They are rare in children. They expand the gland, and may extend into the suprasellar cistern with a dumbbell shape on both sagittal and coronal sections. Sometimes, adenomas can be hemorrhagic, in which case they show high T1 signal intensity and variable T2 signal intensity due to the presence of hemoglobin degradation products in various proportions (Fig. 18.28). They may be mistaken for other lesions, such as craniopharyngiomas or Rathke’s cleft cysts, on MR studies [64, 65]. Differentiation of adenomas from craniopharyngiomas and chiasmatic gliomas is usually relatively straightforward on standard MRI studies. However,

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a

b

c

d Fig. 18.27a–d. GH-releasing macroadenoma in an 11-year-old acromegalic boy with McCune-Albright syndrome. a Sagittal T1weighted image; b coronal T2-weighted image; c Gd-enhanced coronal T1-weighted image; d axial CT scan. Huge lesion of the pituitary fossa extending cranially, with an anterior hemorrhagic portion (arrow, a). The lesion causes deformation of the chiasm and elevation of the A1 segments of the anterior cerebral arteries (arrows, b) in addition to the invasion of the right cavernous sinus (arrowhead, b). Following gadolinium administration, enhancement is moderate and diffuse (c). On CT scan (d), the lesion is spontaneously hyperdense, probably due to intralesional bleeding

a

b Fig. 18.28a, b. Hemorrhagic nonfunctioning microadenoma in a 5-year-old girl. a Sagittal T1-weighted image; b sagittal T2-weighted image. The lesion is markedly hyperintense on T1-weighted images (arrows, a) and shows mixed, but prevailingly hyperintense signal on T2-weighted images (arrows, b)

Sellar and Suprasellar Disorders

proton MR spectroscopy may be helpful in particularly difficult cases. Craniopharyngiomas show a prominent lipid peak, with only small quantities of other metabolites; astrocytomas are characterized by significant quantities of choline, NAA, and creatine, and a higher than normal choline/NAA ratio; adenomas may show a choline or lactate-lipid peak or no metabolites at all [66]. Either physiological pubertal pituitary hyperplasia or other causes of benign pituitary enlargement should also be considered in the differential diagnosis.

studies after restoration of normal hormone levels will usually clear the view (Fig. 18.29).

18.6.4 Langerhans Cell Histiocytosis Langerhans cell histiocytosis, previously known as histiocytosis X, is a rare reactive disorder of the reticuloendothelial system characterized by abnormal proliferation of Langerhans type histiocytes. It rarely involves the CNS, usually in disseminated forms, although isolated CNS disease has been reported [68]. CNS manifestations may result from epidural extension of bone lesions, spreading beneath the dura mater into the brain substance [69]. However, the most common intracranial manifestation is the involvement of the hypothalamic-pituitary axis, causing diabetes insipidus that can occur before, concurrently with, or many years after multisystem disease manifestations [40] (see above). Anterior pituitary dysfunction may be associated with diabetes insipidus [70]. Thin-section sagittal and coronal MR images display a characteristically thickened, intensely enhancing pituitary stalk (Fig. 18.30, 18.31). It should be remembered that the pituitary stalk lacks a bloodbrain-barrier; therefore, it normally enhances with contrast administration. Therefore, a careful evaluation of its thickness is extremely important. Absence of the posterior pituitary bright spot is typically associated (Fig. 18.30, 18.31). More on CNS manifes-

18.6.3 Pituitary Hyperplasia Physiological hyperplasia of the pituitary gland occurs during puberty (see above), whereas pathological pituitary hyperplasia may occur in several circumstances, including CPP, ectopic production of hypothalamic-releasing hormones from hypothalamic and nonpituitary tumors, and administration of exogenous estrogens [11, 16]. In primary hypothyroidism, insufficient amount of circulating thyroxine causes increased levels of thyrotropin-releasing hormones, with consequent pituitary gland enlargement resulting from lack of the normal negative feedback on the hypothalamus [11, 16]. Because benign pituitary hyperplasia can mimic macroadenomas, primary hypothyroidism should be excluded in any patient with pituitary enlargement [16, 67]; follow-up

a

b

Fig. 18.29a, b Pituitary hyperplasia in a child affected with hypothyroidism. a and b Sagittal T1-weighted images. There is marked enlargement of the adenohypophysis at presentation (a). Note dramatic reduction of size following treatment of hypothyroidism (b)

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a

b Fig. 18.30a, b. Langerhans cell histiocytosis. a Sagittal T1-weighted image; b Gd-enhanced sagittal T1-weighted image. The posterior bright spot is not visualized (a). The pituitary stalk is thickened (arrowhead, b)

a

b Fig. 18.31a, b. Langerhans cell histiocytosis and anomaly of the skull base. a Sagittal T1-weighted image; b Gd-enhanced coronal T1-weighted image. The Welcker’s angle (i.e., between the connecting lines of nasion, tuberculum sellae and basion) is about 90° in this patient; normally, the angle is not larger than 120–135°. This is due to the fact that the clivus is verticalized, and the dorsum sellae is elevated in this case. The pituitary gland is deformed and the posterior bright spot cannot be visualized. Following gadolinium administration, marked thickening of the pituitary stalk is seen (arrowhead, b)

tations of Langerhans cell histiocytosis can be found in Chapter 11.

18.6.5 Chiasmatic-Hypothalamic Astrocytoma 18.6.5.1 Epidemiology and Clinical Picture

Astrocytomas arising in the hypothalamus or optic chiasm and nerves account for 3%–5% of all pediatric brain tumors. Patient age is usually 2–4 years at presentation. In around 50% of cases they occur in the

setting of neurofibromatosis type 1 (NF1). Specific findings of chiasmatic-hypothalamic astrocytomas in NF1 are described in Chapter 16. Affected patients usually complain of visual loss that usually progresses slowly, so that tumors are generally large at diagnosis. Endocrine dysfunction is seen in around 20% of cases. Hydrocephalus can result from large tumors extending into the third ventricle or obstructing the foramina of Monro. Small children may present with a diencephalic syndrome (emaciation, pallor, alertness, and hyperactivity). Clinical findings are helpful for differentiating chiasmatic-hypothalamic astrocytomas from other lesions, such as craniopharyngiomas, germ cell

Sellar and Suprasellar Disorders

tumors, hypothalamic hamartomas, tuberculosis, and sarcoidosis (Table 18.7). 18.6.5.2 Biological Behavior and Neuropathology

Histologically, most of these tumors are pilocytic astrocytomas, but fibrillary and anaplastic variants are also possible [64]. They may be multilobular, oval, or rounded in shape, usually with well-defined margins. Cystic-necrotic changes are almost exclusive of isolated forms, whereas NF1-associated tumors are predominantly solid (see Chapter 16). Tumor extension may occur in all directions, i.e., superiorly into the third ventricle, inferiorly into the sella turcica and planum sphenoidale, posteriorly into the interpeduncular fossa with compression and/or displacement of the brainstem and mammillary bodies, anteriorly along the floor of the anterior cranial fossa with displacement of the frontal lobes, and laterally with displacement of the medial temporal lobes. Although the lesion is usually stable, cases showing leptomeningeal spread at presentation have been reported. These chiasmatic-hypothalamic astrocytomas typically belong to the pilomyxoid subgroup

a

c

[71] (Fig. 18.32). Pilomyxoid astrocytomas show a combination of monomorphous pilomyxoid histological pattern, hypothalamic-chiasmatic location, prominent tendency to CSF spread of disease, very young patient age, and less favorable prognosis than pilocytic astrocytomas [71]. Distant spread may occur even before the primary hypothalamic lesion is detected [72]. 18.6.5.3 Imaging Studies

To discriminate between the chiasmatic or hypothalamic origin of these masses is often unsuccessful, since most tumors are of considerable size and have already involved both structures at presentation [64]. In some instances, clinical features are helpful to individuate the primary growth site. However, treatment modalities are not affected by location. MRI depicts these tumors as multilobular or, more rarely, oval or rounded masses that are usually well-marginated (Figs. 18.33, 18.34). Growth occurs mainly along the visual pathways, both anteriorly and posteriorly, but may occur in all directions. Chiasmatic-hypothalamic astrocytomas are usually

b

d

Fig. 18.32a–d. Diencephalic pilomyxoid astrocytoma with leptomeningeal spread. a and b Gd-enhanced sagittal T1-weighted images; c Gd-enhanced axial T1-weighted image; d Gd-enhanced sagittal T1weighted image of the spine. A primary lesion of the hypothalamic region is shown. Several enhancing leptomeningeal nodular metastases are recognizable (a–d). Two of them involve the internal auditory canals (arrows, c), enveloping the facial and vestibulocochlear nerves

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a

b

c

d

Fig. 18.33a–d. Chiasmatic-hypothalamic astrocytoma in a 3-year-old boy. a Sagittal T1-weighted image; b axial T1-weighted image; c axial T2-weighted image; d Gd-enhanced axial T1-weighted image. Huge chiasmatic-hypothalamic mass. The lesion shows heterogeneous signal intensity changes on T1- (a, b) and T2-weighted images (c). Following gadolinium, necrotic changes are seen as persistently hypointense areas (d). Note that the gross morphology of the prechiasmatic portion of the left optic nerve and tract (arrows, b, c) is still recognizable. The mass deforms and compresses the midbrain (arrowheads, a–c) and fills the third ventricle (a) extending beyond the plane of the foramina of Monro. Anteriorly, scalloping of the planum sphenoidale is visible (open arrow, a). The posterior pituitary lobe is not recognizable (a)

hypointense on T1-weighted images and hyperintense on T2-weighted images; high signal intensity extending along the optic tracts may represent either infiltration or edema. Signal intensity may be heterogeneous within large masses. Contrast enhancement is generally marked, but may be moderate or even absent is some cases; it may involve the peripheral portion of the lesion, with a central unenhancing portion that reproduces the shape of the visual pathways (Fig. 18.34). Cystic-necrotic changes are well recognizable after gadolinium injection sequences. Contrast material administration is mandatory not only to assess the extent of the mass, but also to recognize leptomeningeal seeding in case of pilomyxoid forms, which are otherwise undistinguishable from pilocytic forms (Fig. 18.32). In our experience, tumor cysts with solid mural nodules have been rare (Fig. 18.35), contrary to cerebellar and cerebral hemisphere astrocytomas.

On CT, they are usually low-density masses that enhance variably and heterogeneously after iodized contrast administration [73]. Bone windows may reveal enlargement of the optic canals in case of anterior extension [73]. Proton MRS shows increased choline and diminished NAA levels. As described above, MRS can be useful for differentiating among suprasellar astrocytomas, craniopharyngiomas, and pituitary adenomas [66].

18.6.6 Craniopharyngiomas 18.6.6.1 Epidemiology and Clinical Picture

Craniopharyngiomas are benign, partly cystic epithelial tumors with a variably aggressive course. They account

Sellar and Suprasellar Disorders

a

c

a

b

Fig. 18.34a–c. Chiasmatic-hypothalamic astrocytoma in a 6-month-old boy. a Sagittal T1-weighted image; b Gd-enhanced axial T1-weighted image; c Gd-enhanced coronal T1-weighted image. There is a huge chiasmatic-hypothalamic neoplasm that is hypointense on T1-weighted images (a). Following gadolinium injection, note the bizarre appearance of the neoplasm, with thick enhancement enveloping the enlarged optic pathways (arrows, b, c)

b

Fig. 18.35a, b. Chiasmatic-hypothalamic astrocytoma in a 1-year-old boy. a Gd-enhanced sagittal T1-weighted image; b Gd-enhanced axial T1-weighted image. Huge chiasmatic-hypothalamic neoplasm showing a nonenhancing portion (asterisk, a). Marginal cysts are clearly visible in the axial MR images (asterisks, b). Sectorial enhancement of the cyst walls are seen (arrows, b)

for 5%–13% of all intracranial tumors, and 50% of all suprasellar masses in the pediatric age group. They are the most common nonglial tumor in childhood [74, 75]. There is a bimodal incidence peak, at 5–14 years of age and in the 4th–6th decade of life, respectively. Males are more commonly affected than females are [76]. Clinically, affected children commonly present with nonendocrine symptoms, such as headache and visual disturbances (most commonly bitemporal hemianopsia

due to central chiasmatic compression). However, up to 80% have evidence of endocrine dysfunction at diagnosis [77]. Affected children show poor growth due to GH deficiency (75% of cases), and may also have gonadotropin deficiency (40% of cases) and ACTH/TSH deficiency (25% of cases). Hydrocephalus due to obstruction of the aqueduct or foramina of Monro may occur when the mass is sufficiently large. Hearing loss due to posterior fossa involvement has been rarely reported [78].

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18.6.6.2 Biological Behavior and Neuropathology

These tumors arise from remnants of the craniopharyngeal duct, connecting the stomodeal ectoderm with the evaginated Rathke’s pouch. Therefore, they belong to a continuum of ectodermally derived cystic epithelial lesions that includes Rathke’s cleft cysts, epithelial cysts, and epidermoid/dermoid cysts [79]. Due to their histological origin, they are typically located along the pituitary stalk. Therefore, they may be intrasellar (25% of cases), suprasellar, or a combination of both [80]. The typical suprasellar lesion originates from the infundibulo-tuberal region and extends either in front of or behind the chiasmatic region, creating different approach problems to the surgeon [81]. The mammillary bodies and mesen-

a

b

c

d

cephalon are typically displaced posteriorly and slightly to moderately elevated. Occasionally, craniopharyngiomas may purely grow within the third ventricle; in this case, the mammillary bodies are splayed and the midbrain is not elevated. When the pituitary fossa is involved, the tumor has an hourglass shape and erodes the tuberculum and dorsum sellae. Tumor extension into the frontal lobes and into lateral ventricles has been reported [75, 82]. Giant craniopharyngiomas may involve the posterior fossa, where they occupy the prepontine cistern [78]; a finger-glove appearance may result from the basilar artery impinging on the caudal surface of the tumor (Fig. 18.36). Nasopharyngeal involvement is extremely rare. In these cases, involvement is either from the sella or primitively from the sphenoid bone or nasopharynx (“ectopic craniopharyngioma”) [83].

Fig. 18.36a–d. Adamantinous craniopharyngioma in a 4-year-old girl. a Sagittal T1-weighted image; b axial T2-weighted image; c Gd-enhanced axial T1-weighted image; d axial CT scan. Huge neoplasm that is homogeneously hypointense on T1-weighted (a) and hyperintense on T2-weighted images (b). It causes elevation of the floor of the third ventricle (black arrows, a) and compression of the midbrain and pons. The lesions shows caudad extension into the prepontine cistern with a “finger-glove” appearance (white arrow, a). The basilar artery (arrowhead, a), posterior communicating arteries (“PcoA,” b), proximal portion of the posterior cerebral arteries (“PCA,” b), and superior cerebellar arteries (“SCA,” b) are encased by the lesion. The posterior pituitary bright spot is recognizable (open arrow, a). The chiasm (“C,” a) is anterior to the lesion. Following gadolinium, the walls enhance (arrowheads, c). The lesion is homogeneously hypodense on CT scan; small calcifications are seen along its walls (arrow, d)

Sellar and Suprasellar Disorders

a

b

c

d Fig. 18.37a–d. Craniopharyngioma developing into the third ventricle in a 8-year-old boy. a Sagittal T1-weighted image; b axial T2-weighted image; c Gd-enhanced coronal T1-weighted image; d axial CT scan. Hypothalamic mass showing totally suprasellar development into the third ventricle, posterior to the optic chiasm (“C,” a). Note that the mammillary bodies are splayed (arrows, b). The chiasm and the optic tracts are hyperintense (arrowheads, b) due to edema. The lesion is isointense on T1-weighted images (a), markedly hyperintense on T2-weighted image (b), and shows a subtle rim of enhancement along its walls (arrows, c). Punctuate calcifications are visible in the most caudal portion of the mass on CT scan (d)

Finally, unusual ectopic locations such as the pineal region have been rarely reported [82]. Pathologically, craniopharyngiomas are categorized into two variants, adamantinous and squamous-papillary. These forms differ histologically, clinically and radiologically, suggesting a different pathogenesis [84] (Table 18.9). Adamantinous craniopharyngiomas are cystic or predominantly cystic lobulated tumors, typical of childhood and only occasionally found in adults. Histologically, a typical adamantinomatous epithelium with peripheral palisading of a single cell layer bordering clusters of loose stellate cells is found, in association with various amounts of “wet” keratin and keratohyaline granules; other components, such as cysts, cholesterol clefts, inflammation, giant cell reaction, and calcifications, are present in various quantities [74]. Squamous-papillary craniopharyngiomas are typical of adults, and are believed to arise from squamous epithelial cells in the pars tuberalis of the adenohypophysis. They usually appear as predominantly solid or mixed solid-cystic spherical suprasellar masses.

18.6.6.3 Imaging Studies

Castillo and Mukherji [23] defined the “rule of the 90s” that characterizes craniopharyngiomas: 90% are cystic, 90% have calcifications, 90% enhance, and over 90% are suprasellar in location. On MRI, craniopharyngiomas show the most heterogeneous spectrum of signal behavior of all sellar/suprasellar masses. The most common pattern is represented by a cystic lesion that is hypo-isointense on T1-weighted and hyperintense on T2-weighted images, with enhancing walls and subtle calcifications (Figs. 18.36, 18.37). However, some cysts may be hyperintense on T1-weighted images (Fig. 18.38). Although the cysts may contain various amounts of cholesterol, triglycerides, methemoglobin, protein, and desquamated epithelium, increased signal intensity on T1-weighted images basically results from protein concentration greater than or equal to 90 g/L and/or presence of free methemoglobin, whereas the concentration of cholesterol and triglycerides bears no significant influence on signal behavior [85].

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Solid tumor components, often located in the intra- or parasellar region, are iso-hyperintense in T1-weighted images, and show variable signal intensity on T2-weighted images, partly due to the presence Table 18.9. Main differences between adamantinous and squamous-papillary craniopharyngioma Adamantinous craniopharyngioma Age Location

Children Suprasellar

Squamous-papillary craniopharyngioma

Adults Intra-suprasellar or suprasellar Tissue structure Predominantly cystic Predominantly solid Tumor shape Mostly lobulated Mostly spherical Calcifications Yes Yes Contrast Solid portion Global enhancement Cyst walls

of calcification (Fig. 18.38). These solid parts typically enhance following gadolinium administration. Craniopharyngiomas produce variable deformity of the ventricular system, most often an elevation of the floor of the third ventricle that is associated with elevation and deformation of the optic chiasm [74]. The pituitary stalk and the posterior pituitary “bright spot,” albeit compressed and distorted, are usually preserved, even with large craniopharyngiomas (Figs. 18.36, 18.37, 18.39); this sign can be useful in the differential diagnosis with other neoplastic and nonneoplastic conditions occurring in this region. Encasement of adjacent vessels, especially of the circle of Willis (Fig. 18.36), is another recognized feature of craniopharyngiomas and represents an obstacle to radical surgery. MRI may not easily dif-

a b

c

d Fig. 18.38a–d. Adamantinous craniopharyngioma in a 4-year-old girl. a Axial CT scan; b sagittal T1-weighted image; c axial T2weighted image; d Gd-enhanced coronal T1-weighted image. Large neoplasm located in the sellar/suprasellar region characterized by a posterior solid, partially calcified, sellar-extrasellar component on CT scan and by a larger anterior hypodense, cystic portion extending into the left frontal region (asterisk, a). On T1-weighted images, the cystic component is spontaneously hyperintense and deforms and compresses the genu of the corpus callosum (arrow, b); the intrasellar component is more markedly hyperintense. Notice the lesion is anterior to third ventricle (“3 v,” b). On the T2-weighted image, a fluid–fluid level is recognizable within the cystic portion, that is markedly hyperintense also on this sequence (arrowhead, c). Following gadolinium administration, there is mild enhancement along the cyst walls (arrowheads, d)

Sellar and Suprasellar Disorders

ferentiate infiltration of the brain parenchyma from remodeling of the brain around the tumor, although invasion into brain is seen in surgical specimens in 15% of cases [74]. Evidence of invasion of the third ventricle and identification of the optic chiasm are crucial information

a

b

c

d

e

for the neurosurgeon. Invasion of the third ventricle is difficult to demonstrate conclusively with MRI; useful signs include absence of elevation and stretching of the midbrain, increased distance between lamina terminalis and third ventricular floor in sagittal images, and splayed mammillary bodies on axial images (Fig. 18.37).

Fig. 18.39a–e. Adamantinous craniopharyngioma in a 13year-old girl presenting with visual disturbances; neither diabetes insipidus nor endocrine dysfunction were present. a Sagittal T1-weighted image; b sagittal T2-weighted image; c Gd-enhanced sagittal T1-weighted image; d axial CT scan; e three-dimensional reconstruction. Huge mass extending from the sellar floor up to the foramen of Monro. The lesion is markedly hypointense on T1-weighted (a) and hyperintense on T2-weighted images (b), and shows marginal cyst at the superior pole (asterisk, a–c). Following gadolinium administration, the whole solid lesion and the walls of the cyst enhance markedly and slightly inhomogeneously. The anterior third ventricle is amputated (arrows, a) and the mammillary bodies (“MB,” a, b) are displaced. Note that the posterior pituitary lobe, albeit deformed and stretched, is still visible as a thin, spontaneously hyperintense stripe along the posterior margin of the tumor (arrowhead, a). CT scan (d) shows multiple small nodular calcifications prevailingly along the right antero-lateral surface of the mass. Multiplanar, 1 mmthick reformatted images from a 3DRFT sequence (e) allow identification of the position of the optic nerves and tracts (arrowheads, E1 and E3), located laterally to the mass, and of the chiasm (arrows, E2 and E4), located postero-superiorly. This information is crucial for the neurosurgeon

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The optic nerves and chiasm can be markedly distorted and stretched. Although three-dimensional MRI studies with submillimeter triplanar reconstructions may increase diagnostic confidence, they are not always conclusive, and an extremely thinned optic chiasm may be extremely difficult to localize (Fig. 18.39). CT shows variable density patterns, ranging from hypodensity (Fig. 18.36) to isodensity (Figs. 18.38, 18.39). CT is superior to MRI in the identification of calcifications, which represent a hallmark of craniopharyngiomas; therefore, CT scans should always be obtained in case of suprasellar tumors. Morphologically, calcifications may appear as shell-like deposits along the cyst walls (Figs. 18.36, 18.38), or may form fine punctuations or lumps within the substance of the lesion (Figs. 18.37, 18.39). Squamous-papillary forms are rare in childhood and the differential diagnosis with a germinoma may be difficult. Furthermore, the adamantinous forms may show imaging findings quite similar to those of the squamouspapillary forms, thus rendering differential diagnosis practically impossible on imaging alone (Fig. 18.39). Mixed tumors, with histological combination of papillary and adamantinous parts within the same neoplasm, have been described in 15% of cases [86]; however, these mixed tumors are clinically and radiologically similar to the purely adamantinous forms [84].

18.6.7 Suprasellar Germinoma The suprasellar region is the second most common location of intracranial germinomas after the pineal

region. Between 5%–10% of germinomas simultaneously involve both the suprasellar and pineal region at presentation (see Chapter 10). It is unclear whether bifocal disease represents secondary spread of the tumor to the infundibular recess of the third ventricle or, rather, simultaneous development of tumors in two sites [87]. An excess of suprasellar germ cells tumors are encountered in girls [72]. These tumors arise in the second decade of life with incidence peak at 10–12 years. Affected children show evidence of hypothalamic-pituitary dysfunction, most commonly including diabetes insipidus but also delayed sexual development, precocious puberty, hypopituitarism, and/or isolated growth failure. 18.6.7.1 Imaging Studies

CT and MRI features of suprasellar germinomas do not differ significantly from those of pineal germinomas. CT shows a spontaneously hyperdense lesion. On MRI, the mass is iso-hypointense to gray matter on T1-weighted images (Figs. 18.40, 18.41) and isointense on T2-weighted images (Fig. 18.42); contrast enhancement is usually moderate to marked (Figs. 18.40–43). Calcification of a suprasellar germinoma is a rare event [88], whereas cystic-necrotic change appears to be more common than with pineal tumors (Fig. 18.41). Midsagittal T1-weighted images obtained in patients with secondary diabetes insipidus characteristically display absence of the “bright spot” corresponding to the posterior pituitary lobe (Figs. 18.40, 18.41, 18.43). Sometimes, suprasellar germinomas infiltrate the anterior optic pathways (Fig. 18.43). It is important

a

b Fig. 18.40a, b. Suprasellar germinoma in a 11-year-old girl. a Sagittal T1-weighted image; b Gd-enhanced sagittal T1-weighted image. Mass of the hypothalamic-hypophyseal region. The posterior bright spot is not recognizable (a), whereas the anterior pituitary lobe is seen following gadolinium (arrows, b) as a deformed and compressed structure

Sellar and Suprasellar Disorders

a

b Fig. 18.41a, b. Suprasellar germinoma in a 12-year-old girl. a Sagittal T1-weighted image; b Gd-enhanced coronal T1-weighted image. Mass of the hypothalamic-hypophyseal region. Following gadolinium, necrotic areas are easily recognizable as persistent hypointensities. The lesions extends cephalad and amputates the anterior third ventricle (thin arrow, a), reaching a plane immediately below the foramen of Monro (b). Sagittal image shows association with a pineal cyst (arrowhead, a), a persistent cavum veli interpositi (asterisk, a), and a falcine sinus (open arrows, a). The posterior pituitary lobe is not recognizable

b a

Fig. 18.42a–c. Metastatic germinoma in a 10-yearold boy. a Gd-enhanced sagittal T1-weighted image; b Gd-enhanced axial T1-weighted image; c axial T2-weighted image. Huge mass of the hypothalamic-hypophyseal region (a). Secondary lesions involve the pineal gland (arrowhead, a), the fourth ventricle (arrow, a) and the choroid plexus of the right foramen of Luschka (arrow, b). On the T2weighted image a subtle diffusion to the ependyma of the frontal horns is seen (arrows, c); this finding was confirmed on postcontrast T1-weighted images (not shown). The lesion is isointense with gray matter on the T2-weighted image

c

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a

b

c

d Fig. 18.43a–d. Suprasellar germinoma in a 10-year-old girl. a Sagittal T1-weighted image; b-d Gd-enhanced coronal T1-weighted images. There is enlargement of the infundibulum, median eminence, and chiasm (arrowheads, a); the “bright spot” is not visible. Following gadolinium administration, there is marked enhancement of the prechiasmatic optic nerves (arrows, b), optic chiasm (arrows, c), and the lateral walls of the anterior third ventricle (arrows, d)

to be aware that in children suffering from diabetes insipidus showing absence of visualization of the posterior “bright spot,” a small germinoma could not yet be visible on the initial MR images. A close follow-up with repeated imaging studies should therefore be carried out in these patients.

18.6.8 Hamartoma of the Tuber Cinereum (Hypothalamic Hamartoma) Hypothalamic hamartomas are relatively rare nontumoral congenital malformations, composed of normal, albeit heterotopic, neuronal tissue and glia resembling the normal histological pattern of the tuber cinereum. Hypothalamic hamartomas are located in the region of the tuber cinereum, where they attach with a sessile or pedunculated base, either projecting into the interpeduncular cistern or bulging into the third ventricle. Suprasellar locations

have been exceptionally described in the pediatric age group [89]. Clinically, they may be asymptomatic or associated with precocious puberty and/or gelastic seizures. Males are affected more commonly than females are. On MRI, they appear as round to oval masses located within or attached to the tuber cinereum (Figs. 18.44, 18.45). Their size may vary from a few millimeters to 4 centimeters in diameter. Occasionally, large associated cysts may be seen in the suprasellar cistern that may extend into the middle cranial fossa [73]. Characteristic MRI features involve a nonenhancing, well-defined mass that is isointense to gray matter in both T1-weighted (Fig. 18.44) and T2-weighted images [73, 89]. However, the lesion may sometimes be hyperintense on T2-weighted (Fig. 18.45) and FLAIR images. Increased T2 signal intensity can make differentiation from glial and mixed glial-neuronal tumors difficult. After gadolinium administration, the mass typically does not enhance (Fig. 18.45).

Sellar and Suprasellar Disorders

Hypothalamic hamartoblastomas are very rare. They are composed of immature neurons, lacking atypia or mitotic activity, and are more cellular than hypothalamic hamartomas. They are usually associated with the Pallister-Hall syndrome [9].

18.6.9 Suprasellar Arachnoid Cysts Suprasellar arachnoid cysts are described in Chapter 21. Fig. 18.44. Hamartoma of the tuber cinereum in a 27-monthold girl with central precocious puberty. Sagittal T1-weighted image. There is a small mass at the level of the tuber cinereum (arrow), well-differentiated from the mammillary bodies that are located immediately behind (“MB”). The lesion is isointense with gray matter

18.6.10 Lymphocytic Hypophysitis Lymphocytic hypophysitis is an autoimmune disorder of the pituitary gland that occurs especially in adults, but is also described in the pediatric age group [73]. It has been traditionally considered to be confined to the anterior pituitary lobe and causally

a

b

c

Fig. 18.45a–c. Central precocious puberty and gelastic seizures in a 5-yearold boy. a Sagittal T2-weighted image; b Gd-enhanced sagittal T1-weighted image; c Gd-enhanced coronal T1-weighted image. Huge, unenhancing neoplasm that is hyperintense with respect to the cortex on T2-weighted image (asterisk, a) and hypointense on T1-weighted images (asterisk, b). The lesion is attached with a wide sessile base to the inferior surface of the hypothalamus, extending from the median eminence to the midbrain. On coronal planes, the lesion also attaches to the left optic tract (arrow, c)

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related to pregnancy or the postpartum period. However, it is now accepted that three types of hypophysitis may be identified: lymphocytic adenohypophysitis, lymphocytic infundibuloneurohypophysitis, and lymphocytic hypophysitis (i.e., involving both the anterior and posterior pituitary lobes) [90, 91]. The most common clinical presentation of adenohypophysitis is headache and impaired vision; endocrinologic dysfunction may be identified with specific testing. Infundibuloneurohypophysitis may cause diabetes insipidus [91]. Imaging Findings

On MRI, the hypothalamus, infundibulum and pituitary gland may be enlarged. Contrast enhancement is uniformly present [73]. Lymphocytic adenohypophysitis is characterized by symmetrical enlargement of the pituitary gland, often associated with compression of the optic chiasm; enhancement is homogeneous [90].

Lymphocytic infundibuloneurohypophysitis shows absence of the “bright spot” of the posterior lobe on T1-weighted images and thickening of the pituitary stalk (Fig. 18.46); global enlargement of the pituitary gland is associated in case of global hypophysitis [90]. On the whole, the MR appearance of lymphocytic hypophysitis is similar to that of suprasellar germinomas or Langerhans cell histiocytosis, with which it may be confused [73]; follow-up studies after treatment will usually clear the view (Fig. 18.46). Granulomatous hypophysitis is an inflammatory disorder mainly affecting the anterior lobe of the pituitary gland, with possible extension to the posterior lobe, pituitary stalk, and hypothalamus [92]. It is an isolated disorder of the pituitary gland, distinct from systemic granulomatous disorders. On the basis of ultrastructural similarities, a common pathogenetic background for lymphocytic and granulomatous hypophysitis has been suggested. The MRI appearance is similar to that of lymphocytic hypophysitis [92].

a

b

c

Fig. 18.46a–c. Lymphocytic hypophysitis in a 4-year-old girl. a Sagittal T1weighted image and b Gd-enhanced sagittal T1-weighted image at presentation; c Gd-enhanced T1-weighted image at 8 months follow-up after steroid treatment. There is absent visualization of the posterior pituitary bright spot and marked thickening of the infundibulum (arrow, a), showing marked enhancement following gadolinium administration (arrow, b). The MR picture is not specific at this stage. However, follow-up study after steroid treatment shows marked reduction in thickness of the infundibulum, which is now almost normal (arrow, c), supporting the hypothesis of hypophysitis

Sellar and Suprasellar Disorders

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57. Haddad SF, Van Gilder JC, Menezes AH. Pediatric pituitary tumors. Neurosurgery 1991; 29:509-514. 58. Laws ER, Sheithauer BW, Groover RV. Pituitary adenomas in childhood and adolescence. Prog Exp Tumor Res 1987; 30:359-361. 59. Abe T, Lüdecke DK, Saeger W. Clinically nonsecreting pituitary adenomas in childhood and adolescence. Neurosurgery 1998; 42:744-751. 60. Mindermann T, Wilson CB. Pediatric pituitary adenomas. Neurosurgery 1995; 36:259-269. 61. Bills DC, Meyer FB. A retrospective analysis of pituitary apoplexy. Neurosurgery 1993; 33:602-609. 62. Shah S, Pereira J, Becker C, Aronin P. Pituitary apoplexy in adolescence: case report. Pediatr Radiol 1995; 25:S26-S27. 63. Sakamoto Y, Takahashi M, Korogi Y, Bussaka H, Ushio Y. Normal and abnormal pituitary glands: gadopentate dimeglumine-enhanced MR imaging. Radiology 1991; 178:441-445. 64. Kollias SS, Barkovich AJ, Edwards MSB. Magnetic resonance analysis of suprasellar tumors of childhood Ped Neurosurg 1991-92; 17:284-303. 65. Poussaint TY, Barnes PD, Anthony DC, Spack N, Scott RM, Tarbell NJ. Hemorrhagic pituitary adenomas of adolescence. AJNR Am J Neuroradiol 1996; 17:1907-1912. 66. Sutton LN, Wang ZJ, Wehrli SL, Marwaha S, Molloy P, Phillips PC, Zimmerman RA. Proton spectroscopy of suprasellar tumors in pediatric patients. Neurosurgery 1997; 41:388-395. 67. Young M, Kattner K, Gupta K. Pituitary hyperplasia resulting from primary hypothyroidism mimicking macroadenomas. Br J Neurosurg 1999; 13:138-142. 68. Strottman JM, Ginsberg LE, Stanton C. Langerhans cell histiocytosis involving the coprus callosum and cerebellum: gadolinium-enhanced MRI. Neuroradiology 1995; 37:289292. 69. Saatci I, Baskan O, Haliloglu M, Aydingoz U. Cerebellar and basal ganglion involvement in Langerhans cell histiocytosis. Neuroradiology 1999; 41:443-446. 70. Broadbent V, Dunger DB, Yeomans E, Kendall B. Anterior pituitary function and computed tomography/magnetic resonance imaging in patients with Langerhans cell histiocytosis and diabetes insipidus. Med Pediatr Oncol 1993; 21:649-654. 71. Tihan T, Fisher PG, Kepner JL, Godfraind C, McComb RD, Goldthwaite PT, Burger PC. Pediatric astrocytomas with monomorphous pilomyxoid features and a less favorable outcome. J Neuropathol Experimental Neurol 1999; 58:1061-1068. 72. Kleihues P, Cavenee WK. Pathology and Genetics, Tumors of the Nervous System. Lyon, France: IARC Press, 1997:207214. 73. Barkovich AJ. Pediatric Neuroimaging, 3nd edn. Philadelphia: Lippincott Williams & Wilkins, 2000. 74. Eldevik OP, Blaivas M, Gabrielsen TO, Hald JK, Chandler WF. Craniopharyngioma: radiologic and histologic findings and recurrence. AJNR Am J Neuroradiol 1996; 17:14271439. 75. Taguchi Y, Tanaka K, Miyakita Y, Sekino H, Fujimoto M. Recurrent craniopharyngioma with nasopharyngeal extension. Pediatr Neurosurg 2000; 32:140-144. 76. Bunin GR, Surawicz TS, Witman PA, Preston-Martin S, Davis F, Bruner JM.The descriptive epidemiology of craniopharyngioma. J Neurosurg 1998; 89:547-551. 77. Sklar CA. Craniopharyngioma: endocrine abnormalities at presentation. Pediatr Neurosurg 1994; 21 (Suppl 1):18-20.

Sellar and Suprasellar Disorders 78. Buhl R, Lang EW, Barth H, Mehdorn HM. Giant cystic craniopharyngiomas with extension into the posterior fossa. Childs Nerv Syst 2000; 16:138-142. 79. Harrison MJ, Morgello S, Post KD. Epithelial cystic lesions of the sellar and parasellar region: a continuum of ectodermal derivatives? J Neurosurg 1994; 80:1018-1025. 80. Lafferty AR, Chrousos GP. Pituitary tumors in children and adolescents. J Clin Endocrinol Metab 1999; 84:4317-4323. 81. Raybaud C, Rabehanta P, Girard N. Aspects radiologiques des craniopharyngiomes. Neurochirurgie 1991; 37:44-58. 82. Usanov EI, Hatomkin DM, Nikulina TA, Gorban NA. Craniopharyngioma of the pineal region. Childs Nerv Syst 1999;15:4-7. 83. Benitez WI, Sartor KJ, Angtuaco EJC. Craniopharyngioma presenting as a nasopharyngeal mass: CT and MR findings. J Comput Assist Tomogr 1988; 12:1068-1072. 84. Sartoretti-Schefer S, Wichmann W, Aguzzi A, Valavanis A. MR differentiation of adamantinous and squamous-papillary craniopharyngiomas. AJNR Am J Neuroradiol 1997; 18:77-87. 85. Ahmadi J, Destian S, Apuzzo ML, Segall HD, Zee CS. Cystic fluid in craniopharyngiomas: MR imaging and quantitative analysis. Radiology 1992; 182:783-785.

86. Crotty TB, Scheithauer BW, Young WF, Davis DH, Shaw EG, Miller GM, Burger PC. Papillary craniopharyngioma: a clinicopathological study of 48 cases. J Neurosurg 1995; 83:206-214. 87. Packer RJ, Cohen BH, Coney K. Intracranial germ cell tumors. Oncologist 2000; 5:312-320. 88. Chang CG, Kageyama N, Kobayashi T, Yoshida J, Negoro M. Pineal Tumors: clinical diagnosis, with special emphasis on the significance of pineal calcification. Neurosurgery 1981; 8:656-668. 89. Boto GR, Esparza J, Muñoz MJ, Hinojosa J, Muñoz A. Hamartoma of the suprasellar cistern in a 5-year-old girl. Childs Nerv Syst 1999; 15:131-133. 90. Tamiya A, Saeki N, Kubota M, Oheda T, Yamaura A. Unusual MRI findings in lymphocytic hypophysitis with central diabetes insipidus. Neuroradiology 1999; 41:899-900. 91. Sato N, Sze G, Endo K. Hypophysitis: endocrinologic and dynamic MR findings. AJNR Am J Neuroradiol 1998; 19:439-444. 92. Honegger J, Fahlbusch R, Bornemann A, Hensen J, Buchfelder M, Müller M, Nomikos P. Lymphocytic and granulomatous hypohysitis: experience with nine cases. Neurosurgery 1997; 40:713-723.

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Accidental Head Trauma

19 Accidental Head Trauma Paolo Tortori-Donati, Andrea Rossi, and Roberta Biancheri

19.1 Birth Trauma

CONTENTS 19.1

Birth Trauma 893

19.1.1 19.1.2 19.1.2.1 19.1.2.2 19.1.2.3 19.1.3 19.1.3.1 19.1.3.2 19.1.3.3 19.1.3.4 19.1.3.5 19.1.4 19.1.4.1 19.1.4.2 19.1.4.3 19.1.4.4

Introduction 893 Extracranial Hemorrhage 894 Caput Succedaneum 894 Subgaleal Hemorrhage 894 Cephalohematoma 894 Intracranial Hemorrhage 895 Epidural Hematoma 896 Subdural Hematoma 896 Subarachnoid Hemorrhage 896 Intraventricular Hemorrhage 897 Parenchymal Hemorrhage and Contusions 897 Skull Fractures 897 Linear Skull Fractures 897 Depressed Fractures 898 Occipital Osteodiastasis 898 Overlapping of Calvarial Bones 898

19.2

Postnatal Trauma

19.2.1 19.2.2 19.2.3 19.2.4 19.2.4.1 19.2.4.2 19.2.4.3 19.2.4.4 19.2.5 19.2.5.1 19.2.5.2 19.2.5.3 19.2.6

Introduction 898 Imaging Studies 901 Skull Fractures 903 Extra-Axial Hemorrhage 903 Epidural Hematomas 903 Subdural Hematomas 907 Subarachnoid Hemorrhage 909 Intraventricular Hematoma 911 Parenchymal Injury 911 Contusions 911 Cerebral Hematomas 913 Diffuse Axonal Injury 913 Secondary Effects and Sequelae of Head Trauma 917 Brain Swelling/Cerebral Edema 917 Cerebral Herniations 920 Cerebral Ischemia and Infarction 922 Vascular Damage 923 Infections 924 Hydrocephalus 925

19.2.6.1 19.2.6.2 19.2.6.3 19.2.6.4 19.2.6.5 19.2.6.6

References

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19.1.1 Introduction The terms “birth trauma” and “perinatal trauma” refer to injuries occurring during labor or delivery [1]. Although these terms are sometimes used broadly, only the adverse effects caused primarily by mechanical factors (Table 19.1) should be considered under these headings. Perinatal mechanical insults may result in hypoxic-ischemic cerebral injury, probably secondary to disturbances of placental or cerebral blood flow [1], thus causing some overlapping between mechanical and hypoxic-ischemic injury. However, only mechanical injury will be discussed in this Chapter, whereas perinatal hypoxic-ischemic injury is discussed in Chapters 5 and 6. Although improvement of obstetrical management has led to a reduced occurrence of traumatic injuries to both the central and peripheral nervous system, these adverse events still occur quite frequently. The role of computerized tomography (CT) and magnetic resonance imaging (MRI) in the evaluation of the newborn suffering from birth trauma will now be discussed.

Table 19.1. Perinatal traumatic lesions Extracranial hemorrhage Caput succedaneum Subgaleal hemorrhage Cephalohematoma Intracranial hemorrhage Epidural Subdural Subarachnoid Intraventricular Parenchymal Contusions Skull fractures Linear Depressed Occipital osteodiastasis From ref. [1]

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19.1.2 Extracranial Hemorrhage

19.1.2.2 Subgaleal Hemorrhage

Extracranial hemorrhage includes caput succedaneum, subgaleal hemorrhage, and cephalohematoma (Fig. 19.1) (Table 19.2). Just as in other cases of hemorrhage, the appearance of blood on MRI varies according to the age of the bleeding, in relation to the various stages of hemoglobin degradation (Table 19.3).

Subgaleal hemorrhage occurs beneath the galea capitis, i.e., the aponeurosis covering the scalp and connecting the frontal and occipital components of the occipito-frontalis muscle. Both external compressive and dragging forces and coagulation disturbances contribute to its formation [1]. It is more commonly seen after delivery by vacuum extraction, and tends to increase in size in the first few days after delivery [1, 2, 4]. Imaging studies are usually not necessary [5].

19.1.2.1 Caput Succedaneum

Caput succedaneum (Fig. 19.2) is characterized by hemorrhagic edema beneath the skin, more commonly located at the vertex, associated with molding of the head. The edema is soft and superficial, and crosses suture lines [1]. The lesion resolves over the first days of life, without any medical intervention. Imaging studies are usually not necessary [2]. However, it is often demonstrated incidentally as focal extracranial soft tissue swelling on both CT and MRI performed for other indications [3].

19.1.2.3 Cephalohematoma

Cephalohematoma (Fig. 19.3) is a subperiosteal hemorrhage confined by the cranial sutures. It is commonly seen after forceps delivery, and tends to increase in size after delivery. It is more commonly located over the parietal bone. It may be associated with intracerebral lesions [2], and in a variable per-

cephalohematoma frontalis m.

galea capitis

caput succedaneum

temporalis m.

temporalis m.

subgaleal hematoma

Fig. 19.1. Schematic representation of extracranial hemorrhages in newborns. (Redrawn and modified from [55])

occipitalis m.

Table 19.2. Differential diagnosis of traumatic extracranial hemorrhages of the newborn Lesion

Features of external swelling

Increasing after birth

Crossing of suture lines

Marked acute blood loss

Caput succedaneum

Soft, pitting

No

Yes

No

Subgaleal hematoma

Firm, fluctuant

Yes

Yes

Yes

Cephalohematoma

Firm, tense

Yes

No

No

From ref. [1]

Accidental Head Trauma Table 19.3. Evolution of signal intensity in extracerebral hemorrhage of the newborn Age of hemorrhage

T1-weighted images

T2-weighted images

0) magnetic ≈ or ↓ ≈ (or ↓) (no PEDD inter- ↑↑ (PEDD ↑↑ (PEDD ≈ (or ↓) (no PEDD action) interaction) interaction) interaction) ↑ (high water con- ↓↓ T2 PRE ↓↓ T2 PRE ↑↑ no T2 PRE (loss ↓↓ T2 PRE tent) (susceptibility effect) (susceptibility effect) of compartmental- (susceptibility effect) ization)

Hb = hemoglobin; PEDD = proton-electron dipole-dipole; FeOOH = ferric oxyhydroxide; e– = electrons;↑ = increased SI relative to normal gray matter; ↓ = decreased SI relative to normal gray matter; PRE = proton relaxation enhancement (P.M. Parizel, ECR 2000, March 5–10, Vienna)

Accidental Head Trauma

a

b

a

b

Fig. 19.20a, b. Subdural hematoma in a 15year-old boy. a Axial T1-weighted image; b axial T2-weighted image. This large right fronto-parietal subdural collection is markedly hyperintense on the T1weighted image (a) and shows inhomogeneous signal intensity on T2-weighted images (b). In the latter, note absence of the medial hypointense rim representing the dura, whose presence would indicate an epidural hematoma

Fig. 19.21a,b. Chronic subdural hematoma in a 3-month-old boy with craniostenosis. a Axial T1-weighted image; b axial T2weighted image. Bilateral frontal subdural collections are hyperintense compared with CSF on both T1- and T2-weighted images (h, a, b). The thin hypointense line outlining the collections medially on T2-weighted images is the arachnoid (arrowheads, b). The underlying CSF-containing subarachnoid spaces (a, a, b) have lower signal intensity than the subdural collections. Enlargement of the subarachnoid spaces is due to associated craniostenosis

In infants, chronic SDHs should be differentiated from benign enlargement of subarachnoid spaces (see Chapter 21). However, the two conditions may coexist (Fig. 19.21), since patients with benign enlargement of subarachnoid spaces have been demonstrated to be predisposed to extra-axial hemorrhage for minor trauma [51]. 19.2.4.3 Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) usually results from damage to leptomeningeal or cerebral surface

vessels [17]. Less common mechanisms include cerebral contusion with blood leaking into the subarachnoid space from a contused brain surface, intraventricular hemorrhage with ref lux through the fourth ventricular foramina into the subarachnoid space, and rupture of major intracerebral vessels [11]. SAH is much less common than EDHs or SDHs, and often is associated with intraparenchymal damage [5]. Posttraumatic SAH, usually focal and overlying sites of contusion, is commonly found in the posterior interhemispheric fissure paralleling the falx cerebri [5, 17] or along the tentorium cerebelli.

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a

b

d

c

e

Fig. 19.22a–e. Superinfection of a subdural hematoma in a 3-month-old boy. a Axial CT scan; b axial T1-weighted image; c axial T2-weighted image; d Gd-enhanced axial T1-weighted image; e Gd-enhanced sagittal T1-weighted image. This baby had a right parietal subdural hematoma due to head trauma 2 months prior to this admission. CT shows parietal collection that is hyperdense relative to CSF (E, a). The collection is isointense with brain on T1-weighted images (E, b) and hyperintense to CSF on T2-weighted images (E, c). Notice that it does not cross the falcine attachment, and that displaced bridging veins are seen along its medial margin (arrowhead, b), consistent with a subdural location. Following gadolinium injection, both the superficial and the deep margins of the collection enhance markedly (arrowheads, d); there is also adjacent pial enhancement (arrows, e)

Imaging Findings

CT scan is the modality of choice for detecting subarachnoid blood [5]. On CT, acute SAH appears as increased attenuation in the subarachnoid space [5, 17] (Fig. 19.23). Traumatic SAH may be focal, overlying the site of cerebral contusion or subjacent to a SDHs [11], or diffuse. When the hematoma is located close to the posterior falx cerebri, it may be difficult to detect on CT, since the falx itself is hyperdense (“falx sign”). In this case, presence of abnormal thickness and apparently zigzag margins of the falx, as well as high attenuation extending into the cortical

sulci and reaching anteriorly the corpus callosum, are useful clues (Fig. 19.7) [5]. SAH is not easily identified on both T1- and T2-weighted MR images, unless large focal clots are formed [52], probably because the hemoglobin is less concentrated than in clotted blood and the high oxygen tension of CSF inhibits the conversion of hemoglobin to deoxyhemoglobin and methemoglobin [5, 53]. FLAIR sequences are the most sensitive MR sequences to both acute and subacute hemorrhage, and should be used to look for subarachnoid blood [20, 21]. SAH appears hyperintense on FLAIR, whereas CSF is hypointense (Fig. 19.23). Care should be employed not to confuse CSF flow

Accidental Head Trauma

a

b

Fig. 19.23a,b. Subarachnoid hemorrhage. Two different cases. a Axial CT scan; b axial FLAIR image. A fracture of the right temporal bone and an overlying subgaleal hematoma (arrow, a) are seen. Note the presence of diffuse abnormal hyperdensity involving the interpeduncular fossa and opto-chiasmatic, sylvian, and ambient cisterns. Blood also diffusely fills the sulci of the occipital convexity. In a different case, FLAIR reveals hyperintensity of the parietal sulci (arrows, b)

artifacts (especially around the foramina of Monro, the cerebral aqueduct, and the prepontine cistern) with SAH. In the subacute stage, SAH appears as areas of T1 shortening in the subarachnoid space [52], whereas in the chronic stage GE-T2*-weighted images may show diffuse superficial hypointensity related to hemosiderosis [54]. The main differential diagnosis of traumatic SAH is with the increased subarachnoid density seen in case of severe, diffuse cerebral edema, in which the brain becomes relatively hypodense and the dura and circulating blood appear unusually hyperdense by comparison [11]. 19.2.4.4 Intraventricular Hematoma

Intraventricular hematoma (IVH) is found in less than 5% of patients with traumatic brain injury [55], and usually portends a poor prognosis. It is typically related to extension from intraparenchymal bleeding, deep penetrating wounds, tearing of subependymal veins, or diffusion from SAH [55]. Shear injury involving the corpus callosum and IVH are often associated, due to tearing of the subependymal veins on the ventral surface of the corpus callosum caused by rotational forces [56]. CT shows increased attenuation within the ventricular system, sometimes associated with a bloodfluid layer. MRI findings are variable and may rapidly change. Dependent T1 hyperintensity and T2 hypointensity are the most common features [55]. Obstructive hydrocephalus may occur from either

blood accumulation into the cerebral aqueduct or ventriculitis.

19.2.5 Parenchymal Injury 19.2.5.1 Contusions

Cerebral contusions are bruises that may be distinguished into coup and contrecoup types [5, 17]. Coup contusions are directly related to a small surface impact, are seen beneath the site of head impact, and are more frequently located in the frontal and temporal lobes [17]. Contrecoup contusions are located in the brain opposite to the point of impact, whose surface is broader. The geometry of the skull may partly explain these types of lesions. During impact, the motion of the brain relative to the calvarium causes the temporal tips to impact the sphenoid wings and the inferior frontal lobes to impact the orbital roofs and cribriform plate [17]. In the absence of physical blow, extensive neuronal damage may be produced by rotational acceleration forces, as explained by Holburn’s rotational shear force theory [57] (see below). Traumatic or mechanical disruption of capillary vessels causes extravasation of plasma, red blood cells, or whole blood. Traumatic contusions more commonly occur supratentorially, with predilection for the surface of the brain beneath the calvarium, the cortex above and below the sylvian fissure, and the areas of the brain in contact

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with the roof of the orbits, the sphenoid wing, and the anterior portion of the middle cranial fossa [11]. The term “gliding contusions” indicates focal parasagittal hemorrhage in the cerebral cortex and subjacent white matter at the superior margins of the cerebral hemispheres [8]. Gliding contusions should be differentiated from contusions on the surface of the brain. In children aged less than 3–4 years, brain contusions are relatively uncommon, probably due to the smooth surface of the inner calvarium [3, 54]. Furthermore, in infants aged less than 5 months, damage may be restricted to the white matter, because the smooth inner lining of the skull shifts the force from the cortex to the white matter, leaving the surface undamaged [58].

Imaging Findings

Brain contusions may be either hemorrhagic (i.e., hemorrhagic lacerocontusions) or nonhemorrhagic

a

(i.e., simple contusions). Small contusions involve the gray matter of the crest of gyrus, while they spare the sulci. When large, they may extend deeper into the subjacent white matter, without a vascular distribution. Edema and swelling occur over several days post injury, leading to increased mass effect and risk of cerebral herniation [17]. Associated SAH may be found [11]. CT scan is sensitive in diagnosing hemorrhagic lacerocontusions, while it is less sensitive than MRI in detecting simple contusions [5]. Simple Contusions

Initial CT scan may deceivingly be negative when a simple contusion is small or located near bone surfaces. In such cases, MRI is clearly more sensitive, detecting simple contusions as low signal areas on T1-weighted images and high signal lesions on both T2-weighted and FLAIR images, located either in the vicinity of the site of impact (i.e., coup contusions) (Fig. 19.24) or distant to it (i.e., contrecoup contusions) (Figs. 19.25, 19.26).

b

Fig. 19.24a,b. Simple contusions (coup mechanism) in a 1-year-old girl. a Axial T2-weighted image; b axial T1-weighted image. There is a fracture of the right parietal bone (arrow, a) associated with a probable interruption of the dura mater. This has resulted in extracranial CSF leakage, forming collections (L, a) whose signal intensity is clearly distinct from that of soft tissue swelling. Multiple simple coup contusions involving the adjacent brain regions are clearly seen on T2-weighted images (arrowheads, a), whereas T1-weighted images (b) could superficially pass for normal, although faint hypointensities are discernible on closer look

a

b

Fig. 19.25a,b. Simple contusions (contrecoup mechanism) in a 4-year-old girl. a Coronal FLAIR image; b sagittal T2-weighted image. Following head trauma to the right parietal region (arrowhead, a), cortical contrecoup contusions are visible in the left temporal basal region (arrows, a, b), directly opposite to the point of impact

Accidental Head Trauma

a

b

Fig. 19.26a,b. Simple contusions (contrecoup mechanism) in a 9-month-old boy. a Axial T2-weighted image; b sagittal T1-weighted image. Nonhemorrhagic contusions (arrows, a) involve both cerebellar tonsils, which are swollen and herniated into the foramen magnum (arrow, b)

Hemorrhagic Lacerocontusions

Also hemorrhagic lacerocontusions may initially appear on CT as patchy hypodense areas, mixed with small hyperdense foci of petechial hemorrhage [16, 17] (Fig. 19.27). MRI is the modality of choice in the acute stage to reveal the full extent of the lesions and to pick up the hemorrhagic component, which is particularly well depicted by GE sequences, while T1weighted images still show a predominately hypointense lesion (Fig. 19.27). FLAIR sequences, although relatively insensitive to the presence of intraparenchymal blood, are useful for assessing the extent of white matter injury [5]. After 24–48 h, CT scan usually shows more lesions than those identified on initial studies [16]. At this stage, CT shows hemorrhagic lacerocontusions as mottled or speckled density lesions, due to the admixture of hyperdense blood with hypodense edema (Fig. 19.28). Also in this stage, however, MRI shows sensitivity superior to that of CT and offers better evaluation of the extent of injury. T1-weighted images show hemorrhagic components to be hyperintense in the subacute phase (Fig. 19.29), due to the presence of methemoglobin. Between the fourth to seventh day after injury, as liquefaction and edema develop, CT scan shows larger areas of decreased density. In the repair phase (2–3 weeks following injury) the appearance on both CT and MRI is variable, depending on the presence of blood products, necrosis, and edema [17]. At this stage, contrast enhancement may be present, due to newly formed vessels. After complete resorption of the necrotic tissue (6–12 months after injury) a CSFdensity/intensity cavity forms. However, residual hemosiderin may cause T2 shortening. Decreased

size of the involved overlying gyri and enlargement of ventricles and subarachnoid spaces indicates atrophy (Fig. 19.28). 19.2.5.2 Cerebral Hematomas

Cerebral hematomas result from large lacerations that involve larger caliber vessels than in hemorrhagic lacerocontusions, resulting in the accumulation of large masses of blood within the brain parenchyma. They are not necessarily superficial in location and may be multiple. They result from severe blunt or penetrating trauma. We have seen cerebral hematomas in patients falling from great heights, such as balconies. In such cases, additional lesions are present, including skull fractures, extracerebral hematomas, and intraventricular bleeding. The imaging appearance of cerebral hematomas in the pediatric age group is not different from that of adults. Most children will be imaged with CT due to their critical conditions. CT shows large, hyperdense lesions surrounded by perifocal edema (Fig. 19.30). 19.2.5.3 Diffuse Axonal Injury

Diffuse axonal injury (DAI) is one of the most common primary lesions in patients with severe head trauma [56, 59, 60]. The term DAI, indicating focal, irreversible disruption of axons occurring at the moment of injury [8], has replaced the former term “shearing injury,” although, sometimes, they are used interchangeably [61]. DAI is characterized by axonal swelling and retraction balls, usually involving the gray-white matter

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c

b

d

interfaces, centrum semiovale, corpus callosum, and brainstem. The focal traumatic lesions are usually small, ovoid, and multiple. They are most often found near the gray-white matter junction, and range in size from 5 to 15 mm [17]. Lesions may be hemorrhagic or not [17], depending on whether shearing of small white matter vessels occurs. DAI selectively affects white matter tracts, due to the high inertial strain determined by rotational acceleration and deceleration. Although the gray matter is typically spared, secondary involvement in case of large lesions may be observed [17]. Since the extent of microscopic injury is greater than macroscopic abnormalities [17], MR spectroscopy has demonstrated severe DAI even in cases showing only relatively discrete lesions on neuroimaging [15]. Clinically, patients with DAI usually present with severe impairment of consciousness from the moment of impact and may persistently remain in a vegetative state. The outcome may be particularly poor, due to neuropsychiatric deficits.

Fig. 19.27a–d. Hemorrhagic lacerocontusion in a 6-year-old girl. a Axial CT scan; b coronal T1-weighted image; c axial T2-weighted image; d axial T2* gradient-echo-weighted image. CT obtained shortly after blunt head trauma shows ill-defined hypodense area (arrows, a) with faint peripheral hyperdensity (arrowhead, a). MRI performed on following day shows large brain contusion located in the right temporal lobe (c, b), prevailingly hypointense on T1-weighted images (b) and hyperintense on T2-weighted images (c). However, T1 hyperintense components (arrow, b) and T2 hypointensities (arrows, d) that become more prominent on gradient-echo images (arrow, d) reveal the presence of hemorrhage. Notice concurrent subgaleal hematoma (asterisks, b)

Pathophysiology and Neuropathology

The pathophysiology of DAI is related to rotational acceleration and deceleration forces, producing shear-strain neuronal injuries. The theory that severe brain damage could occur without skull deformation, originally proposed by Holburn [57], has been subsequently substantiated by further studies [8, 17, 59]. Shear-strain deformation is described as a change in shape without a change in volume [17]. Shear-strains develop because of differential movements between tissues of different density and rigidity [17]. The maximal damage is at interfaces between the gray and white matter, due to their different physical properties (i.e., different density, rigidity, and cellular architecture) [17, 59, 60]. These properties, together with the direction and magnitude of the rotational acceleration and deceleration forces, account for the occurrence, location, and severity of the lesions [61].

Accidental Head Trauma

b a

Fig. 19.28a–c. Hemorrhagic lacerocontusion in a 14-year-old boy. a Axial CT scan; b axial T2-weighted image; c sagittal T2-weighted image (MRI was performed 1 month later). This patient with bilateral subgaleal hematomas also shows frontobasal hemorrhagic contusion characterized by speckled hyperdensity bilaterally (arrows, a). Also, there is diffuse cerebral edema with effacement of the ventricular system and subarachnoid spaces. Follow-up MRI shows chronic sequelae (arrows, c), with encephalomalacia, atrophy, and hemosiderin deposition. Notice re-expansion of the ventricular system

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Fig. 19.29a,b. Hemorrhagic lacerocontusion in a 2-year-old girl. a Axial T1-weighted image; b coronal T1-weighted image. Hemorrhagic contusions involving the right temporo-parietal cortex are characterized by hyperintense signal on T1-weighted images (arrows, a, b)

DAI occurs in three major anatomical areas (i.e., subcortical white matter, corpus callosum, and brainstem), known as the “triad” associated with DAI [60]. These areas tend to be involved in successive stages of increasing severity [17, 61]. The basal ganglia and cerebellum are less frequently involved [61]. Subcortical Lobar (Frontal and Temporal) White Matter

Diffuse damage to axons in the subcortical white matter is the most common finding of DAI. The gray-white

matter junction in the cerebral hemispheres is the most common site (Figs. 19.31, 32). The parasagittal regions of the frontal lobes and the periventricular areas of the temporal lobes are typically involved [17, 61], whereas the parietal and occipital lobes are less common locations. The peculiar vulnerability of the subcortical white matter to DAI is related to its peripheral location and the abrupt change in tissue density at the interface with the gray matter. In the acute and subacute stages, DAI typically appear as multiple, focal, ovoid lesions, oriented parallel to the axis of the white matter fibers [11].

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Fig. 19.30a,b. Cerebral hematomas. Two different cases. a, b Axial CT scans. a This 11-month-old boy fallen from a second floor balcony has large, prevailingly left-sided cerebral hematomas (arrowheads), associated with blood in the right ventricular trigone, occipital sulci, and along the falx. There is a diastatic occipital fracture (arrow) with extracranial CSF accumulation (L). b This 7-year-old boy involved in a car accident has a large hematoma in the right nucleobasal region showing a dependent fluid–fluid level (arrows). There is associated intraventricular blood (arrowhead)

Corpus Callosum

The corpus callosum, relatively less mobile than the independently mobile cerebral hemispheres, is a typical site of shearing injury (Fig. 19.31). The splenium is more frequently involved, due to its close proximity to the falx that, in its posterior part, is denser and less elastic than the anterior portion [56]. During angular acceleration, the falx inhibits the movements of the cerebral hemispheres through the midline; thus, shearing forces act on connection sites (i.e., corpus callosum-fornix). Usually, focal hemorrhagic lesions are unilateral and off-midline. Occasionally they may be bilateral.

traumatic lesions (Fig. 19.32). DAI lesions tend to occur between the gray matter of the basal ganglia and the white matter of the internal capsule. Differential diagnosis is with hypertensive intracranial hemorrhages and hemorrhagic infarctions [61]. Cerebellum

Cerebellar shearing injuries occur rarely, and are difficult to detect on CT scan. When present, they are always associated with multiple supratentorial lesions. Differential diagnosis with dural calcifications of the tentorium should be considered [11].

Brainstem

Imaging Findings

Shearing lesions located in the dorsolateral midbrain and upper brainstem are observed only in severely injured patients, and are always associated with multiple hemorrhages in the deep white matter and corpus callosum [61]. The most common site is the posterior lateral quadrant of the mesencephalon, adjacent to the superior cerebellar peduncle (which may sometimes be involved too). Differential diagnosis of these lesions is with hypertensive hemorrhage, Duret hemorrhage in transtentorial herniation, perimesencephalic subarachnoid hemorrhage, and vascular malformations [59].

Although CT scan is the modality of choice for evaluating acutely injured patients, it is insensitive to nonhemorrhagic DAI [17]. The discrepancy between a near normal CT and the severe clinical status of some patients after head trauma is well known [62], and should prompt to MRI examination. MRI examination within the first 2 weeks of moderate to severe head trauma is therefore recommended [52]. However, in the acute stage of DAI, CT scan may show petechial foci of hemorrhage, appearing as punctate or linear hyperdense lesions [11], sometimes surrounded by edema [63]. On MRI, the signal intensity of shearing injuries varies depending on whether they are hemorrhagic or nonhemorrhagic, their age, and the type of sequence used [5]. Both kinds of lesions may be found in indi-

Basal Ganglia

Basal ganglia shearing lesions occur only in severely injured patients, in the context of other intracranial

Accidental Head Trauma

vidual patients. In general, hemorrhagic lesions are exquisitely demonstrated by gradient-echo MR images (due to their great sensitivity to the paramagnetic effects of hemoglobin breakdown by-products) as hypointense spots (Figs. 19.31, 32). FLAIR images are also sensitive to hemorrhagic DAI, but due to their sensitivity to edema and axoplasmic leakage [11], lesions will typically appear hyperintense with a central hypointense dot corresponding to the hemorrhagic component (Figs. 19.31, 32). Spin-echo T1- and T2-weighted images show aspecific T1 and T2 prolongation, although faint T1 hyperintensity may sometimes be seen (Fig. 19.32). Nonhemorrhagic lesions are depicted as hyperintense lesions on FLAIR, proton-density, and T2-weighted images (Fig. 19.31). Diffusion-weighted imaging has shown significant decrease in apparent diffusion coefficient in regions of DAI up to 18 days after injury, probably reflecting cellular swelling or cytotoxic edema in the acute phase [64]. MR spectroscopy has shown that diffusely elevated lactate levels in normal-looking regions on conventional MRI correlate with poor outcome, whereas increased lactate confined to areas of macroscopic

injury does not have poor prognostic significance [65]. A marked decrease of NAA within the white matter has been described in the subacute phase [66]. Persistently elevated choline levels have been observed in patients with poor clinical outcome [67].

19.2.6 Secondary Effects and Sequelae of Head Trauma 19.2.6.1 Brain Swelling/Cerebral Edema

The term “congestive brain swelling” indicates expansion of brain tissue due to an increase in the intravascular blood volume, while cerebral edema means an increase in the water content of the brain tissue [8]. The two major forms of cerebral edema are vasogenic edema and cytotoxic edema. Vasogenic edema is characterized by extravasation of plasmalike fluid into the extracellular space due to an incompetent blood-brain barrier, whereas cytotoxic edema is related to impairment of cellular Na-K membrane

Fig. 19.31a–d. Diffuse axonal injury in a 12-year-old boy. a Sagittal T2weighted image; b, c axial FLAIR images; d axial T2* gradient-echoweighted image. Focal hyperintense lesions involve the corpus callosum (arrows, a, b). Additionally, multifocal hypointensities are detected on gradient-echo images in the subcortical white matter of the right frontal lobe (arrows, d), representing hemorrhagic lesions. The larger of these has a very characteristic appearance on FLAIR, showing central low intensity surrounded by a hyperintense halo (arrow, c)

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Fig. 19.32a–c. Diffuse axonal injury in a 13-year-old boy. a Axial FLAIR image; b axial T1-weighted image; c axial T2*-weighted image. Hyperintense lesion with central hypointense dot is visible in the left thalamus on FLAIR (arrow, a). Only faint hypointensity is visible on T1-weighted images (arrow, b). Typical hypointense lesions also involve the frontal subcortical white matter, mainly on the left side (arrows, c)

pumps, allowing sodium and chloride to enter the cell. Normally, the water content is higher into the gray matter than into the white matter (with the exception of the subcortical arcuate fibers). Therefore, there is a greater possibility of water movement through the parallel fiber bundles within the white matter, producing a greater accumulation of water in the white matter in case of vasogenic cerebral edema [8]. On the contrary, cytotoxic edema is more prominent in the gray matter, because active metabolic pathways are located more in the gray matter than in the white matter [8]. DWI may play a prognostic role, allowing one to distinguish between vasogenic edema (which is potentially reversible) and cytotoxic edema (which is not). Early after injury, there is a reduced water motion in the damaged cerebral regions (increased intensity on DWI), while interstitial edema and increased blood volume show increased water motion (decreased intensity on DWI) [5]. Moreover, proton MR spectroscopy shows decreased NAA and increased lactate if significant neuronal injury has occurred, while it is nearly normal in the absence of parenchymal injury [27]. Brain Swelling in Blunt Trauma

In patients who have sustained blunt head trauma, congestive brain swelling may develop rapidly. The

capillary and postcapillary portions of the brain vasculature are responsible for the increase in cerebral blood volume. Although its pathophysiology is not completely clear, it has been suggested that a relaxation of arterioles and/or a relative constriction of the venous outflow may explain it [8]. Hypoxia, hypercapnia, elevations of arterial pressure, and central neurogenic mechanisms may account for cerebrovascular dilatation that, in association with vasomotor paralysis, may cause extremely severe brain swelling [68]. Hypoxia is a major contributor to the pathogenesis of brain swelling in head trauma patients. We have seen quite a few cases of children sustaining car accidents with head trauma, polytrauma, and cardiorespiratory arrest, in whom severe brain swelling was the main imaging finding (see also Chapter 7). When intracranial pressure equals systemic arterial pressure, perfusion of the brain ceases with consequent brain death [8]; imaging findings therefore have been described in Chapter 12. Posttraumatic brain swelling is more common in the pediatric age group than in adults [3, 5, 11]. In the acute stage after head trauma, generalized brain swelling may be the only identifiable feature of brain injury [11]. Severe brain swelling is typically associated with a poor prognosis (Fig. 19.33). While in the first 12 h imaging is usually normal [5], decreased demarcation of the gray-white matter interface with

Accidental Head Trauma

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Fig. 19.33a,b. Brain swelling evolving into encephalomalacia in a 5-month-old boy. a, b Axial CT scans. Following severe head injury, brain swelling associated with bilateral fronto-occipital hypodense areas is seen (a). One month later, cerebral shrinkage, diffuse intraparenchymal foci, dilatation of the ventricular system, and enlargement of the periencephalic spaces is detected. The latter finding is probably related to chronic subdural hematomas

compressed, slit-like ventricles is evident by 24 h after trauma both on CT (Fig. 19.34) and MRI (Fig. 19.35). Other imaging findings include increased density of the falx and tentorium and diffuse enhancement of the subarachnoid spaces (due to vascular stasis), effacement of the cortical sulci of the cerebral surface, obliteration of the basilar subarachnoid spaces and cisterns (i.e., suprasellar, quadrigeminal plate, and ambient cisterns) [11, 16]. Swelling and increased T2 signal intensity in the basal ganglia (especially involving the lentiform nuclei) is a sign of hypoxic damage (see Chapter 7) (Fig. 19.35). The so-called white cerebellum sign (i.e. the cerebellum appearing relatively hyperdense if compared with the edematous cerebral hemispheres) and the reversal sign (i.e., normal density of the thalamus, brainstem, and cerebellum if compared with diffuse hypodensity of the cortex and deep white matter) may be observed [16] (see also Chapter 20). Both transtentorial and subfalcine herniation may occur, and may be complicated by cerebral infarcts (involving the territories of the posterior and the anterior cerebral artery respectively).

may occur [8]. Bilateral basal ganglia hemorrhage is the most common brain imaging finding following a lightning strike (Fig. 19.36) [69]. Although the pathophysiology is still unclear, it is likely that intracranial hemorrhage is directly related to electric currents passing through the brain. Preferential conduction along the Virchow-Robin spaces in the anterior perforated substance has been considered to play a major role in causing basal ganglia injury after lightning strike [68]. Additional brain damage is caused by hypoxia, resulting from cardiac arrest, which

Brain Swelling in Electric Trauma

Electric trauma, including injury by lightning, produce both thermic and functional changes due to ion disturbances and disturbed nerve conduction [8]. Local tissue coagulation necrosis, potentially extending to widespread necrosis, is related to thermic damage. After lightning strikes, venous hyperemia, hemorrhages around the third ventricle and in the floor of the fourth ventricle, and severe brain edema

Fig. 19.34. Brain swelling related to motor vehicle collision in a 3-year-old boy. Axial CT scan. There is diffuse hypodensity of the nervous tissue with loss of gray-white matter demarcation. A small blood collection is recognizable over the left temporal convexity (arrow). The ventricular system is almost completely effaced

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Fig. 19.35a–d. Brain swelling in a 30-month-old boy. a Axial T1-weighted image; b Gd-enhanced axial T1-weighted image; c axial T2-weighted image; d sagittal T1-weighted image. There is severe swelling of the cerebral cortex with effacement of the subarachnoid spaces (a). The size of the lateral ventricles is reduced. Following gadolinium, diffuse congestion of the leptomeningeal vessels is seen (b). T2-weighted image shows swollen, hyperintense cerebral cortex and basal ganglia (arrows, c). Sagittal image shows downward displacement of the cerebellar tonsils (thin arrow, d) as well as deformation of the brainstem that is pushed against the clivus (arrowheads, d). The optic chiasm is displaced against the pituitary gland (thick arrow, d). The third ventricle and aqueduct are no longer recognizable, and the fourth ventricle is small

produces a picture of diffuse brain swelling. Signal abnormalities involving the basal ganglia (especially the lenticular nuclei) are due to their higher metabolic demands (see Chapter 7) (Fig. 19.36). Atrophy of the dorsal and/or lateral columns of the spinal cord is a delayed consequence of electrical trauma that may occur weeks to months after the injury [8]. 19.2.6.2 Cerebral Herniations

Cerebral herniations are caused by mechanical displacement of brain, CSF, and blood vessels from one cranial compartment to another. These compartments correspond to the functional division of

the cranial cavity by bony ridges and dural folds (Fig. 19.37). Brain herniations usually occur in case of severe cerebral injury (Table 19.12). Subfalcine Herniation

Subfalcine herniation is one of the most common forms. It occurs when the cingulate gyrus is displaced across the midline and forced under the inferior margin of the falx cerebri. In case of large herniation, the ipsilateral lateral ventricle is compressed and the contralateral ventricle enlarges due to the obstruction of the foramen of Monro (Fig. 19.8). Vascular displacements include shifting across the midline or compression against the falx of the ipsilateral anterior

Accidental Head Trauma

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Fig. 19.36a–c. Brain injury related to lightning strike in a 3-year-old girl. a, b Axial T2-weighted images; c axial T1-weighted image. Diffuse swelling and abnormal hyperintensity involves the basal ganglia, thalami (a), and deep white matter (b). T1-weighted image clearly shows hemorrhagic foci involving both globi pallidi (arrows, c)

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Fig. 19.37a,b. Schematic representation of the most frequent brain herniations. 1, Subfalcine herniation; 2, uncal herniation; 3, tonsillar herniation; 4, transsphenoidal herniation

b

cerebral artery and its branches, as well as occlusion of the callosomarginal artery producing secondary ischemia and infarction [16, 70]. Transtentorial Herniation

Transtentorial herniation may occur either downward or upward through the tentorial hiatus (i.e., descending or ascending transtentorial herniation). Descending transtentorial herniation is characterized by caudal descent of brain tissue (i.e., the temporal lobe) through the tentorial hiatus. The parahippocampal gyrus is the first portion of the temporal lobe to engage the tentorial hiatus (uncal or medial transtentorial herniation). As a consequence, the midbrain is displaced and the opposite cerebral peduncle is squeezed against the contralateral tentorial edge.

Progression of herniation causes further compression of the midbrain. On imaging, early signs are represented by displacement of the uncus and effacement of the lateral suprasellar cistern. As herniation progresses, the brainstem is displaced and rotated and the ipsilatTable 19.12. Cerebral herniations Subfalcine Transtentorial Descending Ascending Transalar (Transsphenoidal) Descending Ascending Tonsillar Miscellaneous (e.g. transdural/transcranial)

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eral ambient and lateral pontine cistern are widened. Finally, the midbrain is compressed and elongated, and the subarachnoid spaces are obliterated [70]. Hydrocephalus may develop due to distortion and obstruction of the cerebral aqueduct. Ascending transtentorial herniation is characterized by upward herniation of the vermis and cerebellar hemispheres through the hiatus. The quadrigeminal cistern and the midbrain may be secondarily deformed and displaced. Both descending and ascending transtentorial herniations may be complicated by infarctions, due to compression of the posterior cerebral or superior cerebellar arteries against the tentorium (Fig. 19.38). Obstruction of the venous outflow by compression of the vein of Galen may cause further increase of the intracranial pressure [70]. Tonsillar Herniation

Tonsillar herniation is characterized by downward displacement of the cerebellar tonsils through the foramen magnum into the cervical spinal canal. Sagittal MRI is the imaging study of choice (Fig. 19.35). In addition to the extension of the tonsils below the foramen magnum (considered pathological when exceeding 5 mm) [70], displacement of the lower brainstem and loss of CSF spaces surrounding the brainstem are important findings to differentiate acquired tonsillar herniations from congenital conditions (i.e., Chiari I malformation) and normal variations [70]. Transsphenoidal Herniation

posterior frontal lobe over the sphenoid wing into the middle cranial fossa and by displacement of the anterior temporal lobe into the anterior cranial fossa, respectively. 19.2.6.3 Cerebral Ischemia and Infarction

Significant changes in cerebral blood flow may occur after severe head trauma, and ischemic brain injury may represent the main cause of secondary cerebral injury (Table 19.13). In case of arterial occlusion, when the collaterals are inadequate, infarction occurs in the distribution of the corresponding vascular supply [55]. The most common locations of infarction related to posttraumatic displacement of brain structures (Fig. 19.38) include the occipital lobe (when the posterior cerebral artery is compromised), the frontoparietal regions (when the callosomarginal branches of the anterior cerebral artery are compressed by the cingulate gyrus against the falx cerebri) and the basal ganglia or thalami (when the lenticulostriate or thalamoperforating arteries are compromised by diffuse edema). CT findings of acute infarction include increased attenuation of vessels, loss of the gray-white matter differentiation, blurring of the lentiform nucleus, and loss of definition of the insular ribbon [55]. On MRI, absence of the normal flow void within vessels, intravascular enhancement, gyral swelling, and hyperintense signal on T2-weighted images may be seen [55]. FLAIR sequences and, especially, DWI improve early detection of ischemic changes.

Descending and ascending transsphenoidal herniations are characterized by displacement of the

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Fig. 19.38a–c. Descending temporal lobe herniation in a 5-month-old girl. a, b Axial CT scans; c coronal T2-weighted image. A huge epidural hematoma (b) causes herniation of the medial portion of the temporal lobe through the tentorial incisura (arrowheads, a). Note the ischemic injury within the temporo-occipital region (I, b), probably caused by compression of the posterior cerebral artery against the tentorium. MRI performed after drainage of the hematoma confirms large left hemispheric infarction (c)

Accidental Head Trauma Table 19.13. Causes of posttraumatic infarction

Carotid-Cavernous Fistulas

Vasospasm secondary to Subarachnoid hemorrhage Direct vessel injury (laceration) Extrinsic compression of a blood vessel Brain herniation Extra-axial mass Hypoxia / anoxia Thrombosis / distal embolization Vascular dissection Fat embolization due to long bone fracture

19.2.6.4 Vascular Damage

Carotid-cavernous fistulas, arterial dissections, and venous sinus occlusions are the main posttraumatic vascular complications [5].

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Carotid-cavernous fistulas are characterized by a direct communication between the internal carotid artery and the adjacent cavernous sinus [11]. They result either from a tear in the wall of the artery or of one of the dural branches of its intracavernous segment, or from rupture of a posttraumatic pseudoartery into the cavernous sinus [5]. Clinically, patients present with pulsating exophthalmos, proptosis (which may involve the ipsilateral or contralateral orbit depending on the pattern of venous drainage), and deficient ocular motility due to cranial nerve palsies [5]. The most common imaging findings are dilatation and tortuosity of the superior ophthalmic vein and a convex lateral margin to the affected cavernous sinus [11]. Both the cavernous sinus and the adjacent venous structures may be enlarged due to shunting of blood

Fig. 19.39a–d. Traumatic thrombosis of the internal carotid artery and cerebral infarction in a 4-year-old boy. a Axial T2-weighted image; b 3D TOF MR angiography, axial collapsed view; c digital angiography of the left common carotid artery, laterolateral projection; d axial CT scan. While falling from a bicycle, this child was hit in the neck by the handlebars. After approximately 12 h, right faciobrachiocrural hemiparesis appeared. Emergency brain CT was negative (not shown). MRI, however, did reveal swelling and increased T2 signal intensity in the left lenticular nucleus and insula (arrows, a). MR angiography showed complete absence of flow in the left internal carotid and middle cerebral arteries (b). Digital subtraction angiography confirms obstruction of the left internal carotid artery just above the bifurcation (arrowheads, c). Axial CT scan obtained two days later shows full-blown infarction in the left middle cerebral artery territory (asterisk, d)

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through intercavernous connections [5]. Although these findings are seen on combined MRI and MR angiography, the ultimate diagnosis is based on cerebral angiography. Carotid and Vertebral Artery Dissection and Thrombosis

Carotid or vertebral artery dissections and thrombosis may be caused by penetrating or blunt trauma to the neck (Fig. 19.39). In children, carotid dissections may be related to falls when pencils are in the mouth or may be associated with fractures involving the skull base and extending to the carotid canal [3]. T1-weighted MR images with fat saturation through the neck and skull base are useful for diagnosis of arterial dissection, detecting a hyperintense crescentic rim (probably due to methemoglobin) in the vessel wall [5]. Both in the case of dissection and obstruction, MR angiography and catheter angiography detects absence of flow in the involved vessel. CT and MRI of the brain detect ischemia in distal territories (Fig. 19.39). Venous Sinus Occlusions

The neuroimaging diagnosis of venous sinus occlusions, due to either direct damage or thrombosis, is

not different from that of venous thrombosis from other causes (see Chapter 7). 19.2.6.5 Infections

Infections are uncommon posttraumatic complications. They include meningitis due to bacterial seeding from basilar skull fracture and cerebritis/abscess from penetrating injuries (Fig. 19.40). CSF fistulas are due to defects of the bony skull and meninges, most of which result from skull base fractures and a minority are congenital. These defects, while allowing for CSF leakage into the contiguous air-filled cavities at the base of the skull with rhinorrhea or otorrhea, may also predispose to either immediate or delayed, potentially devastating ascending infections [71]. Localization of a skull base CSF fistula can be extremely difficult on imaging. It requires thin-slice, high resolution axial and coronal CT and MRI [72–74] through the whole anterior and middle cranial fossa in case of rhinorrhea, and through the petrous bone and posterior fossa in case of otorrhea. Due to higher spatial resolution, direct coronal plane CT acquisitions are preferable to reformatted images from helical scanning. CT cisternography is an invasive procedure that is often less than rewarding, especially when the leakage is sparse and intermittent [75].

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Fig. 19.40a–c. Brain abscess due to penetrating injury in a 15-month-old girl. a, b Axial CT scans; c Gd-enhanced coronal T1-weighted image. This child had stuck a pencil in her right eye. CT shows bone fragments both within the right orbit (arrow, a) and intracranially (arrows, b), as well as pneumocephalus (arrowheads, b). Moreover, there is an ill-defined iso-hypodense lesion (asterisks, b), that is revealed to be an abscess by contrast-enhanced MRI (c)

Accidental Head Trauma

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Fig. 19.41a,b. Traumatic pneumocephalus. a Axial CT scan; b coronal high-resolution CT scan of the left petrous bone. This 8year-old boy had sustained a car accident with multiple fractures of the facial bones and petrous ridges 3 years prior to this admission. Presently, he complained of headaches and an ill-defined, fluffy sensation, as if, he said, “there were air into my head.” These complaints were initially overlooked by both parents and physicians. On admission, CT revealed huge pneumocephalus (a) with marked dilatation of the lateral ventricles. High resolution CT of the petrous bone showed fracture of the tegmen tympani (arrow, b). CT cisternography (not shown) failed to demonstrate any CSF leakage into the middle ear; moreover, the child did not complain of otorrhea. Supposedly, a ball-valve mechanism, allowing for entrance of air but not for exit of CSF, occurred. The child underwent duraplasty with resolution of the picture

Measurement of β-2 transferrin in the leaking fluid is the gold standard to confirm a CSF fistula in doubtful cases. Radioisotopic studies may be considered when all conventional studies remain inconclusive. Presence of ball-valve mechanisms at the level of the bony defect may allow for entrance of air into the skull cavity while preventing CSF leakage, resulting in acquired pneumocephalus that may be massive (Fig. 19.41). 19.2.6.6 Hydrocephalus

Posttraumatic hydrocephalus due to obstruction of the CSF pathways is a common complication of head injuries in children [5, 17]. It may be related to mass effect (from hematoma, edema, or brain herniation) that traps a portion of the ventricular system [17] or to inflammatory adhesion secondary to the presence of blood in the subarachnoid space [5]. Differential diagnosis between posttraumatic communicating hydrocephalus and cerebral atrophy following trauma may be difficult in children [5]. Clinical findings are crucial, in that an enlarging head circumference indicates hydrocephalus, while a decreasing head size suggests atrophy [5].

References 1. Volpe JJ. Neurology of the Newborn, 4th edn. Philadelphia: W.B. Saunders, 2001. 2. Blaser S, Jay V, Becker LE, Ford-Jones EL. Neonatal brain infection. In: Rutherford M (ed) MRI of the neonatal brain. London: W.B. Saunders, 2002:201–224. 3. Poussaint TY, Moeller KK. Imaging of pediatric head trauma. Neuroimag Clin N Am 2002; 12:271–294. 4. Anton J, Pineda V, Martin C, Artigas J, Rivera J. Posttraumatic subgaleal hematoma: a case report and review of the literature. Pediatr Emerg Care 1999; 15:347–349. 5. Barkovich AJ. Pediatric Neuroimaging, 3rd edn. Philadelphia: Lippincott Williams & Wilkins, 2000. 6. Goodwin MD, Persing JA, Duncan CC, Shin JH. Spontaneously infected cephalohematoma: case report and review of the literature. J Craniofac Surg 2000; 11:371–375. 7. Currarino G. Occipital osteodiastasis: presentation of four cases and review of the literature. Pediatr Radiol 2000; 30:823–829. 8. Graham DI, Genarelli TA. Trauma. In: Graham DI, Lantos PL (eds) Greenfield’s Neuropathology, 6th edn. London: Arnold, 1997:197–262. 9. Ewing-Cobbs L, Kramer L, Prasad M, Canales DN, Louis PT, Fletcher JM, Vollero H, Landry SH, Cheung K. Neuroimaging, physical, and developmental findings after inflicted and noninflicted traumatic brain injury in young children. Pediatrics 1998; 102(2 Pt 1):300–307. 10. Ewing-Cobbs L, Prasad M, Kramer L, Louis PT, Baumgartner J, Fletcher JM, Alpert B. Acute neuroradiologic findings in young children with inflicted or noninflicted traumatic brain injury. Childs Nerv Syst 2000; 16:25–33. 11. Parizel PM, Oszarlak O. Imaging of Craniocerebral Trauma. CD-ROM. Lasion Europe 1999.

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P. Tortori-Donati, A. Rossi, and R. Biancheri 12. Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann Neurol 1986; 19:105–111. 13. Rothman SM, Olney JW. Excitoxicity and the NMDA receptor. Trends Neurosci 1987; 10:299–302. 14. Chen CY, Zimmerman RA, Rorke LB. Neuroimaging in child abuse: a mechanism-based approach. Neuroradiology 1999; 41:711–722. 15. Barlow KM, Gibson RJ, McPhillips M, Minns RA. Magnetic resonance imaging in acute nonaccidental head injury. Acta Paediatr 1999; 88:734–740. 16. Osborn AG. Diagnostic Neuroradiology. St. Louis: Mosby Year Book, 1994. 17. McDaniel T. Head and brain trauma. In: Zimmerman RA, Gibby WA, Carmody RF (eds) Neuroimaging. Clinical and Physical Principles. New York: Springer-Verlag, 2000:699– 729. 18. Duhaime AC, Alario AJ, Lewander WJ, Schut L, Sutton LN, Seidl TS, Nudelman S, Budenz D, Hertle R, Tsiaras W, Loporchio S. Head injury in very young children: mechanisms, injury types, and ophthalmologic findings in 100 hospitalized patients younger than 2 years of age. Pediatrics 1992; 90:179–185. 19. Bruce DA. Imaging after head trauma: why, when and which. Childs Nerv Syst 2000; 16:755–759. 20. Singer MB, Atlas SW, Drayer BP. Subarachnoid space disease: diagnosis with fluid-attenuated inversion-recovery MR imaging and comparison with gadolinium-enhanced spin-echo MR imaging-blinded reader study. Radiology 1998; 208:417–422. 21. Noguchi K, Ogawa T, Seto H, Inugami A, Hadeishi H, Fujita H, Hatazawa J, Shimosegawa E, Okudera T, Uemura K. Subacute and chronic subarachnoid hemorrhage: diagnosis with fluid-attenuated inversion-recovery MR imaging. Radiology 1997; 203:257–262. 22. American Academy of Pediatrics. Section on Radiology. Diagnostic imaging of child abuse. Pediatrics 2000; 105:1345–1348. 23. Chien D, Kwong KK, Gress DR, Buonanno FS, Buxton RB, Rosen BR. MR diffusion imaging of cerebral infarction in humans. AJNR Am J Neuroradiol 1992; 13:1097–1102. 24. Cowan FM, Pennock JM, Hanrahan JD, Manji KP, Edwards AD. Early detection of cerebral infarction and hypoxicischemic encephalopathy in neonates using diffusionweighted magnetic resonance imaging. Neuropediatrics 1994; 25:172–174. 25. Rugg-Gunn FJ, Symms MR, Barker GJ, Greenwood R, Duncan JS. Diffusion imaging shows abnormalities after blunt head trauma when conventional magnetic resonance imaging is normal. J Neurol Neurosurg Psych 2001; 70:530– 533. 26. Wieshmann UC, Summs MR, Clark CA, Lemieux L, Parker GJ, Barker GJ, Shorvon SD. Blunt-head trauma associated with widespread water-diffusion changes. Lancet 1999; 353:1242–1243. 27. Sutton LN, Wang Z, Duhaime AC, Costarino D, Sauter R, Zimmerman R. Tissue lactate in pediatric head trauma: a clinical study using 1H NMR spectroscopy. Pediatr Neurosurg 1995; 22:81–87. 28. Friedman SD, Brooks WM, Jung RE, Chiulli SJ, Sloan JH, Montoya BT, Hart BL, Yeo RA. Quantitative proton MRS predicts outcome after traumatic brain injury. Neurology 1999; 52:1384–1391. 29. Friedman SD, Brooks WM, Jung RE, Hart BL, Yeo RA. Proton MR spectroscopic findings correspond to neuropsychologi-

cal function in traumatic brain injury. AJNR Am J Neuroradiol 1998; 19:1879–1885. 30. Holshouser BA, Ashwal S, Luh GY, Shu S, Kahlon S, Auld KL, Tomasi LG, Perkin RM, Hinshaw DB Jr. Proton MR spectroscopy after acute central nervous system injury: outcome prediction in neonates, infants, and children. Radiology 1997; 202:487–496. 31. Ricci R, Barbarella G, Musi P, Boldrini P, Trevisan C, Basaglia N. Localised proton MR spectroscopy of brain metabolism changes in vegetative patients. Neuroradiology 1997; 39:313–319. 32. Harwood-Nash DC, Hendrick EB, Hudson AR. The significance of skull fractures in children. A study of 1,187 patients. Radiology 1971; 101:151–156. 33. [No authors listed]. The management of minor closed head injury in children. Committee on Quality Improvement, American Academy of Pediatrics. Commission on Clinical Policies and Research, American Academy of Family Physicians. Pediatrics 1999; 104:1407–1415. 34. Schutzman SA, Barnes P, Duhaime AC, Greenes D, Homer C, Jaffe D, Lewis RJ, Luerssen TG, Schunk J. Evaluation and management of children younger than 2 years old with apparently minor head trauma: proposed guidelines. Pediatrics 2001; 107:983–993. 35. Lloyd DA, Carty H, Patterson M, Butcher CK, Roe D. Predictive value of skull radiography for intracranial injury in children with blunt head injury. Lancet 1997; 349:821–824. 36. Quayle KS, Jaffe DM, Kuppermann N, Kaufman BA, Lee BC, Park TS, McAlister WH. Diagnostic testing for acute head injury in children: when are head computed tomography and skull radiographs indicated? Pediatrics 1997; 99:E11. 37. Naim-Ur-Rahman, Jamjoom Z, Jamjoom A, Murshid WR. Growing skull fractures: classification and management. Br J Neurosurg 1994; 8:667–679. 38. Muhonen MG, Piper JG, Menezes AH. Pathogenesis and treatment of growing skull fractures. Surg Neurol 1995; 43:367–372. 39. Kutlay M, Demircan N, Akin ON, Basekim C. Untreated growing cranial fractures detected in late stage. Neurosurgery 1998; 43:72–76. 40. Winston K, Beatty RM, Fisher EG. Consequences of dural defects acquired in infancy. J Neurosurg 1983; 59:839–846. 41. Papaefthymiou G, Oberbauer R, Pendl G. Craniocerebral birth trauma caused by vacuum extraction: a case of growing skull fracture as a perinatal complication. Childs Nerv Syst 1996; 12:117–120. 42. Tandon PN, Banerji AK, Bhatia R, Goulatiq RK. Craniocerebral erosion (growing fracture of the skull in children). Acta Neurochir 1987; 88:1–9. 43. Kashiwagi S, Abiko S, Aoki H. Growing skull fracture in childhood. Surg Neurol 1986; 26:63–66. 44. Rothman L, Rose JS, Laster DW, Quencer R, Tenner M. The spectrum of growing skull fractures in children. Pediatrics 1976; 57:26–31. 45. Dharker SR, Bhargava N. Bilateral epidural hematoma. Acta Neurochir 1991; 110:29–32. 46. Mohanty A, Sastry Kolluri VR, Subbakrishna DK, Satish S, Chandra Mouli BA, Das BS. Prognosis of extradural hematomas in children. Pediatr Neurosurg 1995; 23:57–63. 47. Dhellemmes P, Lejeune JP, Christiaens JL, Combelles G. Traumatic extradural hematomas in infancy and childhood: experience with 144 cases. J Neurosurg 1985; 62:861–864. 48. Zimmerman RA. Examination of head injury: supratentorial. In: Taveras J, Ferrucci J (eds) Radiology - Diagnosis,

Accidental Head Trauma Imaging, Intervention. Philadelphia: JB Lippincott, 1992:1– 18. 49. Kraus JF, Fife D, Conroy C. Pediatric brain injuries: the nature, clinical course, and early outcomes in a defined United States population. Pediatrics 1987; 79:501–508. 50. Woodcock RJ, Davis PC, Hopkins KL. Imaging of head trauma in infancy and childhood. Semin Ultrasound CT MR 2001; 22:162–182. 51. Papasian NC, Frim DM. A theoretical model of benign external hydrocephalus that predicts a predisposition towards extra-axial hemorrhage after minor head trauma. Pediatr Neurosurg 2000; 33:188–193. 52. Gentry LR. Head trauma. In: Atlas SW (ed) Magnetic Resonance Imaging of the Brain and Spine, 2nd edn. Philadelphia: Lippincott-Raven, 1996:611–647. 53. Grossman RI, Gomori JM, Goldberg HI, Hackney DB, Atlas SW, Kemp SS, Zimmerman RA, Bilaniuk LT. MR imaging of hemorrhagic conditions of the head and neck. Radiographics. 1988; 8:441–454. 54. Triulzi F, Baldoli C, Parazzini C. Patologia vascolare, infettiva e traumatica cranio-encefalica. In: Dal Pozzo G (ed) Compendio di Risonanza Magnetica. Cranio e Rachide. Turin: UTET, 2001:1191–1222. 55. Orrison WW Jr, Moore K. Neuroimaging of head trauma. In: Orrison WW Jr (ed) Neuroimaging. Philadelphia: W.B. Saunders, 2000: 884–915. 56. Gentry LR, Thompson B, Godersky JC. Trauma to the corpus callosum: MR features. AJNR Am J Neuroradiol 1988; 9:1129–1138. 57. Holburn AHS. The mechanism of brain injuries. Br Med Bull 1945; 3:147–149. 58. Hadley MN, Sonntag VKH, Rekate HL, Murphy A. The infant whiplash-shake injury syndrome: a clinical and pathological study. Neurosurgery 1989; 24:536–540. 59. Gentry LR, Godersky JC, Thompson B. MR imaging of head trauma: review of the distribution and radiopathologic features of traumatic lesions. AJNR Am J Neuroradiol 1988; 9:101–110. 60. Adams JH, Graham DI, Murray LS, Scott G. Diffuse axonal injury due to nonmissile head injury in humans: an analysis of 45 cases. Ann Neurol 1982; 12:557–563. 61. Parizel PM, Ozsarlak, Van Goethem JW, van den Hauwe L, Dillen C, Verlooy J, Cosyns P, De Schepper AM. Imaging findings in diffuse axonal injury after closed head trauma. Eur Radiol 1998; 8:960–965. 62. Zimmerman RA, Bilaniuk LT, Gennarelli T. Computed

tomography of shearing injuries of the cerebral white matter. Radiology 1978; 127:393–396. 63. Hammoud DA, Wasserman BA. Diffuse axonal injuries: pathophysiology and imaging. Neuroimaging Clin N Am 2002; 12:205–216. 64. Liu AY, Maldjian JA, Bagley LJ, Sinson GP, Grossman RI. Traumatic brain injury: diffusion weighted MR imaging findings. AJNR Am J Neuroradiol 1999, 20:1636–1641. 65. Condon B, Oluoch-Olunya D, Hadley D, Teasdale F, Wagstaff A. Early 1H magnetic resonance spectroscopy of acute head injury: four cases. J Neurotrauma 1998; 15:563–571. 66. Brooks WM, Friedman SD, Gasparovic C. Magnetic resonance spectroscopy in traumatic brain injury. J Head Trauma Rehabil 2001; 16:149–164. 67. Brooks WM, Stidley CA, Petropoulos H, Jung RE, Weers DC, Friedman SD, Barlow MA, Sibbitt WL Jr, Yeo RA. Metabolic and cognitive response to human traumatic brain injury: a quantitative proton magnetic resonance study. J Neurotrauma 2000; 17:629–640. 68. Sharples PM, Matthews DS, Eyre JA. Cerebral blood flow and metabolism in children with severe head injuries. Part 2: cerebrovascular resistance and its determinants. J Neurol Neursurg Psych 1995; 58:153–159. 69. Ozgun B, Castillo M. Basal ganglia hemorrhage related to lightning strike. AJNR Am J Neuroradiol 1995; 16:1370–1371. 70. Johnson PL, Eckard DA, Chason DP, Brecheisen MA, Batnitzky S. Imaging of acquired cerebral herniations. Neuroimag Clin N Am 2002; 12:217–228. 71. Bernal-Sprekelsen M, Bleda-Vazquez C, Carrau RL. Ascending meningitis secondary to traumatic cerebrospinal fluid leaks. Am J Rhinol 2000; 14:257–259. 72. El Gammal T, Sobol W, Wadlington VR, Sillers MJ, Crews C, Fisher WS 3rd, Lee JY. Cerebrospinal fluid fistula: detection with MR cisternography. AJNR Am J Neuroradiol 1998; 19:627–631. 73. Shetty PG, Shroff MM, Sahani DV, Kirtane MV. Evaluation of high-resolution CT and MR cisternography in the diagnosis of cerebrospinal fluid fistula. AJNR Am J Neuroradiol 1998; 19:633–639. 74. Jayakumar PN, Kovoor JM, Srikanth SG, Praharaj SS. 3D steady-state MR cisternography in CSF rhinorrhoea. Acta Radiol 2001; 42:582–584. 75. Domengie F, Cottier JP, Lescanne E, Aesch B, Vinikoff-Sonier C, Gallas S, Herbreteau D. [Management of cerebrospinal fluid fistulae: physiopathology, imaging and treatment]. J Neuroradiol 2004; 31:47–59.

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Nonaccidental Head Injury (Child Abuse)

20 Nonaccidental Head Injury (Child Abuse) Bruno Bernardi and Christian Bartoi

20.1 Epidemiology and Mechanisms of Injury

CONTENTS 20.1

Epidemiology and Mechanisms of Injury 929

20.2

Clinical Presentations

20.3

Imaging Strategies

20.4

Imaging Findings 940

20.4.1 20.4.2 20.4.3 20.4.4

Skull Fractures 940 Intracranial Hematomas 940 Brain Contusions and Diffuse Axonal Injury 941 Edema, Hypoxia-Ischemia, and Infarction 943

20.5

Long-Term Intracranial Changes and Clinical Outcome 944

20.6

Differential Diagnosis

20.7

Medico-Legal Aspects: Notes on Statistics Incidence, Distribution by Family and Perpetrator Characteristics, and Forensic Implications 946 References

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The spectrum of disorders encompassed by the term “child abuse,” originally described by Tardieu in 1886 [1], became a medical entity with the studies of Caffey in 1946 [2], 1972 [3], and 1974 [4], Wooley and Evans in 1955 [5], Kempe in 1962 [6] and 1972 [7], and Silverman in 1972 [8]. Nowadays, the term includes emotional and/or neglect, sexual, and physical abuse. Nonaccidental head injuries (NAHI) represent only 12% of physical injuries in child abuse, but are the leading cause of death in abused children under 2 years of age [9] and the most common cause of traumatic death in infancy [10–12]. Nonaccidental (inflicted) injuries typically occur in children under 2 years of age, particularly in the first year of life. Risk factors include young parents, low socio-economic status, unstable family situation, and disability or prematurity of the child. It should be remembered that children affected by developmental disorders are at higher risk of abuse. The multiple names used to define the syndromes related to inflicted head injuries (i.e., battered child, whiplash shaken-baby syndrome, shaken-baby, and shaking-impact syndrome) reflect the multiple and often controversial theories explaining the mechanism of injury and our incomplete, albeit increasing, understanding of them. Caffey [4] coined the term “whiplash shaken-baby syndrome” to explain the presence of subdural hematomas, massive cerebral edema, metaphyseal fractures, and retinal bleeding resulting from vigorous shaking of the infant by shoulders, trunk or limbs, producing hyperextension of the head that moves like the lash of a whip. The neuroradiological findings may depend mainly on whether the NAHI was caused by blunt impact, shaking with or without impact, strangling, smothering, drowning, or a combination of these mechanisms [13–15]. Inflicted blunt injuries, more frequent after the first year of life, produce lesions usually not different from accidental trauma. Soft tissue bruises are usually present and associated with subgaleal hema-

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tomas, skull fractures with focal underlying injury (subdural hematoma, brain contusion, laceration), opposite side injury (so-called contrecoup lesion), and diffuse lesions (subarachnoid hemorrhage, brain edema, and diffuse axonal injury) [13]. It is generally accepted that rotational, acceleration-deceleration forces, generated during vigorous shaking, are sufficient to produce devastating cerebral damages [16]. Studies on primates have shown that shaking alone, without impact, may cause brain contusion and hemorrhage [17–20]. Nevertheless, Duhaime and colleagues [11, 12] suggested that severe head injuries do not occur from shaking alone. They considered most of the damages to result from inflicted injuries, as the product of the angular deceleration associated with the forceful striking of the head against a surface (shaking-impact trauma) [12, 21]. The severity of the brain damage, due to the angular forces, is increased by the translational or straight forces with sudden deceleration. When the surface of head impact is soft, the straight forces applied are dissipated and brain damage may be not associated with visible external signs. Nevertheless, in the presence of suspected child abuse, one must search for the signs of blunt impact of the head, because the majority of abused children have clinical, radiological, or autopsy evidence of blunt impact [10, 22, 23]. For this reason, Duhaime and colleagues [11, 12] asserted that the term “shaking-impact syndrome” better reflects the mechanism responsible for these injuries than does “shaken baby syndrome.” Not only does the primary insult lead to direct extensive brain injuries, but it also is responsible for initiating secondary brain insults that contribute to the poor outcome. These events include reduced cerebral perfusion pressure, loss of cerebrovascular autoregulation, and diffuse brain edema, contributing to hypoxic-ischemic injury. Hypoxic-ischemic injury may also be related to apnea secondary to thoracic compression and to direct vascular occlusions. Refractory seizures, due to the primary or secondary brain injury, can produce a consumptive asphyxia. Vigorous shaking of the infant, with a relatively large head and weak neck musculature, may lead to flexion-extension cord injuries. Cord stretching produces axonal damage with possible spinal shock and respiratory compromise, one of the possible causes of secondary hypoxic-ischemic brain damage [24]. Immaturity of the skull, brain, and cerebral blood flow autoregulation contributes to the final brain damage as much as the type and the entity of the forces applied and the secondary injuries. The severity and type of injury are determined not only by the force applied but also by its magnitude; for this reason, it is not possible that brain lesions

observed in NAHI could be inflicted unwittingly by the caretaker during normal child-care activities [12]. The prognosis of NAHI in childhood is poor, and worse than in accidental head injury. The mortality rate is 26%–36%, compared to 10%–12% in accidental head injury [25, 26]. The neurological morbidity ranges from 57% to 92%, compared to 22%–38% in accidental head injury [26–29].

20.2 Clinical Presentations The most common neurological presentation is not specific and may not immediately suggest abuse. The infant or child, often pale and in shock, is irritable or lethargic, refuses feeding, is vomiting, and may have seizures. The baby may have tonic-extensor episodes and breathing difficulties, with periodic breathing and cyanotic attacks. In other cases there is evidence of head injury, with acute neurological symptoms and signs associated with bruising, swelling, lacerations of the subcutaneous tissues, and fractured skull. The presence of coma may also result from injury remote from the head. The American College of Radiology [30] has identified the algorithmic sequences of imaging necessary in a child suspected of abuse, depending on the child’s age, signs, and symptoms. The need of a neuroradiological evaluation is essentially related to four different clinical presentations (Table 20.1): I. Evidence of central nervous system (CNS) trauma with acute neurological symptoms, often with a discrepancy between the severity of the lesions and the referred history; II. Chronic neurological symptoms which mimic nontraumatic, progressive neurological diseases, such as recurrent encephalopathy and encephalitis or metabolic diseases, with or without other physical findings; III. Absence of neurological symptoms in a 2-year-old or younger child with evidence of head trauma without a satisfactory explanation; IV. Absence of neurological symptoms in a child of any age, presenting visceral injury that is discrepant with the clinical history and/or with bones fractures or physical examination suggesting abuse. Infants with Evidence of Acute CNS Trauma and Neurological Symptoms

The severity of the imaging findings may be out of proportion to the history of trauma (Figs. 20.1–6). Injuries of different ages are crucial indicators to the probabil-

Nonaccidental Head Injury (Child Abuse) Table 20.1. Non-Accidental Head Trauma: Imaging Protocol

a

b

ity of nonaccidental trauma [31] (Figs. 20.3, 7–9). This is true even when extracranial injuries are not detected by the skeletal survey and physical examination. Recurrent Episodes of Encephalopathy Mimicking Metabolic Diseases or Encephalitis

Presentation with lethargy, irritability, seizures (either isolated or status epilepticus), increased or decreased muscular tone, impaired consciousness, vomiting, breathing abnormalities, and apnea is nonspecific.

Fig. 20.1a,b. Nine-month-old girl with severity of imaging findings out of proportion to the history of trauma. a,b Axial CT scans show diffuse decrease in attenuation of the left cerebral hemisphere with loss of the gray/white matter differentiation due to acute hypoxia. The intermediate window image shows subdural collection along the left frontalparietal region and the posterior falx (arrowheads, b)

NAHI must be considered in the differential diagnosis because this presentation is common in inflicted brain injuries. The clinical examination must include careful charting of all bruises, retinoscopy, and skeletal survey. In cases at risk, the clinical evaluation may need to be extended to the siblings. The outcome of this group of patients with chronic neurological symptoms is often poor. Common clinical sequelae of repeated unknown trauma include blindness, slowing of head growth, mental retardation, and hemi-tetraparesis, often discovered only at the time of the first mag-

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a

Fig. 20.2a–c. Six-month-old female with acute neurological symptoms (seizures) and multiple retinal hemorrhages. History of accidental trauma out of proportion and inconsistent with given history. a Axial T2-weighted image shows reduced gray/white matter differentiation with increased cortical intensity in the left temporal-occipital region (asterisks). There also is a fronto-temporal hyperintense subdural collection (arrows) with slight effacement of the homolateral ventricular system. b Axial diffusionweighted image reveals a larger area of restricted diffusion (i.e., hyperintense) in the left fronto-parietal and occipital region (arrowheads), related to cytotoxic edema. c Single-voxel proton MR spectroscopy, obtained with probe-s sequence, shows grossly elevated lactate doublet with a reduction in NAA. The creatine/choline and creatine/myoinositol ratios are abnormal as well. These findings are consistent with an infarct in evolution

b

c

netic resonance imaging (MRI) examination. Bruising, burns, and multiple rib and metaphyseal fractures (Fig. 20.7) raise the suspicion of abuse and increase the need of accurate neuroradiological evaluation.

Patients with Extracranial Lesions Suggesting Abuse

Lesions such as bone fractures may be found in children without neurological signs and symptoms, despite significant CNS injury detected by CT and/or MRI [12, 32]. Rubin et al. [33] evaluated children under 2 years of age admitted to the hospital with injuries suspicious for child abuse and normal neurological examination at admission. 37.3% of the patients selected for “highrisk” criteria, including rib fractures, multiple fractures, facial injury, or age 50% in association with gliosis [180, 181]. The synaptic changes that result from neuronal cell loss, sprouting, and the establishment of an altered circuitry may result in hypersynchronization and hyperexcitability.

Epilepsy

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Fig. 22.15a–f. a,b 12-year-old boy with focal epilepsy. Sagittal STIR image (a) and Gd-enhanced sagittal T1-weighted image (b) show dysembryoplastic neuroepithelial tumor (DNT) appearing as an unenhancing cortical-based pseudocystic rolandic mass, without peritumoral edema and with scalloping of the inner table. c,d 17-year-old female with refractory epilepsy. Coronal FLAIR image (c) and Gd-enhanced coronal T1-weighted image (d) show DNT appearing as a “bubbly,” well-defined hyperintense superficial mass on the lateral aspect of occipital lobe, surrounded by dysplastic cortex, with nodular enhancement after gadolinium administration (arrow, d). e 8-year-old boy with precocious puberty. Sagittal T1-weighted image shows pedunculated hypothalamic hamartoma (arrow). f 10-year-old girl with gelastic epilepsy. Gd-enhanced sagittal T1-weighted image shows sessile hypothalamic hamartoma impinging the anterior aspect of third ventricle (arrow)

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1016 R. Guerrini, R. Canapicchi, and D. Montanaro Although the majority of the epilepsies with seizures of mesial temporal origin are not preceded by febrile seizures [182, 183], retrospective studies and rare prospective observations have demonstrated that a sequence of prolonged febrile seizure followed by temporal lobe epilepsy does exist, whatever its mechanism and frequency [184–189]. A unifying view on the pathogenesis of HS [190] suggests that a brain insult, such as prolonged febrile seizures or other injury, would produce damage to the hippocampus only in the presence of pre-existing factors that make such a structure vulnerable. These factors are represented by developmental lesions [191] or specific genetic predisposition [192]. 22.3.3.1 Imaging Findings

MRI is far superior to CT for the detection of HS [177, 193]. A better-quality morphological evaluation of the hippocampal region is obtained by using cuts oriented in two orthogonal planes along the long axis of the body of the hippocampus and at a right angle to this [177]. Such an approach prevents from obtaining oblique images of the hippocampus, which can be difficult to interpret due to partial volume effects. Thin-section high resolution fast spin-echo T2, FLAIR, FIRMS, or inversion recovery pulse sequences must be obtained to depict the hippocampal architecture and to assess signal changes. High resolution MRI (slice thickness 1.5 mm) is the method of choice [7]. Volumetric pulse sequences with reformatting of thin sections parallel and perpendicular to the long axis of the hippocampi represent a valid tool. Since CSF artifacts are incompletely suppressed on FLAIR [194], we prefer the fast inversion recovery pulse sequence with white matter signal suppression (FIRMS), which better delineates the hippocampal anatomy (Fig. 22.16). Hippocampal size and shape should be visually assessed after verifying the symmetry of the internal auditory canals. If acquisition has been asymmetric, it is possible to reformat the images straightening any oblique sections, without contrast and spatial resolution loss (Fig. 22.17). The hallmarks of unilateral HS on MRI include: 1. Signal increase on long TR and signal decrease on short TR images involving, on one side, all the mesial temporal lobe, i.e., amygdala (Fig. 22.18) and uncus, as well as the whole hippocampus (Fig. 22.19) or part of it (Fig. 22.20); 2. Volume loss of affected hippocampus compared to the contralateral one (Fig. 22.20); 3. Disruption of internal architecture of hippocampus with failure to differentiate the stratum radia-

tum of white matter from cortical structures and to identify the fimbria or alveus from the Ammon’s horn (Fig. 22.20). At least one of these abnormal features was present in 93% of cases in one series [195], while all four features were found together in only 39%. Additional findings that can help lateralize HS include: 1. Unilateral loss of digitations of hippocampal head (92% of involved heads) (Fig. 22.21); 2. Ipsilateral atrophy of mammillary body (3%) and posterior fornix (39%) (Fig. 22.21), related to involvement of afferent and efferent pathways of the hippocampus; 3. Enlargement of ipsilateral anterior temporal horn (22%–33% of cases) (Fig. 22.21); 4. Collateral white matter narrowing (67%) (Fig. 22.21). The atrophic-gliotic changes may be limited to one part of the hippocampal formation [196] or to patchy areas, and extend to the temporal neocortex often predominating in the anterior segment of the first temporal gyrus [197, 198], but may involve other temporal gyri and even structures outside the temporal lobe (insula; frontobasal and opercular cortex, a lesion termed pararhinal sclerosis). Atrophy of the whole ipsilateral temporal lobe can also be found [199] (Fig. 22.21). Hippocampal sclerosis can be bilateral [200] (Fig. 22.21). For quantitative analysis, hippocampal volumetry requires side-to-side ratios as well as absolute volumes corrected for intracranial volume, which must be compared with appropriated age-matched controls from the same laboratory (Fig. 22.5). The procedure is time-consuming. Volumetric assessment also has limitations in that it relies on subjective definition of the hippocampal boundaries and on side-to-side comparison, which may fail to detect bilateral changes [201]. In addition, hippocampal volumes may be normal in a small subgroup of patients with abnormal signal in one hippocampus as determined by preoperative MRI and pathologically proven HS [202]. Normally, both hippocampi are of equal volume, with a slight prevalence of the right side [203]; any asymmetry greater than 0.3 cm is abnormal [204]. Volumetry can detect up to 90% of cases of HS [203, 205] compared to about 80% by visual assessment [201]. Hippocampal volume loss correlates with the side of seizure onset and with HS as demonstrated in resected tissue specimens [184, 204, 206]. Quantitative MRI may be also used to detect hippocampal gliosis [186, 202]. Actual quantitative measurements of T2 relaxation time (T2 relaxometry) obtained on a

Epilepsy

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e b

f c

Fig. 22.16a–f. a–c Oblique coronal FIRMS MR images: example of normal hippocampal head, body, and tail. d–f Magnified images: excellent depiction of hippocampal anatomy: note head digitations, subiculum, subsectors of Ammon’s horn, dentate gyrus, alveus, fimbria, stratum radiatum and collateral white matter

single-slice multiecho sequence through the hippocampal body may permit the recognition of unilateral or bilateral involvement in patients with apparently normal MRI scans obtained by classical techniques [200, 202]. In most patients with hippocampal atrophy on MRI, PET reveals hypometabolism in the ipsilateral temporal lobe and usually provides little additional information in localizing and lateralizing the seizure focus [207]. On the other hand, PET is of great assistance in lateralizing the seizure focus in patients with temporal lobe epilepsy and a normal MRI [208]. Bilateral temporal hypometabolism suggests bilateral

temporal pathology and possibly a poorer prognosis following temporal lobe surgery [209]. Ictal SPECT is extremely helpful in the presurgical evaluation of temporal lobe epilepsy in selected patients, especially those in whom ictal EEG data is inconclusive. Interictal SPECT provides useful baseline information for assessing ictal studies, while in isolation is of minimal value [210, 211]. MRS correctly identifies the epileptogenic hippocampus by a reduction of the neuronal marker NAA in 75%–95% of patients with temporal lobe epilepsy and MRI-proven MTS, and in 60%–70% of those with normal MRI [212]. It is difficult to achieve a good

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Fig. 22.17a,b. a Rotated coronal FSE T2-weighted image at hippocampal body. b Reformatted coronal image after corrections of head rotation better shows left hippocampal atrophy (arrow)

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c

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Fig. 22.18a–d. a,b Left amygdalo-hippocampal sclerosis. Coronal FLAIR (a) and axial FSE T2-weighted (b) images show hyperintense lesion involving the amygdala and head of hippocampus on the left. c,d Bilateral hippocampal sclerosis. Axial FLAIR (c) and oblique coronal FSE T2-weighted (d) images show hyperintense signal involving the head and body of both hippocampi, more evident on the right

Epilepsy

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Fig. 22.19a–d. Right hippocampal sclerosis. a Axial FLAIR image shows hyperintense lesion involving almost all the right hippocampus. b–d Oblique coronal inversion recovery images show low signal intensity on the right head (arrow, b), body (arrow, c), and tail (arrow, d), with enlargement of the ventricular temporal horn

homogeneity of the magnetic field in the hippocampal region, due to the close proximity of bone, sinuses, and blood vessels. Long-TE spectra are less prone to artifacts caused by lipid contamination and incomplete water suppression. Short-TE spectra are usually preferred as, in addition to the main peaks (NAA, Cho, and Cr), they permit the detection of additional broad components usually referred as “Glnx,” in the region of 2.1–2.5 ppm. However, using 1.5-T, it is very difficult to resolve resonances of glutamate, glutamine, and γ-aminobutyric acid (GABA) [212], that are better resolved at 3 T [14]. Using DWI, calculated ADC is higher in the sclerotic hippocampi (i.e., MTS) than in contralateral normal hippocampi. Increased hippocampal diffusivity in the epileptogenic temporal lobe may be explained by a decrease in hippocampal neuronal density, gliosis, or both [213]. Diffusion tensor imaging may reveal focal temporal anisotropy in patients with temporal lobe epilepsy [214]. The possible coexistence of cortical dysplasia with hippocampal sclerosis, the so-called dual pathology [215], implies that careful imaging screening of additional potentially epileptogenic abnormalities is essential when evaluating patients with either hippocampal

volume loss or cortical dysplasia who are candidates for epilepsy surgery (Fig. 22.22). Dual pathology was reported to occur in 2% of patients with tumors, in 9% of those with vascular malformations, and in 25% of those with cortical dysplasia [216, 217]. Abnormalities other than HS involving the temporo-mesial region, such as cortical dysplasia [218], gray matter heterotopia, vascular malformations, developmental glioneuronal tumors, and neuroepithelial cysts, can be responsible for mesial temporal epilepsy (Fig. 22.23). On the other hand, temporal lobe epilepsy may also be associated with extra-hippocampal lesions (Fig. 22.24). Neocortical temporal lobe epilepsy (NCTLE) is more difficult to diagnose. Studies assessing clinical and neurophysiological features, including interictal and ictal EEG patterns, have detected few distinguishing features [207].

22.3.4 Rasmussen’s Encephalitis The term Rasmussen’s encephalitis, or syndrome, designates a progressive disorder that includes epilepsia partialis continua (continuous myoclonic jerks,

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Fig. 22.20a–d. a,b Right hippocampal sclerosis. a axial and b oblique coronal FSE T2-weighted images show hyperintense signal involving only the central side of the hippocampal head and body (arrowheads). c Left hippocampal sclerosis. Oblique coronal FSE T2-weighted image shows left hippocampal body atrophy compared with the contralateral. Note also thinning of collateral white matter. d Left hippocampal sclerosis. Oblique coronal FIRMS image shows disruption of hippocampal architecture on the left where the stratum radiatum, alveus, fimbria, Ammon’s horn and dentate gyrus are not clearly identifiable. Note thinning of ipsilateral posterior fornix (arrow)

localized to a limited area on one side of the body), other types of seizures (especially complex partial), progressive hemiplegia, abnormal movements, mental deterioration, and possibly aphasia (see also Chap. 12). The onset is usually between 18 months and 14 years with a mean of 7 years and development is usually normal before onset of epilepsy. In about half the patients, a history of infectious or inflammatory episodes can be elicited and may have an etiological role. The syndrome evolves in three phases [219, 220]: a first prodromal phase with relatively low seizure frequency and mild hemiparesis lasts an average of 7 months but may be longer in adolescents. The second phase is characterized by an acute increase of seizures with partial continuous epilepsy in about 50% of patients and progressive hemiplegia in almost all cases [221, 222]. Its median duration was 8 months in a recent study [220]. Most of the atrophy develops during this phase. The third stage follows with a permanent and usually stable hemiparesis. Cognitive decline is an almost constant feature. In most patients the course is very severe. Although the disease becomes burnt-out after several years, it leaves severe deficits. A fluctuat-

ing course is frequent [221]. Stabilization is possible at a limited level of disability in some cases [219]. Neuropathological studies [223–225] show inflammatory signs with glial nodules and perivascular infiltrates containing plasmocytes and lymphocytes together with microglial cells [223]. Such changes are limited to one hemisphere. Attempts at demonstrating a conventional virus or not conventional agents have mostly failed. Oligoclonal bands in CSF were present in several cases [116, 226]. An immunoallergic mechanism seems nowadays the most likely etiologic factor [227]. Antibodies against the glutamate R3 receptor have been demonstrated in some cases [228] and have been thought to play a role in epileptogenesis. Antiepileptic drug treatment is ineffective. Treatment with corticosteroids in large doses or with immunosuppressant agents may be temporarily effective [229, 230]. Immunoglobulins given intravenously have gained some success [230, 231]. Surgical treatment with large resections, especially hemispherectomy or hemispherotomy, is useful [232–234] but should be limited to patients who are already hemiplegic.

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Fig. 22.21a–f. a Right hippocampal sclerosis. Oblique coronal FSE T2-weighted image shows digitation loss in the hippocampal head (arrow). b Left hippocampal sclerosis. Oblique coronal FSE T2-weighted image shows atrophy of ipsilateral mammillary body (arrow). c Right hippocampal sclerosis. Oblique coronal FSE T2-weighted image shows thinning of ipsilateral posterior fornix (arrow). d,e Left hippocampal sclerosis. Oblique coronal inversion recovery images. Note enlargement of ipsilateral ventricular temporal horn (asterisk, d), small ipsilateral mammillary body (arrow, d), and narrowed collateral white matter on the left, consistent with atrophy of the hippocampus without apparent signal abnormality. f Left hippocampal sclerosis. Oblique coronal FSE T2-weighted image shows mild atrophy of ipsilateral temporal neocortex

22.3.4.1 Imaging Findings

Neuroimaging shows progressive atrophy that may involve the fronto-temporal region or a whole hemisphere. Contralateral involvement has been reported in some cases. Unilateral hemispheric atrophy involving predominantly the fronto-temporal region is apparent on CT scan. MRI may suggest the diagnosis in the early

stages [235]. It shows abnormally increased signal on T2-weighted images involving the white matter and the cortex of the frontal and temporal lobes, with perisylvian predominance [220, 236]. The ipsilateral caudate nucleus may also be atrophic, with consequent widening of the frontal horn (Fig. 22.25). Atrophy of the caudate may be an early, and even the first, imaging abnormality in some cases [237]. Indeed, unilateral choreic movements may be the presenting symptom [219] and be responsible for diagnostic

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errors [238]. Atrophy usually progresses to involve the whole hemisphere. The EEG also shows progressive deterioration of background activity. Bilateral discharges are common and usually asymmetric, but do not necessarily indicate bilateral pathology [236]. FDG-PET, Tc-99m SPECT, and proton MRS show hypometabolism, decreased perfusion, and reduced NAA in the affected hemisphere.

22.3.5 Head Trauma Head trauma caused by street or traffic accidents is relatively frequent in children. Several studies have emphasized the differences between early and late posttraumatic epilepsy [239, 240]. All seizures that occur more than 1 week following head trauma are termed late posttraumatic epilepsy. The incidence of late onset seizures is much lower than that of early ones. The incidence of late posttraumatic epilepsy in children varies from 0.2% to 12%. The risk of late epilepsy also varies considerably with the severity of head trauma. It is greatly increased in the case of

Fig. 22.22a–d. Dual pathology. a,b Coronal SPGR T1-weighted image (a) and axial T2-weighted image (b) show right hippocampal atrophy (arrow, a) and small infolding of the cortical ribbon in the right superior frontal gyrus (arrowhead, b). c,d Axial FLAIR (c) and coronal FLAIR (d) images show right hippocampal gliosis (arrow, c) and homolateral frontal Taylor type focal cortical dysplasia (arrowheads, d)

hematoma requiring surgical evacuation, depressed fracture, torn dura, and/or posttraumatic amnesia of 24 h or more. The occurrence of early seizures should not mislead toward a diagnosis of intracranial hematoma. Patients with hematomas have a 35% risk of developing late epilepsy. Patients with depressed fractures have varying risks depending on various combinations of the three factors, while the risk of epilepsy is very small in children with linear skull fractures (Fig. 22.26). CT or MRI evidence of parenchymal damage or intracerebral hemorrhage is associated with a higher incidence of posttraumatic seizures [241, 242].

22.3.6 Vascular Malformations 22.3.6.1 Cavernous Hemangiomas

Among vascular malformations causing epilepsy, cavernous hemangiomas (CHs), or cavernomas, represent 10%–20% of cerebral vascular malformations, are usu-

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h Fig. 22.23a–h. Abnormalities other than hippocampal sclerosis involving the mesial temporal lobe in patients with mesial temporal lobe epilepsy. a,b Axial FLAIR image (a) and coronal T2-weighted image (b) show left unco-amygdalo-hippocampal Taylor type focal cortical dysplasia (arrowheads). c,d Coronal SPGR T1-weighted image (c) and coronal FIRMS image (d) show right temporal periventricular nodular gray matter heterotopia (arrow). e,f Coronal T2-weighted image (e) and Gd-enhanced coronal T1-weighted image (f) show left hippocampal low-grade astrocytoma (arrow). g,h Axial FLAIR (g) and coronal T1-weighted (h) images show right choroidal fissure neuroepithelial cyst (asterisk) impinging on the mesial aspect of the hippocampus.

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Epilepsy Fig. 22.24a–h. Extrahippocampal temporal lesions associated with temporal lobe epilepsy. a,b Sagittal T1-weighted (a) and coronal T2-weighted (b) images show right temporal cavernous hemangioma involving the superior temporal gyrus. c,d Axial gradientecho T2*-weighted image (c) and Gd-enhanced coronal T1-weighted image (d) show calcified, partially enhanced left temporouncal ganglioglioma (arrow). e,f Coronal SPGR T1-weighted image (e) and axial FIRMS image (f) show polymicrogyria involving the right middle temporal gyrus (arrowheads). g,h Coronal T2-weighted image (g) and Gd-enhanced coronal T1-weighted image (h) show area of abnormal cortical architecture (arrowhead, g) with abnormal venous drainage (arrow, h) surrounding the left collateral sulcus

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Fig. 22.25a–c. Rasmussen’s encephalitis. a Axial STIR image; b Sagittal T1-weighted image; c Coronal FLAIR image. Atrophy of right cerebral hemisphere with prominent sulci in the right fronto-temporo-parietal region and with abnormal white matter signal on FLAIR (c). Note marked atrophy of the right caudate nucleus resulting in an enlarged lateral ventricle

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Fig. 22.26a,b. Posttraumatic epilepsy. Magnified axial proton density-weighted (a) and FLAIR (b) images show comminute, depressed fracture of the right parietal bone (arrows, a) with a cortical gliotic focus in the rolandic region (arrowhead, b)

ally hemispheric, and may be multiple. CHs are the most epileptogenic vascular malformations, and epilepsy is usually the sole manifestation of CHs for very long periods and may appear at any age from infancy to adulthood. However, CHs are a rare cause of newly diagnosed epilepsy in children [243]. The seizures are focal and often difficult to control. The risk of hemorrhagic complications is higher in children than in adults [244]. The MRI appearance of cavernomas is divided into four types, depending on the stage of hemorrhage [245]. Type 1 indicates subacute intralesional hemorrhage, with hyperintensity on both T1- and T2-weighted images. Type 2 is the most common appearance, with a center of mixed signal intensity surrounded by a dark hemosiderin ring. Type 3 shows hypointense to isointense signal on T1- and

T2-weighted images, suggesting chronic intralesional hemorrhage. Type 4 is only visualized using gradient-echo T2*-weighted sequences, due to hemosiderin deposition (Fig. 22.27). Hemorrhage may rarely occur around the lesion, producing acute symptoms. CHs are often autosomal dominant [246, 247]. A locus for familial cavernous angiomatosis maps to chromosome 7q (CCM1 locus) [248], and is due to mutations of the KRIT1 gene. Mutations have been detected in both familial [249, 250] and sporadic patients [251]. Two additional loci (CCM2 and CCM3) have been identified in other families [252]. In affected families, seizures occur in 69% of patients and in 64% of symptomatic first degree relatives [247]. fMRI of the perilesional tissue may help plan the surgical strategy (Fig. 22.28).

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Fig. 22.27a–d. Vascular abnormalities and epilepsy. a Sagittal T1-weighted image shows type 1 cavernous hemangioma in right hippocampal region (arrow). b Axial T1-weighted image shows type 2 cavernous hemangioma in the left cingulate region (arrow). c Axial T1-weighted image show isointense type 3 cavernous hemangioma in the right temporopolar region (arrow). d Coronal gradient-echo T2*-weighted image shows type 4 cavernous hemangioma involving the left inferior insular region

22.3.6.2 Developmental Venous Anomalies

22.3.7.1 Herpes Virus Encephalitis

Developmental venous anomalies (DVAs), formerly called venous angiomas, are angiogenically mature “caput medusae”-like enlarged medullary veins that drain into either the dural sinus or a deep ependymal vein through a large collector. They may be epileptogenic, especially when located in the temporo-mesial region or when associated with cortical dysplasia [253] (Fig. 22.24).

In the pediatric population, the sequelae of herpes simplex virus encephalitis (HSVE) are a relatively common cause of postinfectious epilepsy. Neonatal HSVE is commonly due to HSV type 2, while childhood HSVE is due to HSV type 1 in 99% of cases [254]. In HSVE type 2, neuroimaging shows multifocal or diffuse abnormalities that involve the temporal, frontal, and parietal lobes or the periventricular and subcortical white matter (Fig. 22.29). In HSVE type 1, the most characteristic pattern is a destructive lesion in the limbic system, with either unilateral or bilateral distribution (Fig. 22.29).

22.3.7 Infections Infections, as other brain insults, may produce focal cell loss and astroglial proliferation that are commonly associated with epilepsy.

Epilepsy

22.3.8 Neurocutaneous Disorders 22.3.8.1 Neurofibromatosis Type 1

Fig. 22.28. Young man with focal motor seizures of the left hand. fMRI activations during a left hand motor task (top, T1weighted images; bottom, corresponding T2*-weighted images). Responses are identifiable very close to a cavernous hemangioma located at the vertex, in the subcortical with matter underlying the pre- and postcentral cortex

22.3.7.2 Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a rare condition that is often caused by measles virus and is thought to be due to viral reactivation many years after the initial infection. Onset of symptoms is usually insidious, but seizures may be present earlier on. MRI shows progressive, bilateral periventricular and subcortical white matter hyperintense signal abnormalities on T2-weighted images, as well as cortical atrophy. Basal ganglia involvement occurs in 20%– 35% of cases [255] (Fig. 22.29). 22.3.7.3 Cysticercosis

In many countries with limited resources, cysticercosis is the most common identified cause of epilepsy [256]. MRI is very sensitive in demonstrating various stages of the development of noncalcified cerebral cysticercosis, while CT better reveals calcified cysts (Fig. 22.29).

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with variable expressivity and full penetrance by the age of 5 years. The NF1 gene maps to chromosome 17q11. About half of the cases are due to a new mutation [257]. The main clinical characteristics include café-au-lait spots, peripheral neurofibromas, and hamartomas of the iris (Lisch nodules) [258, 259]. About 25% of affected individuals require educational assistance because of learning disabilities. The prevalence of the disease is estimated to be 1:3000. Epilepsy is reported to occur in about 10% of patients. Estimates of the frequency of epilepsy in NF1 have varied, depending on patient recruitment procedures. Riccardi [260] reported a frequency of 3% in 139 cases. Other estimates have given higher values, although never exceeding 20% [261, 262] despite the finding of migration abnormalities. To date, little research has addressed the characterization of epilepsy. All seizure types have been reported, with the exception of typical absences [262]. Neither seizure type appears to predominate over others, nor has a developmental profile been observed apart from a slightly higher frequency of infantile spasms, which appear to have a benign prognosis [263]. The main MRI findings are focal areas of abnormal signal (brainstem, hippocampus, globus pallidus, thalamus, white matter), plexiform neurofibroma (orbit, scalp, skull base, paraspinal), glioma (visual pathway, brainstem), sphenoid wing dysplasia (empty orbit sign), and vascular abnormalities (arterial stenoses, moyamoya) [264] (see Chap. 16). 22.3.8.2 Tuberous Sclerosis

Tuberous sclerosis, or tuberous sclerosis complex (TSC), is a multisystemic disorder involving primarily the central nervous system, the skin, and the kidney [265]. The condition bears a close relationship to cortical dysplasia, from which individual lesions may be impossible to differentiate. A prevalence of 1:10,000–30,000 has been reported. The classical clinical triad of mental retardation, epilepsy, and “adenoma sebaceum” (facial angiofibromas) is present in only one third of the cases. The characteristic brain lesions are cortical tubers, subependymal nodules, and subependymal giant cell

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Fig. 22.29a–f. Infections and epilepsy. a Axial proton density-weighted image. Bilateral opercular syndrome in a 5-year-old girl, resulting from type 2 herpes simplex virus (HSV) encephalitis with bilateral involvement of the posterior perisylvian regions. b. Axial FLAIR image. Partial complex seizures in a 2-year-old boy as sequelae of type 1 HSV encephalitis involving the right mesial temporal lobe. c,d 8-year-old boy with epilepsy that developed 2 years after measles virus infection and subacute sclerosing panencephalitis. Axial T2-weighted image at presentation (c) shows abnormal hyperintense signal involving both peritrigonal regions. Follow-up MRI after 3 years (d) shows increased abnormal signal in the peritrigonal white matter, bilateral putaminal involvement, and diffuse cortical atrophy. e,f Cerebral cysticercosis in a 18-year-old patient from Guatemala who presented with secondarily generalized seizures. Axial FLAIR (e) and Gd-enhanced axial T1-weighted (f) images show cysts with variable inflammatory host response. Note the dot due to protoscolex inside the right frontal lesion (arrow, f)

astrocytomas. Cortical tubers are the lesions that are directly related to epileptogenesis. The pathologic changes observed in cortical tubers are remarkably similar to those seen in focal Taylortype cortical dysplasia [41, 266], which, however, is not associated with any other features of TSC and has no known familial distribution. Some investigators had described dysplasia as “forme fruste” of TSC [56, 267]. In fact, such anomalies should be considered as being distinct from this disease. TSC is transmitted as an autosomal dominant trait, with variable expression. Recurrence in the offspring

of nonaffected parents has rarely been reported and is thought to be related to low expressivity or gonadal mosaicism. Between 50% and 75% of all cases result from new mutations. Two genes, TSC1 and TSC2, were identified. TSC1 [268] encodes a predicted protein named hamartin; TSC2 [269] encodes a predicted protein named tuberin. Both genes are thought to act as tumor suppressors [270]. No obvious phenotypic differences have been found in the families linked to the TSC1 or TSC2 gene mutations, although it has been suggested that patients with TSC1 mutations may have less severe epilepsy and cognitive impairment [271].

Epilepsy

In infants and children, seizures are the most common presenting symptom of TSC. They usually begin in the first 2 years of life. Infantile spasms are the commonest seizure type in the first year of life [272, 273]. Other types of epilepsy, especially with focal seizures, may occur in infants and young children. Roger et al. [274] found 63 of 126 children (50%) with West syndrome, and 63 (50%) with other types (mainly partial epilepsies or Lennox-Gastaut syndrome). The course of epilepsy is severe in about one third of patients. MRI studies may show some correlation between number and location of tubers and epilepsy characteristics. Curatolo and Cusmai [275] thought that the largest tuber corresponds to the main EEG focus, in patients with partial epilepsy as well as in those with infantile spasms. Mental retardation is common in TS and is much more frequently seen in patients who have had sei-

zures, especially those with early onset epilepsy [232, 265]. In addition to mental subnormality, autistic features or other deviant behavior such as hyperkinesia or aggressiveness are frequent in patients with TSC and a history of infantile spasms [276, 277]. The diagnosis of TSC should always be suspected in children with epilepsy, especially with infantile spasms or when there is a history of familial seizures or other neurological or mental disorders. Careful examination of the skin for cutaneous stigmata of the condition is mandatory. MRI carefully demonstrates cortical tubers, subependymal nodules, and subependymal giant cell astrocytoma. White matter lesions located along radial migration lines from ventricle to cortex, due to abnormal glial cell migration, can also be found as linear or wedge-shaped hyperintensities on T2-weighted images and focal lacunar cysts [278]. Some patients with epilepsy and clinically proven TSC may only have a few lesions on MRI (Fig. 22.30).

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Fig. 22.30a–f. Tuberous sclerosis complex (TSC). a–c 19-year-old girl with partial epilepsy and cutaneous stigmata (hypomelanotic macules) typical for TSC, confirmed by molecular genetics. Axial (a) and coronal (b) FLAIR images show right frontal wedge-shaped signal abnormality and left frontal cortical tuber; axial T2-weighted image (c) shows absence of subependymal nodules. d–f 25year-old man with mental retardation, epilepsy, and facial angiofibroma. Coronal FLAIR (d), axial FLAIR (e), and Gd-enhanced T1-weighted (f) images show left frontal cortical tuber (arrows, d,e) and small subependymal giant cell astrocytoma close to the left foramen of Monro (arrowhead, f)

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1030 R. Guerrini, R. Canapicchi, and D. Montanaro Brain abnormalities of TSC have been investigated by means of proton MRS, perfusion (ASL-PI), diffusion (DWI and DTI) [279], and fMRI [280] in combination with MRI. Proton MRS has proven useful in the characterization of the lesions (Fig. 22.31). The pharmacological management of epilepsy in TS is usually difficult, and drug resistance is common [281]. Surgical resection of a tuber can be successful if a single epileptogenic focus can be identified [282, 283]. Anterior callosotomy can markedly reduce drop attacks in selected patients [284]. 22.3.8.3 Sturge-Weber Syndrome

Sturge-Weber syndrome (SWS) is a nonfamilial phakomatosis with a potentially progressive course. The syndrome consists of a venous angioma of the leptomeninges (100% of cases) accompanied by nevus flammeus of the skin supplied by the trigeminal nerve (port-wine stain; 90% of cases) and, less often, by choroidal angioma and glaucoma. The facial and leptomeningeal angioma are usually ipsilateral but both can be bilateral [285, 286]. Angiomatosis occurs more frequently in the occipital region, but can be located anywhere and involve an entire hemisphere. Epilepsy is the most frequent and earliest manifestation of the disorder. Large series of SWS with epilepsy [287–290] have shown that a majority of the seizures were simple partial or complex partial in type with frequent secondary generalization. Unilateral convulsive status was observed by Arzimanoglou and Aicardi in 11 of their 23 patients [287], and was followed by permanent hemiplegia in 6 patients. a

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The diagnosis of the condition is generally obvious in a patient presenting with epileptic seizures. In some cases, however, the pial angiomatosis is present without facial angioma, and in other patients the pial angioma may be bilateral in association with a unilateral facial nevus [291, 292]. Deterioration following bouts of status epilepticus and neurologic deterioration with progressive parenchymal atrophy can occur even if epilepsy is not severe [287]. Surgical treatment would seem to be required in up to 40% of affected children in some series [287, 288]. CT findings include gyral and subcortical calcifications. On MRI, the affected hemisphere is atrophic with hyperpneumatization of the paranasal sinuses, thick diploe, and enlarged ipsilateral choroid plexus. In neonatal cases, the white matter appears hypointense on T2-weighted images in the affected hemisphere because of “accelerated” myelin maturation [293]. After gadolinium administration, subcortical, leptomeningeal, and choroidal serpentine T1 hyperintensity appears, due to angiomatous malformation enhancement. A choroidal angioma is seen in 70% of cases. MR angiography and digital subtraction angiography show pial blush with lack of cortical veins due to failure of the fetal cortical veins to develop normally (Fig. 22.32). A crucial problem is to determine whether the pial angioma is strictly unilateral and what its extent is in order to plan surgical treatment. Gadoliniumenhanced MRI demonstrates the angioma, but is best performed at a distance (no less than 3 weeks) from an episode of status epilepticus in order to avoid enhancement from intracortical leakage following blood-brain barrier alterations, which is not well correlated to the extent of the angioma [294]. c

Fig. 22.31a–c. Tuberous sclerosis complex in a 16-year-old girl. a Axial FLAIR shows multiple hyperintense cortical tubers; a right posterior temporo-parietal tuber shows a microcystic component (arrow). b Perfusion-weighted image shows all tubers are markedly hypointense, consistent with severe hypoperfusion. c MRS reveals aspecific data, including decrease of NAA and a more evident increase of mI. (Courtesy of Dr. M. Tosetti, Pisa, Italy)

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The differential diagnosis includes epilepsy associated with celiac disease, in which calcifications involving the occipital lobes, most often bilaterally, are seen without port-wine facial nevus. On gadolinium-enhanced MRI, no enhancement occurs because of absence of leptomeningeal angiomatosis (Fig. 22.32).

22.3.9 Epilepsy and Cerebral Palsy Cerebral palsy (CP) is the most common neurologic disorder associated with epilepsy, occurring in 15%–

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Fig. 22.32a–h. a–d 18-year-old boy with Sturge-Weber syndrome. Gd-enhanced axial T1-weighted images (a–c) show enhanced leptomeningeal angiomatosis over the left hypoplastic hemisphere (a,b) with ipsilateral enlarged choroid plexus and associated choroidal hemangioma (arrowheads, c). Lateral projection of left internal carotid angiogram, venous phase (d) shows lack of superficial cortical veins and pial blush. e,f 3-month-old boy with Sturge-Weber syndrome. Axial T2-weighted (e) and coronal T1-weighted (f) images show “accelerated” myelin maturation in the left (affected) hemisphere. g,h 8-year-old boy with visual seizures and celiac disease. Axial CT scan (g) shows left occipital calcifications; Gd-enhanced axial T1-weighted image (h) shows absent enhancement

60% of patients [295–297]. In infants born at term, CP results from perinatal or neonatal vascular insults that may produce areas of cerebral infarction or from embolism, hemorrhage, infection, trauma, and perinatal hypoxia (Fig. 22.33). Seizures are presumed to arise from gliotic tissue at the periphery of the infarct zone. The incidence of epilepsy in ex-preterm infants with diplegia was as low as 11% in one series [298], probably as a result of the predominance of deep white matter lesions in such cases. All types of seizures may occur with CP. Partial motor attacks are most common in children with hemiplegia, whereas generalized seizures predominate in dystonic or quadriplegic cerebral palsy. Onset

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Fig. 22.33a,b. Left hemiplegia and partial motor seizures in a 5-year-old boy with neonatal sylvian infarction. a Coronal FLAIR image; b Axial FSE T2-weighted image. Fluid-filled cavity surrounded by gliosis in the territory of the right middle cerebral artery, with ipsilateral ventricular enlargement and hemispheric atrophy

of epilepsy is usually early and its course is variable, including relatively benign epilepsies, especially in children with hemiparesis [299]. Epilepsy associated with cerebral palsy considerably aggravates the total disability of patients and it is an index of severity.

22.4 Seizure-Induced Brain Damage

22.3.10 Epilepsy and Mitochondrial Disorders

Status epilepticus is consistently associated with neuronal necrosis in vulnerable regions of the brain, as evidenced by neuropathologic studies in humans or experimental models. The most vulnerable parts of the human brain to damage from status epilepticus include the CA1 and CA3 zones of the hippocampus, amygdala, cerebellar cortex, thalamus, and cerebral neocortex [306]. Neuronal damage is most likely secondary to excitotoxic mechanisms. A few reports have demonstrated imaging findings consistent with selective neuronal necrosis in human status epilepticus [307]. MRI findings in the acute stage consist of swelling and abnormal signal change on T2-weighted or FLAIR images due to cytotoxic and vasogenic edema, with persistent hyperintense signal due to gliosis and atrophy in the chronic stage. Abnormal enhancement after gadolinium administration can appear in the subacute stage. Transient signal changes, such as gadolinium enhancement, can be observed when MRI is performed during, or shortly after, status epilepticus. Such abnormalities may reflect changes that can occur during status epilepticus, including vasogenic and cytotoxic edema and alterations of the blood-brain barrier [308]. They do not always predict tissue necrosis, and reversibility was demonstrated on follow-up MRI in some

Epilepsy is frequently observed in mitochondrial disorders. Sometimes, seizures have an early onset and may be the most prominent clinical feature [300]. In general, the clinical presentation of epilepsy in mitochondrial disorders is variable [301]. In mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), epilepsia partialis continua is relatively common [302, 303]. In unexplained cases of myoclonic epilepsy, epilepsia partialis continua, and partial seizures, the diagnosis of mitochondrial disorder should always be considered. MRI reveals multiple signal abnormalities involving mainly the gray matter, especially in the parietal and occipital lobes. They cross vascular territories and appear hyperintense in T2- and hypointense in T1-weighted images, with swollen gyri and compressed sulci during the acute stage. The lesions may show resolution and subsequent reappearance on sequential MRI studies. Progressive cortical atrophy and calcification of basal ganglia can be found in late stages [304]. MRS may help identifying associated variations [305] (Fig. 22.8).

22.4.1 Brain MRI Abnormalities Resulting from Prolonged Seizures and Status Epilepticus

Epilepsy

cases [309] possibly due to brain cytotoxic and vasogenic edema without neuronal and glial necrosis (Fig. 22.34). In experimental models, prolonged epileptic seizures produce an increase in lactate, which is believed to be due to high rates of aerobic glycolysis [310]. When the mitochondria fail to exert their protective action on cell energy balance, cytotoxic edema develops due to loss of membrane equilibrium. As a consequence, increase in lactate and decrease in NAA is detected on MRS, and temporary decrease of ADC on DWI [310]. In line with the experimental data, human studies revealed ADC decrease in the epileptogenic region during status epilepticus followed by prompt normalization after seizure cessation [311] (Fig. 22.35).

22.4.2 Hemiconvulsion-Hemiplegia-Epilepsy Syndrome The hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome [312] is characterized by an initial longlasting, unilateral convulsive seizure (hemiconvul-

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sions), immediately followed by persistent hemiplegia and, later, by focal epilepsy. The hemiplegia that immediately follows the convulsions is initially flaccid and subsequently spastic. The hemiconvulsion-hemiplegia complex has its peak incidence during the first 2 years of life. The average interval from initial convulsions to chronic epilepsy is 1–2 years [128]. Approximately two thirds of the late seizures are complex partial seizures [128, 313]. The course is often severe and difficult to control. The incidence of HHE syndrome has considerably declined over the past 20 years [314] in industrialized countries, but cases are still frequent in countries with limited healthcare resources. The causes of the initial convulsions in HHE syndrome include meningitis, subdural effusions, and trauma. Cases without an obvious cause are not rare [315] and may result from the epileptic activity itself in the course of febrile status epilepticus [128, 316]. It has also been suggested that small cryptic hemispheric lesions could trigger seizure activity, which would in turn produce brain damage and new imag-

Fig. 22.34a–d. Status epilepticus. a,b Coronal FLAIR images show transient signal changes involving the right temporo-mesial region in a 8-year-old boy shortly after status epilepticus. c,d Axial T2-weighted and Gd-enhanced T1-weighted images in a 22year-old patient obtained during status epilepticus (c) show transient signal changes with transient gadolinium enhancement surrounding a developmental venous anomaly in the left frontal lobe (arrows). Four months later the picture is normal (d)

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Epilepsy Fig. 22.35a–h. Seizure-induced brain damage in a 22-year-old girl with complex partial seizures of recent onset, rapidly evolving to status epilepticus. On initial imaging, FLAIR images (a) show no significant alterations. However, diffusion-weighted images (DWI) reveal a slight but significant hyperintensity of the right hippocampus (arrow, b). Follow-up MRI 2 weeks later shows a clear-cut hyperintensity on FLAIR images involving the right hippocampus and temporal uncus (arrow, c), with milder contralateral involvement (arrowhead, c). On coronal DWI images there is hyperintensity of the right hippocampus (arrow, d). Notice that the volume of the hippocampus is normal on Gd-enhanced coronal T1-weighted images obtained on the same examination (e). The patient underwent heavy antiepileptic therapy that controlled status epilepticus within 3 days. At follow-up MRI 6 months later, a subtle hyperintensity on axial (f) and coronal (g) FLAIR images was revealed, involving the amygdala, hippocampus, and uncus on both sides, though with left predominance. On T1-weighted volumetric images there is atrophy of right hippocampus (arrow, h)

ing signs. Imaging studies have demonstrated that acquired atrophy can appear very rapidly following status epilepticus [312, 316–318]. Diffuse atrophy of the hemisphere involved in the epileptic discharge is preceded by ipsilateral swelling and edema [316]. This lesion differs from the more limited atrophies observed with ischemic lesions of vascular origin.

22.5 Antiepileptic Drug-Induced Atrophy In some patients, prolonged treatment with phenytoin, especially at high doses, may cause cerebellar symptoms with ataxia and nystagmus, accompanied by atrophic changes of the cerebellum, especially Purkinje cell degeneration [319]. Hormonal treatment with steroids or ACTH produces brain shrinkage, as shown by CT scan or MRI. This complication is reversible, usually within 3 months of discontinuing therapy (see Chap. 11). The rare occurrence of a complicating subdural effusion has been reported [320]. A very rare complication of valproate treatment is reversible pseudoatrophy of the brain. This condition is associated with reversible mental deterioration and sometimes with associated parkinsonism, and may occur in the absence of other signs of drug toxicity [321].

22.6 Surgical Treatment of Epilepsy and Postoperative MRI Changes Although the great majority of children with epilepsy are treated with drugs, surgical treatment is increasingly used for those resistant to medical treatment. In children, the aims of surgery are to reach complete control or at least to significantly reduce the frequency of seizures, to limit the practical consequences of uncontrolled attacks and excessive drug side

effects, and possibly to minimize the noxious effects of epileptic activity on cognitive development. There are two major categories of surgical therapy: (1) resective surgery, which aims at removing the neuronal aggregate that is responsible for seizure generation, and (2) palliative or functional surgery which does not aim at complete seizure control but, rather, at preventing or limiting propagation of seizure activity and its consequences. Although anterior temporal lobectomy is the most commonly performed operation [322], other procedures, including extratemporal cortical resections, multilobar resections, hemispherectomy, and callosotomy, are increasingly used in children as a result of improved diagnosis of extratemporal focal epilepsy and of the multilobar pathology in children with developmental brain abnormalities. Different terms are used to define different anatomofunctional concepts, whose knowledge is essential to the understanding of the strategies of epilepsy surgery. The term epileptogenic zone designates a network of abnormally behaving neurons distributed within a relatively large brain volume, whose margins do not necessarily correspond to those of the lesion. The functional significance of this term is different from that of the ictal-onset zone, which is the cortical area where seizures are initiated but may not be sufficient to sustain seizure activity. It is also different from the symptom-producing zone, which usually exceeds the limits of the epileptogenic zone as seizure activity propagates to remote areas. The zone of functional alteration, defined as the area of cortex that presents evidence (e.g., by EEG, PET, or SPECT) of dysfunction, usually does not coincide with the epileptogenic zone. Additional concepts include the irritative zone, which is the area over which paroxysmal activity is recorded, and the lesional zone, which is anatomically defined [1, 323].

22.6.1 Lesionectomy Removal of an epileptogenic lesion without attempt at defining and removing the epileptogenic area (“lesio-

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Fig. 22.36a–g. Epilepsy surgery. a Lesionectomy with complete removal of epileptogenic zone in left temporo-occipito-mesial Taylor type focal cortical dysplasia. b,c Removal of antero-lateral temporal neocortex and temporo-mesial structures in left hippocampal sclerosis. d Partial resection in left frontal ganglioglioma. e Multilobar resections in tuberous sclerosis complex. f Right subtotal hemispherectomy in hemimegalencephaly. g Hemosiderin deposition after partial resection of left frontal DNT

nectomy”) produces seizure control in a significant proportion of patients [324]. However, delineation and removal of the epileptogenic area associated with the lesion can improve the outcome of lesionectomy [325]. According to some authors, complete removal of the epileptogenic area is the major factor for obtaining adequate surgical results [326] (Fig. 22.36). Exact location and extent of the epileptogenic zone with the support of modern neuroimaging is a crucial factor in this process.

Currently, high-quality MRI is capable of demonstrating brain lesions in a majority of candidates for epilepsy surgery, and operation should be considered reluctantly in the face of a completely normal MRI scan when adequate machines and techniques are used. The place of functional imaging in presurgical assessment is not yet completely defined. In temporal lobe epilepsy, the more common surgical approach involves removal of some portion of the antero-lateral temporal neocortex to obtain an

Epilepsy

optimal access to the mesial structures (Fig. 22.36). Cortical nontemporal epileptogenic zones are difficult to operate on, because a comprehensive resection of all epileptogenic tissue while sparing surrounding eloquent brain regions is difficult. For instance, not all tumors, including indolent lesions, are always resectable without neurological complications (Fig. 22.36). However, in such cases, partial resection may be successful. Monitoring of the lesion by follow-up MRI is probably acceptable when the perspectives for resection are poor [327]. In tuberous sclerosis, surgical resection of a tuber can be successful if a single epileptogenic focus can be identified [282, 283] (Fig. 22.36).

Postsurgical MRI follow-up can show early or late complications of surgical procedures, such as parenchymal hemorrhage, infection, extracerebral collections, and superficial hemosiderosis (Fig. 22.36), or evaluate the anatomic effectiveness of surgical procedures (partial or total exeresis of the epileptogenic tissue) [333].

References 1.

2.

22.6.2 Multiple Subpial Transections Multiple subpial transections (MST) have been used to address seizure foci within eloquent regions of cortex, when there is clinical and neurophysiological evidence that spread of epileptic activity can be disruptive on the function of contiguous or distant cortical areas [328]. MST disrupt the horizontal fiber tracts while preserving the structural integrity of vertical column of neurons, in the assumption that diffusion of epileptic activity is mainly dependent on horizontal spread, whereas the normal cortical functions are mainly mediated by activity within vertical columns.

3.

4. 5.

6.

7. 8.

22.6.3 Hemispherectomy 9.

Hemispherectomy consists of the surgical ablation of neocortical tissue in patients who have little functional use of the contralateral limbs (Fig. 22.36). Currently, various methods of functional hemispherectomy [329, 330] or hemispherotomy [331], in which disconnection predominates over excision, are preferred.

10.

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12.

22.6.4 Callosotomy 13.

Partial callosotomy is a midline disconnection procedure aiming at inhibiting synchronization between the hemispheres without eliminating seizure activity. The procedure includes sectioning of only the anterior two thirds of the corpus callosum in order to prevent interhemispheric spread without causing significant disconnection symptoms [332].

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Cioni G, Canapicchi R, Siciliano G. Proton MR spectroscopy of mitochondrial diseases: analysis of brain metabolic abnormalities and their possible diagnostic relevance. AJNR Am J Neuroradiol 2003; 24: 1958–1966. 306. Delgado-Escueta AV, Wasterlain C, Treiman DM, Porter RJ. Status epilepticus. In: Delgado-Escueta, Wasterlain CG, Treiman DM, Porter RJ (eds) Advances in Neurology, vol. 34: Status Epilepticus. New York: Raven Press, 1983. 307. Men S, Lee DH, Barron JR, Munoz DG. Selective neuronal necrosis associated with status epilepticus: MR findings. AJNR Am J Neuroradiol 2000; 21:1837–1840. 308. Yaffe K, Ferriero D, Barkovich AJ, Rowley H. Reversible MRI abnormalities following seizures. Neurology 1995; 45:104– 108. 309. Lansberg MG, O’Brien MW, Norbash AM, Moseley ME, Morrell M, Albers GW. MRI abnormalities associated with partial status epilepticus. Neurology 1999; 52:1021–1027. 310. Ebisu T, Rooney WD, Graham SH, Mancuso A, Weiner MW, Maudsley AA. MR spectroscopic imaging and diffusionweighted MRI for early detection of kainite-induced status epilepticus in the rat. Magn Reson Med 1996; 36:821–828. 311. Flacke S, W llner U, Keller E, Hamzei F, Urbach H. Reversible changes in echo planar perfusion- and diffusion-weighted MRI in status epilepticus. Neuroradiology 2000; 42:92–95. 312. Gastaut H, Poirier F, Payan H, Salamon G, Toga M, Vigouroux M. H.H.E. syndrome ; hemiconvulsions, hemiplegia, epilepsy. Epilepsia 1960; 1:418–447. 313. Roger J. Prognostic features of petit mal absences. Epilepsia 1974; 15:433. 314. Roger J, Dravet C, Bureau M. Unilateral seizures (hemiconvulsion-hemiplegia syndrome and hemiconvulsionhemiplegia-epilepsy syndrome). Electroencephalogr Clin Neurophysiol Suppl 1982; 35:211–221. 315. Aicardi J, Chevrie JJ. Consequences of status epilepticus in infants and children. In: Delgado-Escueta, Wasterlain CG, Treiman DM, Porter RJ (eds) Advances in Neurology, vol. 34: Status Epilepticus. New York: Raven Press, 1983:115– 125. 316. Soffer D, Melamed E, Assaf Y, Cotev S. Hemispheric brain damage in unilateral status epilepticus. Ann Neurol 1986; 20:737–740. 317. Aicardi J, Baraton J. A pneumoencephalographic demonstration of brain atrophy following status epilepticus. Dev Med Child Neurol 1971; 13:660–667. 318. Kataoka K, Okuno T, Mikawa H, Hojo H. Cranial computed tomographic and electroencephalographic abnormalities in children with post-convulsive hemiplegia. Eur Neurol 1988; 28:279–284. 319. Bruni J. Phenytoin and other hydantoins adverse effects. In: Levy RH, Mattson RH, Meldrum BS, Perucca E (eds) Antiepileptic Drugs, 5th edn. Philadelphia: Lippincott Williams & Wilkins, 2002:605–610. 320. Sato H, Takeshi F, Hara H, Fukuyama Y. Brain shrinkage and subdural effusion associated with ACTH administration. Brain Dev 1982; 4:13–20. 321. Guerrini R, Belmonte A, Canapicchi R, Casalini C, Perucca E. Reversible pseudoatrophy of the brain and mental deterioration associated with Valproate treatment Epilepsia 1998; 39:27–32. 322. Mohamed A, Wyllie E, Ruggieri P, Kotagal P, Babb T, Hilbig A, Wylie C, Ying Z, Staugaitis S, Najm I, Bulacio J, Foldvary N, Luders H, Bingaman W. Temporal lobe epilepsy due to hippocampal sclerosis in pediatric candidates for epilepsy surgery. Neurology 2001; 56:1643–1649.

Epilepsy 323. Talairach J, Bancaud J, Szikla G, Bonis A, Geier S, Vedrenne C. Approche nouvelle de la neurochirurgie de l’épilepsie. Neurochirurgie 1974 ; 20 (Suppl 1):1–240. 324. Bourgeois M, Sainte-Rose C, Lellouch-Tubiana A, Malucci C, Brunelle F, Maixner W, Cinalli G, Pierre-Kahn A, Renier D, Zerah M, Hirsch JF, Goutieres F, Aicardi J. Surgery of epilepsy associated with focal lesions in childhood. J Neurosurg 1999; 90:833–842. 325. Jooma R, Yeh H, Printera MD, Gartner M. Lesionectomy versus electrophysiologically guided resection for temporal lobe tumors manifesting with complex partial seizures. J Neurosurg 1995; 83:231–236. 326. Engel J Jr, Shewmon DA. Overview: who should be considered a surgical candidate. In: Engel J Jr (ed) Surgical Treatment of the Epilepsies. New York: Raven Press, 1992. 327. Duchowny M, Jayakar P, Resnick T, Harvey AS, Alvarez L, Dean P, Gilman J, Yaylali I, Morrison G, Prats A, Altman N, Birchansky S, Bruce J. Epilepsy surgery in the first three years of life. Epilepsia 1998; 39:737–743.

328. Morrell F, Whisler WW, Bieck TP. Multiple subpial transection: a new approach to the surgical treatment of focal epilepsy. J Neurosurg 1989; 70:231–239. 329. Rasmussen T, Villemure JG. Cerebral hemispherectomy for seizures with hemiplegia. Cleve Clin J Med 1989; 56 (Suppl 1):562–568. 330. Villemure JG, Adams CBT, Hoffman HJ, Peacock WJ. Hemispherectomy. In: Engel J Jr (ed) Surgical Treatment of the Epilepsies, New York: Raven Press, 1993:511–518. 331. Delalande O, Pinard JM, Basdevant C, et al. Hemispherotomy: a new procedure for central disconnection. Epilepsia 1992; 33 (Suppl 3):99–100. 332. Sass KJ, Spencer DD, Spencer SS, Novelly RA, Williamson PD, Mattson RH. Corpus callosotomy for epilepsy. II. Neurologic and neurophysiological outcome. Neurology 1988; 38:24–28. 333. Dietrich RB, el Saden S, Chugani HT, Bentson J, Peacock WJ. Resective surgery for intractable epilepsy in children: radiologic evaluation. AJNR Am J Neuroradiol 1991; 12:1149–1158.

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MR Spectroscopy

23 MR Spectroscopy Petra S. Hüppi and François Lazeyras

23.1 Techniques

CONTENTS 23.1 Techniques 1049 23.1.1 1H-Magnetic Resonance Spectroscopy (1H-MRS) 1049 23.1.1.1 Chemical Shift and J-Coupling 1049 23.1.1.2 Localization Techniques 1050 23.1.1.3 Quantitation Techniques 1051 23.1.2 Other Nuclei 1051 23.1.2.1 31P-MRS 1053 23.1.2.2 13C-MRS 1053 23.2

Normal Brain Development: Chemical Composition and Metabolism 1053 23.2.1 Cellular Metabolism 1053 23.2.1.1 Neuroaxonal Unit 1053 23.2.1.2 Astroglia 1054 23.2.1.3 Oligodendroglia 1055 23.2.2 Membrane Constituents (31P, 1H, 13C) 1055 23.2.2.1 Myelin 1056 23.2.3 Energy Metabolism (31P-MRS, 1H-MRS) 1056 23.2.4 Amino Acids and Intermediary Metabolism (1H, 13C) 1057 23.2.5 Age-Dependent Metabolite Pattern 1057 23.3 Pediatric Pathology 1058 23.3.1 Hypoxia-Ischemia 1058 23.3.2 Epilepsy 1061 23.3.2.1 Temporal Lobe Epilepsy (TLE) 1061 23.3.2.2 Extra-Temporal Lobe Epilepsy (ETLE) 1061 23.3.3 Metabolic Disorders/Mental Retardation 1064 23.3.4 Tumor 1066 23.3.5 Trauma/Inflammation/Infection 1066 23.3.6 Conclusions 1067 References

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23.1.1 1 H-Magnetic Resonance Spectroscopy (1H-MRS) 23.1.1.1 Chemical Shift and J-Coupling

From the basic principles of magnetic resonance imaging (MRI) we are familiar with the measurement of the net magnetization of nuclei that are placed in a magnetic field (B0) and excited by a short radiofrequency (RF) pulse exactly in resonance with their precession, such that the resonant signal can be observed. These observed resonant signals vary slightly depending on the location of nuclei within different molecules, as protons in molecules also experience an additional magnetic field arising from interactions with electrons and other surrounding nuclei. The electronic structure of a molecule determines the exact resonance frequencies of nuclei of different parts of the molecule, which can be used to characterize different chemical substances. The size of the change in frequency (called the chemical shift) depends on the strength of interaction between the nucleus and the electronic cloud within the particular molecule. It is of the order of only a few parts per million (ppm) for hydrogen (1H), but up to several hundred ppm for carbon-13 (13C). The nuclearnuclear interactions give rise to splitting of the peak, and the J-coupling constant measures the size of the splitting. The J-coupling constant is expressed in Hz and is independent of the magnetic field B0. Protons in different molecules have unique chemical shifts that allow them to be identified. The frequency components of the electromagnetic signal, the so-called free induction decay (FID) signal generated, may be extracted by Fourier analysis, if an investigation of different molecules containing a certain nucleus is undertaken. The result of this transformation is a plot of signal amplitude vs. frequency: the magnetic resonance (MR) spectrum.

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1050 P. S. Hüppi and F. Lazeyras The MR signal is proportional to the number of nuclei involved, and therefore is a measure of the proton concentration. Molecular concentration is then simply given by dividing the MR signal by this number of protons. Based on this principle, high-field, highresolution MRS is an indispensable tool in analytical laboratories. Since MRS uses only magnetic fields and RF radiation for the creation of a spectrum, it can also be used for the noninvasive monitoring of biochemistry and metabolism in living tissue. 1H-MRS contains a wide array of interesting metabolites, all hidden in the spectrum underneath a large water resonance. Most metabolites overlap each other due to the small range of chemical shift. By the strategy of using additional water suppression pulses, the in vivo brain spectrum then reveals the following metabolites: macromolecules (0.9–1.3 ppm), lactate (Lac) (1.33 ppm), N-acetylaspartate (NAA) (2.01, 2.60 ppm); glutamine (Gln)/ glutamate (Glu) (2.2–2.4 ppm and 3.65–3.85 ppm); creatine/phosphocreatine (Cr) (3.02, 3.94 ppm); choline (Cho) (3.22 ppm); myo-inositol (mI) (3.56, 4.06 ppm); glucose (G); taurine (Tau); scyllo-inositol (scy-ino) (3.35 ppm). The latter resonances show considerable overlap (see Fig. 23.4 for location). 23.1.1.2 Localization Techniques

Three types of localization techniques are generally employed for in vivo spectroscopy. These techniques are surface coil spectroscopy, single voxel spectroscopy (SVS), and chemical shift imaging (CSI). These approaches can be used separately or in combination, and have been described in details by Aue [1]. Surface coil MRS is mostly used for 31P spectroscopy and shows a particular interest in muscle physiology, such as exercise studies. Most clinical MRS studies using 1 H, especially in the brain, are based on SVS or CSI,

although surface coil may be useful in some cases to gain in signal-to-noise. Single Voxel Localization

Single voxel localization (SVS) is by far the most used technique for clinical MRS. The principle is simple: one applies three orthogonal selective slices, resulting in an intersection volume from which the signal arises (Fig. 23.1). In practice, especially for small volumes or volumes close to the skull, additional spatial selective pulses may be applied to improve the localization of the sequence by suppressing the signal coming from outside the volume of interest. Three SVS techniques are usually used: STEAM [2], PRESS [3], and ISIS [4]. STEAM and PRESS provide a volume selection in a single shot, whereas ISIS needs eight encodings to get the complete 3D volume selection. Therefore, ISIS is more sensitive to instabilities. ISIS is more often used in 31P spectroscopy, which has no huge signal background (as water) to suppress. The PRESS technique (Fig. 23.1) collects the second spin echo following a second inversion pulse. STEAM uses three selective 90° pulses which produce a stimulated echo, having half the signal than the PRESS technique. However, the STEAM sequence allows acquisition of shorter echo, allowing for better detection and quantification of more complicated spin systems, such as glutamate and glutamine. Fig. 23.2 shows examples of SVS spectra at short (TE = 25 ms) and long (TE = 288 ms) echo times, obtained in a newborn with ischemic white matter injury. Chemical Shift Imaging

Single voxel spectroscopy often requires a large number of averaging (i.e., 256) in order to gain sufficient signal-to-noise, which ends up with a long

Fig. 23.1. Principle of single voxel spectroscopy. Three generally orthogonal slices are mutually excited, such that a volume (V) corresponding to the common intersection is selected. A simplified PRESS sequence illustrates the principle of three orthogonal slices selection within one TR. Additional RF and gradient pulses (not shown) are added to this basic scheme in order to suppress the water signal and spoil signal from outside the volume of interest. The STEAM sequence is very similar, with three 90° RF pulses

MR Spectroscopy

Nevertheless, the intrinsic advantage of CSI resides in the direct comparison with adjacent tissue (Fig. 23.3) and the possibility to tailor the localization on a specific brain area with subpixel shifting. 23.1.1.3 Quantitation Techniques

TE 25 ms

TE 288 ms

Fig. 23.2. Example of short echo-time (TE: 25 ms) and long echo-time (TE: 288 ms) single voxel PRESS spectra from periventricular ischemic white matter injury in a newborn infant. These spectra are obtained on a clinical system with automatic shimming, phasing, and baseline correction. Long TE simplifies the spectra and four resonances remain visible: lactate (1.3 ppm), N-acetyl-aspartate (2 ppm), creatine + phosphocreatine (3 ppm) and the trimethylamine moiety of choline containing metabolites (3.2 ppm)

acquisition time. Instead of spending the time to accumulate the same spectrum (one gets one single spectrum at the end of the experiment), it is possible to spend this time covering the spatial dimension. This is the idea of chemical shift imaging (CSI), which provides spectra of multiple adjacent voxels for the same acquisition time [5]. One can show that SVS and CSI have the same signal-to-noise ratio per unit of time and for a given volume. In general, CSI is used in conjunction with SVS, which serves as large volume preselection, excluding unwanted tissue (such as lipids of the skull). This volume is then subdivided by CSI into smaller volumes, in the same way as imaging. The final volume size is given by the field of view divided by the resolution. The resolution is generally low, typically between 16 and 32 pixels for each dimension, to keep the acquisition time reasonable. The disadvantage of the technique is spatial contamination due to sparse sampling, the well known “Gibbs ringing” artifact [6]. This contamination is particularly dramatic if subcutaneous fat is acquired, which spreads all over the sampled volume, affecting the quality of the spectra. In this case, spatial saturation bands are often used, but they reduce the sampled volume. Another disadvantage is a suboptimal shimming, which must be optimized on a larger volume than SVS, and cannot correct for local inhomogeneities.

Commercial MRI systems nowadays provide automated reconstruction of acquired imaging and spectroscopy. It is possible to review the results of SVS or CSI data, referred on anatomical high resolution imaging, in a timely fashion. Nevertheless, in order for MRS to become a clinical tool, one needs to automate and quantitate the measured metabolites. Although the principle of spectroscopic quantification is rather simple because the peak area is proportional to the molecular proton concentration, this task is not straightforward in practice. The reasons are low signal-to-noise, resonance distortion due to technical imperfections (shimming, Eddy current, water suppression), overlap between resonances, and baseline distortion. Therefore, accurate estimation of peak intensities by traditional spectral peak integration is often not possible, and more sophisticated approaches using a priori information are necessary. Two of these methods are available: MRUI, which uses a time-domain processing of the data [7], and LCModel which fits the spectra in the frequency domain to a model consisting of linear combination of basis spectra [8, 9]. Prior knowledge enables one to increase the accuracy of peak intensities and correct for experimental imperfections. Unresolved resonances, such as glutamine and glutamate, should be better assessed with these methods. An example of short TE spectrum fitting using LCModel is illustrated in Fig. 23.4. Interindividual comparison necessitates normalization. This can be done using the water peak as an internal reference [10], or an external reference placed in proximity to the studied region. Additional corrections for water content, partial volume, T1, and T2 are necessary for absolute quantitation [11]. Finally, normative data are often necessary before applying MRS routinely, especially in infants, in order to account for metabolite heterogeneity and time evolution. It is important to bear these methodological and technical aspects in mind, when we apply MR techniques to the study of the human body and when we interpret the results obtained.

23.1.2 Other Nuclei The major problem for in vivo MRS using other nuclei is the exceedingly low signal intensity to be detected.

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Fig. 23.3. Long TE chemical shift imaging data obtained at the level of the hippocampi in a normal young adult. In CSI, multiple spectra are acquired simultaneously, allowing direct regional comparison of metabolite levels. Here, the subdivision of the hippocampi into 1 cc voxels shows differential NAA/Cho ratios from the most anterior to the most posterior part of the hippocampus. The spectra at the center of the figure represent the sum of the three spectra of the right and left hippocampi, respectively. The large box represents the PRESS volume selection

Fig. 23.4. Example of spectral quantification using LCModel. This 3 cc spectrum of the normal newborn white matter was evaluated on the basis of 15 in vitro spectra of the main metabolites

MR Spectroscopy

This is due to the low tissue abundance of magnetic nuclei other than protons (i.e., 31P, 13C , 23Na, 19F, 14N) and the limited magnetic field strength applicable for in vivo studies in large bore magnets. For MRS in the pediatric brain, this is an important limitation to the assessment of regional metabolism. 23.1.2.1 31 P-MRS

In the 31P spectrum, the high energy phosphates adenosine-triphosphate (ATP) and phosphocreatine (PCr) are easily detected along with inorganic phosphate (Pi). Phosphorus atoms from other nucleotides are only present in small concentrations or are tightly bound to proteins. These give rise to low or very broad signals, and often underlie the ATP resonances. The 31 P brain spectrum further exhibits two characteristically strong resonances which are of importance in the developing brain, including the phosphomonoester peak (PME) at 6.7 ppm and the broader phosphodiester peak (PDE) at 2.9 ppm. From the chemical shift difference (d) between PCr and Pi in the 31P spectrum, intracellular pH can be estimated to an accuracy of about 0.1 pH units (Henderson-Hasselbach equation: pH=6.75+log10 [(d-3.27)/5.69-d)] [12, 13]. 23.1.2.2 13 C-MRS

For biomedical application, it would seem obvious to perform carbon MRS (13C-MRS). However, the most abundant C-isotope, 12C, has no nuclear spin and is therefore not detectable by MRS. 13C has spin, but its natural abundance is very low (1.1%), so very little signal is available for detection. Furthermore, 13C spectra are very complex due to spin–spin coupling of nearby nuclei, such that more sophisticated techniques are required (such as proton decoupling) for elucidation of the spectrum. However, this approach has limitations in the clinical use, especially in the pediatric population, due to potential tissue heating generated by additional RF deposition from the decoupling pulses. The 13C spectrum of the brain shows signals from glycogen and glucose, amino-acids (glutamine and glutamate, alanine, aspartate, taurine), γ-aminobutyrate (GABA), myo-inositol and scyllo-inositol, glycerol, fatty-acids, Cho, NAA, and Cr. A unique possibility to study metabolic pathways is available with 13C MRS, by means of labeling the metabolites with nonradioactive 13C and measuring their subsequent appearance in metabolic products (i.e., glucose labeling: glycolysis, tricarbonic acid cycle, see below) in various organs [14].

23.2 Normal Brain Development: Chemical Composition and Metabolism The physiologist is usually interested in the intracellular concentration of a chemical species in a particular cell type. However, it must be noted that the in vivo human MR measurement in single voxel MRS is an average (over the sensitive volume) of all tissue types, and for a given tissue type, an average of all cell types and the extracellular space. Therefore, in the brain we generally assess a combination of glial and neuronal cells with different extracellular space, depending on how much white matter, gray matter, or cerebrospinal fluid the volume-of-interest contains. This can in part be overcome by multivoxel techniques, such as chemical shift imaging (CSI). Also, only the mobile proportion of a metabolite will yield an MRS visible signal. Phospholipids, when incorporated in membranes or myelin, are not MR visible. However, if they are broken down or synthesized, then the phosphodiester and monoester products or the diacyl and triacyl group become MRS visible.

23.2.1 Cellular Metabolism 23.2.1.1 Neuroaxonal Unit

NAA, a free amino acid, is present at the second highest concentration in the human central nervous system (CNS) after glutamate. It has been shown to be uniquely localized in the neuronal tissue of the adult brain, while during development it is also found in oligodendrocyte-type-2 astrocyte progenitors cells and immature oligodendrocytes [15]. Therefore, NAA is an ideal indicator of intact central nervous tissue. The free or nonbound NAA possibly serves as a component of the aspartate pool, as an acetyl group donor for the synthesis of fatty acids in myelination, and as precursor for, and breakdown product of, the neurotransmitter N-acetyl-aspartyl-glutamate (NAAG). During early brain development, NAA increases with regional differences; the thalamus expresses NAA early in development, whereas occipito-parietal and periventricular white matter express NAA later in development [16–22] (Fig. 23.5). This difference reflects the high density of neuronal tissue and the active myelination occurring in the thalami early in development, as compared to the later development of the cerebral hemispheres. NAA concentrations in the neonatal period are only about 50% of the

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Fig. 23.5. Averaged spectra from preterm infants (gestational age 32–35 weeks) and full-term newborns illustrating the developmental differences and the differences in specific brain regions, white matter (WM), cortical gray matter (GM), and thalamus (Tha) ROIs. (Adapted from Kreis et al., Magn Reson Med 2002;48(6):949–958 with permission from Wiley-Liss, Inc.)

adult values, and a slow increase of NAA throughout infancy up to adult levels is observed [19]. Acetylcholine (ACho) is an important neurotransmitter for many aspects of memory and cognition, synthesized only within cholinergic neurons. Within those neurons, the concentration of the substrate Cho is rate-limiting for ACho synthesis. Free Cho is transported into the cell via a high-affinity transport system. Free Cho, though, is present in less than 0.1mM in brain tissue, which makes detection with in vivo 1H-MRS rather difficult. Glutamate is the major neurotransmitter for brain excitatory function, whereas GABA is the major neurotransmitter for inhibitory function. They are released from presynaptic terminals and are taken up by astrocytes from the extracellular space, in order to avoid high concentrations of excitotoxic glutamate in the extracellular space. Glutamate taken up by glial cells is converted to glutamine; via specific transporters; glutamine is taken up again by the neuron and reconverted into glutamate. Alternatively, glutamate in the astrocyte can stimulate glycolysis with Lac production. Lac is then released into the extracellular space and can also be taken up by neurons and used for energy generation (Fig. 23.6). 23.2.1.2 Astroglia

Glial proliferation and differentiation are of major importance in the developing brain. Glial cells are the most prominent cell type in the CNS, especially in the white matter in the developing brain. Therefore, they will significantly contribute to any MRS

volume. Astrocytes play a variety of complex nutritive and supportive roles in relation to neuronal metabolic homeostasis. For example, astrocytes take up glutamate and convert it into glutamine. Removal of glutamate from the extracellular space protects the surrounding cells from the excitotoxic effects of glutamate. Glutamate and glutamine are both amino acids that are measured with 1H-MRS when using short echo times. However, absolute quantitation by in vivo spectroscopy is difficult because of high spin-coupling of these metabolites. Increase of glutamate and glutamine has been observed by 1H-MRS in chronic hepatic encephalopathy [23] and after hypoxic-ischemic injury [24]. Osmoregulation is another major metabolic task fulfilled by astroglia. Osmolytes synthesized by astrocytes or present in astroglia include taurine, hypo-taurine, and myo-inositol [25–27]. Developmental changes of myo-inositol have been described by Kreis et al. [19], with a decrease of myo-inositol during the first year of life and a marked reduction of myo-inositol in the first weeks after birth, regardless of gestational age at birth. Hüppi et al. [17, 18] studied myo-inositol concentration by 1H-MRS in preterm and full-term newborns, and found slightly higher concentrations in preterm infants after birth and a reduction of myo-inositol in preterm infants at term compared to full-term infants. In an earlier study, Hüppi et al. [17] had studied taurine concentrations in preterm, term, and adult cerebellum using in vivo 1H-MRS. Other than glial cells, Purkinje cells were also shown to contain taurine. Highest concentrations of taurine in that study

MR Spectroscopy

Fig. 23.6. “Astrocyte-neuron lactate shuttle”: Glutamate stimulates glycolysis and lactate production in astrocytes. Lactate is then transported by monocarboxylate transporters (MCT) into neurons, thereby providing an energy source for neurons

was measured in full-term newborns [17]. A high value around birth would correspond to the neuromodulatory action of taurine in dendritic outgrowth and synapse formation that has been discussed [28]. Taurine biosynthesis from cysteine in brain astrocytes is low in the developing brain [29], but human milk contains high contents of taurine in contrast to bovine milk. This is the reason why taurine is added to infant milk formulas. Recent studies indicate that astroglial cells are also able to synthesize Cr from glycine. This must be considered when interpreting Cr concentrations in brain [30]. 23.2.1.3 Oligodendroglia

Oligodendroglial proliferation and differentiation is an important step of brain development that occurs in the third trimester of pregnancy. It has been shown to begin with the proliferation of the bipotential progenitor cell in the subventricular zone and subsequent migration of the earliest cell in the oligodendroglial lineage in waves into the brain parenchyma. Therefore, the immature white matter contains oligodendroglial cells of different maturational stage. NAA is generally viewed as a marker of the neurono-axonal unit as discussed earlier. In the immature and developing brain, NAA is also present in these oligodendroglial precursor cells [15]. NAA has been shown to be an acetyl group source in the nervous system [31, 32]. The major requirement for acetyl groups is lipid synthesis, which takes place immediately prior to myelin deposition in the developing brain. Marked increase of NAA occurring between 32 and 40 weeks of gestation [16–21], just prior to the initiation of myelination, would support

the importance of NAA in lipid synthesis. Regional differences in age-dependent changes of NAA concentrations during early brain development show stable concentrations in peri-thalamic voxels [16] where myelination is already initiated at 32 weeks, and marked increase in the central cerebral white matter [33] between 32 and 40 weeks of gestation.

23.2.2 Membrane Constituents (31P, 1H, 13C) Phospholipid constituents of all cell membranes consist mainly of phosphatidylcholine and phosphatidylethanolamine, but also of phosphatidylinositol. Therefore, inositol is actively incorporated into CNS cells. Phosphatidylinositol is further utilized for the formation of phosphatidylinositol-4,5-biphosphate (PIP2), which is the substrate used to generate the second messengers diacylglycerol and inositol triphosphate (IP3), that are important metabolites of signal transduction [34]. This universal signaling system operates in all stages of the life history of a cell, immature and mature. The inositol-lipid signal pathway has been hypothesized to play a role in neuronal plasticity, regulation of cell growth, and longterm depression, relevant to memory and learning [35]. Monitoring of free myo-inositol as measured by 1 H-MRS can be an important indicator of brain maturation and activity. The biosynthesis of phospholipid precursors is a metabolic pathway that can be elucidated with in vivo 31P-MRS. The 31P brain spectrum exhibits two strong characteristic resonances, which are of importance in the developing brain: the phosphomonoester peak (PME) at 6.7 ppm and the broader phosphodiester peak (PDE) at 2.9 ppm. PME represents

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1056 P. S. Hüppi and F. Lazeyras precursors to the brain phospholipids, whereas PDE represents both phospholipids and their degradation products. The PME signal includes contributions from phosphorethanolamine, phosphocholine, and ∂-glycerophosphate, which are precursors of the phospholipids [36]. The PDE signal is comprised of mobile brain phosphoglycerides, phospholipid degradation products, and sphingomyelin. The PME/PDE ratio decreases with age in the newborn up to about 70 weeks postconceptional age, and indicates maximal phospholipid synthesis [37, 38]. Another method of indirectly observing changes in lipid metabolism and membrane formation is by assessing changes in the Cho signal using 1H-MRS. This resonance in vivo contains contributions from various metabolites containing N(CH3)3 groups, that is, mostly phosphocholine and glycerophosphocholine, but also metabolites like betaine and carnitine. The prominent Cho signal appearing in 1H MRS during early brain development compared to adult brain most likely represents the high levels of substrate needed for the formation of cell membranes and myelin [16–19]. 23.2.2.1 Myelin

Myelination is a complex but orderly process which occurs in predictable topographic and chronological sequences that have been described by different anatomic methods, including MRI. The most dramatic changes in myelination occur between midgestation and the end of the second postnatal year. The process of myelin formation occurs in several stages, in which oligodendrocyte proliferation and differentiation is followed by lipid deposition and myelin sheath formation [39]. The mature myelin sheath consists of cholesterol (28%), galactocerebroside (22%), phosphatidylethanolamine (12%), phosphatidylcholine (11%), sphingomyelin (8%), phosphatidylserine (5%), phosphatidylinositol (1%), sulfatide (4%), fatty acids, and proteins. During development (i.e., mid-gestation), prior to active myelination, the following phospholipids are detected from highest to lowest concentration: phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, and phosphatidylinositol [40]. With the appearance of galactocerebroside and sphingomyelin, phosphatidylcholine decreases. Recent quantitative 1H-MRS results have further shown a decrease of phosphoethanolamine during this period [41]. In several 1H-MRS studies on brain development, a decrease of the Cho resonance has been noted [16, 17, 19]. Depending on the studied region, this decrease

was most prominent only after the first 2 years of life, which corresponds with the time point of relative completion of myelination. Postnatally, Cho is uniquely provided by nutritional intake, whereas antenatally it is provided via the placenta. No significant differences of in vivo Cho concentration in preterm versus full-term infants have been noted [18]. Instead, Cho was reduced in preterm infants with reduction of myelination due to perinatal white matter injury, as compared with healthy preterm infants [33]. The macromolecular resonances (0.9–1.3 ppm) are currently poorly understood. Their biochemical composition is unknown, but they contain -CH3 and -CH2 molecules that are MR visible. They are thought to represent proteolipid moieties that may be related to myelin or other complex protein-lipid molecules of membranes, that may be become mobile under certain conditions (i.e., development, disease state). They are particularly easily visible in immature white matter and after hypoxic-ischemic injury (Fig. 23.2; see also Fig. 23.8).

23.2.3 Energy Metabolism (31P-MRS, 1H-MRS) Neurons have a poor ability to regenerate. Thus, continuous provision of energy supply is essential for the function and integrity of the brain. Mitochondrial oxidative phosphorylation is the principal energy source for neurons. Adenosine-triphosphate (ATP) is the main carrier of free energy in the brain, and is hydrolyzed to adenosine-diphosphate (ADP) and inorganic phosphate (Pi). The ATP/ADP*Pi ratio is an index of the cellular energy reserve of the cell, and is called “phosphorylation potential.” Phosphocreatine (PCr) is the stored form of high-energy phosphates, from which ATP can be mobilized rapidly. In the in vivo 31P spectrum, high-energy phosphates ATP, PCr, and also inorganic Pi are easily detected. Phosphorus atoms from other nucleotides are either present in only small concentrations or are tightly bound to proteins, giving rise to low or very broad signals, respectively. These signals often underlie the ATP resonances. Slow age-dependent changes of these metabolites during postnatal brain development must be distinguished from acute and rapid alterations resulting from disease. In various studies, an age-dependent increase in the PCr/ATP and PCr/Pi ratios has been demonstrated in human newborns, comparing preterm and term infants [12, 20, 37, 42–44]. This increase is most likely associated with an increase in the metabolic rate and high energy turnover demonstrated with other methods, including positron emission tomography (PET)

MR Spectroscopy

[45]. More recently, these metabolites have been quantified with absolute values, confirming the agedependent increase of PCr and ATP in early human brain development [38, 46]. This increase may represent an important factor in the protection of the developing brain to hypoxia and in reducing seizure susceptibility [47]. Total Cr and PCr can also be determined by 1HMRS, as shown earlier. They show similar age-dependent modifications, with a fast increase before and around term and only minimal increase from infancy to adult values [41]. Lactate (Lac) occupies a special position in energy metabolism. Being an end-product of anaerobic glycolysis, the Lac concentration must rise whenever the glycolytic rate in a tissue volume exceeds the tissue’s capacity to catabolize Lac or export it to the bloodstream. This takes place in the event of hypoxia or hypoxia-ischemia and in various metabolic disorders (see below) [48–50]. Whereas Lac has always been recognized as a possible alternative fuel for the brain, only recently pathways have been described that define the role of Lac as a neuronal energy substrate in the brain during physiological activation [51]. The astrocyte seems to be the cellular component responsible for the production of Lac, which otherwise does not cross the blood-brain barrier very easily. Glutamate uptake into astrocytes stimulates glycolysis within the astrocyte, with production of Lac that, then, is taken up by neurons and metabolized into energy [52] (Fig. 23.6). Further evidence suggests that this Lac shuttle between astrocytes and neurons is much more active in the immature brain [53]. This could explain the higher Lac peaks seen with 1H-MRS in the immature normal brain [16, 21, 41, 54].

23.2.4 Amino Acids and Intermediary Metabolism (1H, 13C) Intermediary metabolism involves graded changes that cellular compounds undergo as they are transformed through chemical reactions into other mol-

ecules. Glutamate and glutamine are amino acids of the intermediary metabolism that are oxidized to keto-analogues and ammonia. Further oxidation of the so-formed keto-acids allows the end product, pyruvate, to enter the tricarboxylic acid cycle (TCA cycle), and ultimately to serve as an energy source. In recent 1H-MRS studies using model-based quantitation, glutamate concentration has been shown to increase during early brain development [41]. Glucose is another important brain metabolite. Glucose transport into the brain and absolute brain glucose concentrations have been evaluated in vivo using 13 C-MRS in adults [14]. Brain glucose levels in relation to serum glucose levels can be determined. Amino acid metabolism can be further studied dynamically by 13CMRS. (1-13C) glucose is given as a tracer and followed by 13C-MRS, where specific incorporation of labeled glucose into amino acids in the brain can be seen. With this technique, label exchange between cytosolic amino acids and their mitochondrial TCA cycle counterparts can be studied (Fig. 23.7) [55].

23.2.5 Age-Dependent Metabolite Pattern As has been shown, it is important to know normal spectral variations associated with age and anatomical location in the healthy control population when using MRS for the assessment of pathological conditions in the pediatric population. Several papers have been published regarding the changes that occur in 1 H-MRS and 31P-MRS in the developing brain, and most of the results are in good agreement (Table 23.1). In two more recent in vivo studies with single voxel short echo-time 1H-MRS, a new linear combination model fitting was used, which allows considerable extension of the range of observable metabolites in human brain, including metabolites such as acetate, alanine, aspartate, GABA, glucose, glutamine, glutamate, glycine, Lac, myo-inositol, macromolecular contributions, N-acetylaspartylglutamate (NAAG), o-phosphoethanolamine, scyllo-inositol, taurine, and threonine, in addition to the main peaks described earlier. Fig. 23.7. 13C MRS detection of label incorporation (13C-glucose) into cytosolic amino acids in the human brain. (Adapted from Gruetter et al. A mathematical model of compartmentalized neurotransmitter metabolism in the human brain. Am J Physiol Endocrinol Metab (2001)281:E100E112, with permission from the American Physiological Society)

1057

1058 P. S. Hüppi and F. Lazeyras a

b

c

Fig. 23.8a–c. Full term newborn 48 h after anoxic ischemic insult due to uterine rupture. Diffusion weighted image (DWI) (b) shows with increased signal intensity due to diffusion restriction in the lateral thalami and the posterior putamen. c 1H-MRS over lesion shown in b demonstrates marked increase of lactate and macromolecules/lipids with low NAA for a full-term infant

Changes during the neonatal period and early infancy are characterized by an increase in NAA in both gray and white matter structures [16–18, 56]. During childhood, NAA is constant in white matter locations [57]. During the newborn period and the first year of life, Cr also increases with age, whereas after the first year of life its concentration remains stable [19, 57]. Myo-inositol was shown to be highest in the neonatal period and in the cerebellum and to decrease thereafter [19, 41, 57]. The study by Kreis et al. [41] further revealed developmental changes in newborns of different gestational age; while glutamate, taurine, and macromolecular contributions increased with increasing gestational age, Lac and ophosphoethanolamine were shown to decrease with increasing gestational age. Table 23.1 presents a summary of concentrations values obtained in different studies. Also, Vigneron et al. [58] recently defined agedependent and anatomical variation in metabolite levels by MR spectroscopic imaging, which permits, as explained earlier, calculation of the 3D distribution of the major cerebral metabolites (i.e., Cho, Cr, and NAA) in the developing human brain.

23.3 Pediatric Pathology 23.3.1 Hypoxia-Ischemia When oxidative phosphorylation is impaired, energy metabolism follows the alternative route of anaerobic glycolysis and produces lactic acid. Lac has a chemical shift of 1.3 ppm, and presents as a doublet peak in the in vivo 1H-MRS due to coupling effects. Groenendal et al. [5] first described markedly elevated Lac levels in five infants with severe perinatal asphyxia; all patients died within the neonatal period. 1H-MRS data have been generated that demonstrate regional differences in Lac elevation after hypoxic-ischemic events in newborns. Single volume 1H-MRS in these patients showed greater increase of the Lac/NAA ratio in the basal ganglia than in the occipito-parietal cerebrum [21]. This corresponds to the signal abnormalities observed with early diffusion-weighted imaging (DWI) after term hypoxia-ischemia [60]. Figure 23.8 illustrates the typical changes in 1H-MRS after term perinatal hypoxia-ischemia.

34 41 40

GA

ROI

Rem Asp

3.8± 0.4

7.2± 1.1

1.3± 0.6

0.4± 0.4

6.7± 0.4

1.7 5.5

1.4± 0.4

4.2

8.4

3.9

1.3

6.2 1.5± 0.5

5.8

4.0

0.4

4.7

0.4± 0.2

8.5± 0.5

8.5

5.7

3.3 4.2

7.1

1.5

5.8 5.2 3.8

2.8

7.2

2.2 1.4

0.6± 0.3

0.3

2.0

0.3

0.8 0.9

0.3± 0.3

5.4 4.1

NAA NAAG PE

7.0

2.5 2.3

Lactot mI

1.2

2.8 3.9

GSH

8.2

2.9 2.6

Glu

5.3

2.8 2.3

Gln 2.0 3.3

0.0 0.0

GABA Glc 9.4 7.4

4.8 5.0 6.5

Crtot

34

41

37 36

Kreis [41]

Kreis [41]

Cady [46] Cady

Thalamus

Thalamus

ROI

PTT + FT

PT

Rem 3.7± 1.3 3.1± 0.8

Asp

125 ml, incl. Thalamus 31P-MRS T2 weighted 2.5 8ml, centered on Thalamus ratios to Cr Cady [16] 36 centered on Thalamus Hüppi [18] 29 (autopsy data) Thalamus (autopsy data) Hüppi [18] 40 Thalamus Pouwels [57] 56 LC-Model, Thalamus impure, n=3 Pouwels [57] adult Thalamus LC-Model, impure, n=44

GA

Reference 1.6± 1.0 1.9± 0.6

0.3± 0.9 0.3± 0.5

6.5± 0.7 8.1± 0.9

3.0

5.8

6.5

7.4

3.2 1.7

14.0

5.9

5.8± 1.9 6.2± 0.6

Glu

(6.5) 0.2 (Std) 10.5 6.4 9.9 7.7 1.1

2.2± 1.1 2.0± 0.7

Gln

GABA Glc

Crtot

3.4± 0.9 2.4± 0.8

GSH

2.7

1.8

2.0± 0.7 1.5± 0.8

5.8

7.1 4.7 3.5

8.8

3.0

0.7

1.5

1.0

2.5

7.7

1.4± 1.4 2.8± 1.2

5.4± 1.5 3.5± 1.2 4.5

4.1± 0.4 5.6± 0.7

0.7± 0.6 0.8± 0.3

Tau

1.7± 0.4

1.0

0.3

2.6

1.9 3.2

Tau

NAA NAAG PE

2.2 4.1 4.3

8.3± 1.6 6.2± 0.9

Lactot mI

Table 23.1b. Averaged metabolite concentrations [mmol/kgww] for locations in and around thalamus taken from the literature for reference.

3.0 Average GM, WM 2.9 Average GM, WM par WM + occipital GM Hüppi [18] 29 (autopsy data) motor cortex GM/WM Hüppi [18] 40 (autopsy data) motor cortex GM/WM Hüppi [56] 32 (MRS based motor cortex on Cr as Std) GM/WM Hüppi [56] 40 (MRS based motor cortex on Cr as Std) GM/WM Cady [16] 36 occipital WM centered Pouwels [57] 66 pariet. GM, par.-occ. LC-Model, 6 WM GM+10 WM Pouwels [57] adult par.-occ.WM LC-Model, n=61 Pouwels [57] adult pariet. GM LC-Model, n=45 Kreis [41] 1.3± adult occipital GM n=5 0.7

Kreis [41] Kreis [41] Kreis [11]

Reference

1.5± 0.1

1.1

1.5

8.8

5.0

9.0

10.3

4.7± 0.6 6.4± 0.6

1.7

2.0

4.6

4.5

3.7± 0.6 3.8± 0.5

NAtot Chtot

9.2± 0.5

8.7

7.8

1.8 1.6

2.7

6.5 3.4 5.9

2.9

2.1 2.1 2.4

4.5

2.8 4.2 5.2

NAtot Chtot

17.8

9.1± 1.6 7.5± 0.8

mItot

5.1± 0.4

6.4

7.6

11.1 8.8 10.3

mItot

9.5

10.6

19.9

7.4± 1.5 8.0± 0.7

Glx

8.4± 0.8

12.3

7.2

10.9

5.7 6.5

Glx

Table 23.1a. Averaged metabolite concentrations [mmol/kgww] for white and gray matter locations taken from the literature for reference. (Adapted from Kreis et al. Magn Reson Med 2002; 48(6):949–958, with permission from Wiley-Liss, Inc.)

MR Spectroscopy

1059

1060 P. S. Hüppi and F. Lazeyras Neurons have a poor ability to regenerate. Thus, continuous provision of energy supply is essential for the function and integrity of the brain. Lac occupies a special position in energy metabolism. Being an endproduct of anaerobic glycolysis, the Lac concentration must rise whenever the glycolytic rate in a volume of tissue exceeds the tissue’s capacity to catabolize Lac or export it to the bloodstream. This occurs with hypoxia or hypoxia-ischemia. Early spectroscopy (2 mm in diameter in normal individuals [62], but the exact thickness of the filum terminale may be difficult to measure with MRI. The terminal filum is the tethering agent and these patients respond to sectioning of the terminal filum [15]. Posterior spina bifida, scoliosis and kyphoscoliosis are associated in a high percentage of cases.

a Fig. 39.38a–c. Filar lipoma, 2-year-old boy. a, b Sagittal and coronal T1-weighted images show that the filum terminale is largely replaced by fat (arrows). The spinal cord is tethered and low. c Axial T1-weighted image shows the hyperintense fatty filum (arrow) clearly stands out against the hypointense cerebrospinal fluid

b

c

Abnormally Elongated Spinal Cord

This abnormality has not been reported previously to our knowledge. It may be considered a variant of the previous one; it is characterized by the absence of a normally tapered conus medullaris. The spinal cord does not show significant changes in caliber down to the sacrum, where it connects to the bottom of the thecal sac (Fig. 39.40). This abnormality might be embryologically related to a complete lack of retrogressive differentiation of the secondary neural tube. It may occur in isolation or in association to other CSDs, such as dermal sinuses, intradural lipomas, or lipomyelomeningoceles.

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a

c

b

Fig. 39.39a–c. Tight filum terminale. a Schematic of the malformation shows thickened filum terminale and low conus medullaris. (Modified from E.S. Crelin, F.H Netter, R.K. Shapter. Development of the nervous system: a logical approach to neuroanatomy. CIBA Clinical Symposia 1974; 26:1). b, c Tight filum terminale, 4-month-old girl. b Sagittal T1-weighted image shows thickened filum terminale (arrow) with tethered, low conus medullaris. The spinal canal is abnormally large. c Axial T1-weighted image confirms thickening of the filum terminale (arrow)

Dermal Sinus

Fig. 39.40. Abnormally elongated spinal cord, 8month-old girl. Sagittal T2weighted images show that the spinal cord is abnormally low, with the tip of the conus medullaris lying at L5. There is no taper of the conus. An associated dermal sinus is barely visible (arrowheads)

The dermal sinus is an epithelium-lined fistula that extends inward from the skin surface and can connect with the CNS and its meningeal coating. It is found more frequently in the lumbosacral region, although cervical, thoracic, and occipital locations are possible (Fig. 39.41) [63, 64]. It is a common abnormality (23.7% of all CSDs) [1]. On clinical examination, a midline dimple or pinpoint ostium is found (Fig. 39.41), often in association with hairy nevus, capillary hemangioma, or hyperpigmented patches. The cutaneous opening of a dermal sinus tract differs from that of a sacrococcygeal fistula. Dermal sinus tracts are found above the natal cleft and usually are directed superiorly. By comparison, sacrococcygeal pits are found within the natal cleft extending either straight down or inferiorly. They are anatomically located below the level of the cul-de-sac of the subarachnoid space and do not require further imaging evaluation [65]. Although the cutaneous abnormality usually is evident at birth, some patients are not referred to medical attention until they develop complications such as local infection or meningitis and abscesses that may result from bacteria invading the CNS along the dermal sinus tract.

Congenital Malformations of the Spine and Spinal Cord

a

Fig. 39.41a–c. Dermal sinus. a Photograph of the low-back of a child showing cutaneous orifice. Note the ostium lies above the intergluteal crease. Instead, sacrococcygeal fistulas open into the intergluteal crease. b Lumbar dermal sinus, 3-month-old boy. Sagittal T1-weighted image shows lumbar dermal sinus (arrow). Cerebrospinal fluid was seen leaking from a cutaneous pinpoint ostium. c Thoracic dermal sinus, 2-month-old boy. Sagittal T1-weighted image shows dermal sinus coursing obliquely through the subcutaneous fat (arrow)

b

Embryologically, dermal sinus tracts are traditionally believed to result from focal incomplete disjunction of the neuroectoderm from the cutaneous ectoderm [66]. However, such theory has been questioned [4]. The dermal sinus could derive from ectodermal differentiation of the dorsal portion of the neurenteric canal. As such, it could be isolated or associated to diastematomyelia, depending on the severity of the malformation. Dermal sinuses may open in the subarachnoid space and cause leakage of CSF. Meningitis and abscesses are recognized complications of these fistulas [64]. They also may connect to a hypertrophic or fibrolipomatous filum terminale, as well as to a low-lying conus medullaris or intraspinal lipoma. They may originate from the skin overlying a lipomyelocele, which therefore is pierced by the dermal sinus tract (Fig. 39.42). Generally, the dermal sinus courses obliquely and downward. It is easily recognized on midline sagittal scans as a thin hypointense stripe within the subcutaneous fat, whereas it is more difficult to detect on axial scans. The intrathecal portion of the tract usually is not detectable on MRI, which makes it difficult to assess the true extent of the tract itself and, particularly, whether it pierces the dura and involves the CNS. In a considerable percentage of cases, dermal sinuses are associated with a dermoid, generally

c

located at level of the cauda equina or near the conus medullaris (Fig. 39.43). This association was found in 11.3% of cases in our series [1], but may be higher. The dermoid probably results from encystment of part of the dermal sinus tract. It may subsequently increase in size due to progressive accumulation of desquamative debris within the cyst. Dermoids also may result from iatrogenic implantation of skin cells during back surgery or during spinal taps performed with needles lacking a trocar. Abscess formation and rupture in the subarachnoid spaces with subsequent chemical meningitis are other well-recognized complications of spinal dermoids (Fig. 39.44) [63]. The behavior of these dysontogenetic masses on MRI is variable depending on their content. Some portions may be hyperintense on T1-weighted images, but the mass may be isointense to CSF on both T1- and T2-weighted images and, therefore, may be difficult to discern. Infected dermoids exhibit intense contrast enhancement that may be ring-like if an abscess develops (Fig. 39.16).

Persistent Terminal Ventricle

The “fifth ventricle” of the historic scientific literature [67] is a small ependyma-lined cavity within the

1583

1584 P. Tortori-Donati, A. Rossi, R. Biancheri, and A. Cama

a

Fig. 39.42a, b. Dermal sinus in a 1-month-old boy with lipomyelocele. a Photograph of the patient shows cutaneous orifice piercing a subcutaneous mass cranial to the intergluteal crease. b Sagittal T1-weighted image shows lumbar dermal sinus (arrowhead) coursing obliquely through the subcutaneous lipoma. Associated lipomyelocele is shown

b

a

d

b

c

Fig. 39.43a–d. Dermal sinus with dermoid. a Schematic representation shows the anatomic relationship between a dermal sinus and a dermoid. The latter usually is located among the nerve roots of the cauda equina or near the conus medullaris, and is found in up to 50% of patients with dermal sinus. (Modified from E.S. Crelin, F.H Netter, R.K. Shapter. Development of the nervous system: a logical approach to neuroanatomy. CIBA Clinical Symposia 1974; 26:1). b–d Dermal sinus with dermoid, 8-year-old girl. b Slightly parasagittal T2-weighted image shows sacral dermal sinus coursing obliquely downward in subcutaneous fat (arrow). c Midsagittal T2-weighted image shows a huge dermoid in the thecal sac (arrowheads), extending upward to the tip of the conus medullaris. The mass gives slightly lower signal than cerebrospinal fluid and is outlined by a thin low-signal rim. d Pathological specimen shows hair within the excised mass

Congenital Malformations of the Spine and Spinal Cord

a

b

conus medullaris that always is identifiable on postmortem examinations but must achieve a certain size to be visible on MRI (Fig. 39.45) [68]. Embryologically, it is related to incomplete regression of the terminal ventricle during secondary neurulation, with preservation of its continuity with the central canal of the rostral spinal cord. The latter point is critical because failure of regression of the terminal ventricle associated with inefficient connection to the central canal above may produce a terminal myelocystocele, which is a much more severe abnormality. By itself, the persistent terminal ventricle is asymptomatic; however, cases have been reported in which a huge cystic dilation was associated with low-back pain, sciatica, and bladder disorders, presumably secondary to thinning of the cord by the cyst [68]. It is unclear whether these “terminal ventricle cysts” are developmental variants or result from pathological changes leading to obstruction of the terminal ventricle [68]. Differentiation with hydromyelia is based on the location immediately above the filum terminale, whereas intramedullary tumors are excluded by the lack of gadolinium enhancement. Diastematomyelia is easily excluded when coronal and axial sections are obtained. The size of the “cyst” usually remains unchanged on follow-up scans.

39.6.2.2 Complex Dysraphic States

Because gastrulation is characterized by the development of the notochord, spinal dysraphisms originating during this period will characteristically show a complex picture in which not only the spinal cord,

Fig. 39.44a, b. Ruptured dermoid, 23-yearold man. a Axial CT shows nondependent layering hypodense material in the right frontal horn (arrow). b Axial T1-weighted image shows the intraventricular nondependent material is hyperintense (arrow). No real differential diagnosis exists, since fat in the ventricles is pathognomonic for a ruptured dermoid. This patient had a ruptured lumbosacral dermoid

but also other organs, deriving from or induced by the notochord, are severely abnormal. Therefore, disorders of gastrulation are also called complex dysraphic states [4]. In the vast majority of cases, these abnormalities are covered by skin, and no tell-tale subcutaneous masses are present. The only exception are hemimyelocele and hemimyelomeningocele, two exceedingly rare abnormalities that were described in the “open spinal dysraphism” section. Failures of notochordal development have been categorized in two subsets: (i) disorders of midline notochordal integration, which result in longitudinal splitting, and (ii) disorders of notochordal formation, which result in the absence of a certain notochordal segment [1].

A. Disorders of Midline Notochordal Integration

The prospective notochord cells are derived from the node. They stream in equal numbers from both sides of the node past the primitive pit to migrate between the ectoderm and the endoderm in the midline. Midline integration [1] is the process by which the two paired notochordal anlagen fuse in the midline to form a single notochordal process. This midline integration most likely involves a cell adhesion molecule, probably fibronectin [70]. If the primitive streak is too wide, prospective notochordal cells migrate too laterally, i.e., too far off the midline. Therefore, they may fail to integrate in the midline, thereby remaining separate and developing independently over a variable segment, i.e., forming two paired notochordal processes. The intervening space will be occupied by primitive streak cells (Fig. 39.46) [4]. The cause of

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1586 P. Tortori-Donati, A. Rossi, R. Biancheri, and A. Cama

b

a

e e

c

d

Fig. 39.45a–e. Persistent terminal ventricle. a Schematic representation of a cystic dilatation of the terminal ventricle. Note the cavity is contained within the conus medullaris, which differentiates it from hydromyelia. b Sagittal T2-weighted and c axial T1weighted images show intramedullary cavity involving the conus medullaris, at the anatomic site of the terminal ventricle. d Sagittal and e axial T1-weighted images in a different case show terminal ventricle (arrows) associated with filar lipoma (arrowheads). (b, c: courtesy of A.G. Osborn, Salt Lake City, UT, USA)

Fig. 39.46. Embryogenesis of disorders of midline notochordal integration. The primitive streak is abnormally wide; prospective notochordal cells therefore begin ingression more laterally than normal. As a result, two notochordal processes are formed. The caudal neuroepithelium, comprising two columns of tissue which flank and are separated by the primitive streak, fail to become integrated to form a single neuroepithelial sheet, and instead forms two “hemineural plates.” The type of resultant malformation depends upon the level and extent of the abnormality, and the success of subsequent reparative efforts. (Reproduced from M.S. Dias et al. [4], with permission of S. Karger AG, Basel, Switzerland)

failed midline notochordal integration has been the source of continuing debate among authors. Several possible explanations have been proposed, such as persistent endodermal-ectodermal adhesion within the primitive streak [71]; initial teratogenic or spontaneous mutation of the developing notochord [72]; and formation of an accessory neurenteric canal that is subsequently invested with mesenchyme which, together with a pinch of endoderm at the base of the fistula, forms an endomesenchymal tract that splits the notochord and neural plate [29]. Regardless of the underlying cause, the eventual type of malformation depends on the level and extent of the defect as well as the success of subsequent reparative efforts [4, 71]. The so-called split notochord syndrome includes several, apparently quite different entities, such as dorsal enteric fistulas, neurenteric cysts, diastematomyelia, dermal sinuses, and gut duplications. The inherent differences among these entities result from the different developmental fate of the intervening primi-

Congenital Malformations of the Spine and Spinal Cord

tive streak tissue toward endoderm, mesoderm, or ectoderm; however, they usually share some degree of vertebral abnormality (block vertebrae, butterfly vertebrae, hemivertebrae), indicating a common original notochordal abnormality.

Dorsal Enteric Fistula

Dorsal enteric fistula is an exceedingly rare condition but is the most severe complex dysraphic state. It consists of a cleft connecting the bowel with the dorsal skin surface through the prevertebral soft tissues, vertebral bodies, spinal canal and its contents, neural arch, and subcutaneous tissues. The involved segment of both the vertebral column and spinal cord is split to form two columns that surround the cleft. We have never encountered a case of complete dorsal enteric fistula, and only few cases are available for review in the recent literature. In the case reported by Hoffman et al. [73], there was bifurcation of the spine and spinal cord at the lumbar level with continuation to a conus bilaterally. Castillo et al. [74] reported a case with duplication of L5 and sacrum and doubling of the spinal cord in a child with prior surgery of a cystic mass in the lower back whose nature was not ascertained. Embryologically, the dorsal enteric fistula could be related to failure of notochordal integration with full-length persistence of a neurenteric canal. There is a reportedly strong association with malformations of visceral organs, such as renal dysplasia, diaphragmatic hernias, pulmonary hypoplasia, cardiac anomalies [4], and the OEIS complex [73].

Neurenteric Cysts

Neurenteric cysts are found within the spinal canal and are lined with a mucin-secreting, cuboidal or columnar epithelium that resembles the alimentary tract [4]. Their content is variable, and the chemical composition may be similar to CSF in some cases. The typical location is intradural in the cervicothoracic spine anterior to the cord (Fig. 39.47) [75, 76]; however, neurenteric cysts also may be found in the lumbar spine and even in the posterior fossa. In a minority of cases, they are located posterior to, or even within, the spinal cord. Histologically, these cysts have been classified into three types based on the microscopic features of the cyst wall and its contents [77]. The walls of type A cysts mimic gastrointestinal or respiratory epithelium and have a basement membrane supporting single or pseudostratified cuboidal or columnar

cells, which may be ciliated. Type B cysts also contain glandular organization and usually produce mucin or serous fluid. Type C cysts are the most complex and contain ependymal or glial tissue within the cyst. Embryologically, neurenteric cysts are related to endodermal differentiation of primitive streak remnants that remain trapped between a split notochord. As such, neurenteric cysts are the intraspinal counterpart of gut duplications, in which the abnormality develops in close vicinity to the gastrointestinal tract rather than to the spinal cord. In fact, the differential diagnosis between neurenteric cysts and gut duplication is based on location [78]. Because of their embryogenesis, vertebral abnormalities such as anterior and posterior spina bifida are common associated findings, but a number of neurenteric cysts are not associated with other dysraphic elements. These “solitary” cysts are composed mainly of endodermal derivatives (type A or B cysts), whereas “dysraphic” cysts also exhibit mesenchymal and ectodermal elements (type C cysts). This possibly indicates an earlier timing in the development of “dysraphic” cysts than in solitary cases that could result from later insults [79]. Owing to the common underlying embryological mechanism, it is not surprising that neurenteric cysts frequently are associated with diastematomyelia, in which case they may be located in the cleft between the two hemicords. Patients with these lesions may present with progressive signs of spinal cord compression that may be acute [79, 80]. On MRI (Fig. 39.47), neurenteric cysts usually are isointense to hyperintense relative to CSF on long relaxation time sequences. On T1-weighted images, they appear isointense or slightly hyperintense to CSF, which is consistent with the high-protein content fluid within the cysts [76, 81]. Absence of contrast enhancement is the rule; however, we have seen one case of a neurenteric cyst that enhanced following intravenous gadolinium administration [1].

Diastematomyelia

Split cord malformations have been classically called diastematomyelia (from the Greek διαστηµα = cleft) and diplomyelia (διπλουζ = double). Although from a strict etymological perspective diastematomyelia refers to cord splitting and diplomyelia to cord duplication, there has been no widespread consensus regarding the use of these terms in the radiological literature, mainly due to the inherent difficulty in assessing true cord duplication preoperatively. These malformations account for 3.8% of all CSD [1].

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Embryologically, the two paramedian notochordal anlagen are prevented from integrating in the midline. Failure of midline notochordal integration produces two separate, variably elongated notochordal columns, each inducing a separate hemi-neural plate. The resulting malformation depends on the developmental fate of the intervening primitive streak tissue. If it further develops toward bone and cartilage, the two hemicords eventually will be contained into two individual dural sacs separated by a osteocartilaginous spur. Conversely, if the primitive streak tissue is reabsorbed or leaves a thin fibrous septum, the two hemicords eventually will lie within a single dural tube. Regardless of the presence of an intervening spur, bone anomalies are present in 85% of cases, and scoliosis is present in 50% of cases [82]. In 1992, Pang et al. [29] suggested that terms such as diastematomyelia and diplomyelia be abandoned to introduce the term “split cord malformation” (SCM). They also proposed categorizing these abnormalities into two types based on the state of the dural tube and the nature of the median septum. Type I SCM consists of two hemicords contained within individual dural tubes, separated by a bony or osteocartilaginous septum that extends from the vertebral body to the neural arches. This rigid median septum is entirely extradural. In type II SCM, a common dural tube houses both hemicords, and there is no rigid median septum. These main features of the two types of SCM never overlap, and the classification can be made readily by preoperative neuroimaging studies [82]. Although the term SCM has gained some consensus, we believe it is a translation of the Greek term, diaste-

Fig. 39.47a–d. Neurenteric cyst. a Sagittal PD-weighted image shows an intradural cyst ventral to the spinal cord at the C7-T2 level. b Axial T2-weighted MRI shows that the spinal cord (arrows) is thinned and displaced to the left. c Axial T1-weighted MRI reveals a neurenteric canal (arrow) in the first thoracic vertebra. a–c (Reproduced with permission from A.J. Martin, C.C. Penney. Spinal neurenteric cyst. Arch Neurol 2001;58:126-127. Copyrighted 2001, American Medical Association). d Histological specimen in a different case shows the cyst is lined by gastrointestinal epithelium

matomyelia. Moreover, the term diastematomyelia is widely used both in the literature and in the everyday clinical practice. Therefore, we support the continued use of “diastematomyelia” although we stand by Pang’s categorization into two types. Diastematomyelia Type I. This is the least common of the two varieties, representing 25% of cases [1]. Clinically, patients usually present with scoliosis and TCS. Cutaneous birthmarks, such as hemangiomas, dyschromic patches, and hairy tufts (Figs. 39.11, 48), often indicate the underlying malformation. A hairy tuft lying high along the back, often in the form of a faun tail nevus, is a very reliable clinical marker of diastematomyelia [1], and the correlation between hypertrichosis and diastematomyelia is higher than any other combination of cutaneous abnormality and underlying spinal cord lesion [30]. Vertebral anomalies are the rule and include bifid lamina, widened interpediculate distance, hemivertebrae, bifid vertebrae, fused vertebrae, and narrowing of the intervertebral disk space. Scoliosis also is common and is seen in 30%–60% of these individuals. The radiological hallmark [29, 83] is the osseous or osteocartilaginous septum with resulting double dural tubes, each containing a hemicord (Fig. 39.48). Although in the archetypal case the spur is bony and connects the vertebral body and neural arch along a midsagittal plane, “atypical” spurs are common. The spur may course obliquely (Fig. 39.49), and may be complete or incomplete, in which case it may originate either from the vertebral body (Fig. 39.50) or from the neural arch (Fig. 39.51). In some cases, it divides the

Congenital Malformations of the Spine and Spinal Cord

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Fig. 39.48a–h. Diastematomyelia type I. a Schematic of the malformation. The spinal canal is split in two halves by a bony or cartilaginous septum (the “spur”). Each half contains a dural sac and a hemicord, usually possessing a single set of posterior and anterior nerve roots. Dorsal paramedian nerve roots connecting to the spur may also be present. b–j Diastematomyelia type I, 3-year-old girl. b Photograph of the girl’s low back. There is marked hirsutism along the midline of the back. c Conventional X-rays, anteroposterior view show increased interpeduncular distance and a bony structure projecting into the spinal canal (open arrow). d Sagittal and e coronal T1-weighted images show bony spur (thin arrow) projecting into the spinal canal. The spur is located at the T12-L1 level. The two hemicords are visible on the coronal plane (arrowheads, e), whereas the intervening subarachnoid space between the two hemicords is seen above the spur on the midsagittal plane. There is a tight filum terminale that tethers the spinal cord inferiorly (thick arrow, d) There also is hydromyelia involving the spinal cord above the splitting (open arrow). The T11 and T12 vertebral bodies are rudimentary. f–h Axial T2-weighted images show the malformation sequence from cephalad to caudad: f hydromyelia (H), g split spinal cord (arrowheads) within single dural sac, and h split spinal cord (arrowheads) with dual dural sacs and intervening bony spur (open arrow) that connects the vertebral body to an abnormally thick neural arch. i Axial CT scan and j reformatted sagittal CT scan show the sclerotic bony spur (S) connecting anteriorly with the vertebral body and posteriorly with a rudiment of the spinous process that is separated from the laminae by bony spina bifida (arrows, i). There are two dural sacs (asterisks, i) separated by the spur

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Fig. 39.49a–c. Type I diastematomyelia plus hydromyelia, 1-year-old girl. a Coronal T1-weighted image shows hyperintense, asymmetrically oriented septum (thick arrow). Both hemicords show hydromyelia (thin arrows). The spinal cord above the splitting also shows hydromyelia. b Axial T2-weighted and c axial T1-weighted images show hemicords (arrowheads, b) containing dilated central canals, and intervening bony spur at a slightly lower level (open arrows, c). Notice tethering paramedian nerve roots (arrow, b).

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spinal canal unequally, and the two hemicords will be asymmetric. In young children, the spur may be mostly cartilaginous and progressively ossify as the child grows. In particularly complex cases, two adjacent clefts are present, thereby producing a sort of “tripartite” cord [29]. Exact recognition of the distorted anatomy becomes very difficult, even with MRI. In most cases of diastematomyelia type I, the cleft is located at the thoracic or lumbar level and lies at the caudal end of the splitting. The two hemicords usually surround the spur tightly before fusing with each other to form a normal spinal cord below, whereas rostrally the splitting is much more elongated. Therefore, there is a craniocaudal sequence of partial clefting, complete diastematomyelia with single dural tube, and diastematomyelia with dual dural tubes

Fig. 39.50a,b. Type I diastematomyelia with incomplete spur, 4-month-old boy. a Axial CT and b axial T1-weighted image show incomplete bony spur (S) projecting from the posterior wall of the vertebral body into the spinal canal. The two hemicords are clearly visible (arrowheads). There is associated posterior spina bifida

(Fig. 39.48). Hydromyelia is a common associated finding and may involve the normal cord both above and below the splitting, as well as one or both of the hemicords (Figs. 39.48, 49) [82]. In the vast majority of cases, the hemicords fuse again below the spur to form a normal cord. In rare cases the cleft may be terminal, in which case two hemicones and hemifilum (generally hypertrophic and tethered) form. Failure of neurulation of one hemicord produces a hemimyelocele or hemimyelomeningocele (Fig. 39.18) (see section on open spinal dysraphisms). Diastematomyelia Type II. The cutaneous stigmata of diastematomyelia type II are similar to those of type I. Again, hypertrichosis is a remarkable telltale signature. The radiological hallmark is repre-

Congenital Malformations of the Spine and Spinal Cord

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Fig. 39.51a–f. Type I diastematomyelia with incomplete spur, 1-month-old girl. a Sagittal T2-weighted image shows apparently intramedullary hypointense lesion at the L3 level (open arrow), connected to the posterior wall of the spinal canal by hypointense stripes. b Coronal T1-weighted image reveals diastematomyelia (arrowheads) with intervening spur that contains hyperintense fatty tissue (open arrow). c, d Axial T2-weighted images show incomplete, atypical bony spur (open arrows) projecting from the neural arch to the interior of the spinal canal and splitting the spinal cord into two halves (arrowheads, c). e, f Axial CT scans confirm presence of bony spur (open arrows) containing hypodense fatty marrow (asterisk, f). The neural arch is abnormal with wide schises to both sides of the spur base

sented by a single dural sac housing both hemicords (Figs. 39.52, 53) [29, 83]. No osteocartilaginous spur is present, although a midline, nonrigid, fibrous septum sometimes is detected at surgery (Fig. 39.52). In these cases, clinical signs of TCS may appear, and indeed the assumption that diastematomyelia type II does not produce TCS is incorrect [30]. Moreover, cord tethering may be caused by an associated meningocele manqué (see below). Diastematomyelia type II may be difficult to appreciate on sagittal MR images, where the only tell-tale sign is an apparent thinning of the spinal cord that results from partial averaging with the intervening subarachnoid space between the two hemicords (Figs. 39.52, 53). Conversely, coronal and axial MR images clearly depict the cord splitting. The fibrous septum may be very thin and usually is appreciated best with high-resolution coronal or axial T2-weighted MR images (Fig. 39.52). However, it may be absent or remain undetected in the majority of cases. In some cases, the cleft is partial and the splitting incomplete; these are the mildest forms of cord splitting (Fig. 39.54) [19]. Hydromyelia may be present with the same features as in type I. Bilateral

hydromyelia generates an “owl’s eye” sign on the axial plane (Fig. 39.55). Associated vertebral anomalies are usually milder than in type I, and are represented by butterfly vertebrae in most cases. However, posterior spina bifida often is present. Scoliosis may be present. Diastematomyelia type II more commonly involves the thoracolumbar spine; however, cervical forms do occur, either in isolation (Fig. 39.56) or in association with other abnormalities, such as cephaloceles and Chiari I malformation. As previously stated, whether each neural plate is complete or is a “hemineural” plate has been the source of much debate, as it implies cord duplication versus cord splitting. It has been traditionally believed that the evaluation of paramedian nerve roots (Fig. 39.49) may clarify this question, as only truly duplicated cords would possess double sets of dorsal and ventral roots, whereas split hemicords would only have one [83]. However, Pang et al. [29] showed that both types of diastematomyelia may possess paramedian nerve roots, depending on the fate of neural crest cells (which will produce the nerve roots); therefore, their mere presence cannot be used to determine the type of malformation. Although one could speculate that a

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Fig. 39.52a–d. Type II diastematomyelia with fibrous septum, 11-year-old girl. a Schematic of the malformation on an axial view. The two hemicords are contained within a single dural tube that is divided in two halves by a thin, intervening fibrous septum. b The only tell-tale sign of the abnormality on this sagittal T1-weighted image is an apparent thinning of the spinal cord (thick arrow), which actually results from the intervening subarachnoid space between the two hemicords. There is concurrent vertebral segmentation defect with rudimentary intervertebral disk (arrowhead). c Coronal and d axial T2-weighted images show the two hemicords (arrows) are contained within a single dural sac, which is divided in two halves by an intervening hypointense band (arrowheads). A fibrous septum was found at surgery

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Fig. 39.53a–d. Type II diastematomyelia without septum, 13year-old girl. a Schematic of the malformation on an axial view. The two hemicords are contained within a single dural tube. There is no intervening septum. b Sagittal T2-weighted image shows a low spinal cord with apparent focal thinning (black arrow) resulting from b partial averaging with the intervening subarachnoid space between the two hemic cords. Hydromyelia involves the cord above the splitting (white arrow). There is associated tight filum terminale (arrowhead). c Coronal T2-weighted image shows split cord (arrowheads). However, this could simply represent hydromyelia. d Axial T2-weighted image clearly shows the two hemicords (arrows) contained in a single dural tube, with no intervening spur

Congenital Malformations of the Spine and Spinal Cord

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Fig. 39.54a–c. Type II diastematomyelia, partial splitting, 4-monthold girl. a Schematic of the malformation on an axial view. The two hemicords are only partially separated and remain connected along their medial wall. There is a single dural tube. b Coronal T1weighted image shows low signal sling within the conus medullaris (arrow). c Axial T2-weighted image shows partial cord splitting (arrows)

Fig. 39.56a, b. Cervical type II diastematomyelia, 3-month-old girl. a Coronal T1-weighted image does not distinguish between diastematomyelia and hydromyelia (arrowheads). b Axial T2-weighted image shows a split cord (arrows) housed within a single dural tube

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true duplication may be radiologically assessed only when hydromyelia is detected within each “hemicord,” as it implies complete duplication of the central ependymal canal and, therefore, of the surrounding spinal cord, one should nevertheless consider that also nonhydromyelic hemicords have necessarily completed their neurulation (and therefore possess a nondilated central canal); otherwise, a hemimyelo(meningo)cele would result from lack of neurulation of one hemi-

Fig. 39.55a, b. Type II diastematomyelia with bilateral hydromyelia: the “owl’s eye sign.” 1-year-old girl. a Coronal T1-weighted image shows hydromyelia involving both the hemicords and the spinal cord both above and below the split. b Axial T1-weighted image shows ring-like appearance of the hydromyelic hemicords housed within a single dural tube, generating the “owl’s eye sign”

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cord [1]. Moreover, the fact itself that the malformation is covered by skin implies that neurulation must have been completed. Recent evidence suggests that there is a continuous spectrum of abnormality ranging between partially cleft cord in a single dural tube at one end and completely duplicated cord within dual dural tubes with intervening bony spur at the other end. As such, both types of diastematomyelia represent incomplete

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1594 P. Tortori-Donati, A. Rossi, R. Biancheri, and A. Cama duplications in which both hemicords display welldifferentiated lateral halves and hypoplastic medial halves [4], and the dispute as to whether the cord is cleft or duplicated loses its meaning [1].

myelia (40% of cases), but also may occur in patients with filar lipomas, dermoids, and neurenteric cysts. It can even exist at sites distant from the tether site [84]. Identification of a meningocele manqué on MRI may be difficult or even impossible, and the diagnosis usually is made at surgery.

Meningocele Manqué

Meningocele manqué refers to the dysraphic element of dorsal tethering bands composed of fibrotic or atretic neural tissue connecting the spinal cord to dura or surrounding structures. These fibroneurovascular stalks probably are related to either a form of limited dorsal myeloschisis or to dorsal paramedian nerve roots that course posteriorly and try to find their way dorsally to exit the dura [17, 83]. As such, meningocele manqué occurs more frequently in patients with diastemato-

B. Disorders of Notochordal Formation

As previously stated, it now is clear that the eventual location of each prospective notochordal cell along the longitudinal embryonic axis is genetically programmed; therefore, the embryo has a genetically encoded segmental organization. The great “organizer” of such segmental arrangement is the node (Fig. 39.57). Rostrocaudal patterning is controlled by

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Fig. 39.57a–f. Gene expression in the Hensen’s node. a Sagittal section of a 5 somite stage chick embryo showing the cellular arrangement. b, c Sagittal sections hybridized with probes revealing the expression of two homeobox genes, HNF-3β (b) and Ch-Tbx6L (c). d. Sagittal section showing superimposed expression of the two homeobox genes. The basal membrane is represented as a continuous line between the floor plate (FP) and notochord (No) and is prolonged caudally by dots at level of the primitive pit, in the region where the FP and the notochord are not clearly resolved. Three different zones in Hensen’s node expressing HNF-3β can be distinguished, named a, b, and c in the craniocaudal direction. Zone a is an anterior zone in which prospective notochordal cells and the floor plate of the neural tube are separated by a basement membrane. Zone b is intermediate, constitutes the bulk of the node, and corresponds to the primitive pit, where the two compartments are not separated. Zone c is the caudalmost and contiguous to the primitive streak, and contains cells that are randomly mixed. e Dorsal and f sagittal schematic views of Hensen’s node show the three segregation zones. Zone c, with the tip of the primitive streak (TPS), contains a stem-cell-like population (dots) that has the capacity to yield both notochord and floor plate. The axial paraxial hinge (APH) is necessary for caudalward movement of Hensen’s node, deposition of midline cells and survival of embryonic tissues. (Reproduced from Le Douarin et al. [86], with permission from Elsevier Science Ltd.)

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Congenital Malformations of the Spine and Spinal Cord

both maternal and embryonic genes, involving the sequential expression of gap, pair rule, segment polarity, and homeobox genes [6]. The role of the notochord in the establishment of a floor plate and development of neurons was elucidated by van Straaten et al. [86] by means of experimental removal of notochordal segments in chick embryos. These authors showed that after notochordectomy the amount of spinal cord neurons was remarkably reduced, and that there is a clear segmental coincidence between lack of the notochord and a reduced spinal cord size. Moreover, depending on the segmental level of the notochordal extirpation along the cranio-caudal axis, these authors were able to obtain segmental spinal dysgenesis and caudal agenesis phenotypes (Fig. 39.58). Because notochordal cells derive in an orderly fashion from the primitive streak through the node and primitive pit, it is tempting to speculate that a pre-existing abnormality of the node could determine segmental abnormalities of the notochord, eventually resulting in intermediate or caudal level aplasia of the spine and spinal cord. Studies conducted in the chick and zebrafish embryos by Le Douarin [87] seemed to suggest that there is segregation of genetic expression domains within the node during gastrulation. These studies showed that the node is divided in three zones, named a, b, and c in the craniocaudal direction (Fig. 39.57). Zone a is an anterior zone in which prospective notochordal cells and the floor plate of the neural tube are separated by a basement membrane. Zone b is intermediate, constitutes the bulk of the node, and corresponds to the primitive pit, where the two compartments are not separated. Zone c is the most caudal, is contiguous to the primitive streak, and contains cells that are randomly mixed. These studies also showed that removal of zone b does

not prevent formation of the caudal neural tube, but results in interrupted midline cells and a small-sized neural tube that lacks a floor plate and motoneurons. Conversely, removal of zone c results in apoptotic removal of the caudal neural tube and paraxial mesoderm [87]. It should be emphasized that, according to current views (M. Catala, personal communication), the reproducibility of these observations is questionable. However, these observations permit advancement of the following unified theory of embryogenesis to explain disorders of notochordal formation (Fig. 39.59). • Programmed cell death or apoptosis is a process of cell elimination that occurs during normal development and represents a crucial phenomenon in various steps of embryogenesis [88]. • During abnormal gastrulation, prospective notochordal cells that are wrongly specified in terms of their rostrocaudal positional encoding are eliminated (“positional apoptosis”) [89]. Eventually, fewer cells or even no cells will form the notochord at a given abnormal segmental level. • The consequences of such a segmental notochordal paucity are manifold and affect the development of the spinal column and spinal cord as well as of other organs that rely on the notochord as inductor. • If the prospective notochord is depleted, a wide array of segmental vertebral malformations including segmentation defects, indeterminate or block vertebrae, or absence of several vertebrae, will result. • Because of lack of neural induction and absence of a floor plate, fewer prospective neuroectodermal cells, or even no cells at all, will be induced to form the neural tube in the pathological segment [90].

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b Fig. 39.58a, b. Notochord removal experiments in chick embryos. a Caudal agenesis phenotype: removal of the caudalmost portion of the notochord results in absence of the tail bud (arrowhead) b Segmental spinal dysgenesis phenotype: removal of an intermediate portion of the notochord results in focal spinal aplasia (open arrow).The tail bud is present (arrowhead). (Courtesy H. van Straaten, Maastricht, the Netherlands)

1596 P. Tortori-Donati, A. Rossi, R. Biancheri, and A. Cama Fig. 39.59. Embryogenetic theory of disorders of notochordal formation. Upper image: At the beginning of gastrulation, the bilaminar embryonic disk, Hensen’s node with primitive pit, and primitive streak are schematically depicted on a longitudinal view. Middle row: schematic depiction of apoptotic elimination of prospective chorda-mesodermal cells. Left: normal; middle: caudal apoptotic depletion; right: intermediate apoptotic depletion. Lower row: Eventual notochordal formation. The notochord induces the overlying ectoderm to specialize into neural ectoderm. Left: normal; middle: caudal regression (i.e., caudal agenesis) phenotype: the caudal portion of the notochord does not form, and the overlying ectoderm is not induced to form neuroectoderm; right: segmental spinal dysgenesis phenotype: an intermediate segment of the notochord does not form, resulting in segmental interruption of the neuroectoderm

• The resulting malformation essentially depends on the segmental level and the extent of the abnormality along the longitudinal embryonic axis [91], with subsequent interference on the processes of primary and/or secondary neurulation. • In the vast majority of cases, the abnormality involves the caudal extremity of the embryo, and probably causes premature arrest of the caudal migration of the node, resulting in the caudal agenesis constellation. • Much more rarely, the abnormality involves an intermediate notochordal segment, in which case caudal movement of the node is not prevented, but the abnormal notochordal cells are apoptotically removed, thereby resulting in segmental spinal dysgenesis.

Caudal Agenesis (Caudal Regression Syndrome)

Caudal agenesis, or caudal regression syndrome, is a heterogeneous constellation of anomalies comprising total or partial agenesis of the spinal column, anal imperforation, genital anomalies, bilateral renal dysplasia or aplasia, and pulmonary hypoplasia [91]. The lower limbs usually are dysplastic with distal leg atrophy and a short intergluteal cleft; fusion or agenesis results in the most severe cases (sirenomelia) (Fig. 39.60), but sirenomelic fetuses are not viable due to concurrent bilateral renal agenesis [92]. Etymologically, the term “caudal agenesis” should be preferred, as “caudal regression” implies a concept of excessive regression of the embryonic tail that cannot be adequately applied in tail-less animals, such as

humans. However, the traditional denomination is still viable, and is commonly used by the majority of investigators. Agenesis of the sacrococcygeal spine may be part of syndromic complexes such as OEIS (omphalocele, cloacal exstrophy, imperforate anus, and spinal deformities) [54], VACTERL (vertebral abnormality, anal imperforation, cardiac anomalies, tracheoesophageal fistula, renal abnormalities, limb deformities) [55], and the Currarino triad (partial sacral agenesis, anorectal malformation, and presacral mass: teratoma and/or meningocele) (Fig. 39.61) [94–96]. Lipomyelomeningocele and terminal myelocystocele are associated in 20% of cases. There is a definite association with maternal diabetes mellitus (1% of offspring of diabetic mothers). It is believed that hyperglycemia occurring early during gestation could influence further development of the node and the tail bud in genetically predisposed embryos. Caudal agenesis in humans can be inherited as an autosomal dominant condition, and mutations in the HLXB9 gene, which codes for a homeotic transcription factor, has been shown to cause caudal agenesis in both familial and sporadic cases [12]. Overall, caudal agenesis is not uncommon, accounting for 16.3% of all CSDs [1]. Sacral agenesis occurs in approximately one per 7,500 births, without gender predisposition. The congenital spectrum of vertebral abnormality may range from agenesis of the coccyx to absence of the sacral, lumbar, and lower thoracic vertebrae, but the vast majority of these anomalies involve only the sacrum and coccyx. The sacrum may be totally or subtotally absent, with S1 through S4 present in individual cases. Sacral aplasia may sometimes be

Congenital Malformations of the Spine and Spinal Cord

Fig. 39.60. Sirenomelia. This fetus shows aplasia of the lower body with rudimentary single lower limb. (Reproduced from R.A.J. Nievelstein et al. MR imaging of anorectal malformations and associated anomalies. Eur Radiol 1998;8:573581, with permission)

asymmetric, with resulting total hemisacrum (all sacral elements present on one side, entire opposite side missing) or subtotal hemisacrum that may, in turn, be unilateral (all sacral segments present on one side, part of opposite side missing) or bilateral (part of each side is missing but to different extent) [97]. The heterogeneous spectrum of vertebral malformation requires anteroposterior and lateral X-ray films for full appreciation. These radiographic studies constitute an essential part of the neuroradiological workup. Helical CT with multiplanar reconstructions and 3D rendering may be useful to clarify difficult cases, especially those with complex sacral abnormalities such as subtotal uni- or bilateral hemisacrum. However, radioprotection issues must be carefully weighted when considering pelvic CT in young children. Traditionally, caudal agenesis has been categorized into two types depending on the location and shape of the conus medullaris: either high and abrupt (type I) or low and tethered (type II). Although these two types were believed to be embryologically related to disordered primary or secondary neurulation, respectively [98], both are actually consistent with an earlier abnormality of gastrulation. Segmental maldevelopment of the caudal notochord and axialparaxial mesoderm results in an abnormality that interferes with either secondary neurulation alone, or both primary and secondary neurulation, depending on the longitudinal extent of the original notochordal damage. Therefore, the crucial embryological

watershed between the two varieties is the interface between primary and secondary neurulation (i.e., the junction between the true notochord and the tail bud), corresponding to the caudal end of the future neural plate [1, 9]. This site has been the source of continuing debate among authors: although traditionally believed to lie at S1–2 [9], recent results suggest it to correspond to S3–5 [7]. Based on this theory, the degree of spinal cord aplasia correlates with the severity of the spinal malformation, with a greater degree of vertebral aplasia in type I than in type II [97]. However, caudal agenesis is a very heterogeneous entity in which individual cases may show peculiarities that jeopardize strict classification schemes. Generally, a correct categorization requires that a careful combined analysis of plain X-ray films, CT images (where available), and MR images is performed. Despite the inherent difficulties, we believe this categorization is useful because: (i) it correlates the malformation to a corresponding embryological derangement, and (ii) it explains the neurological picture, as patients with caudal agenesis type I typically have a fixed neurological deficit due to spinal cord dysplasia, whereas tethered cord syndrome (TCS) with neurological deterioration may occur in patients with caudal agenesis type II [96]. The two types will now be analyzed in greater detail. Caudal Agenesis Type I (Figs. 39.61–65). If not only the tail bud, but also part of the true notochord fails to develop, interference is generated with both the processes of primary and secondary neurulation. The node is depleted earlier, and downward migration of the primitive streak terminates more cranially than normal. Depending on the severity of the original damage, the eventual degree of vertebral aplasia will range from absence of the coccyx and lower midsacrum to aplasia of all coccygeal, sacral, lumbar, and lower thoracic vertebrae. However, the last vertebra is L5 through S2 in the majority of patients. Owing to the same embryologic mechanism, there is aplasia of the caudal metameres of the spinal cord. This results in an abrupt (without the normal taper) spinal cord terminus that nearly always is club or wedge shaped (extending lower dorsally than ventrally) (Fig. 39.61) [6, 97–99]. The spinal cord terminus is high-lying (most often opposite T12) in most cases (Fig. 39.62), but it may lie opposite to L1 in a minority of cases (Fig. 39.63). Generally, the more cephalad the cord terminus, the more severe the spinal malformation with a greater number of absent vertebrae (Fig. 39.64). However, a strict metameric correspondence between the level of the cord terminus and the last vertebra may not be consistently present.

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a

a

b

Fig. 39.62a, b. Caudal agenesis, type I. 5-year-old boy. a Sagittal T1-weighted and b sagittal T2-weighted images show partial sacrococcygeal agenesis, with S2 as the last vertebra. The cord terminus is wedge-shaped and lies opposite T12. Note “double bundle” arrangement of the nerve roots of the cauda equina (thin arrows, b). The dural sac tapers abruptly at L4–5 and ends at S1, an unusually high level (thick arrow, a)

b

c

Fig. 39.61a–c. Caudal agenesis, type I. 4-month-old boy with Currarino triad. a Photograph of the patient shows absence of the anal orifice. The child has anorectal atresia. b Sagittal T1weighted image shows complete sacrococcygeal agenesis; the last vertebra is L5, as confirmed by X-ray films (not shown). There is abrupt, slightly wedge-shaped termination of the spinal cord opposite T11–12 (white arrowhead). Note “double bundle shape” of the nerve roots of the cauda equina (thin white arrows). Associated caudal anomalies include anterior meningocele (asterisk) and histologically proven hamartoma (thick black arrow). c Coronal T1-weighted image shows rounded, “cigar” shape of the abrupt cord terminus

The cauda equina also is frequently abnormal, and the nerve roots have an abnormal course that has been termed the “double bundle shape,” i.e., a separation of the anterior and posterior spinal roots (Figs. 39.61–63) [97]. The caudal dural sac tapers below the cord terminus, and ends at an unusually

high level (Figs. 39.62, 63). Associated caudal anomalies, such as anterior meningoceles and teratomas, may be found (Fig. 39.61), although much less frequently than in type II. Unlike in type II, the cord is not tethered to these caudal anomalies. This accounts for the negligible proportion of TCS with progressive neurological deterioration in these patients, contrary to patients with caudal agenesis type II. Generally, these patients have a stable neurological defect due to their “fixed” spinal cord dysplasia [97], and their motor deficit tends to parallel the extent of the bony abnormality. Conversely, sensory findings are much less predictable from the radiographic appearance. Moreover, the determination of sensory impairment may be problematic in young children [98]. In exceptional cases, a normally positioned, blunt conus is found in patients with isolated coccygeal agenesis (Fig. 39.65). In these “transitional” cases,

Congenital Malformations of the Spine and Spinal Cord

Fig. 39.65. Caudal agenesis, transitional type I/II. 2-yearold girl. Sagittal T1-weighted image shows that most of the sacrum is present. X-ray films (not shown) displayed isolated coccygeal agenesis. However, there is a blunt cord terminus opposite the upper L1 endplate (arrow). The apparent mismatch between a type II vertebral anomaly and a type I cord terminus is explained by an abnormality of the tail bud with complete absence of the process of secondary neurulation. This results in isolated absence of the sacrococcygeal metameres of the spinal cord

Fig. 39.63. Caudal agenesis, type I. 8-year-old boy. Sagittal T1weighted image shows subtotal sacrococcygeal agenesis, with a rudiment of S1 as the last visible vertebra, articulating with medialized ileum (I). The cord terminus is blunt and lies opposite the lower half of L1 (arrow), a somewhat atypically “low” position for a type I. There is terminal hydromyelia and “double bundle” arrangement of the nerve roots of the cauda equina. The dural sac tapers progressively and ends abnormally high (arrowheads)

a

b

c

d

Fig. 39.64a–d. Caudal agenesis, type I: lumbar/thoracolumbar agenesis. a, b Lumbar agenesis, 8-year-old girl. a X-ray film, anteroposterior view shows agenesis of the lumbar and sacrococcygeal spine with ilioiliac approximation and reduced pelvic diameters. Only a rudiment of T12 articulating with an abnormal pair of ribs (arrowheads) is visible. b Sagittal T1-weighted image shows the spinal cord terminates abruptly opposite T9 (open arrow). c, d Thoracolumbar agenesis, 20-day-old boy. c X-ray film, anteroposterior view shows agenesis of the sacrococcygeal, lumbar, and lower thoracic spine. Only ten pairs of ribs are visible. d Sagittal T1-weighted image shows the spinal cord terminates at midthoracic level, which is several metameres above the last visible vertebral body

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1600 P. Tortori-Donati, A. Rossi, R. Biancheri, and A. Cama the vertebral abnormality resembles that of type II, and the shape of the spinal cord that of type I. These cases probably represent pure forms of interference with secondary neurulation, resulting in aplastic coccygeal spinal cord metameres. Therefore, they could probably be equally well categorized within the type II, due to the common embryologic origin.

Caudal Agenesis Type II (Figs. 39.66–68). If the whole or a part of the tail bud fails to develop but the true notochord is unaffected, primary neurulation occurs normally, but there is interference with the process of secondary neurulation. There is a minor degree of vertebral dysgenesis compared to type I, with up to S4 present as the last vertebra. As a con-

d

a

b

c

Fig. 39.66a–d. Caudal agenesis, type II. Cord tethering to lipomas. a 3-month-old boy. Sagittal T1-weighted image shows the spinal cord is low and tethered (arrow) to an intradural lipoma (L). The vertebral anomaly is less severe than in type I. S3 is present in this case. b 1-year-old girl. Sagittal T1-weighted image shows the spinal cord is low and tethered to a filar lipoma (open arrows). Rudimentary S4 is present. c, d 7-year-old boy. Sagittal T1-weighted image (c) shows the spinal cord is tethered to a caudal lipoma, which contains cerebrospinal fluid-filled loculations (arrows). Notice overgrowing posterior fatty tissue, which may produce a pseudo-mass in the low-back; this must be clinically differentiated from closed spinal dysraphisms with mass. Coronal T1-weighted image (d) shows subtotal bilateral hemisacrum (arrowheads); a rudiment of S3 is present to the right, confirming the type II attribution

a

b

Fig. 39.67a, b. Caudal agenesis, type II. Cord tethering to anterior meningocele. 32-year-old woman. a Sagittal T1-weighted and b sagittal T2-weighted images show the thecal sac largely communicates with a huge cerebrospinal fluid-filled, presacral mass. This anterior meningocele became clinically manifest with constipation and low-back pain at an adult age. The cord (arrowheads, a) is tethered to the neck of the meningocele

Congenital Malformations of the Spine and Spinal Cord

studies performed in these patients may be difficult to interpret, especially when looking for small teratomatous masses along the walls of anterior meningoceles, in the presacral space, or deep within the pelvic cavity. In these cases, presaturation slabs must not be placed anterior to the spinal column in order not to miss presacral malformed components.

Segmental Spinal Dysgenesis

b

a Fig. 39.68a, b. Caudal agenesis, type II. Cord tethering to caudal tumors. a 1-month-old boy. Contrast enhanced sagittal T1weighted image shows isolated coccygeal agenesis and enhancing tissue (arrows) surrounding a low spinal cord. Histological diagnosis: teratoma. b 4-year-old girl. Sagittal T1-weighted image shows huge pelvic mass that invades the spinal canal and displaces the epidural fat (arrow). The spinal cord is tethered to the mass and shows terminal hydromyelia (open arrow). There is subtotal sacrococcygeal agenesis with concurrent lumbar vertebral segmentation defects. Histological diagnosis: embryonal carcinoma

sequence, only the most caudal portion of the conus medullaris (corresponding to the metameres formed by secondary neurulation) is absent. Partial agenesis of the conus is difficult to recognize, because the conus itself is stretched caudally and tethered to a tight filum, lipoma (Fig. 39.66), terminal myelocystocele, or lipomyelomeningocele. In some cases, the cord tapers progressively to tether to the neck of an anterior sacral meningocele (Fig. 39.67). In such cases, the anomaly may be discovered in later childhood or adolescence, when the patient develops constipation, urinary incontinence, dysmenorrhea, dyspareunia, or back pain. Teratomas or other caudal tumors (Fig. 39.68) can be found in a minority of patients. Low-back masses must be differentiated from overgrowing fatty tissue that is sometimes present at the level of the buttocks in these patients. More often than in type I, imaging

The clinical-radiological definition of segmental spinal dysgenesis (SSD) includes (i) segmental agenesis or dysgenesis of the lumbar or thoracolumbar spine; (ii) segmental abnormality of the underlying spinal cord and nerve roots; (iii) congenital paraplegia or paraparesis; and (iv) congenital lower limb deformities [90]. Segmental vertebral anomalies may involve the thoracolumbar, lumbar, or lumbosacral spine. As previously stated, although SSD is an autonomous entity that shows peculiar clinical and neuroradiological features, SSD and caudal agenesis probably represent two faces of a single spectrum of segmental malformations of the spine and spinal cord. The main difference is the location of the causal notochordal derangement along the longitudinal embryonic axis [90]. As is the case with caudal agenesis, the embryogenesis of SSD may be related to genetically induced notochordal derangement during gastrulation that, in turn, results in depauperation of the corresponding prospective neuroectoderm [90]. However, if one considers that the caudal agenesis is far more common than SSD [1], it becomes clear that the caudal extremity of the embryo must be far more susceptible to damage during early embryonic development than are intermediate segments. In SSD, the neuroradiological picture depends on the severity of the malformation and its segmental level along the longitudinal embryonic axis. The severity of the morphological derangement correlates with residual spinal cord function and the severity of the clinical deficit [90]. SSD is not a unique malformation, but rather a continuous spectrum of abnormalities. However, two distinct subsets may be identified based on a combined evaluation of the abnormality of the spinal cord and adjacent spine [90]. In both varieties, other forms of CSD (such as dermal sinuses), renal, and cardiac abnormalities, may be associated. Type I SSD. In the most severe cases, the spinal cord at the level of the abnormality is thoroughly absent, and the bony spine is focally aplastic due to the absence of one or more vertebrae. As a result, the spine and spinal cord are “cut in two” (Figs. 39.69, 70), i.e., there are two

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1602 P. Tortori-Donati, A. Rossi, R. Biancheri, and A. Cama a

c

b

Fig. 39.69a–c. Type I segmental spinal dysgenesis, 8-month-old boy. a Photograph of the patient shows low-back gibbus (arrow) and hypotrophic lower limbs with equinocavovarus feet. b Lateral X-ray film shows acute angle kyphosis with complete disconnection of the two spinal segments. c Sagittal T2-weighted image shows an acute thoracolumbar kyphosis with complete interruption of the spinal column and lower thoracic vertebral segmentation defect. There are two completely separated spinal cord segments; the upper ends several vertebral levels above the gibbus (arrowhead) and shows central high signal, whereas the lower is bulky and low (thick arrow). Note extreme narrowing of spinal canal at the gibbus apex (thin arrow). (a, c Reproduced from P. Tortori-Donati et al. [89], with permission from the American Society of Neuroradiology)

a

b

c

Fig. 39.70a–c. Type I segmental spinal dysgenesis, 7-year-old girl. a Anteroposterior X-ray film shows the spine is “cut in two,” i.e., segmental agenesis of several vertebrae produces complete disconnection of the upper and lower segments of the spine. Congenital scoliosis results. Kyphosis was shown by laterolateral X-rays (not shown). b, c Sagittal T2-weighted images show an acute thoracolumbar kyphosis with complete interruption of the spinal column. There are two completely separated spinal cord segments; the upper ends several vertebral levels above the gibbus (arrowhead, b), whereas the lower is bulky and low (thick arrow, c). Note concurrent horseshoe kidney (K) lodged in the concavity of the spine, a typical arrangement in these patients

Congenital Malformations of the Spine and Spinal Cord

disconnected upper and lower spinal segments, each containing a spinal cord segment, which are reciprocally displaced so that acute angle kyphosis results and a bony spur is palpable along the child’s back. Between the two spinal segments, the spinal canal is extremely narrowed or even totally interrupted, and only surgical exploration may determine if a hypoplastic fibroneural stalk, remnant of the spinal cord, is present; sometimes only fibroconnectival tissue is found. The lower spinal cord segment is invariably bulky and low-lying [90]. In the majority of cases, there is concurrent agenesis of the lower sacrum and coccyx; in other words, most patients with type I SSDs also have caudal agenesis. This is probably due to a double-level segmental notochordal abnormality. A horseshoe kidney is typically lodged in the concavity of the kyphosis (Fig. 39.70). Newborns with type I SSD are paraplegic at birth and invariably show hypotrophic and deformed lower limbs with equinocavovarus feet. Type II SSD. In less severe cases, there is focal hypoplasia of the spinal cord, which will therefore appear narrower than normal on MRI studies (Fig. 39.71) [90]. There is no complete disconnection of either the spinal cord or the spine, although bony stenosis of the spinal canal and minor vertebral abnormalities, such as butterfly vertebrae or segmentation defects, are present in the pathological segment. Concurrent partial sacrococcygeal agenesis is present only in a minority of cases, unlike with type I SSD. This minor form of SSD corresponds to a clinical picture that is relatively milder, with some degree of preserved motor function in the lower limbs.

39.7 Hydromyelia and Syringomyelia The term “syrinx” refers generically to a fluid collection in the spinal cord. Syringomyelia refers to a cavity in the spinal cord extending lateral to or independent of the central canal, whereas hydromyelia refers to a dilated central canal of the cord. Because most cavities involve both the parenchyma and the central canal simultaneously, and true hydromyelia may be practically impossible to differentiate from syringomyelia, the term hydrosyringomyelia is often used. However, syringomyelia is very rare in the pediatric population. Hydrobulbia refers to involvement of the medulla oblongata by the cavity. Hydromyelia may be associated with tonsillar ectopia (Chiari I malformation) (Fig. 39.72), hydro-

a b Fig. 39.71a, b. Type II segmental spinal dysgenesis: two different cases. a 1-month-old boy with congenital paraparesis. Coronal T1-weighted image shows thoracolumbar scoliosis due to right L1 hemivertebra (arrowhead). The spinal cord shows high tapering at T11–12 followed by a hypoplastic segment (open arrow). The conus medullaris lies at L3–4 (thick arrow). b 8year-old boy with congenital paraparesis. Sagittal T1-weighted image shows indeterminate vertebrae at the upper lumbar level resulting in congenital kyphosis without complete disconnection of the spine. The spinal cord at the dysgenesis level is thin (arrowheads). The conus medullaris is bulky and low (arrows)

cephalus, trauma, spinal cord tethering, or neoplasm. It is idiopathic (“isolated hydromyelia”) in 15% of cases (Fig. 39.73) [100]. There still is no ultimately proven mechanism accounting for the formation of hydromyelia, although it may be surmised that several mechanisms probably play a role in the different conditions. A mechanical theory [101] proposes that the foramen magnum becomes blocked at the base of the brain; as a consequence, pressure builds within these cavities and a passage into the central canal of the spinal cord is reopened. Others [102] have invoked mechanisms where fluid is forced into the spinal cord from the surrounding subarachnoid spaces in response to a pressure gradient through microscopic pathways existing in the spinal cord. Recently, Greitz et al. [103] produced an explanation based on two general principles. First, spinal cord cysts are caused by and formed by mechanical distension of the cord. Second, the cysts are filled by extracellular fluid from the microcirculation of the cord, not by CSF.

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a

b

Fig. 39.72a, b. Holocord hydromyelia in Chiari I malformation, 13-year-old girl. a Sagittal T1-weighted image of the brain shows ectopic cerebellar tonsils in the foramen magnum (arrow). b Sagittal T1-weighted image of the spine shows hydromyelia that involves the whole thoracic spinal cord and conus medullaris, and causes enlargement of the spinal cord. Multiple haustrations are a typical finding with Chiari Iassociated hydromyelia. The cavity extended cranially to C4 (not shown)

According to Milhorat et al. [104], hydrosyringomyelia may be classified into three major pathologic types: • Communicating hydromyelia: there is communication of the central canal syrinx with the fourth ventricle; it occurs in association with hydrocephalus; • Noncommunicating hydromyelia: the central canal syrinx is separated from the fourth ventricle by a variably elongated segment of syrinx-free spinal cord; it occurs with a wide variety of congenital and acquired disorders (Chiari malformations, arachnoiditis, extramedullary compressive lesions);

a

b

Fig. 39.73a, b. Isolated hydromyelia, 2-year-old boy. a Sagittal T1-weighted and b sagittal T2-weighted images show hydromyelia at the T4–10 level, causing slight enlargement of the spinal cord. There is no Chiari I malformation, and the conus medullaris lies opposite L1

• Syringomyelia: parenchymal (extracanalicular) syringes that are found in the watershed area of the spinal cord in association with conditions that directly injure the cord (trauma, infarction, hemorrhage). As the fluid accumulates within the cavity, it compresses the surrounding spinal cord with development of symptoms. The clinical presentation is variable depending on the location and extent of the syrinx. Syringomyelia is invariably symptomatic, whereas true hydromyelia may be clinically silent or produce fluctuating, aspecific signs. The classical picture is segmental weakness and atrophy of the hands and arms with loss of reflexes and segmental anesthesia or numbness, stiffness, pain, scoliosis, and incontinence. However, symptoms may also be provoked by the underlying cause of the syrinx. For instance, a syrinx may be caused by a Chiari malformation (Fig. 39.74) and the symptoms may be headaches or neck pain, even though the syrinx may be lower in the spinal cord. Examination of the entire spinal cord with sagittal images is mandatory in the presence of hydromyelia.

Congenital Malformations of the Spine and Spinal Cord

a

a

Fig. 39.74a,b. Concurrent hydromyelia and syringomyelia in Chiari I malformation, 7-yearold boy. a Sagittal T1-weighted and b coronal T1-weighted images show Chiari I malformation with near-holocord hydromyelia (i). Concurrent, eccentric syringomyelia (s) is visible on the coronal section. T: cerebellar tonsils

b

b

Both T1- and T2-weighted images should be obtained. Hydromyelia may be localized or diffuse (“holocord” hydromyelia) (Fig. 39.72). Metameric haustrations are typical of Chiari-associated hydromyelia. On T2-weighted images, areas of flow-void within large cavities result from CSF pulsations [105]. Axial T2weighted images should be obtained if hydromyelia is suspected, but not unequivocally demonstrated on sagittal projections. This is especially useful in case of minimal dilation of the central ependymal canal, which is usually thoroughly asymptomatic and is discovered incidentally (Fig. 39.75). In case of posttraumatic syringomyelia, increased signal of the spinal cord adjacent to the cyst in proton-density and T2-weighted images has been traditionally related to gliosis due to parenchymal

Fig. 39.75a, b. Dilated central ependymal canal, asymptomatic 12-year-old girl. a Sagittal T2-weighted image shows hyperintense sling within the spinal cord (arrows), extending as far as the conus apex. b Axial T2-weighted image confirms minimal dilation of the central ependymal canal (arrow). The spinal cord is not enlarged

damage [105]. However, recent evidence suggests that it may sometimes represent an ancillary sign of disease advancement [106]. T2 prolongation and spinal cord enlargement may also be found in cases of nontraumatic obstruction of CSF pathways. These signs are believed to represent a “presyrinx” state that is potentially reversible after restoration of CSF pathways patency [107]. A potential application of this sign is in asymptomatic children with Chiari I malformation, in whom recognition of a presyrinx state may dictate surgical decompression of the foramen magnum before true hydromyelia develops. It should be remembered that failure to examine the entire spinal neuraxis may result in missing cavities that are separated from the primary or larger cavity by a syrinx-free spinal cord segment. Obvi-

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1606 P. Tortori-Donati, A. Rossi, R. Biancheri, and A. Cama ously, the craniocervical junction must always be examined in order to detect a Chiari I malformation. A simple (primary) syrinx must also be differentiated from a tumor cystic component. Benign syringes have smooth internal margins, thinned adjacent parenchyma, inner fluid isointense to CSF, and do not enhance with gadolinium administration.

Acknowledgements

The authors are indebted to Dr. Martin Catala (Faculté de Médecine Pitié-Salpêtrière, Paris, France) for revising this manuscript and providing insight into the more recent embryological theories.

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52. McLone DG, Naidich TP. Terminal myelocystocele. Neurosurgery 1985; 16:36–43. 53. Peacock WJ, Murovic JA. Magnetic resonance imaging in myelocystoceles. Report of two cases. J Neurosurg 1989; 70:804–807. 54. Carey JC, Greenbaum B, Hall BD. The OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects). Birth Defects Orig Artic Ser 1978; 14:253–263. 55. Smith NM, Chambers HM, Furness ME, Haan EA. The OEIS complex omphalocele-exstrophy-imperforate anus-spinal defects: recurrence in sibs. J Med Genet 1992; 29:730–732. 56. Nishino A, Shirane R, So K, Arai H, Suzuki H, Sakurai Y. Cervical myelocystocele with Chiari II malformation: magnetic resonance imaging and surgical treatment. Surg Neurol 1998; 49:269–273. 57. Altman NR, Altman DH. MR imaging of spinal dysraphism. AJNR Am J Neuroradiol 1987; 8:533–538. 58. Hendrick EB, Hoffman HJ, Humphreys RP. The tethered spinal cord. Clin Neurosurg 1983; 30:457–463. 59. Hansasuta A, Tubbs RS, Oakes WJ. Filum terminale fusion and dural sac termination: study in 27 cadavers. Pediatr Neurosurg 1999; 30:176–179. 60. Brown E, Matthes JC, Bazan C 3rd, Jinkins JR. Prevalence of incidental intraspinal lipoma of the lumbosacral spine as determined by MRI. Spine 1994; 19:833–836. 61. Uchino A, Mori T, Ohno M. Thickened fatty filum terminale: MR imaging. Neuroradiology 1991; 33:331–333. 62. Yundt KD, Park TS, Kaufman BA. Normal diameter of filum terminale in children: in vivo measurement. Pediatr Neurosurg 1997; 27:257–259. 63. Scotti G, Harwood-Nash DC. Congenital thoracic dermal sinus: diagnosis by computer assisted metrizamide myelography. J Comput Assist Tomogr 1980; 4:675–677. 64. Barkovich AJ, Edwards MSB, Cogen PH. MR evaluation of spinal dermal sinus tracts in children. AJNR Am J Neuroradiol 1991; 12:123–129. 65. Weprin BE, Oakes WJ. Coccygeal pits. Pediatrics 2000; 105: E69. 66. Elton S, Oakes WJ. Dermal sinus tracts of the spine. Neurosurg Focus [serial online]. January 2001; 10:Article 4. Available at: http://www.neurosurgery.org/focus/jan01/101-4.pdf. Accessed November 20, 2001. 67. Kernohan JW. The ventriculus terminalis: its growth and development. J Comp Neurol 1924; 38:10–125. 68. Coleman LT, Zimmerman RA, Rorke LB. Ventriculus terminalis of the conus medullaris: MR findings in children. AJNR Am J Neuroradiol 1995; 16:1421–1426. 69. Sigal R, Denys A, Halimi P, Shapeero L, Doyon D, Boudghène F. Ventriculus terminalis of the conus medullaris: MR imaging in four patients with congenital dilatation. AJNR Am J Neuroradiol 1991; 12:733–737. 70. Pang D. Ventral tethering in split cord malformation. Neurosurg Focus [serial online]. January 2001; 10:Article 6. Available at: http://www.neurosurgery.org/focus/jan01/101-6.pdf. Accessed November 20, 2001. 71. Prop N, Frensdorf EL. A postvertebral endodermal cyst associated with axial deformities: a case showing the “endodermal-ectodermal adhesion syndrome.” Pediatrics 1967; 39:555–562. 72. Faris JC, Crowe JE. The split notochord syndrome. J Pediatr Surg 1975; 10:467–472. 73. Hoffman CH, Dietrich RB, Pais MJ, Demos DS, Pribham HFW. The split notochord syndrome with dorsal enteric fistula. AJNR Am J Neuroradiol 1993; 14:622–627.

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90. Tortori-Donati P, Fondelli MP, Rossi A, Raybaud CA, Cama A, Capra V. Segmental spinal dysgenesis. Neuroradiologic findings with clinical and embryologic correlation. AJNR Am J Neuroradiol 1999; 20:445–456. 91. Duhamel B. From the mermaid to anal imperforation: the syndrome of caudal regression. Arch Dis Child 1961; 36:152–155. 92. Valenzano M, Paoletti R, Rossi A, Farinini D, Garlaschi G, Fulcheri E. Sirenomelia. Pathological features, antenatal ultrasonographic clues, and a review of current embryogenic theories. Hum Reprod Update 1999; 5:82–86. 93. Raffel C, Litofsky S, McComb JG. Central nervous system malformations and the VATER association. Pediatr Neurosurg 1990-91; 16:170–173. 94. Currarino G, Coln D, Votteler T. Triad of anorectal, sacral, and presacral anomalies. AJR Am J Roentgenol 1981; 137:395–398. 95. Dias MS, Azizkhan RG. A novel embryogenetic mechanism for Currarino’s triad: inadequate dorsoventral separation of the caudal eminence from hindgut endoderm. Pediatr Neurosurg 1998; 28:223–229. 96. Gudinchet F, Maeder P, Laurent T, Meyrat B, Schnyder P. Magnetic resonance detection of myelodysplasia in children with Currarino triad. Pediatr Radiol 1997; 27:903–907. 97. Pang D. Sacral agenesis and caudal spinal cord malformations. Neurosurgery 1993; 32:755–779. 98. Nievelstein RAJ, Valk J, Smit LME, Vermeji-Keers C. MR of the caudal regression syndrome: embryologic implications. AJNR Am J Neuroradiol 1994; 15:1021–1029. 99. Barkovich AJ, Raghavan N, Chuang SH. MR of lumbosacral agenesis. AJNR Am J Neuroradiol 1989; 10:1223–1231. 100. Sherman JL, Barkovich AJ, Citrin CM. The MR appearance of syringomyelia: new observations. AJNR Am J Neuroradiol 1986; 7:985–995. 101. Williams B. The distending force in the production of “communicating syringomyelia.” Lancet 1969; 2:189–193. 102. Aubin ML, Vignaud J, Jardin Bar D. Computed tomography in 75 clinical cases of syringomyelia. AJNR Am J Neuroradiol 1981; 2:199–204. 103. Greitz D, Ericson K, Flodmark O. Pathogenesis and mechanisms of spinal cord cysts: a new hypothesis based on magnetic resonance studies of cerebro spinal fluid dynamics. Int J Neuroradiol 1999; 5:61–78. 104. Milhorat TH, Capocelli AL, Anzil AP, Kotzen RM, Milhorat RH. Pathological basis of spinal cord cavitation in syringomyelia: analysis of 105 autopsy cases. J Neurosurg 1995; 82:802–812. 105. Da Costa Machado MA, Matos de Souza PE, De Sousa Matos H, Barbosa VA, Bastos CA, Vieira LC. Syringomyelia. Imaging findings and review of the pathogenesis in 28 cases. Int J Neuroradiol 1999; 5:285–291. 106. Jinkins JR, Reddy S, Leite CC, Bazan C 3rd, Xiong L. MR of parenchymal spinal cord signal change as a sign of active advancement in clinically progressive posttraumatic syringomyelia. AJNR Am J Neuroradiol 1998; 19:177–182. 107. Fischbein NJ, Dillon WP, Cobbs C, Weinstein PR. The “presyrinx state”: a reversible myelopathic condition that may precede syringomyelia. AJNR Am J Neuroradiol 1999; 20:7–20.

Tumors of the Spine and Spinal Cord

40 Tumors of the Spine and Spinal Cord Paolo Tortori-Donati, Andrea Rossi, Roberta Biancheri, Maria Luisa Garrè, and Armando Cama

CONTENTS 40.4.4.1 40.4.4.2 40.4.4.3 40.4.4.4 40.4.4.5 40.4.5 40.4.5.1 40.4.5.2 40.4.5.3

40.1

Introduction

40.2

Intramedullary Tumors

40.2.1 40.2.1.1 40.2.2 40.2.2.1 40.2.3 40.2.3.1 40.2.4 40.2.4.1 40.2.5 40.2.5.1 40.2.6

Astrocytoma 1611 Imaging Findings 1612 Ganglioglioma 1613 Imaging Findings 1616 Ependymoma 1616 Imaging Findings 1617 Hemangioblastoma 1618 Imaging Findings 1618 Cavernous Hemangioma 1619 Imaging Findings 1619 Differential Diagnosis of Pediatric Intramedullary Tumors 1619

40.3

Intradural-Extramedullary Tumors

40.3.1 40.3.2 40.3.2.1 40.3.3 40.3.4 40.3.4.1 40.3.5 40.3.5.1 40.3.6 40.3.6.1 40.3.7

Leptomeningeal Metastases 1620 Myxopapillary Ependymoma 1621 Imaging Findings 1621 Nerve Sheath Tumors 1622 Meningioma 1623 Imaging Findings 1623 Atypical Teratoid Rhabdoid Tumor 1624 Imaging Findings 1624 Primitive Neuroectodermal Tumors 1624 Imaging Findings 1624 Dysontogenetic and Nonneoplastic Masses 1625

40.4

Extradural Tumors

40.4.1

Benign Bone Tumors and Tumor-Like Conditions 1628 Vertebral Hemangioma 1628 Osteoid Osteoma 1628 Osteoblastoma 1630 Osteochondroma 1631 Aneurysmal Bone Cysts 1632 Eosinophilic Granuloma 1635 Intermediate Bone Tumors 1636 Chordoma 1636 Sacrococcygeal Teratoma 1637 Malignant Bone Tumors 1638 Ewing’s Sarcoma 1638 Osteosarcoma 1638 Chondrosarcoma 1640 Lymphoma and Leukemia 1640 Vertebral Metastases 1640 Tumors of the Epidural Space 1642

40.4.1.1 40.4.1.2 40.4.1.3 40.4.1.4 40.4.1.5 40.4.1.6 40.4.2 40.4.2.1 40.4.2.2 40.4.3 40.4.3.1 40.4.3.2 40.4.3.3 40.4.3.4 40.4.3.5 40.4.4

1609 1611

1627

Extraosseous Sarcomas 1642 Chloroma 1642 Germ Cell Tumors 1643 Cellular Schwannoma 1643 Cavernous Hemangioma 1643 Extraspinal Tumors with Spinal Invasion 1644 Neuroblastoma 1644 Nerve Sheath Tumors 1647 Extramedullary Erythropoiesis 1647 References 1648

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40.1 Introduction Spinal and spinal cord tumors are much rarer than intracranial tumors in the pediatric age group; it is estimated that the ratio of spinal to intracranial tumor in the pediatric population is 1:10. Their classification is based on anatomic criteria into intramedullary, intradural-extramedullary, and extradural tumors (Fig. 40.1). In our experience, approximately 25% of primitive spinal tumors in the pediatric age group have been intramedullary, 12% intradural-extramedullary, and 63% extradural. Conventional X-rays often represent the initial examination, due to the aspecific clinical presentation. Intradural (both intra- and extramedullary) tumors may produce a host of radiologic signs, basically including enlargement of the spinal canal with widened interpeduncular distance and scalloping of the vertebral bodies and peduncles. Because these signs are the result of slow, relentless tumor growth, they usually become manifest late during the course of the disease. Extradural tumors may be revealed more promptly by X-rays when there is evident involvement of bone. Magnetic resonance imaging (MRI) is the imaging method of choice for the vast majority of these conditions, providing useful information concerning the extent, location, and internal structure of the mass

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a

d

b

e

c

f

that critically narrow the differential diagnosis and guide surgery [1]. Use of phase-array surface coils allows for evaluation of the entire spine in a single sequence on the sagittal plane, thereby allowing for significant reduction of imaging time. The MRI technique must include unenhanced sagittal T1- and T2weighted images, and contrast-enhanced T1-weighted images in all three planes of space. Axial T2-weighted images are also extremely useful to evaluate spinal cord compression from extrinsic tumors. In our experience, fast spin-echo techniques have been preferable over conventional spin-echo sequences both for T1and T2-weighted imaging. Gradient echo techniques are indicated to confirm the presence of blood degradation by-products.

Fig. 40.1a–f. Classification of spinal tumors according to location. a–c Schematics on coronal planes; d-f corresponding cases on coronal MR images. a, d Intramedullary tumor; b, e intradural-extramedullary tumor; c, f extradural tumor

Obviously, computerized tomography (CT) still plays an important role in the assessment of bone tumors, and is indicated to confirm the presence of calcifications. In our experience, we prefer spiral volumetric acquisitions in order to improve the quality of multiplanar reformatting. Catheter angiography has few indications. It may be indicated in the presurgical evaluation of neuroblastomas to identify the course of the great spinal artery of Adamkiewicz, which obviously cannot be sacrificed during surgery, other than to study vascular tumors such as hemangioblastomas and aneurysmal bone cysts. We have had no first-hand experience regarding the use of MR angiography in the evaluation of spinal tumors. As for advanced MR imaging modalities, such as MR

Tumors of the Spine and Spinal Cord

spectroscopy and diffusion-weighted imaging, there have not been extensive applications to spinal tumors in the scientific literature, and their role remains to be fully appreciated.

40.2 Intramedullary Tumors Intramedullary tumors account for 4%–10% of all primary neoplasms of the central nervous system (CNS) [1], and for 25% of intraspinal tumors in the pediatric age group. Although they may affect any age, they tend to prevail in children between 1 and 5 years of age. There is no gender prevalence. In our experience, astrocytomas have, by far, been the most common intramedullary tumor in the pediatric age group, accounting for 82% of cases, followed by gangliogliomas. Ependymomas, while frequent in adults, are distinctly uncommon in children; we have never encountered a case of ependymoma outside the setting of neurofibromatosis type 2 in patients under 14 years of age, and a search among other pediatric centers in Italy has yielded only one pediatric case studied with MRI. The presentation, duration, and course of the disease may be extremely variable. The clinical picture is often insidious. Most patients have a prolonged period of symptoms prior to establishment of a diagnosis. Symptoms may sometimes be elicited by trauma or efforts. Back pain generally represents the earliest and most persistent complaint. It may be localized or diffuse, acute or dull, continuous or intermittent, and frequently is nocturnal. One should remember that back pain is an extremely uncommon cause of complaint in the pediatric age group. Therefore, children with back pain should be referred to MRI to rule out intraspinal pathology. Unfortunately, it has been our experience that back pain tends to be frequently overlooked by both parents and physicians. This has often resulted in significant diagnostic delays and larger tumors at presentation. Other signs include rigidity and contracture of the paravertebral muscles, secondary to thecal sac enlargement, involvement of adjacent bone, and impairment of cerebrospinal fluid (CSF) dynamics. Progressive scoliosis may be the initial complaint, and may cause delays in the diagnosis if underestimated. Head tilt and torticollis are due to involvement of the spinal roots of the accessory (11th cranial) nerve, innervating the trapezius and sternocleidomastoid muscles; often, they represent early signs of cervico-medullary neoplasms. The latter may also cause other lower cranial nerve pal-

sies with dysphagia, dyspnea, and dysphonia. Motor disturbances generally occur later in the course of disease, whereas somatosensory deficits may be difficult to evaluate, especially in small children. Slowly growing tumors may present with long-lasting weakness and spinal or limb muscle atrophy [2, 3]. Finally, hydrocephalus with raised intracranial pressure may rarely represent the clinical presentation of intramedullary tumors. Causes of hydrocephalus may be represented by obstruction of the spinal subarachnoid spaces, CSF seeding, or increased CSF protein content [4]. The logical consequence is that children with unexplained tetraventricular hydrocephalus should undergo spinal MRI to rule out intradural neoplasia. Intramedullary neoplasms manifest as enlargement of the spinal cord showing heterogeneous signal intensity on MRI. Generally, cord expansion is already marked when the patient comes to medical attention, often with enlargement of the spinal canal and vertebral scalloping. The logical consequence is that absence of this feature should suggest a nonneoplastic condition, such as inflammation, as the most likely diagnosis [1]. Structurally, intramedullary tumors may be solid or associated with cysts. These cysts may be neoplastic or nonneoplastic. Neoplastic cysts are located within the tumor mass, and result from necrosis and degeneration within the neoplasm. They contain an admixture of protein, hemorrhage, and necrotic tumor, accounting for inhomogeneous signal intensity that is usually higher than that of CSF on both T1- and T2-weighted images. Neoplastic cysts typically show peripheral enhancement on gadolinium-enhanced sequences. Conversely, nonneoplastic cysts are located at the cranial and caudal poles of the tumor, and result from reactive dilatation of the central canal caused by either tumor fluid secretion or mechanical blockage of the ependymal canal. Their signal intensity closely resembles that of CSF, and their walls do not enhance. Differentiation of neoplastic from nonneoplastic cysts is crucial, because intratumoral cysts must be removed surgically, whereas reactive cysts can be drained and aspirated, but not resected [5]. Edema may be extensive, and may involve the spinal cord both cranial and caudad to the tumor. Discrimination of tumor from nonneoplastic areas such as polar cysts and edema is obviously crucial for correct surgical planning.

40.2.1 Astrocytoma Spinal cord astrocytomas account for 4% of all CNS tumors. In the pediatric age group, astrocytomas

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1612 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama account for the vast majority of intrinsic spinal cord neoplasms. Males are affected slightly more frequently than females are. Although they usually are isolated lesions, they also represent the most likely diagnosis in patients with neurofibromatosis type 1 harboring intramedullary neoplasms [6]. Pathologically, low-grade (i.e., pilocytic and fibrillary) astrocytomas account for the vast majority of cases in the pediatric age group, whereas anaplastic astrocytomas and glioblastomas are very rare [1, 7]. In our experience, pilocytic astrocytomas have accounted for 75% of all intramedullary tumors in the pediatric age group, while 7% have been fibrillary astrocytomas. A notable difference between the two neoplasms is patient age at presentation. Pilocytic astrocytomas typically affect children between 1 and 5 years, whereas fibrillary astrocytomas tend to occur in somewhat older children (i.e., around age 10 years). Histologically, these tumors do not differ from their intracranial counterparts (see Chap. 10). Pilomyxoid astrocytomas are a recently recognized subset of low-grade astrocytomas showing a more aggressive behavior and a worse prognosis than classical pilocytic astrocytomas [8]; they electively involve the spinal cord and hypothalamic-chiasmatic region, and typically display leptomeningeal seeding at presentation. 40.2.1.1 Imaging Findings Pilocytic Astrocytoma

MRI shows enlargement of the spinal cord, causing widening of the spinal canal with frequent scalloping and erosion of the adjacent bone. Surrounding edema may be variably severe; in some cases it involves the whole cord both cranial and caudal to the tumor. Edema corresponds to noncystic areas showing prolonged T2 signal and absence of enhancement on postcontrast T1-weighted images. Spinal cord astrocytomas frequently involve a large portion of the cord, and the tumor mass typically involves multiple vertebral levels in length. “Holocord” extensions, i.e., the lesion involving the whole length of the spinal cord, are believed to account for 60% of cases in the general population. In our experience, this figure must be much lower. We found that most “holocord” enlargements were actually caused by extensive spinal cord edema, rather than tumor, with the largest tumor examined in the post-MRI spanning 12 vertebral levels in length (Fig. 40.2). There usually is no cleavage plane between the tumor and the surrounding

unaffected tissue, which makes radical surgery difficult. These tumors originate and grow eccentrically into the cord with respect to the ependymal canal [1]. Although this represents a notable difference from ependymomas, this information is of little practical importance in diagnostic terms, as all these tumors typically already involve the whole cross-section of the spinal cord at presentation [9]. The cervico-medullary junction and the cervicothoracic cord are the most common locations of pilocytic astrocytomas. They may be structurally solid or show areas of necrotic-cystic degeneration, either within the solid core or marginally. Solid pilocytic astrocytomas tend to prevail in the cervical-high thoracic spine, whereas partly cystic ones do not show particular predilections for a given segment of the spinal cord. In our experience, about 40% of pilocytic astrocytomas are solid (Fig. 40.3), whereas 60% show a “cyst with mural nodule” appearance similar to that of pilocytic astrocytomas of the posterior fossa. Neoplastic cysts must be differentiated from extratumoral syringes, which may be located both cranial and caudad to the tumor and do not enhance. This differentiation is important, as nonneoplastic cysts are caused by tumor secretion or perturbed CSF dynamics and consistently are reabsorbed after surgical excision of the mass. Differentiation between the two varieties is based on their appearance after gadolinium administration, as only the walls of neoplastic cysts will enhance (Fig. 40.4). The solid tumor mass shows abnormal signal behavior on both T1-weighted and T2-weighted images. In general, solid components are iso- to hypointense on T1-weighted images and hyperintense on T2-weighted images. Necrotic-cystic components display higher relaxation times than solid portions both on T1- and T2-weighted images (Figs. 40.2–4). Some degree of contrast enhancement is present in the majority of, but not all, spinal cord pilocytic astrocytomas. The pattern of enhancement is highly variable and does not define tumor margins (Fig. 40.5). Leptomeningeal seeding is extremely uncommon at presentation. Leptomeningeal carcinomatosis is not invariably associated with higher grade, as it represents a typical feature of pilomyxoid astrocytomas [8] (Fig. 40.6). Fibrillary Astrocytoma

Fibrillary astrocytomas of the spinal cord are said to possibly show contrast enhancement [1]. This represents a notable difference from intracranial astrocytomas. Enhanced areas probably represent more active portions of the tumors [1]. However, all fibril-

Tumors of the Spine and Spinal Cord

a

b

c

d

Fig. 40.2a–d. “Holocord astrocytomas”: tumor versus edema in two cases. a, c Sagittal T2-weighted images; b, d. Gd-enhanced sagittal T1-weighted images. a, b 6-year-old boy with pilocytic astrocytoma. Most spinal cord enlargement is due to edema (asterisks, a, b). The actual tumor spans 5 vertebral levels in length (arrows, a, b). There is moderate spinal canal enlargement. c, d 3-year-old girl with pilocytic astrocytoma. This was the largest intramedullary tumor in our experience after MRI was introduced at our institution in 1988. Enlargement of the spinal canal is marked. The tumor spans 12 vertebral levels in length (arrows, c, d), while edema is surprisingly mild (asterisks, c, d). Even such a large tumor as this cannot be properly called holocord

Oligodendroglioma

Other exceedingly rare forms of gliomas (not properly astrocytomas) include oligodendrogliomas [10, 11], which may be low-grade or, exceptionally, anaplastic [12]. In a single case we observed, MRI features were aspecific and did not allow differentiation from pilocytic astrocytomas, the only relevant differential feature being age (Fig. 40.8).

40.2.2 Ganglioglioma

a

b

Fig. 40.3a,b. Solid pilocytic astrocytoma in a 18-month-old boy. a Sagittal T1-weighted image; b sagittal T2-weighted image. This cervical cord tumor has a solid structure, is slightly hypointense with normal cord on T1-weighted images (a) and hyperintense on T2-weighted images (b). Enhancement was mild and diffuse (see Fig. 40.5b)

lary astrocytomas we studied with MRI were solid, T1 isointense, T2 hyperintense tumors that did not enhance (Fig. 40.7). One case presented with apparently idiopathic scoliosis.

Gangliogliomas are the second most common intramedullary tumor in the pediatric age group, and have been reported to account for as many as 30% of spinal cord tumors in children under 3 years of age [13]. In our series, they have been 15% of all pediatric intramedullary tumors. Mean age at presentation is said to be 12 years in the general population [14], but in the pediatric age group they affect mostly children between 1 and 5 years, as is the case with pilocytic astrocytomas. The duration of symptoms before the diagnosis is made can be prolonged, and many patients present only with progressive, long-standing weakness [15] or distal muscle atrophy.

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Fig. 40.4a–d. Neoplastic versus nonneoplastic cysts in two patients with pilocytic astrocytoma (a, b 3-year-old boy and c, d 3year-old girl). a, c Sagittal T1-weighted images; b, d Gd-enhanced sagittal T1-weighted images. Notice that both cases look similar on unenhanced images (a, c). However, gadolinium administration disclosed enhancing (i.e., neoplastic) cyst walls in one case (arrowheads, b), and nonenhancing (i.e., nonneoplastic) cyst walls in the other (arrowheads, d)

a

b

c

Fig. 40.5a–c. Pattern of contrast enhancement in three cases of pilocytic astrocytoma. a–c Gd-enhanced sagittal T1-weighted images. a 12-month-old girl; absent enhancement. b 18-month-old boy; mild, diffuse enhancement; c 6-year-old boy; marked enhancement with central necrosis

Histologically, gangliogliomas are composed of a mixture of neoplastic mature neuronal elements (ganglion cells) and neoplastic glial cells, primarily astrocytes. Some authors have argued that, because the neuronal elements tend to be clustered and most biopsy samples are small, there probably is a tendency for underestimation of the real incidence of this tumor [14]. Inconsistencies with regard to the diagnostic criteria for immunohistochemical diagnosis may add to the confusion [14, 16]. Although gangliogliomas typically are low-grade tumors (grade I-II) with a low potential for malignant degeneration, they have

a significant propensity for local recurrence [17], and the glial element may progress to high grade. We have seen an operated ganglioglioma recur as glioblastoma multiforme. The favored location of intramedullary gangliogliomas is in the cervical and upper thoracic cord with extension to the medulla through the foramen magnum. Holocord involvement has been said to be more frequent with gangliogliomas than with other spinal cord tumors, probably as a result of low growth rate [13]. However, we have not had similar results. Just as astrocytomas, gangliogliomas originate eccentri-

Tumors of the Spine and Spinal Cord

b

Fig. 40.6a,b. Pilomyxoid astrocytoma in a 17-month-old boy. a Gd-enhanced sagittal T1-weighted image; b Gd-enhanced axial T1-weighted image. Enhancing intramedullary tumor at cervico-thoracic level (asterisks, a) is associated by leptomeningeal spread at presentation (arrows, a, b)

a

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Fig. 40.7a,b. Fibrillary astrocytoma in a 10-year-old boy. a Sagittal T2-weighted image; b Gd-enhanced sagittal T1-weighted image. Solid lesion of the lower thoracic cord showing homogeneous T2 hyperintensity (arrows, a) and lack of enhancement (arrows, b)

a

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Fig. 40.8a,b. Oligodendroglioma in a 9-year-old boy. a Sagittal T2-weighted image; b Gd-enhanced sagittal T1-weighted image. There is a solid tumor of the thoracic cord showing isointensity on T2-weighted image (white arrows, a) and essentially homogeneous enhancement (white arrows, b). There are large, nonenhancing, reactive cysts (asterisks, a, b) both cranial and caudal to the tumor mass, giving a false impression of a holocord tumor. Serpiginous enhancement posterior to the cord (arrowheads, b) is due to venous congestion

1615

1616 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama cally in the cord, although they will have involved the whole spinal cord cross-section at presentation in the vast majority of cases. Structurally, solid components are usually associated with neoplastic cysts, reactive (i.e., nonneoplastic) cysts, or both. Propensity for cyst formation has been reported to be a common characteristic of intracranial and intramedullary gangliogliomas [1]. Again, our experience has been different, with all tumors appearing predominately solid in our series. Structural bone changes such as scalloping and erosion are commonly found. Scoliosis is present in about 50% of cases [14]. 40.2.2.1 Imaging Findings

On neuroradiological examination, presence of calcification is probably the single most suggestive feature of gangliogliomas. The tumor mass can be extensively calcified, as shown by CT. Calcification also influences signal behavior on MRI (Fig. 40.9). In the absence of gross calcification, the MRI appearance of gangliogliomas is nonspecific, and probably does not allow differentiation from astrocytomas. Solid portions of gangliogliomas have been shown to have mixed iso-hypointensity on T1-weighted images, and heterogeneous iso-hyperintensity on T2-weighted images [14]. Perifocal edema is said to be limited or thoroughly absent [14], just as with intracranial gangliogliomas; however, we saw gangliogliomas associ-

a

b

ated with extensive spinal cord edema (Fig. 40.10). Tumor enhancement following gadolinium administration can be focal or patchy, whereas it rarely involves the whole tumor mass; thorough absence of enhancement has also been described, albeit in a minority of cases [15]. Gadolinium administration is also helpful to discriminate neoplastic cysts (whose walls enhance) from reactive cysts (whose walls do not enhance). Leptomeningeal dissemination of spinal cord gangliogliomas is a rare event. However, we saw an exceptional case of spinal cord desmoplastic infantile ganglioglioma, a low-grade tumor that usually involves the cerebral hemispheres of newborns (see Chap. 10) that was associated with leptomeningeal metastases at presentation (Fig. 40.11).

40.2.3 Ependymoma Spinal cord ependymomas are extremely rare in the pediatric age group outside the setting of neurofibromatosis type 2 (see Fig. 16.29, Chap. 16). They are slightly more frequent in males. Just like astrocytomas, ependymomas may extend over large portions of the cord, and may be holocord in some cases, although perhaps less frequently than astrocytomas. Their most common location is the cervical cord, followed by the thoracic cord [18]. They are biologically

c

Fig. 40.9a–c. Calcified ganglioglioma in a 7-year-old boy presenting with hypotrophy of the upper limbs that was noticed 2 years before this imaging. a Sagittal T1-weighted image; b sagittal T2-weighted image; c CT scan (sagittal reconstruction). Huge lesion involving the whole cervical spinal cord, showing extensive calcification (c). Abnormal T1 and T2 shortening is probably due to the paramagnetic effects of calcium-related ions. The lesion did not enhance following gadolinium (not shown). The spinal canal is enlarged

Tumors of the Spine and Spinal Cord

a

b

Fig. 40.10a,b. Ganglioglioma in a 2-year-old girl. a Sagittal T2weighted image; b Gd-enhanced sagittal T1-weighted image. A gross ovoid nodule, spanning three vertebral metameres, is evident within a globally enlarged spinal cord. The solid tumor (T) markedly enhances following gadolinium administration. Diffuse edema (E) causes marked expansion of the spinal cord and gives an impression of holocord extension

more aggressive than astrocytomas, and may produce CSF seeding. Histologically, several variants exist, among which the cellular type is the most common. Cellular ependymomas (grade I/II of the WHO classification) [19] are friable masses showing low columnar or cuboidal cells arranged into perivascular pseudorosettes. Owing to their origin from the ependyma lining the central canal, these tumors initially involve the central regions of the cord and subsequently grow to the periphery, displacing, rather than infiltrating, the surrounding tissue; therefore, a cleavage plane usually separates the tumor from the adjacent healthy tissue, facilitating surgical removal. Macroscopically, these tumors are red-brownish due to their marked vascularity, which accounts for frequent intralesional hemorrhages which constitute their hallmark also on neuroimaging. These hemorrhages are usually located at the cranial and caudal poles of the lesion, and may rarely account for an acute presentation with subarachnoid hemorrhage. Polar nonneoplastic cysts are more frequent than neoplastic cysts [1], whereas calcification is rare. 40.2.3.1 Imaging Findings

Signal behavior of solid portions on MRI is iso- or hypointense on T1-weighted images, and hyperintense on T2-weighted images. The vast majority of

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Fig. 40.11a–c. Desmoplastic infantile ganglioglioma with leptomeningeal seeding at presentation in a 12-month-old boy. a Sagittal T2-weighted image; b, c Gd-enhanced sagittal T1-weighted images. The tumor (T) is located at the cervico-medullary junction. Secondary localizations are evident in the hypothalamus, interpeduncular cistern, obex, inferior vermis, ventral surface of the medulla oblongata, pial spinal cord surface, and cauda equina (arrowheads, b, c)

1617

1618 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama these tumors enhance with gadolinium administration, either heterogeneously or uniformly [5, 18] (Fig. 40.12). Just as with other intrinsic spinal cord tumors, differentiation of neoplastic from reactive cysts is based on the presence or absence of circumferential enhancement, respectively. Unlike with posterior fossa ependymomas, calcification is exceptional [20]. The appearance of spinal cord ependymomas on MRI is not different from that of astrocytomas. The most significant difference is represented by hemorrhage, which is said to be typical of ependymomas, although it is present only in a minority (20%–33%) of cases [1, 20]. The cause of intratumoral bleeding is poorly understood, although it may be related to the highly vascular connectival stroma or the vulnerability of the tumor-cord interface [5]. These hemorrhagic areas produce the “cap sign,” a markedly hypointense rim surrounding the cranial and/or caudal poles of the lesion on T2-weighted images that results from magnetic susceptibility effects [20]. Use of gradient-echo sequences improves the detection of the cap sign. One should consider that the “cap sign,” albeit suggestive, is not pathognomonic of ependymomas (Fig. 40.13). In the absence of the cap sign, one should consider that astrocytomas are markedly more frequent than

a

b

Fig. 40.12a,b. Ependymoma of the conus medullaris in a 2-yearold boy. a Sagittal T2-weighted image; b Gd-enhanced sagittal T1-weighted image. There is an intrinsic lesion that markedly expands the conus medullaris. The lesion is hyperintense to cord on T2-weighted images (a) and enhances moderately (b). (Courtesy of Dr. Carla Carollo, Padua, Italy)

ependymomas in the pediatric age group. Therefore, ependymomas usually seem a rather unlikely diagnosis in the majority of cases.

40.2.4 Hemangioblastoma Hemangioblastomas are characterized by a highly vascular nodular mass abutting the leptomeninges, usually associated with cyst formation. These tumors may be sporadic or as a manifestation of von HippelLindau syndrome, in which case they commonly are multiple and associated with renal cysts or carcinomas (see Chap. 16). In either case, spinal cord hemangioblastomas are only exceptionally encountered in the pediatric age group. The majority of hemangioblastomas arise in the thoracic or cervical cord. Presenting signs are similar to those caused by other spinal cord tumors. 40.2.4.1 Imaging Findings

Spinal hemangioblastomas may display several distinct appearances [21]. The most common is diffuse cord

a

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Fig. 40.13a,b. The “cap sign.” a Sagittal FSE T2-weighted image; b sagittal gradient-echo T2*-weighted image. The solid component of this extensive cervico-thoracic lesion is surrounded by a hypointense rim that is barely visible on FSE T2-weighted images (arrow, a) and becomes prominent on gradient-echo images (arrows, b). Histological diagnosis was melanocytoma

Tumors of the Spine and Spinal Cord

expansion that basically results from extensive syringes, associated with a solid nodule that usually is small with respect to the syrinx, and may become apparent only after gadolinium administration due to its intense, homogeneous enhancement. The solid nodule usually is located near the surface of the cord. In most cases it is intramedullary with possible extension beyond the surface of the cord. In rarer instances, the nodule is exophytic or completely extramedullary [21]. On unenhanced studies, the solid nodule is iso- to hypointense on T1-weighted images and hyperintense on T2-weighted images [1, 21]. Prominent draining veins may be visible along the cord surface, raising the suspicion of a vascular malformation. In doubtful cases, catheter angiography will clear the view by demonstrating a highly vascular mass with prolonged blush. Screening MR imaging of the whole neuraxis is recommended to identify patients with von HippelLindau syndrome [21].

40.2.5 Cavernous Hemangioma

endothelial cells embedded in a collagenous matrix. Although the majority of spinal cavernous hemangiomas involve the vertebral body (see below), cavernous malformations may primitively involve the epidural space, the intradural extramedullary compartment, and the spinal cord [22]. Affected children characteristically present with an acute deficit and rapid deterioration, due to intralesional bleeding with ensuing hematomyelia, intradural hematoma, or extradural hematoma, depending on the primitive location of the lesion. 40.2.5.1 Imaging Findings

Just as in the brain, signal behavior on MRI depends on the state of degradation of hemoglobin by-products found within the lesion (Fig. 40.14). Gradient-echo imaging is especially useful to recognize hypointense components within the mass related to hemosiderin. Because cavernous hemangiomas are frequently multiple, gradient echo imaging of the whole neuraxis should be performed in order to identify additional lesions.

Cavernous hemangiomas are not tumors, but vascular malformations composed of vascular spaces lined by 40.2.6 Differential Diagnosis of Pediatric Intramedullary Tumors

a

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Fig. 40.14a,b. Intramedullary cavernous hemangioma in a 1-year-old girl. a Sagittal T1-weighted image; b sagittal T2weighted image. A hyperintense intramedullary nodule (arrow, a, b) is surrounded by a dark rim (arrowheads, a, b). Findings are consistent with recent bleeding surrounded by hemosiderin deposits and suggested cavernous hemangioma as the leading diagnosis, which was confirmed histologically. The surrounding spinal cord is edematous

Differentiation of astrocytomas from other intramedullary tumors is practically unfeasible on neuroimaging in most cases. The main differential criteria from ependymomas is the presence, in the latter, of a cap sign. However, this sign is present in only a minority of ependymomas and is not pathognomonic of these tumors. Extensive calcification and mixed signal intensity on unenhanced T1-weighted images could suggest ganglioglioma as a leading diagnosis. However, one should remember that astrocytomas are much more frequent than gangliogliomas or ependymomas in the pediatric age group. A number of statements has appeared in the literature concerning differentiation of gangliogliomas from astrocytomas. For instance, it has been stated that holocord extension is more typical of gangliogliomas [13, 14]. However, true holocord tumors seem to be very rare in the pediatric age group, whereby “holocord” enlargements are mostly caused by edema. Furthermore, one study found tumoral cysts to be more typical of gangliogliomas than astrocytomas [14]. This observation is counteracted by our experience, in which all gangliogliomas of the spinal cord have been solid tumors. It can be speculated that

1619

1620 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama some differences between our observations and those reported in the literature may be due to the fact that most studies have included both pediatric and adult cases [13, 14]. Differentiation from nonneoplastic lesions is of much greater relevance from a management standpoint. In general, most nonneoplastic conditions are not associated with significant cord enlargement, and entities such as multiple sclerosis and acute disseminated encephalomyelitis are typically associated with concurrent brain involvement. However, a few nonneoplastic conditions can present with cord enlargement, although usually not as marked as with tumor. These include acute transverse myelitis, which may produce slight cord enlargement with T2 hyperintensity and gadolinium enhancement, although it has a different clinical presentation (see Chap. 41). Optic neuromyelitis, or Devic disease, is a demyelinating disease characterized by the association of optic neuritis with enhancing lesions of the cervical spinal cord that may subsequently cavitate [23] (see Chaps. 15 and 41). Hydrosyringomyelia, either isolated or associated with Chiari I malformations or dysraphic states, is easily ruled out by the lack of contrast enhancement (see Chap. 39). Arteriovenous malformations typically display serpiginous flow-void representing the nidus (see Chap. 43). Although in all these disorders the spinal cord lesion may superficially resemble tumor, laboratory investigations, brain MRI, and follow-up will clear the view.

40.3 Intradural-Extramedullary Tumors Intradural-extramedullary tumors in the pediatric age group are mostly represented by leptomeningeal metastases from primary brain tumors. Primitive tumors in this location are the least common among spinal tumors in the pediatric age group. In our experience, the majority of these tumors have been seen in neurofibromatosis patients, and have been schwannomas and neurofibromas. We then have had an anecdotal experience with a host of other neoplasms, including filar ependymomas, meningiomas, and atypical teratoid rhabdoid tumors. Other entities in this location include dysontogenetic masses and other nonneoplastic mass lesions. Clinical features basically are represented by pain and signs of cord or nerve root compression, depending on the location of the mass. Leptomeningeal metastases are usually silent from a clinical standpoint.

40.3.1 Leptomeningeal Metastases Spinal leptomeningeal metastases are almost exclusively secondary to CNS tumors and result from seeding of CSF spaces. The most important primitive malignancies are primitive neuroectodermal tumors (PNETs) (including medulloblastomas), choroid plexus carcinomas, glioblastoma multiforme, and mixed gliomas. Cerebral ependymomas are unlikely to produce metastases at presentation, whereas spinal seeding is more common after surgery. Intramedullary tumors are generally low-grade, and therefore are unlikely to seed the CSF, although a subset of low-grade pilomyxoid astrocytomas and gangliogliomas does metastasize (Figs. 40.6, 11). Leptomeningeal involvement also occurs in hemolymphoproliferative disorders such as leukemias, either at presentation or as a relapse; in these cases, leptomeningeal involvement usually occurs from hematogenous spread or from contiguous infiltrated bone marrow. The presence of spinal leptomeningeal metastases is often associated to intracranial disease spread, and generally portends a poorer prognosis regardless of the nature of the primitive tumor, with a significant reduction of patient survival [24]. A notable exception is represented by pilomyxoid astrocytomas which, despite being low-grade tumors, typically present with leptomeningeal metastases that tend to remain stable for long periods in the follow-up. Identification of leptomeningeal metastases is crucial in that it modifies treatment planning, often determining whether chemotherapy and spinal irradiation must be contemplated. The clinical picture is variable and often aspecific, and may be completely silent in a significant amount of cases. Involvement of multiple spinal segments may result in complex sensorimotor disturbances. Unfortunately, the diagnosis of dissemination of primary tumor to the spine may not be straightforward [25]. Contrast-enhanced MRI and cytologic examination of the CSF are the gold standards in the identification of leptomeningeal metastases. Recent evidence suggests that the sensitivity of contrastenhanced MRI may be higher than that of CSF cytologic analysis [24]. Conversely, baseline MRI studies are often inconclusive. At our institution, spinal MRI is performed just after brain MRI in the evaluation of brain tumors both at presentation and in the followup, at the additional cost of approximately 6–7 min. Sagittal T1-weighted images are usually sufficient for diagnostic purposes. Axial T1-weighted images may be used for confirmation of doubtful findings. MRI features of leptomeningeal metastases are essentially

Tumors of the Spine and Spinal Cord

four, i.e., nodular metastases, neoplastic leptomeningitis, cystic dissemination, and sedimentation [26]. Nodular metastases and neoplastic leptomeningitis are usually found in patients with primitive CNS tumors, and are usually visible only after gadolinium administration. Nodular metastases are small, discrete, globular enhancing masses, whereas the term neoplastic leptomeningitis (or meningeal carcinomatosis) designates a diffuse enhancing coating of the spinal cord and nerve roots. Although enhanced sagittal T1-weighted images are usually sufficient to make the diagnosis, axial T1-weighted images confirm doubtful findings. At the level of the spinal cord, axial sections demonstrate a diffuse enhancement of the external surface of the cord (Fig. 40.6), whereas at the level of the thecal sac there will be enhancement of thickened nerve roots. Cystic dissemination is an unusual pattern of leptomeningeal spread of CNS tumors which may involve the basal cisterns, posterior fossa, and spine [27]. It is characterized by a dissemination of multiple cystlike lesions over the surface of the CNS with possible intraparenchymal involvement, usually associated with classical, enhancing leptomeningeal spread. Low-grade neoplasms of the spinal cord and brainstem have accounted for all cases of cystic dissemination reported so far [27]. Sedimentation is typical of hemolymphoproliferative disorders such as leukemia, lymphoma, and histiocytosis [28]. It results from accumulation of neoplastic cells into the caudal thecal sac due to diffuse infiltration and gravity phenomena; on MRI, sedimentation results in an abnormal intermediate signal intensity replacing the normal CSF signal intensity in the thecal sac in all sequences [28] (see Fig. 11.3, Chap. 11). Often, the whole thecal cul-de-sac is filled up to the conus medullaris. Surprisingly, patients with huge sedimentations are often asymptomatic, and the condition is discovered when MRI is performed after repeatedly unsuccessful attempts at lumbar tap [28]. Although the diagnosis is relatively straightforward, a few pitfalls must be considered. First, infectious leptomeningitis gives an MRI picture that is practically undistinguishable from that of neoplastic leptomeningitis [29]. The different clinical picture and knowledge of the primary tumor are usually sufficient to rule out infection. Because spinal MRI is usually obtained after injection of contrast material, some concern could arise in the differentiation from filar lipomas, which are spontaneously bright on T1-weighted images. The application of fat-saturated sequences will clear the view in doubtful cases. In the period immediately subsequent to surgical removal of the primary tumor, hyperintense blood

products within the spinal canal may mimic metastases [30]. A final, albeit very important, point to be made is physiologic enhancement of perimedullary veins, which often is visible as a thin, slightly irregular outlining of the anterior and posterior surfaces of the spinal cord on postcontrast sagittal T1-weighted images, especially at the level of the conus medullaris. Although this appearance may superficially resemble that of neoplastic leptomeningitis, axial T1-weighted images will clearly demonstrate that enhancement is in the expected anatomic location of perimedullary veins over the surface of the cord.

40.3.2 Myxopapillary Ependymoma Myxopapillary ependymomas account for 13% of all spinal ependymomas in the general population; however, they are relatively more frequent in the pediatric age group. Histologically, they are characterized by the presence of areas of mucoid degeneration into the mass. They are thought to arise from the ependymal glia of the filum terminale; therefore, they typically present as intradural extramedullary lesions involving the lumbar and sacral canal [31]. Very rarely, myxopapillary ependymomas involve the sacrococcygeal region, arising from vestiges at the distal portion of the neural tube [32]; in this unusual location, they enter differential diagnosis with chordomas. Affected patients present with lower back, leg, or sacral pain and weakness or sphincter dysfunction [1]. Propensity for hemorrhage accounts for occasional presentations with subarachnoid hemorrhage [5]. Their macroscopic appearance is that of a rounded or oval, smoothly marginated mass, located into the thecal sac at level of the cauda equina. They are histologically heterogeneous, showing an admixture of papillary and cellular areas with abundant mucin production. 40.3.2.1 Imaging Findings

On MRI, the lesion is iso- to hyperintense on T1weighted images and hyperintense on T2-weighted images, probably as a result of the proteinaceous nature of mucin. Contrast enhancement is moderate to marked and homogeneous (Fig. 40.15). The main differential diagnosis is with nerve sheath tumors, such as neurofibromas and schwannomas. However, the latter are extremely rare outside the setting of neurofibromatosis. Large masses may extend into the neural foramina, expand the spinal canal, and erode the adjacent vertebrae (Fig. 40.16) [31].

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1622 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama

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Fig. 40.15a–c. Myxopapillary ependymoma of the filum terminale in a 14-year-old boy. a Sagittal T1-weighted image; b sagittal T2-weighted image; c Gd-enhanced sagittal T1-weighted image. Intradural-extramedullary tumor at L1-2 level is T1 isointense (a), T2 hyperintense (b), and enhances moderately and homogeneously (c)

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40.3.3 Nerve Sheath Tumors Schwannoma

Schwannomas, or neurinomas, originate from Schwann cells in the sheaths of spinal root and nerves. As such, they grow extrinsically with respect to the axon. They are separated from the adjacent tissues by a thin capsule, which facilitates surgical removal. Isolated spinal schwannomas are rare in the pediatric population, whereas they are more frequent

Fig. 40.16a–c. Myxopapillary ependymoma of the filum terminale in a 9-year-old boy. a Sagittal T1-weighted image; b sagittal T2-weighted image; c Gd-enhanced sagittal T1-weighted image. Huge intradural lesion obliterating almost the whole lumbar dural sac and extending to the terminal portion of the spinal cord. The lesion is characterized by a caudal solid portion that causes vertebral scalloping and appears hypointense on T1-weighted images (arrows, a), isointense on T2-weighted images (arrows, b), and markedly enhances following gadolinium administration (arrows, c). A large, bilocular cranial cystic portion (asterisk, a–c) shows neoplastic walls. There is spinal cord edema (arrowhead, b)

in young adults with neurofibromatosis type 2 (see Chap. 16). Their location may be intradural, extradural, or both, depending on where they originate along the course of the spinal root or nerve; however, intradural tumors are more common. When they are located in the lumbar thecal sac, they may attain a considerable size before becoming clinically manifest, causing enlargement of the spinal canal, scalloping and bone erosion. Extradural tumors may expand the neural foramina with a “dumb-bell” development that is common with other extradural neoplasms, such as neurofibromas and neuroblastomas.

Tumors of the Spine and Spinal Cord

On MRI, schwannomas are said to be iso- to hypointense on T1-weighted images and iso- to hyperintense in T2-weighted images. Contrast enhancement is usually moderate to marked and homogeneous (Fig. 40.17). Neurofibroma

Neurofibromas are composed of an admixture of Schwann cells and fibroblast, and tend to infiltrate, rather than dislocate, the root or nerve from which they originate. Therefore, radical surgery is usually much more difficult to attain than with schwannomas. Neurofibromas are typically found in patients with neurofibromatosis type 1 (see Chap. 16). They may be solitary or multiple, and sometimes may resemble a string of beads when they affect multiple nerve roots in the thecal sac. Dumb-bell neurofibromas extend through, and cause enlargement of, the neural foramina. On MRI, their signal behavior is similar to that of schwannomas, with iso- to hypointensity on T1weighted images, hyperintensity on T2-weighted images, and marked contrast enhancement.

40.3.4 Meningioma Meningiomas are very uncommon tumors in the pediatric age group. Affected patients usually are

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adolescents with neurofibromatosis 2 (see Chap. 16). In such instances, meningiomas may be multiple, and are generally associated with schwannomas and, possibly, spinal cord ependymomas. Isolated meningiomas are rare, and typically belong to a particular histological variant called clear cell meningioma. Clear cell meningiomas are typical of younger patients, are prevailingly located in the spinal canal and cerebellopontine angle, and show a more aggressive behavior, with higher recurrence rate and propensity for leptomeningeal dissemination, than adult subtypes [33–36]. Despite their biological aggressiveness, clear cell meningiomas have a bland histological appearance, characterized by a sheetlike proliferation of polygonal cells that have a clear cytoplasm on hematoxylin staining due to glycogen accumulation [36]. 40.3.4.1 Imaging Findings

On MRI, clear cell meningiomas are round to ovoid, well-demarcated masses that are isointense to the spinal cord both on T1- and T2-weighted images. Contrast enhancement is moderate to marked and essentially homogeneous (Fig. 40.18). The presence of a dural tail sign is not mandatory, just as with conventional meningiomas. On the whole, there are no significant imaging features that allow for differentiation of clear cell meningiomas from the other various meningioma subtypes [35].

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Fig. 40.17a–d. Schwannoma in a 11-year-old boy. a Sagittal T1-weighted image; b sagittal T2-weighted image; c Gd-enhanced sagittal T1-weighted image; d Gd-enhanced coronal T1-weighted image. Small solid tumor of the intradural-extramedullary compartment showing T1 isointensity (arrow, a), mild T2 hyperintensity (arrow, b), and homogeneous enhancement (arrow, c, d)

1623

1624 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama 40.3.5 Atypical Teratoid Rhabdoid Tumor Atypical teratoid rhabdoid tumors (ATRT) are highly malignant neoplasms that are ubiquitous in the CNS. Although most are located in the brain, they may primitively involve the spinal compartment [37], either as extra-axial (i.e., intradural-extramedullary) or intra-axial (i.e., intramedullary) tumors. Owing to their marked aggressiveness, they may not respect the anatomic boundaries. Therefore, a primitively extraaxial lesion may infiltrate the spinal cord extensively and vice versa, so that the actual origin of the tumor may be difficult to assess on neuroimaging. ATRTs predominate in the first 2 years of life, and may be congenital. 40.3.5.1 Imaging Findings

Neuroimaging features (Fig. 40.19) are similar to those of intracranial ATRTs [38]. These tumors are structurally heterogeneous due to the presence of hemorrhage and necrotic-cystic change that may be extensive. Solid portions are low signal on both T1and T2-weighted images due to marked cellularity with high nuclear-to-cytoplasmatic ratio. Contrast enhancement is inhomogeneous and reflects the necrotic nature of the mass. Owing to their malignant behavior, MRI of the whole neuraxis must be

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performed in order to identify possible secondary spread or multicentric disease.

40.3.6 Primitive Neuroectodermal Tumors Primitive neuroectodermal tumors (PNETs) are tumors composed of undifferentiated or poorly differentiated cells and belong to a wide category of infantile, aggressive neoplasms (also including neuroblastomas and Ewing sarcomas) that are characterized histologically by a monotonous hypercellularity composed of small, round cells with hyperchromatic nucleus and scant cytoplasm [19]. Most PNETs arise in the brain, either supratentorially or infratentorially (i.e., medulloblastomas). However, PNETs are not confined to the brain and not even to the CNS. Intraspinal PNETs are very rare and tend to occur in an older population group than intracranial PNETs [39–41]. Extradural, intradural-extramedullary, and intramedullary locations are possible. 40.3.6.1 Imaging Findings

Imaging features of intraspinal PNETs are nonspecific. However, we saw a single case originating from a intradural-extramedullary location in the cervical spine and causing spinal compression (Fig. 40.20).

c

Fig. 40.18a–c. Clear cell meningioma in a 5-year-old girl. a Sagittal T1-weighted image; b. sagittal T2-weighted image; c. Gdenhanced sagittal T1-weighted image. Huge intradural lesion extending from D12 to L4, characterized by isointensity with cord on both T1-weighted (a) and T2-weighted images (b). Marked enhancement following gadolinium administration (c). The spinal canal is enlarged. The conus medullaris is deformed and compressed, and shows signal changes consistent with edema (white arrow, b). Notice venous congestion over the ventral and dorsal surface of the spinal cord (white arrows, c)

Tumors of the Spine and Spinal Cord

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Fig. 40.19a–d. Atypical teratoid rhabdoid tumor in a 2-year-old girl. a Sagittal T1-weighted image; b sagittal T2-weighted image; c Gd-enhanced sagittal T1-weighted image; d Gd-enhanced axial T1-weighted image. Huge lesion extending from T11 to L2, mildly hypointense on T1-weighted images (a) and iso- to hyperintense on T2-weighted images (b). Enhancement is marked and inhomogeneous. Spinal cord edema is present (arrow, b). Axial planes show the mass is intradural and markedly compresses and displaces the conus medullaris to the left (arrowhead, d). Note that the T1 signal from CSF in the thecal sac below the mass is increased due to stasis and increased protein concentration. At surgery, the lesion was found to originate from the right T12 nerve root

The lesion showed isointensity with spinal cord both on T1- and T2-weighted images, suggesting a hypercellular tumor, and enhanced homogeneously. Leptomeningeal metastases were found at 8 months follow-up despite combined surgery and chemotherapy.

40.3.7 Dysontogenetic and Nonneoplastic Masses Dermoid

Dermoids account for 10% of all spinal tumors in the pediatric age group. In a significant proportion of cases, they are associated with dermal sinuses. Such association was present in 11% of cases in our experience [42], but may be higher. Dermoids originate from ectopic ectodermal cell rests. As such, they may be either primitive or iatrogenic, i.e., secondary to inadvertent inclusion of skin debris during surgery or lumbar taps using needles that lack a trocar (see Chap. 39). Structurally, dermoids have a cystic structure lined by squamous epithelium associated with dermal appendages, such as hair, sweat glands,

and sebaceous gland. They contain a fluid containing cutaneous debris with variable concentrations of keratin, which tends to influence their signal behavior on MRI. Dermoids are benign lesions whose growth rate is extremely low and is basically related to accumulation of debris within the cyst. Complications include abscessation and rupture of the cyst with dissemination of its content into the subarachnoid spaces, causing chemical meningitis. The identification of dermoids on MRI may be problematic due to their hydration, accounting for their hypointensity on T1-weighted images and hyperintensity on T2-weighted images, similar to the signal intensity of CSF. This is especially true when one tries to detect small dermoids in the vicinity of the surgical breach in scoliotic patients previously operated for myelomeningocele. Proton-density and FLAIR sequences, as well as diffusion-weighted imaging, may be extremely useful in these cases. Contrast enhancement is usually absent, except in case of superinfection. Rupture of dermoids with dissemination of their content results in dependent hyperintense material disseminated into the ventricles and subarachnoid spaces.

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1626 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama Epidermoid

Arachnoid Cysts

Epidermoids have a cystic structure and are derived from ectoderm, like dermoids. Unlike the latter, they are lined by squamous epithelium lacking cutaneous appendages. They are relatively infrequent in the pediatric age group. The signal behavior is similar to that of dermoids. In general, hydration of the mass results in a signal intensity similar to that of CSF both on T1- and T2weighted images. As is the case with dermoids, protondensity, FLAIR, and diffusion-weighted images are more sensitive.

Arachnoid cysts are CSF collections, housed within a splitting of the arachnoid membrane, that do not communicate with the subarachnoid space. In the spine, arachnoid cysts may be located in the subdural or, less often, epidural space. Spinal arachnoid cysts are commonly located dorsal to the cord in the thoracic region, and may either be asymptomatic or cause signs of spinal cord compression. They may be congenital or result from adhesions provoked by previous infection or trauma. As such, they may complicate surgery for spinal dysraphism, and cause subsequent neurologic deterioration with signs of cord tethering (Fig. 40.21). On MRI, signal intensity of arachnoid cysts parallels that of CSF in all sequences. However, some arachnoid cysts may contain proteinaceous fluid or blood, thereby resulting in increased T1 and T2 relaxation times which may pose diagnostic problems.

Neurenteric Cysts

Neurenteric cysts are lined with a mucin-secreting, cuboidal or columnar epithelium that resembles the alimentary tract [42]. Their content is variable, and the chemical composition may be similar to CSF in some cases, which is reflected by a variable pattern of signal intensity on MRI. Their typical location is in the cervicothoracic spine anterior to the cord (see Chap. 39).

a

c

b

Fibromatosis

Fibroblastic proliferations in children include a group of rare disorders which have no clinical or morpho-

d

Fig. 40.20a–d. Primitive neuroectodermal tumor in a 17-year-old girl. a Sagittal T2-weighted image; b Gd-enhanced coronal T1-weighted image; c Gd-enhanced axial T1-weighted image; d Gd-enhanced sagittal T1weighted image obtained after 8 months. There is an intradural-extramedullary mass in the cervical spine at C4-C5 level asterisk, a–c) which causes contralateral displacement of the spinal cord (sc, c), which appears edematous caudal to the lesion (arrow, a). After 8 months, a metastatic nodule was discovered in the distal thecal sac (arrow, d)

Tumors of the Spine and Spinal Cord

b

Fig. 40.21a,b. Arachnoid cyst in a 13-year-old boy with prior myelomeningocele surgery. a Sagittal T2-weighted image; b axial T1-weighted image. A cystic lesion isointense with CSF is located at T10–12 level (asterisk, a). The cyst walls are barely discernible (arrows, a). The cyst expands the spinal canal and is located posteriorly to the spinal cord, which is reduced to a thin stripe (arrow, b)

a

logical counterpart in adult life. They often have unusual microscopic features that pose special diagnostic problems; high cellularity and rapid growth can mimic sarcomas, but they usually are low-grade

lesions and surgical excision is curative [43]. Fibrous proliferations peculiar to childhood include fibrous hamartoma, infantile desmoid fibromatosis, fibromatosis colli, and digital fibromatosis. The CNS is an uncommon site. In a case we observed, there was a huge spinal intradural enhancing lesion, enveloping and displacing the spinal cord (Fig. 40.22). Histiocytosis

Langerhans cell histiocytosis is an ubiquitous disorder characterized by the proliferation and accumulation of macrophages and dendritic cells in various tissues and organs, including the CNS (see Chap. 11). While histiocytosis usually involves the spine in the form of a vertebral eosinophilic granuloma (see below), unusual locations include the intradural-extramedullary compartment, probably resulting from meningeal proliferation [44] (Fig. 40.23).

40.4 Extradural Tumors

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Fig. 40.22a,b. Fibromatosis in a 2-year-old boy. a Sagittal T1weighted image; b Gd-enhanced sagittal T1-weighted image. The spinal canal is expanded due to the presence of abundant enhancing tissue anterior to the spinal cord

Extradural tumors account for approximately two thirds of all spinal tumors in the pediatric age group. They may be categorized into bone tumors (benign, intermediate, and malignant), tumors of the epidural space, and extraspinal tumors invading the spine. Localized back pain and tenderness are the usual causes of complaint. Signs of myelopathy or radiculopathy are caused by compression of the spinal cord

1627

1628 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama thickened, sclerotic trabeculae that have a compensatory function. Most vertebral hemangiomas are dormant lesions that do not cause symptoms and do not grow. However, some show an aggressive behavior which is characterized by expansion of involved bone, epidural extension, and vertebral collapse. These patients usually experience local pain and may develop signs of spinal cord and nerve root compression. GorhamStout syndrome is a rare, severe form of massive osteolysis characterized by an aggressive angiomatosis and leading to cancellation of the bony structure (“ghost bone”) [45]. Imaging Studies

a

b

Fig. 40.23a,b. Langerhans cell histiocytosis in a 2-year-old girl. a Sagittal T1-weighted image; b. Gd-enhanced sagittal T1weighted image. The thecal sac is filled by abundant enhancing tissue that envelops the conus medullaris

and nerve roots by the spinal mass. Neuroimaging of extradural tumors usually requires both MRI and CT. MRI exquisitely depicts extradural soft tissue components as well as bone marrow infiltration; moreover, T2-weighted MR images detect signal changes in the spinal cord secondary to compression from the tumor. CT detects the osteolytic or osteosclerotic nature of the lesion and the degree of involvement of bone. Scintigraphy is often an useful adjunct, especially in the detection of metastases and the characterization of osteoid osteomas.

40.4.1 Benign Bone Tumors and Tumor-Like Conditions 40.4.1.1 Vertebral Hemangioma

Vertebral hemangiomas are usually discovered incidentally during an MRI investigation performed for other reasons. These lesions involve the vertebral body and may be solitary or multiple; they are composed of capillary and cavernous spaces, lined by endothelium and surrounded by adipose tissue and

On X-rays, vertebral hemangiomas produce a typical appearance of vertical sclerotic densities in the vertebral body, simulating a palisade (Fig. 40.24). On CT, there is a salt-and-pepper appearance resulting from the thickened trabeculae surrounded by low-attenuation fat. On MRI, end-stage, dormant angiomas are hyperintense both on T1- and T2-weighted images due to fatty and vascular components, separated by hypointense stripes corresponding to the sclerotic trabeculae. The affected vertebra is usually morphologically normal, although partial collapse can be seen (Fig. 40.24). Instead, potentially aggressive hemangiomas (Fig. 40.25) are low intensity on T1and bright on T2-weighted images, and cause bone expansion, resulting in a swollen appearance with convexity of the vertebral walls, sometimes associated with enhancing epidural components that may cause thecal sac compression. 40.4.1.2 Osteoid Osteoma

Approximately 10% of all osteoid osteomas are located in the spine. The posterior vertebral elements are involved more frequently than the body. This represents a common feature of benign vertebral tumors, and a notable difference from malignant ones. Affected patients usually are between 6 and 17 years of age. The typical presentation is with nocturnal pain that promptly recedes with nonsteroid anti-inflammatory medications. However, this is not always the case, with a few patients presenting with aspecific pain that does not respond to medication. Additionally, osteoid osteomas are the most common cause of painful scoliosis in older children and adolescents. Histologically, the tumor is composed of a richly vascularized nidus of osteoid bone containing a sclerotic center, surrounded by marked reactive osteosclerosis.

Tumors of the Spine and Spinal Cord

a

b

c

Fig. 40.24a–e. Vertebral hemangioma in an adolescent. a Conventional X-rays, anteroposterior projection; b axial CT scan; c axial T1-weighted image; d sagittal T1-weighted image; e sagittal T2weighted image. Conventional X-rays show palisade appearance of a thoracic vertebral body (arrow, a). Abnormality appears to also partly involve the vertebral body above (arrowhead, a). Both axial CT (b) and T1-weighted image (c) display the typical palisades of sclerotic bone, appearing bright on CT (b) and dark on MRI (c). Sagittal MRI shows both T2 and T3 bodies are abnormally hyperintense (d, e). Pronounced anterior swelling of the T3 body (arrow, d, e) is probably due to collapse of the anterior vertebral wall

d

e

Fig. 40.25a–c. Evolutive vertebral hemangioma in a 5-year-old girl. a Sagittal T2-weighted image; b. sagittal T1-weighted image; c. Gdenhanced sagittal T1-weighted image. The T9 vertebral body is bright on T2-weighted images, isointense on T1-weighted images, and enhances slightly more than the other vertebral bodies. The posterior vertebral wall is slightly convex (arrow, a) and the anterior wall is not concave, giving the appearance of a slightly swollen vertebral body

b

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a

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1630 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama Reactive inflammatory soft-tissue masses often surround the bony lesion and may extensively involve the paravertebral regions [46, 47].

as conspicuous as thin-section CT in the detection of osteoid osteomas [49]. 40.4.1.3 Osteoblastoma

Imaging Findings

Radionuclide bone scans are extremely sensitive in the detection of these tumors (Fig. 40.26). CT is the preferred neuroimaging modality; it shows a rounded hypodense lesion, corresponding to the nidus, surrounded by a markedly hyperdense sclerotic ring. Sometimes a calcified spot may be seen within the nidus, resulting in a target appearance of the lesion in the axial plane (Fig. 40.26). The nidus is more often located in the posterior neural arch, i.e., involving the lamina, articular process, or peduncle. The bone into which the osteoid osteoma is embedded is typically sclerotic and hyperostotic. A scoliotic curve is often present. On MRI, the nidus is hyperintense on T2-weighted images and enhances markedly; the surrounding osteosclerotic component results in a hypointense ring. Accuracy of MRI in identification of osteoid osteomas is 65% [48]. Therefore, reliance on MRI alone may potentially cause a missed diagnosis. However, MRI is sensitive in detecting associated bone marrow edema and soft tissue mass, thereby prompting further imaging with CT and scintigraphy (Fig. 40.27). In one study, gadolinium-enhanced was

It is an established conviction that differentiation of osteoblastomas from osteoid osteomas depends solely on their size, which exceeds 2 cm in diameter [50]. While it may be true that the two tumors are undistinguishable histologically, it has been our experience that osteoblastomas often show an aggressive behavior and bleed extensively during surgery. Aneurysmal bone cyst components may be associated within the framework of the tumor and may account for bleeding. There is a predilection for the neural arch, as is the case with osteoid osteomas. However, these lesions may also extend into the vertebral body and soft tissues. Patients present with aspecific pain that does not recede with salicylates. Structurally, the lesion is a lytic, partly calcified mass that may involve the adjacent paraspinal or epidural soft tissues. Imaging Findings

In typical cases, CT shows an expansile lytic lesion, possibly associated with sclerotic components (Fig. 40.28). However, while histologically benign, osteoblastomas may show atypical features that

c

a

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Fig. 40.26a–c. Osteoid osteoma in a 12-year-old girl with painful scoliosis. a Radionuclide bone scan; b conventional X-rays, anteroposterior view; c axial CT scan, bone window. Bone scintigraphy shows markedly increased uptake in the right half of L4 (arrow, a). Notice left thoracolumbar scoliotic curve, confirmed by X-rays (b). Radiogram also shows a sclerotic right L4 peduncle (arrow, b). CT shows the typical appearance of an osteoid osteoma, i.e., a target lesion characterized by central sclerosis and surrounding radiolucency (arrow, c), embedded within a sclerotic, hyperostotic lamina (arrowheads, c)

Tumors of the Spine and Spinal Cord

b

a

a

c

Fig. 40.27a–c. Osteoid osteoma in a 11-year-old boy. a Gd-enhanced fat-suppressed coronal T1-weighted image; b Gd-enhanced fat-suppressed axial T1-weighted image; c axial CT scan. MRI shows ill-defined, diffuse enhancement involving the paravertebral muscles prevailingly to the left (arrowheads, a, b). The osteoid osteoma is barely visible (arrow, b), but was missed on initial reading of these films. It was visualized only in retrospect, when MRI was compared to CT, clearly showing the lesion (arrow, c), located within a hyperostotic, sclerotic lamina (arrowheads, c)

b

c

d

Fig. 40.28a–d. Osteoblastoma in a 4-year-old boy. a Axial CT scan; b axial T1weighted image; c Gd-enhanced coronal T1-weighted image; d 2D TOF MR angiography, coronal MIP. There is a partly lytic, partly sclerotic lesion involving the C3-C4 vertebral bodies on the right (asterisks, a–c). The lesion envelopes the homolateral vertebral artery, which appears thin and displaced contralaterally (arrow, b, d). MRA also shows feeding vessels, probably originating from the ascending cervical artery (arrowhead, d)

mimic aggressive lesions, such as extensive osseous destruction, hemorrhage, and soft tissue components, which may extend into the epidural space and cause thecal sac and cord compression (Fig. 40.29). On MRI, signal intensity is heterogeneous both on T1and T2-weighted images. Gadolinium enhancement is marked. Vascularity may be prominent, as shown by catheter angiography (Fig. 40.29). These lesions may bleed extensively during surgery. When possible, pre-

surgical embolization should be considered in order to prevent massive bleeding during the operation. 40.4.1.4 Osteochondroma

Osteochondromas are bone-like outgrowths capped by cartilage and composed of cortical and trabecular bone that is continuous with the native bone [51].

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1632 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama

b

c

a

d

e

Fig. 40.29a–j. Osteoblastoma in a 2-year-old boy with back pain and right lower limb tremor progressing to paresis and then inability to walk within 2 days. a–c MRI at presentation (a Sagittal T2-weighted image; b axial T1-weighted image; c Gd-enhanced coronal T1-weighted image). d, e CT performed 2 days after first operation (d axial CT scan; e coronal reformatted CT). f, g MRI after 20 days (f sagittal T2-weighted image; g coronal T1-weighted image). h Axial CT scan after 21 days; i digital subtraction angiography, selective catheterization of right L2 artery. j Histological specimen, hematoxylin-eosin. At presentation, MRI shows collapse of the L2 vertebral body, which also appears bright on T2-weighted images (asterisk, a). Additionally, there is a huge soft tissue mass that involves extensively the intraspinal compartment between L1 and L3 (black arrows, a) as well as the paravertebral regions posteriorly (white arrow, a) and to the right (asterisks, b; arrowheads, c). Lesion contains hemorrhagic components (h, a–c) and is associated with prominent epidural vein dilatation (arrow, c). During surgery, massive arterial bleeding occurred as the posterior spinal elements were approached, prior to any access to the dural sac. Hemoglobin concentration dropped to 6 mg/dl. Manual compression was performed for 8 h before achieving hemostasis. At this time, histology was inconclusive. CT scan performed 2 days after surgery shows extensive lytic mass with huge intraspinal soft tissue component (asterisk, d), delimited...

These lesions may be solitary or multiple; the latter usually are part of osteochondromatosis (multiple exostoses). Most lesions are found during the first or second decade, and may grow rapidly during puberty with subsequent quiescence. Malignant degeneration into chondrosarcomas occurs in 1% of solitary osteochondromas, and in 25% of patients with multiple exostoses.

posed of cancellous bone and surrounded by cortical bone, both continuous with the bone from which they originate. Dense, sclerotic cartilage outlines the lesion. CT is the preferred modality for imaging these tumors. MRI shows a mixed pattern of signal intensity. 40.4.1.5 Aneurysmal Bone Cysts

Imaging Findings

Spinal osteochondromas are rare, and involve preferentially the neural arch and spinous process. They appear as bone-like pedunculated outgrowths com-

Whether aneurysmal bone cysts (ABC) represent true tumors remains the subject of debate. These lesions are probably not actual neoplasms but, rather, reactive lesions that may result from trauma or coexist

컄

Tumors of the Spine and Spinal Cord

f

h

g

i

j

Fig. 40.29a–j (Continued)... medially by a thin calcified shell (arrowheads, e) and displacing contralaterally the dural sac (ds, d). The right peduncle of L2 is completely destroyed. After 20 days, MRI reveals significant structural modifications. The mass now has a solid appearance with “foamy,” heterogeneous T2 hyperintensity (f) and T1 isointensity (g). At the same time, CT now shows diffuse hyperdensity with innumerable, tiny calcified spots, while the degree of dural sac compression has increased (arrow, h). Catheter angiography displays extensive vascularity (i). The lesion was embolized and then successfully removed surgically. Histology (j) showed diffuse osteoid matrix with osteoblasts associated with areas consistent with aneurysmal bone cyst (arrowheads, j)

with other bone lesions, both benign and malignant [52, 53]. In our experience, ABC have accounted for 42% of all benign bone tumors in the pediatric age group. They are located preferentially in the lower thoracic or lumbar spine; in our experience, 75% were located between T11 and S2, whereas the cervical spine was affected in 25%. They originate from the neural arch in about 60% of cases, but may extend to the body along one, or rarely both, vertebral pedicles. The remainder originate primarily in the vertebral body. They may cross disk spaces to involve adjacent vertebral levels [52, 53]. These osteolytic lesions have a multicystic structure composed of wide, communicating loculations

that contain unclotted blood, separated by thin calcified shells. Affected patients usually are older children or adolescents. In our series, 87% of patients were 10 years of age or older. Presentation is with local pain that may be associated with myelopathy or radiculopathy if the lesion compresses the thecal sac. Pathologic fracture may also lead to cord or nerve root compression. Imaging Findings

On neuroimaging (Fig. 40.30), ABC are osteolytic, expansile, sometimes destructive lesions, occasionally extending into the adjacent soft tissues. X-rays

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1634 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama

b

a

d c

e

f

g

Fig. 40.30a–g. Aneurysmal bone cyst of T11 in a 12-year-old boy with localized back pain. a Conventional X-rays, anteroposterior view; b axial CT scan, bone window; c coronal reformatted CT; d coronal T1-weighted image; e sagittal T2-weighted image; f axial T2-weighted image; g catheter angiography, selective injection of left T11 artery. X rays show scoliosis and absence of left T11 pedicle (arrowhead, a). CT shows lytic expansile lesion of the posterior neural arch of T11 to the left, delimited by a thin calcified shell (arrowheads, b). Coronal reformation shows dependent fluid-fluid level within the lesion (arrow, c). MRI shows extradural lesion replacing left T11 pedicle and compressing cord (d). Lesion has heterogeneous T2 signal (e) and shows multiple dependent fluid-fluid levels (thin arrows, f). The spinal cord, albeit displaced, does not show signal abnormalities (thick arrow, f), consistent with the normal neurologic picture. Angiography (g) shows lesion vascularity. This lesion was embolized and then surgically removed

typically show absence of a pedicle. On CT, the lesion appears to be composed of multiple cystic spaces separated by thin, calcified shells, often containing scattered calcified spots. On MRI, signal intensity is variable depending on the various degradation stages of blood contained within the cysts [52,

53]. The neuroradiologic hallmark, visible both on CT and MRI, is represented by multiple dependent intralesional fluid-fluid levels (Fig. 40.30). Although fluid-fluid levels may be suggestive of ABC, one must be aware that they may also be found in other tumors, including giant cell tumors and telangiectatic osteo-

Tumors of the Spine and Spinal Cord

sarcomas [54]. However, these tumors are typical of adults and, in our experience on pediatric spine tumors, fluid-fluid levels were only found in ABC. Rarely, a single, large fluid-fluid level may be found (Fig. 40.31). Even rarer are cases of purely solid ABCs [55]. Due to their hypervascular nature, aneurysmal bone cysts may be amenable to embolization prior to excision and curettage, in order to reduce bleeding during surgery [56].

of the growth plates allows for subsequent total or subtotal reconstitution of vertebral height, a phenomenon that is thought to be more efficient in younger patients [58]. Involvement of the posterior elements of the spine is exceptional [59]. Patients present with pain, accompanied by general symptoms such as fever and weight loss. In our experience, 75% of cases have involved a cervical vertebral body. Imaging Findings

40.4.1.6 Eosinophilic Granuloma

Langerhans cell histiocytosis, formerly known as histiocytosis X, is a reactive disorder of unknown etiology which presents a wide clinical spectrum, ranging from a multisystem disease to a single-system disease confined to the skeleton. The key histopathological feature is a proliferation of reticuloendothelial elements showing the phenotypic markers of epidermal Langerhans cells. These are normally found in the skin, where they present antigens to T lymphocytes, but in other organs they may cause tissue damage by production of cytokines and prostaglandins [57]. The clinicopathologic expression of Langerhans cell histiocytosis is variable, and includes generalized forms (Letterer-Siwe and Hand-Schuller-Christian diseases) and solitary lesions (eosinophilic granuloma). Eosinophilic granulomas of the spine affect the vertebral body, and typically result in collapse (vertebra plana of Calvè). Vertebral collapse is usually complete in younger children, whereas it may be incomplete in older children, resulting in a wedge-shaped configuration. As the end plates remain intact, the disk space is consistently unaffected. Furthermore, preservation

a

X-rays and CT with multiplanar reconstructions typically show a osteolytic lesion causing a variable degree of thinning of the involved vertebra, which is often reduced to an irregularly sclerotic sling (Fig. 40.32). The adjacent disks are spared, and typically show compensatory swelling. MRI is best suited to demonstrate both the vertebral lesion and the associated soft tissue components, which may involve the anterior epidural space (Fig. 40.32). The lesion is hypointense on T1-weighted images, hyperintense on T2-weighted images, and shows marked enhancement with gadolinium administration. Patients with suspected Langerhans cell histiocytosis should undergo MRI of the hypothalamic-pituitary axis in order to detect possible involvement of the pituitary stalk. One should remember that eosinophilic granuloma is the most common but not the only cause of vertebra plana in children. We have seen vertebral collapse in patients with lymphoma (Fig. 40.33). Other conditions that have been associated with vertebra plana include neoplastic and nonneoplastic lesions, such as Ewing’s sarcoma, osteosarcoma, aneurysmal bone cyst, infantile myofibromatosis, Gaucher’s disease, and chronic recurrent multifocal osteomyelitis [60–65].

b

Fig. 40.31a,b. Aneurysmal bone cyst of C2 in a 13-year-old girl. a Sagittal T1-weighted image; b axial T2-weighted image. Both sequences display a large cavity originating from the posterior neural arch of C2 to the right and containing a single fluid-fluid level (arrows, a, b)

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1636 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama

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Fig. 40.32a–d. Eosinophilic granuloma in a 5-year-old boy. a Conventional X-rays, laterolateral view; b sagittal T2-weighted image; c Gd-enhanced sagittal T1-weighted image; d Gd-enhanced axial T1-weighted image. X-rays show collapse of the C4 vertebral body (arrow, a). On MRI, T2 hyperintense, markedly enhancing pathologic tissue completely replaces bone marrow and extends both anteriorly in the prevertebral space and posteriorly into the epidural space (arrowheads, b, c). Notice the adjacent disks are completely spared. Axial view shows abundant pathologic tissue (arrowheads, c) engulfing the disk space (ds, c) and compressing the spinal cord (sc, c)

d

40.4.2 Intermediate Bone Tumors 40.4.2.1 Chordoma

a

b

Fig. 40.33a,b. Vertebra plana: eosinophilic granuloma versus lymphoma. a, b Sagittal T1-weighted images. a Eosinophilic granuloma in a 8-year-old girl. Complete collapse of the T12 body with compensatory swelling of the adjacent disks. b Lymphoma in a 10-year-old boy. In itself, vertebral collapse (here involving L2) is undistinguishable from that of histiocytosis. However, the other vertebral bodies are abnormally hypointense, indicating diffuse bone marrow infiltration from the underlying disease

Chordomas arise from notochordal cell remnants, and can therefore be located anywhere along the craniospinal axis; however, the vast majority involve the two extremities, i.e., the clivus or the sacrum. The sacrococcygeal region accounts for half of all chordomas in the general population. The cervical spine is another, albeit rare, location for chordomas (about 15% of cases), whereas thoracic and lumbar locations are exceptional. Histologically, these lesions belong to two varieties: classical chordomas, characterized by strands of physaliphorous cells embedded in a mucinous matrix, and chondroid chordomas, in which the tumor matrix contains cartilaginous cells. Despite their slow-growing nature, these lesions are locally invasive with a high tendency for recurrence, and aggressive behavior with distant metastases has been described [66]. The histological pattern (typical or chondroid chordomas) does not appear to affect

Tumors of the Spine and Spinal Cord

recurrent-free survival rate [67]; however, it has been suggested that sacral chordomas in the pediatric age groups are more aggressive than their adult counterparts [68]. Primarily malignant chordomas may contain areas of sarcomatoid dedifferentiation [69]. Imaging Findings

On X-rays and CT, chordomas appear as osteolytic lesions that often involve adjacent vertebrae, often resulting in extensive bone destruction. They also typically extend into the soft tissues of the paravertebral and epidural regions. On MRI, signal behavior is heterogeneous, but prevailingly iso- to hypointense on T1-weighted images and hyperintense on T2weighted images (Fig. 40.34). Contrast enhancement is usually moderate to marked. Soft tissue extensions often span several vertebral segments. Sacrococcygeal chordomas show a characteristic tumoral lobulation that is well depicted by MRI, frequently involve the adjacent muscles and spinal canal, but most often spare the rectal wall [70]. Cervical chordomas may display a “dumb-bell” morphology on axial images without bone involvement and with enlargement of the neural foramen, mimicking a neurogenic tumor [71]. 40.4.2.2 Sacrococcygeal Teratoma

Sacrococcygeal teratoma is the most frequent congenital tumor, and typically affects neonates. Teratomas derive from all three germ cell layers, that is,

a

ectoderm, mesoderm, and endoderm. They may be isolated or associated with anorectal malformations and caudal agenesis, in the so-called Currarino triad [72]. These lesions are usually huge masses, sometimes as large or even larger than the newborn itself (Fig. 40.35). The mass is well capsulated and lobulated, solid or partially cystic. Hemorrhage, osteocartilaginous tissue, and teeth may also be found within the mass. Two thirds of cases are represented by mature teratomas, whereas the remainder are immature teratomas, whose prognosis is worse. Mature forms are characterized by the association of parenchymal tissue, fat, and calcifications. Immature teratomas lack adipose tissue and are usually characterized by elevated growth rate and tendency to metastatic spread. Rarely, other germ cell tumors, such as yolksac tumors, may involve the sacrococcygeal region in newborns with caudal agenesis. Although the majority of teratomas in infancy and childhood are benign, there is a tendency toward malignant transformation as the child gets older [70]. Sacrococcygeal teratomas are categorized anatomically into four groups. • Type I (46.7% of cases): the lesion prevailingly grows externally, without a significant presacral component; • Type II (34.7% of cases): prevailingly external lesion, but with a relatively significant intrapelvic component; • Type III (8.3% of cases): prevailingly intrapelvic mass; • Type IV (9.4% of cases): purely intrapelvic mass, without external portions.

b Fig. 40.34a,b. Chordoma of the upper cervical spine in a 11-year-old boy. There is a huge mass (asterisks, a, b) that destroys C2 and partly involves C1 and C3. Although the epidural spaces are extensively involved, the spinal cord (sc, b) is not compressed. Anterior extension causes compression of the oropharynx (arrowheads, a, b). Lesion is T1 isointense (a) and T2 hyperintense (b). Enhancement was mild (not shown)

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1638 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama nonspecific systemic signs such as fever, weight loss, anemia, and increased erythrosedimentation rate. Histologically, this highly malignant tumor is characterized by hypercellularity composed of small rounded cells with prominent nucleus and scant cytoplasm, similar to neuroblastomas and PNETs. The close relationship among these entities is reinforced by the possible occurrence of mixed forms (Ewing-PNETs). Most cases are characterized by lytic vertebral involvement, typically associated with an accompanying soft tissue mass that may involve both the paravertebral spaces and the intraspinal epidural compartment, with possible thecal sac compression. Ewing’s sarcoma may spread across the disk space to the adjacent vertebra, a feature that may mimic infection [70]. Rarely, purely extraosseous tumors may be found (see below). Imaging Findings Fig. 40.35. Sacrococcygeal teratoma in a newborn with Currarino triad. Sagittal T1-weighted image. Giant sacrococcygeal mass is heterogeneous due to the presence of a huge cystic component, hyperintense fatty tissue, and a solid part. The size of the mass can be appreciated when compared with that of the sacrum (arrowhead). There was associated anorectal atresia

The external component is readily visible to the observer. It lies at level of or caudad to the intergluteal cleft, thereby allowing a ready differentiation from closed spinal dysraphisms associated with subcutaneous masses (lipomyelocele, lipomyelomeningocele, meningocele, and myelocystocele), in which the mass is located cranially to the intergluteal cleft [42].

40.4.3 Malignant Bone Tumors 40.4.3.1 Ewing’s Sarcoma

Ewing’s sarcoma is the most common primary bone tumor in the pediatric age group, accounting for 50% of spinal bone malignancies in our series. Most tumors involve the long and flat bones, while fewer than 10% are primitively located in the spine [73]. In most cases, there is multifocal bone involvement. In the spine, the lumbosacral region is the most common location [70, 73] (two thirds of cases in our series). Presentation usually is by the end of the first decade of life. In our series, 62% of patients were older than 9 years, and none were younger than 3 years. Local pain, radiculopathy, and signs of spinal cord compression are usual complaints, commonly associated with

Conventional X-rays and CT show permeative osteolytic changes involving the affected bone, associated with sclerotic and calcific depositions. Vertebral collapse may occur (Fig. 40.36), whereas periosteal reactions are uncommon in the spine, unlike with long bone tumors. Involved vertebrae may show various appearances on conventional X-rays, including ivory vertebra [60], vertebra plana [74], and a pseudoangiomatous appearance [75]. Other than bony involvement, CT also shows extraosseous soft tumor components, which usually are abundant. MRI is more advantageous to demonstrate the extension of the soft tissue mass, which may prevail over the degree of bone involvement (Fig. 40.37). Often, the extraosseous soft tissue components tend to envelope the affected bone, producing a sort of tumoral coating to the involved vertebrae; this has been a useful diagnostic finding in our experience (Figs. 40.36, 37). Extradural extension and thecal sac compression are exquisitely depicted by MRI. The mass is iso- to hypointense both on T1- and T2-weighted images, reflecting hypercellularity with high nuclear-to-cytoplasmatic ratio. Signal inhomogeneity with T1 and T2 prolongation results from necrotic-cystic change within the mass. Contrast enhancement is usually marked and heterogeneous. 40.4.3.2 Osteosarcoma

Only 4% of osteosarcomas primarily involve the spine in the general population [76]. It is very rare in the pediatric age group, whereas it affects more frequently adults in their fourth decade [76]. In the sacrum, the

Tumors of the Spine and Spinal Cord

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Fig. 40.36a–c. Ewing’s sarcoma in a 9-year-old girl. a Conventional X-rays, laterolateral projection; b sagittal T2-weighted image; c axial T1-weighted image. X-rays show collapse of the T9 vertebral body (arrow, a) associated with a prevertebral opacity (arrowheads, a). Sagittal T2-weighted image confirms vertebral body collapse (thick arrow, b) associated with a huge prevertebral hypointense soft tissue mass (arrowheads, b) and a smaller epidural component impinging on the cord (thin arrow, b). Axial image shows typical finding of engulfment of the vertebral body (VB, c) by the huge soft tissue mass (arrowheads, c). Epidural components impinge on the spinal cord bilaterally (arrows, c). Notice marked anterior displacement of the aorta (A)

c

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Fig. 40.37a–d. Ewing’s sarcoma in a 4-year-old boy. a Sagittal T1-weighted image; b sagittal T2-weighted image; c axial T1-weighted image; d Gdenhanced coronal T1-weighted image. In this case, the huge intraspinal soft tissue component is markedly prevalent over bony involvement, revealed by abnormal signal intensity of the S1 vertebral body (arrow, a, b). Notice that the huge intraspinal mass is extradural in location, as revealed by the typical meniscus displacement of the epidural fat (arrowhead, a). Axial images reveal the typical appearance of the mass (arrowheads, c) that engulfs the sacrum. Perhaps surprisingly, the left S1–2 neural foramen is spared (open arrow, c). Coronal image shows the full extent of the mass, which is characterized by mild, prevailingly peripheral enhancement with large central unenhanced components

d

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1640 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama tumor prevailingly originates from body and sacral ala, whereas nonsacral osteosarcomas typically (79%) arise in the posterior elements with partial body involvement [76]. Both sclerotic and lytic lesions are found, often in association with soft tissue masses, mimicking Ewing’s sarcomas and osteoblastomas. Imaging appearance is nonspecific. Owing to its rarity, osteosarcoma often seems an unlikely diagnosis. We saw a single case that was undistinguishable from a Ewing’s sarcoma (Fig. 40.38). 40.4.3.3 Chondrosarcoma

Chondrosarcomas are exceptionally found in children. However, patients with Ollier disease (a nonhereditary disorder which usually presents in childhood and consists of multiple enchondromas) are especially prone to develop chondromas and chondrosarcomas involving multiple sites, including the head, neck, and spine [77] (Fig. 40.39). These lesions show mixed osteolytic and osteosclerotic changes associated with matrix calcification. 40.4.3.4 Lymphoma and Leukemia

Vertebral involvement from lymphoma and leukemia is common (see Chap. 11). MRI reveals replacement of normal bone marrow signal intensity with

a

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an abnormal intermediate signal intensity resulting from neoplastic infiltration. Posterior epidural mass formation (see Fig. 11.12, Chap. 11), sometimes mimicking disk herniation, and cortical destruction with vertebral collapse are relatively common complications [28]. On MRI, hemolymphoproliferative tissue is low signal on both T1- and T2-weighted images [78] (Fig. 40.40). 40.4.3.5 Vertebral Metastases

Extradural metastases may involve the vertebral bones, paravertebral regions, epidural space, or all three. They may produce a variable degree of compression of the thecal sac and spinal cord. Primary tumors that may spread to the extradural space prominently include neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma, Wilms’ tumor, and hematological malignancies. Vertebral metastases from medulloblastoma have been greatly reduced by the addition of chemotherapy to surgery and craniospinal irradiation [79]. Tumor spread occurs basically along the hematogenous and lymphatic routes to the richly vascularized bone marrow. Therefore, vertebral bodies are usually affected more prominently than neural arches. Involvement of the epidural space occurs with direct spread from adjacent infiltrated bone. Clinical features prominently include back and radicular pain. Accompanying signs include hypoes-

c

Fig. 40.38a–c. Osteosarcoma in a 9-year-old girl. a Sagittal T1-weighted image; b sagittal T2-weighted image; c Gd-enhanced, fat-suppressed axial T1-weighted image. Tumor mass infiltrates the S1 body and left sacral ala, and shows huge soft tissue component (asterisks, a–c) that engulfs the affected bone. Signal intensity is low on both T1- and T2-weighted images, consistent with a hypercellular tumor. Overall, imaging characteristics are equivalent to those of Ewing’s sarcoma, and the histological diagnosis came as a relative surprise

Tumors of the Spine and Spinal Cord Fig. 40.39a–d. Chondrosarcoma of the skull base in a 6-year-old girl with Ollier syndrome. a Coronal T1-weighted image; b axial T1-weighted image; c, d axial T2-weighted images. Mass lesion involving the left lateral mass of the atlas and extending cranially along the petroclival suture to the dorsum sellae (asterisks, a–d)

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thesia, paresthesia, hyposthenia, and neurovegetative disturbances. Metastatic vertebrae may show variable appearances, ranging from normal morphology to pathologic fracture and collapse [26]. Conventional X-rays are not particularly sensitive in detecting vertebral metastases if the vertebral bone is morphologically normal. Radionuclide scans are the accepted screening modality. MRI features are aspecific. The infiltrative tissue is usually hypointense on T1-weighted images and hyperintense on T2-weighted images. Contrast enhancement usually occurs both in the healthy and pathologic vertebrae, resulting in a paradoxical isointensity of the involved vertebrae with the adjacent normal vertebrae; use of fat saturation techniques allows to circumvent this problem. Although T2-weighted MR imaging of the spine is usually accomplished using fast spin-echo techniques, one should be aware of the fact that yellow bone marrow hyperintensity will usually mask the pathologic tissue; therefore, fat-suppressed sequences should be employed also for T2-weighted imaging. The diagnosis is greatly facilitated by the presence of multiple lesions and the knowledge of the primary tumor. Differentiation from nonneoplastic conditions, such as bacterial or tuberculous spondylodiscitis, is usually relatively straightforward on

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Fig. 40.40a, b. Vertebral infiltration in a 6-year-old girl with acute myeloid leukemia. a Sagittal T1-weighted image; b. sagittal T2-weighted image. Several vertebral bodies are slightly hypointense on T1-weighted (arrows, a) and markedly hypointense on T2-weighted images (arrows, b). Also notice involvement of posterior elements (arrowhead, b)

1641

1642 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama clinical grounds; moreover, intervertebral disks are typically involved by infectious processes, and spared by metastases. Differentiation of solitary metastases from primary bone tumor may be problematic, and may require histological confirmation.

40.4.4 Tumors of the Epidural Space

40.4.4.2 Chloroma

40.4.4.1 Extraosseous Sarcomas

A subset of small round cell tumors, histologically and ultrastructurally similar to both the skeletal form of Ewing’s sarcoma and PNETs, may exclusively involve the extradural space with a likely origin from the meninges. These neoplasms possibly extend to the paravertebral spaces through the neural foramina, but do not show significant bony involvement [80–82]. Affected patients present with signs of spinal cord compression that may be progressive. Imaging Findings

The neuroimaging characteristics of these tumors are related to their hypercellularity with high nuclearto-cytoplasmatic ratio. Therefore, they are iso- to hyperdense on unenhanced CT, slightly hypointense on T1-weighted images, and iso- to hypointense in T2-

a

weighted images. Contrast enhancement is marked, and may be heterogeneous due to necrotic-cystic changes within the mass. The main differential diagnosis is with hematological disorders, such as chloromas and extramedullary erythropoiesis. Differentiation from a classical Ewing’s sarcoma is based on the absence of any detectable vertebral involvement (Fig. 40.41).

b

Just as in the intracranial compartment, chloromas are the most common extraosseous spinal masses in patients with leukemia. These highly vascularized lesions are composed of immature granulocytes, and are therefore also called granulocytic sarcomas. They are almost exclusively found in patients with acute myeloid leukemia. These masses have a broad meningeal base. Imaging Findings

On MRI, they are iso- to hyperintense on T1-weighted images, iso- to hypointense on T2-weighted images, and show moderate to marked gadolinium enhancement (see Fig. 11.7, Chap. 11). Extreme responsiveness to chemotherapy contraindicates surgery, with the exception of masses causing spinal cord compression.

c

Fig. 40.41a–c. Extraosseous sarcoma in a 3-year-old boy. a Sagittal T1-weighted image; b sagittal T2-weighted image; c Gd-enhanced sagittal T1-weighted image. Huge cervical extradural tumor is not associated with detectable vertebral involvement. Lesion is isointense on both T1- (a) and T2-weighted images (b), consistent with a hypercellular tumor. Enhancement is mild and inhomogeneous (c)

Tumors of the Spine and Spinal Cord

40.4.4.3 Germ Cell Tumors

Germ cell lineage tumors include germinomas, nongerminomatous tumors (i.e., embryonal carcinomas, yolk sac tumors, choriocarcinomas, and teratomas) and mixed tumors. Although rarely reported in the literature [83], the epidural space at lumbosacral level is not an unlikely location of nongerminomatous germ cell tumors in our experience; these have accounted for 30% of tumors of the epidural space in our series, and have often been associated with caudal agenesis (see Fig. 39.68, Chap. 39).

due to the extent of the soft tissue mass, frequent evidence of bony erosion and destruction, and confusing histologic features, such as abundant, pseudosarcomatous cellularity with low to moderate mitotic activity and nuclear atypia [84, 85]. There is no association with neurofibromatosis. The nerve roots of the posterior neck, mediastinum, and retroperitoneum are the most common sites of origin. Most reported patients have been adults [86]. Imaging Findings

Isolated germ cell tumors give nonspecific MRI findings (Fig. 40.42). Association of a large solid mass with caudal agenesis is strongly suggestive. Germ cell tumor markers, such as beta-human-chorionic gonadotropin, alpha-fetoprotein, and placental alkaline-phosphatase, are very helpful adjuncts in the diagnostic workup.

In the spine, we have seen a case of a large epidural soft tissue mass obliterating the lumbar spinal canal. The MRI appearance (Fig. 40.43) was that of a huge soft tissue mass giving homogeneous isointense signal with cord on both T1- and T2-weighted images and enhancing moderately and homogeneously. These features were believed to be consistent with those of a highgrade lesion. The lesion tended to involve the neural foramina, which might have supported a diagnosis of nerve sheath tumor. The diagnosis was histological.

40.4.4.4 Cellular Schwannoma

40.4.4.5 Cavernous Hemangioma

Cellular schwannoma is a variety of peripheral nerve sheath tumor showing a predominantly compact cellular growth. Although benign, this rare tumor can give the erroneous impression of a malignant tumor

Other than within the spinal cord and vertebra (see above), cavernous hemangiomas of the spine may be located in the extradural compartment. These lesions are not tumors, but vascular malformations; however,

Imaging Findings

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Fig. 40.42a–c. Yolk sac tumor in a 17-month-old girl. a Coronal T1-weighted image; b sagittal T2-weighted image; c Gd-enhanced sagittal T1-weighted image. Huge soft tissue mass fills the spinal canal at lumbosacral level. Extradural location is revealed by typical meniscus appearance of the displaced epidural fat (arrowheads, a, c). Tumor is isointense with cord on T1-weighted images (a), hyperintense on T2-weighted images (b), and does not enhance (c)

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1644 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama

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they are briefly mentioned here because they may enter the differential diagnosis with neoplasia. Most lesions are in the thoracic spine and on the dorsal side of the spinal cord [87]. They grow slowly, probably because of recurrent hemorrhaging and thrombotic phenomena with organization and recanalization [88]. The clinical course is slowly progressive, with myelopathy that may be exacerbated by sudden bleeding.

Fig. 40.43a–d. Cellular schwannoma in a 18-month-old girl. a Sagittal T1-weighted image; b sagittal T2-weighted image; c Gdenhanced coronal T1-weighted image; d Gd-enhanced axial T1weighted image. Huge intraspinal lesion extending from L2 to S4 and expanding the spinal canal, with pronounced scalloping of the posterior vertebral walls (arrows, a). The lesion is extradural, as shown by the typical meniscus displacement of the epidural fat (arrowhead, a, c) and deviation of the caudal nerve roots. The tumor is characterized by a slight hyperintensity to cord on T1weighted images (a), marked signal loss resulting in isointensity with cord on T2-weighted images (b), and moderate, homogeneous enhancement (c, d). These features initially suggested a high-grade neoplasm, a hypothesis that was contradicted by histology. The lesion (asterisks, d) extends to the presacral regions through sacral foramina bilaterally (arrows, c, d)

nant blood; they enhance prominently [87–89]. Hemorrhage alters the signal intensity of the mass, which typically will display hyperintense T1 signal and low T2 signal with fresh bleeding (Fig. 40.44). As these lesions are located outside the blood-cord barrier, a hemosiderin ring is uncommon [88]. On CT studies, these neoplasms appear as intermediate or slightly hyperdense extradural masses, frequently found beyond or beneath the intervertebral disk [88].

Imaging Findings

Extradural cavernous hemangiomas typically show paravertebral extension through the intervertebral foramina, have lobulated contours, and tend to encircle the spinal cord [89]. The appearance of these lesions depends on the presence of hemorrhage. Nonhemorrhagic lesions appear iso- to hypointense to the spinal cord on T1-weighted images and hyperintense on T2-weighted images due to the presence of stag-

40.4.5 Extraspinal Tumors with Spinal Invasion 40.4.5.1 Neuroblastoma

Neuroblastomas are solid tumors originating from the neural crests, involving the adrenal glands (40%

Tumors of the Spine and Spinal Cord

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of cases), the paravertebral sympathetic chains (25% of cases), the organ of Zuckerkandl, and the carotid and aortic glomi. They are the most common nonCNS solid tumors in the pediatric age group, and typically affect children younger than 5 years. Urinary secretion of vanillylmandelic and homovanillic acids is very characteristic, although it may not be present in 100% of cases. When present, it is very helpful in confirming the diagnosis. Pathologically, the mass is typically huge, and shows extensive necrotic-hemorrhagic areas and calcification. Histologically, a regular pattern of small rounded cells with high nuclear-to-cytoplasmatic ratio is found, similar to Ewing sarcomas and PNETs. There is a continuous histological spectrum ranging from high-grade forms (neuroblastoma) through intermediate forms (ganglioneuroblastomas), to lowgrade forms (ganglioneuroma). Maturation from high- to low-grade may occur either spontaneously or

Fig. 40.44a–c. Extradural cavernous hemangioma in a 7-yearold boy. a Coronal T1-weighted image; b sagittal T2-weighted image; c axial T1-weighted image. There is an extradural mass at the level of T1–2 on the right. The lesion is spontaneously T1 hyperintense (asterisks, a, c) and markedly T2 hypointense (asterisks, b). The lesion involves the right neural foramen with a nonhemorrhagic hypointense portion (arrowheads, c), and envelops the spinal cord (sc, c)

as a consequence of medical treatment. Unfortunately, there are no radiologic criteria permitting a differentiation of high-grade from low-grade tumors. Children with dumb-bell neuroblastomas are usually younger than 5 years (60% of cases in our series); 40% of our cases affected children younger than 2 years. A wide spectrum of clinical presentations are possible, on account of the variable location and size of the mass. Obviously, neurologic signs are ominous in that they reveal intraspinal extension and spinal cord or nerve root compressions. However, thoracic tumors may become manifest with dyspnea due to occupation of large portions of the chest with atelectasis. A rare, but specific, presentation of neuroblastomas is Kinsbourne syndrome, characterized by the tetrad of opsoclonus (“dancing eyes”), myoclonus, ataxia, and irritability. Kinsbourne syndrome affects 1%–2% of all infants with neuroblastoma, either clinically overt or occult; it is thought to have an immune

1645

1646 P. Tortori-Donati, A. Rossi, R. Biancheri, M. L. Garrè, and A. Cama pathogenesis, due to the interaction between tumor antigens and antibodies with common tumoral and cerebral antigenicity, causing toxic effects on the dentato-rubro-thalamic pathways [90]. Imaging Findings

From a neuroradiological perspective, tumors originating from the paravertebral sympathetic chains are more relevant. Although these large masses prevailingly grow into the chest and/or abdomen, they typically display a “dumb-bell” growth through one or more neural foramina, extending a variably sized component into the spinal canal [91]. These intraspinal extradural masses compress and displace the thecal sac and spinal cord, and may result in permanent neurologic damage if left untreated. Metastases may be found either at presentation or during the follow-up, and may cause vertebral body collapse with spinal cord compression. X-rays may directly show calcified paraspinal masses. More often, indirect signs such as lytic or sclerotic changes in the adjacent bone are seen. Enlargement of one or more neural foramina and widened

interpeduncular distance are found in case of intraspinal development. MRI adequately depicts the intraspinal extension of the mass [91–93] (Figs. 40.45, 46). Often, the intraspinal component extends for variable metameres both cranial and caudad to the entrance foramen. Such development is optimally depicted on the coronal plane. The lesion is usually hypointense on T1-weighted images and iso- to hypointense on T2-weighted images due to high cellularity and nuclear-to-cytoplasmatic ratio. However, necrotic-cystic change, hemorrhage, and calcification result in heterogeneous signal behavior. Contrast enhancement is usually marked. MRI also detects compression and dislocation of the spinal cord. Intramedullary hyperintense signal on T2-weighted images reflects cord edema in the setting of compression-related myelopathy. Metastases are unfortunately common and may involve both the vertebral bodies and the meninges (Fig. 40.47). Differential diagnosis of neuroblastomas is with malignant nerve sheath tumors, which may show an identical appearance on imaging (see Fig. 16.22, Chap. 16).

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Fig. 40.45a–d. Thoracic neuroblastoma with intraspinal invasion in a 6-year-old boy. a Coronal T1-weighted image; b sagittal T2-weighted image; c Gd-enhanced sagittal T1-weighted image; d axial Gd-enhanced axial T1-weighted image. Huge thoracic mass (asterisks, a–d) extends an intraspinal component through four markedly enlarged neural foramina (arrows, a). This component, hypointense on T2-weighted images (b) and enhancing with contrast material administration (black asterisk, c, d), compresses and engulfs the spinal cord (arrow, d). The mass has numerous hemorrhagic components (arrowheads, a). Three pathologic vertebrae are seen (arrowheads, b)

Tumors of the Spine and Spinal Cord

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Fig. 40.46a–c. Retroperitoneal neuroblastoma with bilateral dumb-bell extension in a 3-year-old boy. a Gd-enhanced coronal T1-weighted image; b sagittal T2-weighted image; c Gdenhanced axial T1-weighted image. Coronal image shows large tumor masses to both sides of the lumbar spine (asterisks, a) and a pathologic L4 vertebral body. The size of the intraspinal extradural component is huge (b). Axial image shows bilateral dumb-bell extension through widened neural foramina (double arrows, c) and marked compression of the thecal sac (single arrow, c). Notice marked elevation and displacement of the right psoas muscle (arrowheads, a, c)

c

40.4.5.2 Nerve Sheath Tumors

Both schwannomas and neurofibromas are known for their typical dumb-bell development through an enlarged neural foramen. These tumors are described in greater detail in a previous section, and also in the chapter on phakomatoses (see Chap. 16), as neurofibromas and schwannomas are typically associated with neurofibromatosis type 1 and 2, respectively. Isolated forms do, however, occur (Fig. 40.48). Fig. 40.47. Metastatic neuroblastoma. Gd-enhanced sagittal T1-weighted image. The vertebral bodies are diffusely inhomogeneous due to the presence of hypointense infiltration and hyperintense postirradiation fatty marrow. Furthermore, there is extensive neoplastic leptomeningitis (arrows) with infiltration of the outer aspects of the spinal cord

40.4.5.3 Extramedullary Erythropoiesis

Thalassemic patients may have multiple paravertebral or epidural masses resulting from extramedullary hematopoiesis. These masses are a result of compensatory hypertrophy of hematopoietic bone marrow at the level of the costovertebral junctions

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Fig. 40.48a–d. Dumb-bell schwannoma of the left S1 nerve root in an adolescent. a Sagittal T1-weighted image; b sagittal T2-weighted image; c Gdenhanced axial T1-weighted image; d Gd-enhanced coronal T1-weighted image. There is a rounded, smoothly marginated mass that markedly expands the left S1–2 neural foramen. The lesion is T1 isointense (asterisk, a), T2 hyperintense (asterisk, b), and enhances homogeneously (asterisk, c, d). The bottom of the thecal sac is compressed (arrowhead, c)

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Fig. 40.49a–c. Extramedullary erythropoiesis in a thalassemic boy. a Coronal T1-weighted image; b coronal T2-weighted image; c axial T1-weighted image. Multiple, bilateral paravertebral masses (asterisks) are present. Notice that the intraspinal compartment is spared. Abnormal tissue is T1 isointense (a, c) and T2 hyperintense (b)

b

or vertebral bodies. Typically, there are paravertebral masses that abut the external orifice of the neural foramina without extending into the spinal canal [94] (Fig. 40.49); however, spinal cord compression from epidural masses has been reported [94, 95].

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Infectious and Inflammatory Disorders of the Spine

41 Infectious and Inflammatory Disorders of the Spine Mauricio Castillo and Paolo Tortori-Donati

41.1 Introduction

CONTENTS 41.1

Introduction 1653

41.2

Disorders Predominantly Affecting the Spinal Cord 1653 Acute Transverse Myelopathy 1654 Idiopathic ATM 1654 Acute Disseminated Encephalomyelitis 1655 Multiple Sclerosis 1658 Devic’s Disease (Neuromyelitis Optica) 1659 Spinal Cord Infections 1660 Spinal Cord Abscess/Granuloma 1660 Viral Myelitis 1662 Parasites 1663

41.2.1 41.2.1.1 41.2.1.2 41.2.1.3 41.2.1.4 41.2.2 41.2.2.1 41.2.2.2 41.2.2.3 41.3 41.3.1 41.3.1.1 41.3.2 41.3.2.1 41.3.3 41.3.3.1 41.3.3.2 41.3.3.3 41.3.4 41.3.4.1 41.4 41.4.1 41.4.1.1 41.4.1.2 41.4.2 41.4.2.1 41.4.2.2 41.4.2.3

Disorder Predominantly Affecting the Nerve Roots and the Meninges 1664 Bacterial Meningitis 1664 Imaging Studies 1664 Acute Demyelinating Polyradiculoneuritis (Guillain-Barré Syndrome) 1665 Imaging Findings 1665 Hereditary Polyneuropathies 1665 Hereditary Motor and Sensory Neuropathies 1665 Hereditary Sensory and Autonomic Neuropathies 1670 Metabolic and Degenerative CNS Disorders 1670 Arachnoiditis 1670 Imaging Findings 1671 Disorders Predominantly Affecting the Vertebra, Discs, and Epidural Space 1671 Inflammatory Diseases 1671 Juvenile Rheumatoid Arthritis 1671 Juvenile Ankylosing Spondylitis 1672 Infectious Diseases 1673 Infectious Discitis and Osteomyelitis 1673 Tuberculous Spondylodiscitis 1674 Epidural Abscess 1675 References

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Inflammatory and infectious disorders of the spine are less common in children than in adults. The most common infectious spinal disorder in children is bacterial meningitis, which generally does not require imaging studies and is diagnosed and treated on a clinical and physical examination basis. In bacterial meningitis, imaging studies are reserved for patients suspected of harboring complications from the disease. For purposes of clarity, inflammatory and infectious spinal disorders in childhood will be divided as follows: 쐌 those predominantly affecting the spinal cord, 쐌 those predominantly affecting the nerve roots and meninges, 쐌 those predominantly affecting the vertebrae, discs, and epidural space. The use of magnetic resonance imaging (MRI) and, when needed, computed tomography (CT) and radiographs will be emphasized. Although many of the disorders discussed in this chapter also show brain abnormalities, discussions will be limited to the abnormalities found in the spine and spinal cord.

41.2 Disorders Predominantly Affecting the Spinal Cord Disorders primitively involving the spinal cord may be grouped into two basic categories: (1) inflammatory, basically represented by acute transverse myelopathy, and (2) infectious, which in turn may be bacterial, viral, fungal, or parasitic. Inflammatory spinal cord diseases are much more frequent than primitive spinal cord infection.

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1654 M. Castillo and P. Tortori-Donati 41.2.1 Acute Transverse Myelopathy Acute transverse myelopathy (ATM) is a focal inflammatory disorder of the spinal cord resulting in motor, sensory, and autonomic dysfunction. Individuals of all ages may be affected, with bimodal peaks between the ages of 10 and 19 years and 30 and 39 years. Although the terms “acute transverse myelopathy” and “acute transverse myelitis” have often been used interchangeably, the former is a broad header that includes idiopathic forms (corresponding to acute transverse myelitis) and forms with known cause, such as postinfectious/postvaccination (i.e., acute disseminated encephalomyelitis–ADEM), Devic’s disease, multiple sclerosis, ischemic, paraneoplastic, autoimmune, and postirradiation myelitis. 41.2.1.1 Idiopathic ATM

Clinical presentation is with pain, paresthesias, leg weakness, and sphincter dysfunction, all of which progress to nadir between 4 h and 21 days (usually 24 h) following the onset of symptoms. It is believed that stroke-like evolution (i.e., nadir reached earlier than 4 h) indicates vascular causes (spinal cord infarction). Signs and/or symptoms are usually bilateral, though not necessarily symmetric, and there usually is a clearly defined sensory level. Cerebrospinal fluid

(CSF) analysis reveals signs of spinal cord inflammation, such as pleocytosis or elevated IgG index. The diagnosis of idiopathic ATM (Table 41.1) is one of exclusion, and basically involves three consecutive steps, as follows [1]: 1. Rule out compressive etiology: this requires contrast enhanced MRI of the entire spinal cord; if cord compression is ruled out and MRI indicates primary spinal cord involvement, MRI of the brain should also be performed; 2. Define presence or absence of spinal cord inflammation by performing lumbar puncture with CSF analysis; 3. Define extent of demyelination: brain MRI is analyzed for signs of involvement of the white matter and optic nerves. If none is found, idiopathic ATM is likely. If the white matter is involved, ADEM or multiple sclerosis should be considered. Finally, if the optic nerves are the only involved structure, Devic’s disease is likely. Visual evoked potentials are a very significant diagnostic adjunct. Imaging Findings

MRI criteria for “myelitis” (Fig. 41.1) [2, 3] include normal or slightly expanded spinal cord showing diffuse or patchy hyperintensity on T2-weighted images, usually involving more than one vertebral level in length. There may be patchy enhancement after gadolinium administration. The conus medullaris is involved more frequently.

Table 41.1 Criteria for idiopathic ATM Inclusion criteria

Exclusion criteria

Development of sensory, motor, or autonomic dysfunction attributable to the spinal cord Bilateral signs and/or symptoms (though not necessarily symmetric)

History of previous radiation to the spine within the last 10 years Clear arterial distribution or clinical deficit consistent with thrombosis of the anterior spinal artery Abnormal flow voids on the surface of the spinal cord c/w AVM Serologic or clinical evidence of connective tissue disease (sarcoidosis, Behçet’s disease, Sjögren’s syndrome, SLE, mixed connective tissue disorder, etc.)* CNS manifestations of syphilis, Lyme disease, HIV, HTLV-1, Mycoplasma, other viral infection (e.g., HSV-1, HSV-2, VZV, EBV, CMV, HHV-6, enteroviruses)*

Clearly defined sensory level Exclusion of extra-axial compressive etiology by neuroimaging (MRI or myelography; CT of spine not adequate) Inflammation within the spinal cord demonstrated by CSF pleocytosis or elevated IgG index or gadolinium enhancement If none of the inflammatory criteria is met at symptom onset, repeat MRI and lumbar puncture evaluation between 2 and 7 d following symptom onset meet criteria Progression to nadir between 4 h and 21 d following the onset of symptoms (it patient awakens with symptoms, symptoms must become more pronounced from point of awakening)

Brain MRI abnormalities suggestive of MS*

History of clinically apparent optic neuritis * Do not exclude disease-associated ATM AVM arteriovenous malformation, SLE systemic lupus erythematosus, HTLV-1 human T-cell lymphotropic virus-1, HSV herpes simplex virus, VZV varicella zoster virus, EBV Epstein-Barr virus, CMV cytomegalovirus, HHV human herpes virus. From [1]

Infectious and Inflammatory Disorders of the Spine

Prognosis of idiopathic ATM is variable, with 1/3 of patients recovering with few or no sequelae (Fig. 41.2), 1/3 left with moderate degree of permanent disability, and 1/3 having severe disabilities (Fig. 41.3) [1]. Rapid progression of signs and symptoms at presentation usually portends a poorer prognosis. 41.2.1.2 Acute Disseminated Encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) has been associated with viral infections or vaccination.

a

d

b

Postinfectious ADEM has been related to viruses such as measles, rubella, chickenpox, mumps, influenza, Epstein-Barr virus, Coxsackie B, cytomegalovirus, herpes simplex virus, hepatitis A virus, adenoviruses, as well as with Borrelia, Mycoplasma pneumoniae, and nonspecific infection of the upper respiratory tract. Postvaccination ADEM can be induced by several vaccines, including polio, rabies, smallpox, influenza, rubella, and plasma-derived form of hepatitis B [4]. In most patients, postvaccination myelitis is a presumptive diagnosis based on the temporal rela-

c

e

Fig. 41.1a–e. Idiopathic acute transverse myelitis in a 14-year-old girl. a Sagittal T1-weighted image; b sagittal T2weighted image; c Gd-enhanced sagittal T1-weighted image; d axial T2-weighted image; e Gd-enhanced axial T1-weighted image. There is a slightly swollen lower thoracic cord and conus medullaris showing hyperintensity on T2-weighted images (arrows, b, d) and mild contrast enhancement (arrows, c, e). Signal abnormalities prevail in the posterior portion of the cord in this case

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1656 M. Castillo and P. Tortori-Donati

a

d

b

e

tionship between vaccine administration and onset of symptoms. Most reactions to the live poliovirus vaccine manifest as clusters of Guillain-Barré-like illness, and occur 40–50 days after the administration of the vaccine; imaging findings are identical to those described for poliomyelitis (see below). ADEM secondary to hepatitis B vaccination is rare, but its incidence is increasing due to the widespread use of this vaccine in children [5]; symptoms generally occur 1–3 weeks after vaccination. ADEM may also occur

c

f

Fig. 41.2a–f. Idiopathic acute transverse myelitis in a 13-year-old boy: findings at presentation and during follow-up. a Sagittal T1weighted image; b sagittal T2-weighted image and c Gd-enhanced sagittal T1weighted image at presentation. There is a slightly swollen conus medullaris showing T2 hyperintensity that prevails anteriorly (arrows, b). Absence of enhancement shows there is no blood-cord barrier breakdown. d Sagittal T1-weighted image; e sagittal T2-weighted image and f Gd-enhanced sagittal T1weighted image at 20 days follow-up. Findings are now back to normal (arrows, e)

after vaccination for tetanus; unlike other postvaccination reactions, transverse myelitis occurs acutely after the vaccine is given. Finally, some vaccines, such as DPT (diphtheria-pertussis-tetanus) and influenza, may result in a polyneuropathy. Unlike idiopathic ATM, ADEM typically is characterized by extensive involvement of the brain (see Chap. 15). About 30% of patients with ADEM will also show lesions in their spinal cord [6]. The process usually is monophasic, i.e., it occurs once in the

Infectious and Inflammatory Disorders of the Spine

a

b

c

d

e

f

g

h

Fig. 41.3a–h. Idiopathic acute transverse myelitis in a 12-year-old boy: findings at presentation and during follow-up. a Sagittal T1-weighted image and b sagittal T2-weighted image on admission. There are not clear-cut abnormalities. c Sagittal T1-weighted image, d sagittal T2-weighted image and e Gd-enhanced sagittal T1-weighted image after 1 day. Slight swelling and clear-cut T2 hyperintensity of the lower thoracic cord and conus medullaris (arrows, d) are now visible. Notice that there is no contrast enhancement. f Sagittal T1-weighted image, g sagittal T2-weighted image and h Gd-enhanced sagittal T1-weighted image after 10 days. Clinical picture is not significantly modified despite medical treatment. T2 signal alterations are now reduced at the conus medullaris, although a hyperintense focus is now visible more cephalically (arrowhead, g). Notice, however, disruption of the blood-cord barrier, revealed by patchy contrast enhancement (arrows, h). Long-term evolution was towards cord atrophy with significant residual disability

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1658 M. Castillo and P. Tortori-Donati life of the patient. However, acute relapsing-remitting disseminated encephalomyelitis (ARDEM) has also been documented [5]. The disorder commonly begins 1–2 weeks after a viral, and seemingly minor, illness. Often, the initial illness may be subclinical. Once the symptoms are present, they become more obvious 1–2 days after the diagnosis but may progress for up to 2 weeks. CSF analysis may show increased proteins and leukocytosis. The thoracic spinal cord is involved more often than the cervical region. Histologically, there is necrosis and inflammation; perivascular lymphocytic infiltration and demyelination also are present.

cauda equina may also be seen, suggesting that transverse myelitis and Guillain-Barré syndrome may have a similar etiology. In one series, contrast enhanced MRI was able to detect abnormalities in the spinal cords of only 40% of patients [8]. It has been suggested that the following MRI findings may be helpful in distinguishing idiopathic ATM from ADEM: normal size or segmental enlargement of the cord, most commonly thoracic; central hyperintensity in T2-weighted images affecting three to four vertebral levels; central dot into the core of hyperintensity; and focal nodular or diffuse contrast enhancement at the periphery of the spinal cord [3].

Imaging Findings

41.2.1.3 Multiple Sclerosis

MRI is the best method to assess these patients. T2-weighted images may show multiple, more or less well-defined areas of increased signal intensity within the cord (Fig. 41.4) [7]. Some of these regions may be confined to the gray matter, others are located in the white matter, and some involve both. Holocord involvement is possible. Segmental disease generally involves 2–3 vertebral bodies in length, and may expand the cord slightly. In ADEM, generally there is no enhancement after gadolinium administration, while enhancement is not uncommon in idiopathic ATM [2]. In the latter condition, enhancement of the

Multiple sclerosis (MS) is rare in children, and spinal cord involvement is even rarer (see Chap. 15). Spinal cord plaques occur preferentially in the dorsolateral cord, and may be found at any segment [9, 10]. A predilection for the cervical segment has been reported in the early stages of the disease [10]. Imaging Findings

The MRI findings in childhood and juvenile MS mimic those of adult-onset MS [11]. T2-weighted

a Fig. 41.4a,b. Acute disseminated encephalomyelitis in a 14-year-old comatose girl 10 days after onset of tonsillitis. a Axial FLAIR image of the brain; b sagittal T2-weighted image of the spinal cord. Severe and diffuse ADEM. Multiple areas of abnormal signal intensity involve the brain and the whole spinal cord (arrowheads, b)

b

Infectious and Inflammatory Disorders of the Spine

images show one or more elongated, poorly marginated, hyperintense intramedullary lesions (Fig. 41.5). Acute demyelinating lesions may display mass effect and enhance after gadolinium administration [10] (Fig. 41.6). Tumefactive plaques in the spinal cord have been reported in association with swelling and MR signal changes mimicking a neoplasm [12].

Fig. 41.5. Multiple sclerosis in an adolescent. Sagittal T2weighted image. Patchy areas (arrows) of increased signal intensity in the spinal cord are evident

41.2.1.4 Devic’s Disease (Neuromyelitis Optica)

Devic’s disease is defined as a monophasic or multiphasic illness involving severe ATM, acute unilateral or bilateral retrobulbar optic neuropathy, and no clinical involvement beyond the spinal cord or optic nerves [13]. Optic neuritis precedes or is simultaneous with ATM in 80% of cases (usually < 3 months), whereas ATM precedes optic neuritis in 20% of cases. Whether Devic’s disease is a variant of MS or an autonomous entity has been the subject of much debate. Although initially considered to represent a variant of MS, Devic’s disease is now regarded a separate entity. Differential criteria include clinical, laboratory, and imaging findings [13]. Clinical features include (1) involvement of the brain is absent in Devic’s and present in MS, (2) optic neuritis is usually bilateral in Devic’s and unilateral in MS, and (3) ATM is a very uncommon presentation of MS, whereas it is found in 20% of Devic’s cases. CSF findings show (1) presence of neutrophils and markedly elevated proteins in Devic’s, as opposed to MS, and (2) oligoclonal bands are found in 90% of MS cases. On imaging, (1) brain white matter lesions are typically absent in Devic’s, and (2) swelling and cavitation of the spinal cord is much more common in Devic’s than in MS.

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Fig. 41.6a–d. Multiple sclerosis: tumefactive plaque. a, b Sagittal T2-weighted images; c axial T2-weighted image; d Gd-enhanced axial T1-weighted image. Hyperintense area within the left lateral bundle at the level of the vertebral body of C4 (arrows, a–c). The spinal cord is swollen and shows marked enhancement (arrow, d)

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1660 M. Castillo and P. Tortori-Donati Histologically, there is demyelination and necrosis but little or no inflammation. Devic’s disease affects females more often than males and is mostly a disease of adults, although it occasionally is seen in children. Imaging Findings

MRI shows areas of high T2 signal intensity into the spinal cord [14]. These lesions are generally, but not necessarily, longer than two vertebral bodies; they occasionally involve the entire span of the cord, and may enhance with gadolinium administration. The cord may be expanded and may show cavitation (see Fig. 15.4, Chap. 15). Although the zones of necrosis

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Fig. 41.7a,b. Devic’s disease in a 11-year-old girl. a Sagittal proton-density-weighted image; b Gd-enhanced sagittal T1weighted image. This girl presented with bilateral optic neuritis, paraparesis, and interscapular pain. Long TR images show slight spinal cord swelling with diffuse hyperintensity (a). Contrastenhanced image shows central spinal cord cavitation with mild, inhomogeneous marginal enhancement (arrows, b) Table 41.2. Organisms more frequently involved in spinal cord infections Streptococci Staphylococci Mycobacteria Toxoplasma Listeria Fungi Viruses Schistosoma

may contain hemorrhage, this is not evident on imaging studies. Differential diagnosis with intramedullary tumors may be difficult if the cavity is huge and enhancement is marked [15] (Fig. 41.7); however, spinal cord tumors markedly expand the cord and, often, the spinal canal, while Devic’s disease does not.

41.2.2 Spinal Cord Infections 41.2.2.1 Spinal Cord Abscess/Granuloma

Bacterial spinal cord abscesses are extremely rare [16]. Children may account for up 20%–50% of cases in some series. Among causative organisms (Table 41.2) [16, 17], Schistosoma is particularly common in children. Tuberculosis is also gaining new ground in Western countries. Fungal infections may also involve the spinal cord and produce granulomas. Fungal disease include Candida, Aspergillus, and Nocardia. These are mostly seen in adults who are immunosuppressed, i.e., organ-transplantation patients or those with acquired immunodeficiency syndrome (AIDS). Predisposing conditions include congenital heart disease, disorders of the immune system, patients harboring long-term intravascular access lines, underlying spinal cord tumors, and dermal sinuses. Dermal sinuses may give rise to intraspinal abscesses outside and inside of the spinal cord [18] (see Chap. 39). Most patients have a history of infection elsewhere and spinal cord involvement may be secondary to either hematogenous or lymphatic spread. The process begins as a myelitis and, if left untreated, may progress to frank abscess formation. Imaging Findings

MRI shows increased T2 signal intensity and expansion of the cord. A thin hypointense stripe surrounding the lesion indicates a capsule. After contrast administration there is ill- or well-defined marginal enhancement according to the stage of the inflammatory process [16] (Figs. 41.8, 9). Fungal disease tends to produce multiple lesions that may be small, solid, or enhance in a ring-like pattern. They are accompanied by high T2 signal intensity extending beyond the area of enhancement. After initiation of treatment, the signal on T2-weighted images decreases and ring enhancement becomes prominent. With adequate therapy, the enhancement slowly resolves.

Infectious and Inflammatory Disorders of the Spine

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Fig. 41.8a–d. Spinal cord abscess/granuloma in a 10-year-old boy, immunosuppressed due to chronic myeloid leukemia. a Sagittal T2-weighted image; b Gd-enhanced fat-suppressed sagittal T1-weighted image; c, d Gd-enhanced coronal T1-weighted images. There is a small intramedullary lesion showing a tiny hypointense periphery on T2-weighted images (arrowhead, a) and a strongly enhancing capsule (arrowhead, b). Brain imaging shows additional ring-enhancing lesions in the right cerebellar hemisphere (arrow, c) and left parietal lobe (arrow, d). Candidosis was eventually diagnosed. (Courtesy of Dr. Majda Thurnher, Vienna, Austria)

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Fig. 41.9a–c. Tubercular myelitis and granulomas. a Sagittal T1-weighted image; b sagittal T2-weighted image and c Gd-enhanced sagittal T1-weighted image. In this patient with known tuberculosis, there is marked swelling of the thoracic cord showing increased T1 and T2 relaxation times (arrow, a–c). Discrete intramedullary nodular lesions show higher T1 signal, lower T2 signal, and ring-like enhancement (arrowhead, a–c). (Courtesy of Dr. Turgut Tali, Ankara, Turkey)

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1662 M. Castillo and P. Tortori-Donati 41.2.2.2 Viral Myelitis

Viral myelitis may be due to poliovirus, herpes zoster infection, and cytomegalovirus (CMV), especially associated with AIDS. Poliomyelitis

Poliomyelitis is very uncommon today [19]. Most cases of polio and polio-like clusters are related to prior vaccination (particularly the “live” type). The risk of developing poliomyelitis after oral vaccination is 1:2,500,000 doses. Poliomyelitis may also be encountered in immunosuppressed patients. The spread of the disease is generally via the fecal-oral route. Only 7–10 cases per year are reported in the United States. Most cases of poliovirus infection are asymptomatic, and many present with only nonspecific aseptic meningitis. Only the paralytic type of the disease will be addressed here. This type of the disease predominantly affects the motor neurons. Spinal cord involvement predominates in about 50% of polio patients and is the most common variant of the disease encountered in children. The classic clinical presentation is that of fever, nuchal rigidity, and spasm of the paraspinal muscles. Rapid progression of symptoms may occur and portrays a poor prognosis. Weakness generally is asymmetric, and quadriplegia is common in patients under

1 year of age. CSF analysis shows slightly elevated proteins and mononuclear cells; analysis for viral DNA in the CSF makes the diagnosis fast and reliable. Histologically, there is parenchymal and perivascular inflammation, gliosis, and destruction of the anterior horn cells leading to atrophy. Treatment is supportive. MRI is the imaging method of choice when poliomyelitis is suspected. The spinal cord shows increased T2 signal intensity involving the ventral gray matter horns [19]. The cord may be mildly expanded at that level. The lesions enhance, and the anterior roots of the cauda equina may also enhance (Fig. 41.10). Similar findings to those described for the lumbar region may be seen elsewhere in the spine (Fig. 41.10). The brainstem may also be involved, and this involvement may be documented by MRI [20]. Herpes Zoster

Myelitis secondary to herpes zoster infection has also been reported [21]. The symptoms and MRI findings generally correspond closely with the dermatomal distribution of the lesions. The presence of a sensory abnormality accompanied by the characteristic vesicular rash should make one suspect a herpes zoster myelitis. The cases reported, and the ones that I (MC) have seen, show fairly typical imaging characteristics. In T2-weighted images, the spinal cord shows a focal, somewhat rounded, hyperintense lesion involving

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Fig. 41.10a–d. Poliomyelitis. Two different cases. Case #1: a, b. Gd-enhanced axial T1weighted images. Case #2: c Gd-enhanced sagittal T1-weighted image; d Gd-enhanced axial T1-weighted image. Gd-enhanced axial T1-weighted images show enhancement in the anterior gray matter horns at the level of the conus medullaris (curved arrows, a). The anterior roots in the cauda equina also enhance (arrows, b). In a different patient with Chiari I malformation, sagittal and axial images of the cervical spine show mild enhancement (arrows, c, d) in the anterior gray matter horns

Infectious and Inflammatory Disorders of the Spine

one half of the cord ipsilateral to the cutaneous rash (Fig. 41.11). Contrast enhancement may occur. It is not clear if the myelitis is due to an allergic reaction, autoimmune vasculitis, demyelination, or as a result of direct viral infection. Viruses are generally absent in the CSF. Cytomegalovirus

Cytomegalovirus (CMV) may also involve the spinal cord and the nerve roots. Most patients are adults. MRI with gadolinium shows contrast enhancement in the posterior aspect of the cord, particularly in the lower thoracic segment. The enhancing lesion extends to the dura occasionally. The surface of the spinal cord may show a somewhat nodular pattern of enhancement. In T2-weighted images, the cord shows long segments of hyperintensity. The dorsal nerve roots of the cauda equina may enhance (Fig. 41.12). Patients with this disease typically have AIDS. Human Immunodeficiency Virus

AIDS patients may present with a myelopathy [22]. This myelopathy is thought to be a direct injury by the human immunodeficiency virus. Histologically, it results in vacuolar degeneration. There is demyelination of the posterior and lateral columns. On MRI, there is high T2 signal in the regions of myelopathy; these areas may enhance after gadolinium is given. The findings are nonspecific, and seldom encountered in children. Enterovirus 71

Enterovirus 71 (EV71) infection is an emerging epidemic disease associated with childhood acute flaccid paralysis. The most typical spinal MRI findings are

those of unilateral involvement of the anterior horn cells of the spinal cord and ventral roots, appearing as hyperintense lesions on T2-weighted images. Following contrast administration, enhancement of the ventral roots, sometimes associated with enhancement of the anterior horn cells, may be seen. Bilateral anterior horn abnormalities have been associated with poor outcome [23]. 41.2.2.3 Parasites

Among parasitic infections, cysticercosis is the most common form affecting the central nervous system [24, 25] (see Chap. 12). Involvement of spinal cord occurs in about 5% of patients with cerebral cysticercosis [26]. In my (MC) experience, spinal cord cysticercosis in children is very rare. Most cysticercosis in the spine actually occurs within the subarachnoid spaces. These lesions are cystic with or without areas of enhancement similar to those found in the intracranial cisterns. Most parasites lodge in the distal thecal sac. Classically, the cysts are known to move according to the position of the patient. Since myelography is no longer commonly employed in these patients, this feature is seldom seen. Most intramedullary spinal cord lesions that I (MC) have seen are either cystic (Fig. 41.13) or cystic with a peripheral nodule of contrast enhancement, or appear as nonspecific ring-enhancing lesions which may also have surrounding edema. In some cases of spinal cord cysticercosis surgery may be indicated. Surgery may be reserved for patients with severe neurological deficits. Myelotomy with delivery of the cysts is performed. With surgery, even patients with paraplegia may have a favorable outcome.

Fig. 41.11a–d. Herpes zoster myelitis. a Gd-enhanced sagittal T1-weighted image; b axial gradient-echo T2*-weighted image; c Gd-enhanced axial T1-weighted image. There is an area of demyelination involving the right lateral spinal cord bundle at level of C3 (arrow, b), showing marked gadolinium enhancement (arrow, a, c)

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1664 M. Castillo and P. Tortori-Donati and physical examination basis. Infectious agents may enter the CNS through hematogenous spread, direct implantation (usually traumatic), local extension (secondary to sinusitis, mastoiditis, otitis, brain abscesses) and spread along the peripheral nervous system. Etiologies vary with patient age. In neonates, Streptococcus group B infections account for nearly 50% of cases, followed by E. coli and Listeria. In young infants, Haemophilus influenzae accounts for about 40%–60% of cases, followed by Neisseria meningitidis and Pneumococcus. In older children and adults, Pneumococcus, Neisseria meningitidis, and Staphylococcus are the main causative agents. 41.3.1.1 Imaging Studies Fig. 41.12. Cytomegalovirus myelitis and radiculitis. Gdenhanced axial T1-weighted image. There is marked enhancement (arrows) of the dorsal roots of the cauda equina

41.3 Disorder Predominantly Affecting the Nerve Roots and the Meninges 41.3.1 Bacterial Meningitis Bacterial meningitis is an infectious process involving the dura, leptomeninges, and CSF. Although it is the most common infectious spinal disorder in children, imaging studies are usually not required, and the condition is diagnosed and treated on a clinical

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The hallmark of acute-stage bacterial meningitis is infiltration of the arachnoid with inflammatory cells. In this stage, a purulent exudate diffusely covers the surface of the brain and spinal cord. This results in enhancement of the surface of the spinal cord and nerve roots on contrast-enhanced MRI. Imaging studies are usually reserved for patients suspected of harboring complications from the disease, rather than for establishment of the diagnosis. However, neuroimaging has allowed early and precise etiologic diagnosis, monitoring of treatment, and identification of complications, thereby resulting in decreased morbidity and mortality. On imaging, differential diagnosis is basically with diffuse leptomeningeal carcinomatosis (so-called neoplastic leptomeningitis). However, the latter occurs only in presence of CNS malignancy.

Fig. 41.13a,b. Cysticercosis. a Sagittal T1-weighted image; b sagittal T2-weighted image. Sagittal T1-weighted image (a) shows a cystic lesion in the lower thoracic spinal cord. On T2-weighted image, the lesion is hyperintense (b)

Infectious and Inflammatory Disorders of the Spine

41.3.2 Acute Demyelinating Polyradiculoneuritis (Guillain-Barré Syndrome) Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating disorder involving the spinal and peripheral nerves [27, 28]. It is presumably caused by a prior viral disease, and such a prodromal illness, usually a respiratory illness or gastroenteritis within 2 weeks before onset, may be identified in about 65% of patients; an autoimmune mechanism directed against Schwann cells is considered to play an important role. GBS usually occurs in children, especially males, between 4 and 12 years of age. Clinically, it is characterized by acute onset of lower extremity weakness, progressing to paralysis and ascending to involve the upper limbs, diaphragm, and possibly cranial nerves. Sensory disturbances may be present in up to 40% of cases, and are represented by pain (perhaps the earliest clinical symptom), and paresthesia. Paralysis of the respiratory muscles is a common complication (Table 41.3). GBS progresses rapidly, then plateaus, and resolves or improves over a period of 2–18 months. Histologically, there is demyelination and acute mononuclear cells. The nerves become thick and swollen. CSF analysis shows elevation of proteins during the initial part of the disease and a lack of inflammatory cells. If the weakness becomes progressive and lasts for more than 2 months, the patients are said to have a chronic inflammatory demyelinating polyneuropathy. This type of polyneuropathy is said to comprise about 10% of pediatric neuropathies. Plasmapheresis is effective in adults when performed early in the course of the disease; favorable results have been reported also in children [4]. Intravenous immunoglobulins are considered to be an effective and safe treatment [4]. 41.3.2.1 Imaging Findings

MRI findings reflect the pathology of the disease [29]. After gadolinium administration, there is enhancement predominantly of the anterior nerve roots of the cauda equina (Fig. 41.14). Although the nerve roots are thickened, they do not display hyperintensity on T2-weighted images. Therefore, unenhanced studies are usually inconclusive (Fig. 41.15). Enhancement of posterior nerve roots may also occur, to the extent that in some cases there will be global thickening and enhancement of the whole cauda equina (Fig. 41.16). Posterior nerve root involvement may initially pre-

Table 41.3. Clinical manifestations of Guillain-Barré syndrome Onset of disease at about 7 years of age Slightly more common in boys Weakness in nearly 75% of patients Pain in 55% of patients Ataxia in 44% of patients Paresthesias in 20% of patients Shortness of breath is rare and may indicate bulbar involvement

vail, especially when pain predominates (Fig. 41.17). It should be underlined that in the very early stage of disease enhancement may be mild, if not thoroughly absent. Usually, progression to global enhancement of both anterior and posterior nerve roots occurs in a matter of a few days. On occasion, the anterior gray matter horns in the distal spinal cord will also show contrast enhancement and hyperintensity on T2-weighted imaging. Involvement of cranial nerves in the same inflammatory process is called Miller-Fisher syndrome [30]. Affected patients complain with ophthalmoplegia, ptosis, facial weakness, and ataxia. MRI shows enhancement of multiple cranial nerves (Fig. 41.18). Differential diagnosis is with neuroborreliosis (Lyme disease) (see Fig. 12.43, Chap. 12).

41.3.3 Hereditary Polyneuropathies Hereditary neuropathies may occur as isolated forms, in association with CNS involvement, or as part of multisystem disorders [28]. 41.3.3.1 Hereditary Motor and Sensory Neuropathies

The most common degenerative disorders of the peripheral nervous system in childhood are represented by hereditary motor and sensory neuropathies (HMSNs) [1, 28] (Tables 41.4, 5). HMSN Type I

HMSN type I is genetically heterogeneous, usually showing a dominant inheritance, although autosomal recessive and X-linked cases have been reported [31]. It is generally referred as Charcot-Marie-Tooth disease type 1 (CMT 1). Most cases (CMT 1A) are due to duplication within band 17p11.2 which includes the gene encoding peripheral myelin protein 22 (PMP22). CMT 1B is related to mutations of the P0 gene that

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1666 M. Castillo and P. Tortori-Donati Table 41.4. Classification of the hereditary motor and sensory neuropathies (HMSNs)

Table 41.5. HMSN types I, II, III: pathologic and imaging findings

HMSN type I Charcot-Marie-Tooth (CMT) 1A, 1B, 1C HMSN type II CMT 2A, 2B HMSN type III Déjerine-Sottas X-linked CMT Complex forms* With spasticity (type V) With optic atrophy (type VI) With deafness (type VII) With pigmentary retinopathy (type VIII)

HMSN type

Pathologic findings

Imaging findings

Type I: Hypertrophic Charcot-MarieTooth Type II: Neuronal CharcotMarie-Tooth Type III: Déjerine-Sottas

Segmental demyelination, few “onion bulbs,” few enlarged nerve roots Segmental demyelination, no “onion bulbs,” no enlarged nerve roots Segmental demyelination, many “onion bulbs,” many enlarged nerve roots

Occasional enlarged nerves roots of cauda equina No specific imaging findings Many enlarged peripheral or spinal nerves roots, ± enlarged cranial nerves

* Classification still uncertain. Refsum syndrome, sometimes termed HMSN type IV, is usually not included among the HMSN. From [31], modified

From [35], modified

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maps to chromosome 1q21–23, while CMT 1C shows no linkage to chromosomes 1 or 17. The clinical onset of CMT 1 is usually in the first decade of life, and is characterized by foot deformity or gait disturbances. Disease progression is slow. Spinal deformities will develop in about 10% of patients.

Fig. 41.14a–c. Guillain-Barrè syndrome in a 2-year-old boy. a Gd-enhanced sagittal T1-weighted image; b, c Gd-enhanced axial T1-weighted images. There is enhancement of the anterior nerve roots of the cauda equina (arrows, a–c). Posterior nerve roots are not involved

Pathologically, it is characterized by extensive segmental demyelination-remyelination with development of “onion bulbs” around the nerve fibers. Degeneration of the posterior columns, loss of anterior horn cells, and degeneration of the anterior and posterior spinal roots have been described in postmortem examinations [31].

Infectious and Inflammatory Disorders of the Spine

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Fig. 41.15a–c. Guillain-Barrè syndrome in a 10-year-old girl. a Sagittal T1-weighted image; b sagittal T2-weighted image; c Gd-enhanced sagittal T1-weighted image. Both unenhanced T1- and T2-weighted images are unrevealing (a, b). Pathology is only disclosed by contrastenhanced imaging (arrows, c)

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Fig. 41.16a–f. Guillain-Barrè syndrome in a 4-year-old girl. a–c Gd-enhanced sagittal T1-weighted images; d–f. Gd-enhanced axial T1-weighted images. There is global thickening and enhancement of both anterior and posterior nerve roots of the cauda equina

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Fig. 41.17a–f. Guillain-Barrè syndrome in a 1-year-old boy. a–c Gd-enhanced sagittal T1-weighted images; d–f Gd-enhanced axial T1-weighted images. Enhancement prevails in the posterior nerve root groups (arrows, a, c–f)

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Fig. 41.18a–c. Miller-Fisher syndrome in a 7-year-old boy. a–c Gd-enhanced axial T1-weighted images. There is symmetric enhancement of the facial nerves (arrows, a), abducens nerves (arrowheads, a), trigeminal nerves (thick arrows, b), and oculomotor nerves (open arrows, c). This patient also had diffuse enhancement of the caudal nerve roots (not shown)

MRI shows significant thickening of the nerve roots in both their intradural and extradural segments (Fig. 41.19) [32]. This may be seen in the cervical, thoracic, and lumbar regions. The thick nerve roots usually show no contrast enhancement [32]. However, enhancement of hypertrophic spinal nerve roots and

ganglia has been reported in a case of CMT 1 with atypical manifestations, such as progressive bladder dysfunction and severe low back pain (Fig. 41.20) [33]. The dorsal root ganglia will also eventually become thick. Spinal cord impingement from enlarged intradural roots has been reported [33, 34].

Infectious and Inflammatory Disorders of the Spine

HMSN Type II

HMSN type II corresponds to the classic description of CMT disease [32]. It usually is inherited as an autosomal dominant trait, although autosomal recessive forms are known. The clinical picture is similar to that of HMSN type I with a later onset (during the second or third decade) and a slower course. Contrary to the type I disease, axonal degeneration is the main pathological finding and no “onion bulbs” are present. There are no specific imaging findings of HMSN type II. HMSN Type III

HMSN type III, also known as Déjerine-Sottas disease (DSD) [32], is a highly heterogeneous group of

neuropathies with variable age of onset and clinical severity. The most typical form is characterized by hypotonia and slow motor development presenting during the first year of life. Pathological findings are similar to those of HMSN type I, but more severe [31]. The congenital forms of hereditary neuropathies, including hypomyelinating neuropathies with “onion bulbs,” are usually considered as HMSN type III forms [31]. Approximately 15% of cases of DSD show cranial nerve involvement [35]. Imaging findings are similar to those described above for HMSN type I. Abnormal thickening and clumping of the spinal nerve roots of the cauda equina, either with normal signal intensity [35] or showing foci of hyperintensity in T2-weighted images, probably due to edema or demyelination [35], have been

b Fig. 41.19a,b. Charcot-Marie-Tooth disease. a Gd-enhanced sagittal T1-weighted image; b Gd-enhanced axial T1-weighted image. Sagittal image (a) shows involvement of all nerve roots in the cauda equina. The roots are enlarged and occupy most of the thecal sac leaving little space for CSF. Axial image (b) shows marked thickening and enhancement of all nerve roots in the cauda equina

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Fig. 41.20a,b. Charcot-Marie-Tooth disease type I and atypical clinical features (progressive urinary bladder dysfunction and severe low back pain). a Sagittal T2-weighted image; b Gdenhanced fat-suppressed coronal T1-weighted image. Marked thickening of spinal nerve roots completely filling the spinal canal is seen on the sagittal image (a). Spinal ganglia hypertrophy and enhancement are well depicted in fat-suppressed image (b). (Case courtesy of Dr. M. Cellerini, Florence, Italy, reproduced with permission from [33])

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1670 M. Castillo and P. Tortori-Donati reported. Diffuse enhancement of the cauda equina nerve roots in absence of any abnormalities on precontrast MRI has been reported in a patient with the congenital form of DSD (Fig. 41.21) [33]. Spinal cord impingement and compression from enlarged intradural roots has been reported as well [33, 35].

tion of dorsal roots and ganglia [31]. Signal intensity changes reflecting this degeneration may be demonstrated by MRI.

HMSN Type IV

A peripheral neuropathy may occur in several metabolic and degenerative CNS disorders (Table 41.6). I (MC) have seen cases of Krabbe’s disease in which the initial presentation was characterized by thickening of the cranial nerves (particularly cranial nerve II), and one case in which the initial presentation was thickening of the nerve roots in the cauda equina.

The formerly used term HMSN type IV corresponds to Refsum disease, and is usually not included among the HMSNs. It is a peroxisomal disorder due to an abnormal accumulation of phytanic acid due to phytanic acid oxidase deficiency (see Chap. 13). Spinal imaging findings are nonspecific, subtle, and similar to those previously described for HMSN I. It should be underlined that the role of MR imaging in the assessment of HMSNs is still debated. Although MRI may depict enlarged nerve roots in those types of HMSNs characterized by hypertrophic nerve changes (i.e., HMSN type I and II), this does not modify the classic approach to diagnosis [36]. However, it has been suggested that MRI may be useful for atypical cases [33, 36]. 41.3.3.2 Hereditary Sensory and Autonomic Neuropathies

The hereditary sensory and autonomic neuropathies (HSANs) are a genetically heterogeneous group of disorders pathologically characterized by degenera-

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41.3.3.3 Metabolic and Degenerative CNS Disorders

41.3.4 Arachnoiditis Arachnoiditis may follow infections or aseptic inflammatory processes. It is unusual in children, and affects mostly males. Most childhood cases of arachnoiditis are idiopathic but an antecedent of prior infectious meningitis, tuberculosis, trauma, neurofibromatosis type 1, irradiation, and syringomyelia may be elicited in some patients [37, 38]. The symptoms are secondary to adhesions in the cord and nerve roots (Table 41.7). These adhesions may also lead to the formation of CSF-containing cysts in the subarachnoid space, which may compress adjacent neural structures. Adhesions may also compromise

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Fig. 41.21a–d. Lumbosacral spine in a patient with the congenital hypomyelinating form of Déjerine-Sottas disease. a Sagittal T1-weighted image; b Gd-enhanced sagittal T1-weighted image; c Gd-enhanced, fat-suppressed coronal T1-weighted image; d Gdenhanced coronal T1-weighted image. Marked, diffuse enhancement of the cauda equina nerve roots (b) in the absence of root enlargement (a, b). Fat-suppressed image (c) enables better contrast between enhanced spinal ganglia and surrounding fat-suppressed fat tissue signal compared with corresponding nonfat-suppressed image (d). (Case courtesy of Dr. M. Cellerini, Florence, Italy, reproduced with permission from [33])

Infectious and Inflammatory Disorders of the Spine Table 41.6. Metabolic and degenerative CNS disorders in which a peripheral neuropathy may occur Lysosomal disorders Metachromatic leukodystrophy Krabbe leukodystrophy Mucopolysaccharidoses Oligosaccharidoses Fabry’s disease Farber’s disease Gaucher’s disease Niemann-Pick disease GM2 gangliosidosis Lipoprotein deficiencies Bassen-Kornzweig disease (abetalipoproteinemia) Hypobetalipoproteinemia Tangier disease Disorders with defective DNA repair Cockayne syndrome Ataxia-telangiectasia Xeroderma pigmentosum Peroxisomal disorders Adrenomyeloneuropathy Refsum disease Mitochondrial disorders NARP (neuropathy, ataxia, and retinitis pigmentosa), Leigh syndrome Congenital Disorder of Glycosylation (CDG syndrome) type Ia Cerebrotendinous xanthomatosis Chediak-Higashi disease Lowe syndrome Vitamin E deficiency Vitamin B1, B6, B12 and folate deficiency Amyloidosis Porphyria

Table 41.7. Clinical manifestations of arachnoiditis Chronic symptom progression Spotty or localized pain Migratory paresthesias Symptoms out of proportion to the findings on imaging studies Weakness which may also be progressive Eventual development of spastic paraparesis Rectal and urinary sphincter dysfunction

On MRI, mild degrees of arachnoiditis are difficult to identify [38]. Signs of moderate to severe arachnoiditis include clumping of the nerve roots, empty thecal sac sign (Fig. 41.22), enhancement of the nerve roots, and rarely an intradural mass of low T2 signal intensity which may also enhance after gadolinium administration. Tuberculosis is a rare cause of arachnoiditis. Patients with tubercular arachnoiditis show increased T1 signal in the CSF, loss of the cord-CSF interface in all sequences, a “shaggy” cord appearance, intramedullary spinal cord high T2 signal intensity, meningeal enhancement, clumping of the nerve roots of the cauda equina, nerve root enhancement, and spinal cord enhancement.

From [32, 34], modified

the vascular supply to the spinal cord and nerve roots. Constant traction from spine movement makes the symptoms worse. Common symptoms are pain and paresthesias. The symptoms usually are progressive, but occasionally resolve spontaneously. Anti-inflammatory drugs and steroids usually are used to treat arachnoiditis. This treatment, however, is not satisfactory in most patients. Surgery generally is not indicated. Arachnoiditis may occasionally lead to the formation of syringomyelia. 41.3.4.1 Imaging Findings

The diagnosis of arachnoiditis is easily performed by myelography [37]. The findings are clumping and thickening of the nerve roots, adherence of the roots to the walls of the thecal sac (empty sac sign), loss of the normal configuration (blunting) of the nerve roots sleeves and distal theca, and occasionally the formation of a mass (fibrosing or ossifying arachnoiditis). Because myelography is no longer frequently obtained in children, one almost never observes the above-described signs.

41.4 Disorders Predominantly Affecting the Vertebra, Discs, and Epidural Space 41.4.1 Inflammatory Diseases 41.4.1.1 Juvenile Rheumatoid Arthritis

Although juvenile rheumatoid arthritis (JRA) commonly involves the peripheral joints, discussion will center on the involvement of the spine, particularly the cervical region. JRA is generally diagnosed before 16 years of age, particularly when joint symptoms persist for more than 6 weeks and an underlying infection has been excluded [39]. JRA is more common in girls than in boys. It is primarily a synovitis, but results in secondary alteration of the vertebrae. The growth of the vertebrae and discs may be arrested and spinal deformities may ensue. Chronically, facet and uncovertebral joint ankylosis and vertebral body fusion may also be found (Fig. 41.23). Symptoms of spine involvement are evident in about 60% of patients with JRA, whereas imaging abnormalities may be present (but clinically silent) in up to 80% of cases. The earli-

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1672 M. Castillo and P. Tortori-Donati Calcifications in the paraspinal ligaments is said to be typical for JRA. When the thoracic spine is involved, scoliosis, fusions, and disc disease may be found. Contrast-enhanced MRI may be used to discriminate between joint effusion and pannus, as the latter shows enhancement [40]. In many patients, there is little relationship between symptoms and MRI findings. 41.4.1.2 Juvenile Ankylosing Spondylitis

Fig. 41.22. Postinfectious arachnoiditis. Axial T2-weighted image. The lumbar and sacral nerve roots (arrowheads) are adhered to the walls of the thecal sac giving the appearance of an “empty sac”

est signs of spinal involvement occur in the cervical region and include stiffness and pain. Imaging Findings

The disease generally begins at the C2–3 level and then extends caudally or cephalad. The dens becomes eroded, first anteriorly and then posteriorly (Fig. 41.23). Atlantodental subluxation is common. Unlike adults, this subluxation in children seldom results in neurological symptoms. Bone softening and basilar invagination may also occur (Fig. 41.23).

a

Juvenile ankylosing spondylitis (JAS) is a seronegative arthritis that predominantly involves the axial skeleton and occurs most often in middle-age men. However, about 10%–15% of cases begin during childhood [40]. In JAS, involvement of the sacroiliac joints occurs late in the course of the disease. From a clinical standpoint, the most important differential diagnosis is that of JRA. JAS occurs much more commonly in boys than in girls. Imaging Findings

Unlike JRA, JAS begins in the lower axial skeleton and extends superiorly. Involvement of the cervical region early in the course of the disease is very rare. Radiographs may not be sensitive for early detection of sacroiliac joint disease, and CT offers a better diagnostic imaging test. CT may show indistinct joint margins and subchondral sclerosis. In the spine, the earliest finding is sclerosis of the anterior margins of the vertebral end plates. Syndesmophyte formation leading to the so-called bamboo spine is rare in

b Fig. 41.23a, b. Rheumatoid arthritis. Two different cases. a Sagittal T2-weighted image; b sagittal T1-weighted image. Parasagittal T2-weighted image shows fusion (arrows, a) of most cervical spine facet joints. In a different patient, the dens is eroded (arrow, b) and there is basilar invagination (note high position of the dens in relation to the basion)

Infectious and Inflammatory Disorders of the Spine

children. The complications seen in adults (“banana” fractures, epidural hematomas, atlantoaxial subluxation, erosive dural ectasia, spinal cord infarction, and aseptic bone destruction) generally are not seen in children.

41.4.2 Infectious Diseases

Bacterial discitis is more commonly diagnosed between 1 and 5 years of age. Although the clinical diagnosis is fairly straightforward, many patients present with nonspecific findings such as failure to walk, abdominal pain, and chronic back pain. The onset of discitis may be gradual and subtle, progressing over the course of 2–4 weeks. The clinical differential diagnosis includes infection, Scheuermann disease, tuberculosis, fungal infection, spinal epidural abscess, osteoid osteoma, tumor, and vertebra plana.

41.4.2.1 Infectious Discitis and Osteomyelitis

Imaging Findings

It generally is assumed that in children the disc is hypervascular and that infection begins there. There is now evidence that spine infection in children generally begins in the vertebral body adjacent to the end plate in the form of microabscesses [41]. Because there are many perforating vascular channels extending into the end plate and into the disc, the infection rapidly extends into these two structures. Once the disc is involved, the infection extends again superiorly and inferiorly to affect the adjacent vertebral bodies (Fig. 41.24). Bacteriological data is difficult to compile, as most bacterial discitis and osteomyelitis are treated empirically, based on imaging studies abnormalities. In addition, the incidence of discitis versus osteomyelitis is rapidly changing due to early diagnosis done using MRI. Despite this, staphylococci and Diplococcus pneumoniae account for most cases of discitis. In children with sickle cell disease, there is an increased incidence of salmonella discitis and osteomyelitis. In the past, osteomyelitis was more common, while nowadays discitis is more frequently diagnosed. Regardless of these factors, staphylococci and streptococci are the most common organisms involved.

MRI is the best method to evaluate children suspected of harboring spinal discitis/osteomyelitis [42]. In children, the L3–4 and L4–5 interspaces are predominantly affected. In the very early stages, imaging studies are consistent with a picture of discitis, showing a reduction in the height of the intervertebral disc associated with swelling of the anulus, which appears hyperintense in T2-weighted images. Enhancement after gadolinium administration is evident (Fig. 41.25). Signal changes of the vertebral plates and subchondral regions are initially very subtle. As the disease progresses, the end plates may be irregular and not seen well. With advancing disease, the end plates and vertebrae become bright in T2weighted sequences. All of these abnormalities may show gadolinium enhancement (Fig. 41.26). Later on, infection may spread into other vertebral bodies via the venous plexus. In this situation, the adjacent vertebrae show abnormal signal intensity in the region of the canal for the basivertebral vein. The MRI findings lag behind clinical improvement due to adequate antibiotic treatment. When following these patients with MRI, the most important feature which predicts

a

b

Fig. 41.24a,b. Proposed pathogenesis of bacterial spondylodiscitis. a Infection starts in the disc and propagates to the vertebral endplates. b Infection starts in the vertebral endplate and propagates to both the vertebral body and the disc, whence it may further propagate to the adjacent vertebra

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1674 M. Castillo and P. Tortori-Donati recovery is absence of progression. The abnormalities may remain stable or improve slightly with the passing of time. Progression of disease indicates a failure of medical treatment. Epidural abscesses will be addressed below. I (MC) have seen several cases of fungal discitis and vertebral osteomyelitis. In all patients, the infection was mainly in the disc space. All patients were adults and immunosuppressed. The most common organisms in my experience are Cryptococcus, Candida, and Aspergillus. The imaging findings are nonspecific and the diagnosis requires biopsy. An article describing the imaging features of coccidioidal spondylitis concluded that the imaging findings were also nonspecific [43]. 41.4.2.2 Tuberculous Spondylodiscitis

a

b

Fig. 41.25a, b. Bacterial discitis: early MRI signs in a 3-year-old girl. a Sagittal T2-weighted image; b Gd-enhanced sagittal T1-weighted image. There is swelling and T2 hyperintensity of the posterior annulus of the fourth lumbar disc (arrow, a), that also enhances markedly with gadolinium (arrow, b). Notice associated mild hyperintensity of the adjacent vertebral bodies (arrowheads, a)

a

b

Spinal tuberculosis (TB) is common in children, particularly in Third World countries. As opposed to the adult form of the disease, childhood tuberculosis is generally more extensive and results in large abscess formation. Unlike adult TB, children seldom develop paraplegia [44]. The disease is due to Mycobacterium tuberculosis and infection in the chest and/or genitourinary tract precedes spinal involvement in the majority of patients. The most frequent site for childhood spinal TB is the thoracolumbar junction [45]. Pain and signs of

c

Fig. 41.26a–c. Bacterial spondylodiscitis: full-blown MRI picture. a Sagittal T2-weighted image; b sagittal STIR image; c Gd-enhanced fat-suppressed sagittal T1-weighted image. The disc space is narrowed (white arrow, a–c). The central portion of the disc is markedly hyperintense (black arrow, a, b) and enhances strongly (black arrow, c). Notice blurring of the vertebral endplates (arrowheads, a–c). There is marked hyperintensity and enhancement of the adjacent vertebral bodies. Salmonella spondylodiscitis was eventually diagnosed. (Courtesy of Majda Thurnher, Vienna, Austria)

Infectious and Inflammatory Disorders of the Spine

chronic infection are the most typical clinical manifestations. In one series, 76% of children affected were younger than 5 years of age, nearly 50% of children had neurological deficits on hospital admission, 50% of patients recovered within 6 months of appropriate therapy, and paraspinal abscesses were found in 62% of patients. Diagnosis is difficult and may be confirmed only by positive histology and/or culture. Often, the diagnosis is based on clinical manifestations, radiographic findings, and response to antibiotics. TB in the lumbosacral region is uncommon, and other etiologies such as brucellosis should be considered when this area is primarily involved [46]. Craniocervical involvement may also be seen in children, and is accompanied by significant abscess formation. Cervical involvement is almost always accompanied by neighboring nodal disease. Epidural abscesses are discussed below. Imaging Findings

According to the location of the infection, three patterns have been described: anterior, paradiscal, and central (Fig. 41.27). In the anterior type (Fig. 41.28) the infection begins in the anterior (and generally also inferior) vertebral body, and extends under the anterior longitudinal ligament to involve other vertebrae. In the paradiscal type (Fig. 41.29) the infection begins in the lateral

a

b

sides of the disc and results in narrowing of the disc space. Paradiscal disease is the least common form in children. In the central type (Figs. 41.30, 31) the infection begins in the middle of the vertebral body, may produce a vertebra plana, and may eventually result in acute angle kyphosis (i.e., Pott’s disease) (Fig. 41.32). TB may also involve the posterior elements in an isolated fashion. Before frank abscess formation there is a stage characterized by development of masses of granulation tissues (Fig. 41.33). 41.4.2.3 Epidural Abscess

An epidural abscess is a collection of pus between the bone and the dura mater [41]. When found in children, they are more common in females. Epidural abscesses are commonly secondary to pyogenic or tuberculous discitis and osteomyelitis [47]. In the absence of discal and vertebral involvement, the infection usually is from hematogenous spread of primary foci in the urinary tract, skin, lungs, and teeth. Patients with AIDS and long term vascular access catheters are also prone to develop epidural abscesses. Rarely, epidural abscesses are a complication of lumbar tap. The most common clinical signs are pain, fever, and rapidly progressing neurological symptoms (Table 41.8). In children, neurological signs may be absent or masked by prior administration of antibiot-

c

Fig. 41.27a–c. Tubercular spondylodiscitis: the three modes of propagation. a Anterior type: infection starts in the anterior vertebral body and spreads under the anterior longitudinal ligament to the adjacent vertebrae. The disk space is relatively spared until late during the course of disease. b Paradiscal type: infection starts in the vertebral endplate, as in bacterial spondylodiscitis. The disc space is involved in the early stages of disease. This is the rarest form in children. c Central type: infection starts in the central vertebral body and may propagate to adjacent vertebrae under the posterior longitudinal ligament, thereby resulting in thecal sac compression. Also in this variety, the disk space is initially relatively spared

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1676 M. Castillo and P. Tortori-Donati

c

a

b

d

e

Fig. 41.28a–e. Tubercular spondylodiscitis: anterior type in an 11-year-old boy. a, b Sagittal T2-weighted images; c, d Gd-enhanced axial T1-weighted images; e Gd-enhanced coronal T1-weighted image. There is a narrowed, hypointense disk space in the thoracic spine (thin arrow, a, b). Infection starts in the anterior portion of upper vertebra and generates a huge preparavertebral abscess (arrowheads, a, b; see also c–e). Infection propagates to the lower vertebral body, which is T2 hyperintense as the upper one (a, b)

a

b

c

Fig. 41.29a–c. Tubercular spondylodiscitis: paradiscal type in a 13-year-old boy. a Sagittal T2-weighted image; b Gd-enhanced sagittal T1-weighted image; c Gd-enhanced coronal T1-weighted image. There is narrowing of the disc space which appears hyperintense on T2-weighted images (arrow, a) and enhances markedly (arrow, b). Notice huge left paraspinal abscess originating from the disc space and propagating below the pillars of the diaphragm (arrowheads, c)

Infectious and Inflammatory Disorders of the Spine

d

a

b

c

e

Fig. 41.30a–e. Tubercular spondylodiscitis: central type in a 2-year-old girl. a Sagittal T1-weighted image; b sagittal T1-weighted image; c Gd-enhanced sagittal T1-weighted image. d, e Axial CT scans, bone window. Infection involves the central portion of the L3 vertebral body (arrowhead, d, e). Although the posterior body wall appears interrupted on CT and bulges slightly on MRI (thick arrows, a–c), there is no frank spinal canal invasion. The L2-3 disc space is essentially uninvolved (thin arrows, a–c)

d

a

b

c

e

f

Fig. 41.31a–f. Tubercular spondylodiscitis: central type with spinal canal invasion in a 8-year-old boy. a Sagittal T1-weighted image; b sagittal T2-weighted image; c Gd-enhanced sagittal T1-weighted image. d Gd-enhanced axial T1-weighted image; e axial CT scan, bone window; f sagittal T2-weighted image after 8 months. In this case, infection start in the central portion of the L4 vertebral body (arrowheads, e), disrupts the posterior vertebral wall, and propagates into the spinal canal below the posterior longitudinal ligament (arrows, a–c). The thecal sac is markedly compressed (arrow, d). The L3–4 disc space is irregular and probably already involved, albeit without frank, diffuse enhancement. MR examination performed after 8 months following therapy shows pathological tissue is completely absent; however, the L3–4 disc is dehydrated and marked reduction of the height of the L4 vertebral body is evident

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1678 M. Castillo and P. Tortori-Donati

b

a

d

c

Fig. 41.32a–d. Pott’s disease. a Schematic depiction; b sagittal reformatted CT; c 3D CT rendering; d sagittal T1-weighted image. There is marked vertebral deformity with resulting kyphosis and stenosis of the spinal canal

a

b

Fig. 41.33a,b. Tuberculosis. Two different cases. a, b Axial CT scans. Very large paraspinal and intra–abdominal abscesses with very little bony changes (a). The anterior margin of the visualized vertebra is slightly irregular. In a different patient (b), there is a large suboccipital abscess from posterior spinal tuberculosis affecting the C1 and C2 vertebrae

Table 41.8. Clinical manifestations of spinal epidural abscess Rapid progression of signs and symptoms Localized and/or radicular pain Headache and fever Rapidly progressing or acute onset paresis Back swelling, tenderness, and other local signs of infection Rectal and urinary sphincter dysfunction Sensory level which may change and progress rapidly

ics. From the clinical viewpoint, the differential diagnosis mainly includes ATM, tumor, trauma, tuberculosis, and herniated disc. Epidural abscesses have a poor prognosis and high mortality. Rapid progression is generally an indication for the need of surgical decompression, and most patients will remain with deficits. Fortunately, children tend to recover in a more complete fashion than adults. Lumbar puncture is contraindicated in

Infectious and Inflammatory Disorders of the Spine

patients suspected of having an epidural abscess, and MRI is the diagnostic method of choice in such instances. Imaging Findings

Early on, MRI may detect a prominent epidural space showing intermediate signal intensity in both T1-

and T2-weighted images. The abnormality enhances homogeneously after gadolinium administration, and is most often a phlegmon (Fig. 41.34). Surgery is not indicated in these patients, as they improve considerably after appropriate antibiotic therapy. In cases of frank abscess formation, there is a rim enhancing abnormality in the epidural space [48] (Fig. 41.35). The nonenhancing center generally corresponds to

b

a Fig. 41.34a, b. Epidural phlegmon. a Gd-enhanced fat-suppressed sagittal T1-weighted image; b Gd-enhanced axial T1-weighted image. Sagittal image shows posterior epidural phlegmon (arrows, a) enhancing homogeneously. There is compression of the spinal cord. In the same patient, axial image confirms the location of the phlegmon (asterisk, b) within the epidural space, with contralateral displacement of the spinal cord (sc, b). There was no osteomyelitis in this patient

c

a

b

Fig. 41.35a–c. Dorsal epidural abscess in a 3-month-old boy. a Sagittal T1-weighted image; b Gd-enhanced sagittal T1weighted image; c Gd-enhanced axial T1-weighted image. Huge epidural abscess extending posteriorly along several metamers (arrowheads, a, b), deforming and compressing the spinal cord (sc, c). Following contrast material, there is marked enhancement of the peripheral portions with a persistently hypointense core representing pus (arrows, b, c)

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1680 M. Castillo and P. Tortori-Donati

a

Fig. 41.36a,b. Phlegmon and epidural abscess. a Sagittal T2-weighted image; b Gd-enhanced sagittal T1-weighted image. T2-weighted image (a) shows that the C6 vertebra is hyperintense. There are bright collections anteriorly (open white arrow) in the precervical space and posteriorly (open black arrow) in the ventral epidural space. The spinal cord is mildly compressed. Following gadolinium, homogeneous enhancement in the epidural collection which is most likely a phlegmon is seen (b), while the precervical one shows central lack of enhancement compatible with an abscess

b

pus, and surgical drainage is indicated in nearly all patients showing this type of abnormality. A phlegmon originating from osteomyelitis shows the same findings of that isolated, and is associated with signal changes of the vertebral body from which it originates (Fig. 41.36). Findings on postcontrast MRI are detailed in Table 41.9. The abscesses are generally 2–4 vertebral bodies in length. In many patients with epidural abscesses, the spinal cord will show increased T2 signal intensity above, below, and at the level of the abscess. This finding is presumed to represent cord edema secondary to compromised venous drainage, secondary to involvement of Batson’s plexus. Occasionally, arterial compromise with subsequent cord ischemia may also occur. The sensitivity of MRI for the detection of epidural abscesses is said to be over 90%. Table 41.9. Postcontrast MRI findings in epidural abscess Enhancement of disc and adjacent bone Diffuse enhancement of disc/vertebra complex Diffuse enhancement of the pathologic tissue (phlegmon) or peripheral enhancement around pus collection Dural enhancement Prominence of epidural venous plexus

5.

6. 7.

8.

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Gallucci M, Caulo M, Cerone G, Masciocchi C. Acquired inflammatory white matter diseases. Childs Nerv Syst 2001; 17:202-210. Barkovich AJ. Pediatric Neuroimaging, 3rd edn. Philadelphia: Lippincott Williams & Wilkins, 2000:102-106. Tartaglino LM, Heiman-Patterson T, Friedman DP, Flanders AE. MR imaging in a case of postvaccination myelitis. AJNR Am J Neuroradiol 1995; 16:581-582. Campi A, Filippi M, Comi G, Martinelli V, Baratti C, Rovaris M, Scotti G. Acute transverse myelopathy: spinal and cranial MR study and clinical follow-up. AJNR Am J Neuroradiol 1995; 16:115-123. Kaye EM. Disorders primarily affecting white matter. In: Swaiman KF, Ahswal S (eds) Pediatric Neurology: Principles and Practice, 3rd edn. St. Louis: Mosby, 1999: 849852. Osborn AG. Diagnostic Neuroradiology. St. Louis: Mosby, 1994. Tartaglino LM, Friedman DP, Flanders AE, Lublin FD, Knobler RL, Liem M. Multiple sclerosis in the spinal cord: MR appearance and correlation with clinical parameters. Radiology 1995; 195:725-732. Glasier CM, Robbins MB, Davis PC, Ceballos E, Bates SR. Clinical, neurodiagnostic and MR findings in children with spinal and brain stem multiple sclerosis. AJNR Am J Neuroradiol 1995; 16:87-95. Mandler RN, Davis LE, Jeffery DR, Kornfeld M. Devic’s neuromyelitis optica: a clinicopathologic study of 8 patients. Ann Neurol 1993; 34:162-168. DeLara F, Tartaglino L, Friedman D. Spinal cord multiple sclerosis and Devic neuromyelitis optica in children. AJNR Am J Neuroradiol 1995; 16:1557-1558. Tortori-Donati P, Fondelli MP, Rossi A, Rolando S, Andreussi L, Brisigotti M. La neuromielite ottica. Una ulteriore sfida nella diagnosi differenziale con le neoplasie intramidollari. Rivista di Neuroradiologia 1993; 6:53-59. Murphy KJ, Brunberg JA, Quint DJ, Kazanjian PH. Spinal cord infection: myelitis and abscess formation. AJNR Am J Neuroradiol 1998; 19:341-348. Friess HM, Wasenko JJ. MR of staphylococcal myelitis of the cervical spinal cord. AJNR Am J Neuroradiol 1997; 18: 455-458. Dev R, Husain M, Gupta A, Gupta RK. MR of multiple intraspinal abscesses associated with congenital dermal sinus. AJNR Am J Neuroradiol 1997; 18:742-743. Malzberg MS, Rogg JM, Tate CA, Zayas V, Easton JD. Polio-

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Spinal Trauma

42 Spinal Trauma Paolo Tortori-Donati, Andrea Rossi, Milena Calderone, and Carla Carollo

42.1 Introduction

CONTENTS 42.1

Introduction

42.2

Developmental Anatomy

42.3 42.3.1 42.3.2

Biomechanical Features and Injury Mechanisms 1685 Cervical Spine 1685 Thoracolumbar Spine 1686

42.4 42.4.1 42.4.2 42.4.3

Imaging Techniques X-Rays 1686 CT 1686 MRI 1687

42.5 42.5.1 42.5.1.1 42.5.1.2 42.5.1.3 42.5.1.4 42.5.2 42.5.2.1 42.5.2.2 42.5.2.3 42.5.3 42.5.4 42.5.5 42.5.5.1 42.5.5.2 42.5.5.3

Spinal Column Trauma 1687 The Cranio-Cervical Junction 1687 Atlanto-Occipital Dislocation 1688 Atlas Injuries 1689 Axis Injuries 1689 Atlanto-Axial Subluxation 1690 The Mid-Inferior Cervical Spine 1691 Compression Fractures 1692 Hyperflexion Fractures 1692 Teardrop Fractures 1692 The Cervico-Thoracic Junction 1693 The Thoracic Spine 1693 The Lumbar Spine 1694 Chance Fracture 1694 Burst Fractures 1695 Fractures of The Neural Arch 1695

42.6

Child Abuse and Spinal Trauma 1696

42.7 42.7.1 42.7.2 42.7.3

Spinal Cord Lesions 1696 Clinical Features 1696 Spinal Cord Injury Without Radiological Abnormality (SCIWORA) 1697 Chronic Cord Lesions 1697

42.8 42.8.1 42.8.2

Delivery Trauma 1697 Spinal Cord Injury at Birth 1697 Brachial Plexus Injury 1698

42.9

Spondylolysis and Spondylolisthesis 1698

42.10 42.10.1 42.10.2 42.10.3

Other Traumatic Lesions 1701 Disc Herniations 1701 Slipped Vertebral Apophysis 1701 Disc Space Calcification 1701 References

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1703

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The developing spine is an osteo-cartilaginous complex in which the cartilaginous component is prevalent, especially in the first years of life. This confers to the spine a wide degree of motility and deformability and allows efficient absorption of traumatic vectors. As a consequence, vertebral fractures are rare events in the pediatric age group. Overall, pediatric traumas account for only 5%–10% of all spinal traumas in the general population. There are two incidence peaks, i.e., one under 5 years of age with lesions affecting mostly the upper cervical spine, and one after 10 years of age [1] with involvement of the lower cervical and thoracolumbar spine. Three different age groups may be identified on the basis of the different anatomical characteristics and mechanical properties of the involved segments: infancy (0–3 years), early childhood (3–8 years), and late childhood and adolescence (9–18 years). In infants, there is a disproportioned development of the head and neck in that the musculature of the neck is not yet completely developed and can only partially control the movements of the head, adding a further component to the hypermotility of the cervical spine. For such reasons, head trauma in children younger than 3 years of age is often associated with spinal cord lesions, whose clinical consequences can be masked by the overlying cerebral dysfunction. Therefore, in case of head trauma it is important to always consider the possibility of an associated cervical spinal cord lesion. In the same age group, epiphyseal detachments of the atlas, axis, or odontoid process are possible, as well as atlanto-axial and atlantooccipital dislocations or fractures of the neurocentral cartilages and of the posterior arch. Fractures of the ossified structures are very rare below age 8 years. In older children and adolescents, the superior and inferior segments of the spine are affected with similar frequency, and it is possible to find lesions similar to those typical of adults, such as compression or burst fractures, fractures of the zygapophyseal complex, dislocations, and ligamentous lesions that lead to spinal instability. All these situations often require surgical intervention.

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1684 P. Tortori-Donati, A. Rossi, M. Calderone, and C. Carollo About 50% of spinal traumas occur in car accidents (cervical whiplash) and other vehicular mishaps including bicycle and motorcycle accidents [3]. Airbag-related injury to the cervical spine in children traveling in the vehicle’s passenger front seat is a growing cause of cervical spine injury that may be fatal [4]. Thirty percent of spinal traumas are related to sports activities, especially in the adolescent age. Less frequent causes are child abuse and firearms lesions. Spinal trauma can also occur at birth in case of complicated deliveries, due to the even higher cervical laxity in newborns. The spinal cord is frequently involved, and diagnosis can be carried out by clinical examination and MRI.

42.2 Developmental Anatomy The infantile skeleton grows in length essentially through the action of epiphyseal cartilages, found in all long bones and in the vertebral bodies. This process is called enchondral ossification. For each vertebra, there are three primitive ossification nuclei surrounded by cartilaginous tissue, one producing the vertebral body and two resulting in the lateral masses and neural arches, connected ventrally by the neurocentral synchondrosis and dorsally by the spinous cartilage. The ossification process begins during the second month of fetal life and continues throughout childhood until the end of adolescence [1]. Vertebral growth is considered complete when fusion of the epiphyseal plates is accomplished, usually between 16 and 20 years of age. A comprehensive knowledge of the anatomical and biomechanical characteristics of the spine in relation to the different phases of its development is of paramount importance for a correct diagnosis of pediatric traumatic vertebral lesions. Misdiagnoses are usually due to the difficulty of recognizing not-yet-ossified vertebral components, the persistence of cartilaginous structures, and the presence of physiological variants that can be mistaken for fractures (Table 42.1). The lateral masses of C1 are normally ossified at birth, and complete ossification of the posterior arch occurs around 5–6 years. The anterior arch may not be ossified at birth, but is usually recognizable as a bone structure within the first year of life, and fuses with the lateral masses around 3 years of age. The dens, derived from two primary ossification centers, is normally fused in the midline at birth, but sometimes a lucent cleft may persist until complete closure between 1 and 2 years of age. The ossification center of the dens tip appears as early as 1 year of age,

Tab. 42.1. Normal features and common variations in the developing spine • The neurocentral and interspinous synchondroses are fused between 3 to 8 years, beginning from the first dorsal segment • Intervertebral motility of C1–C2 is wider than in adults • The anterior arch of C1 can be partially ossified at birth, but ossification is usually completed in most children by 12 months • The ossification nucleus for the tip of the dens appears in the first months of life and fuses with the inferior portion of the axis within 10 years of age • Accessory lateral tubercles may be present on the lateral masses of C1, and should be considered normal variants • Sometimes the posterior arch of C1 can have a ring-like aspect (posticus ponticus) • The spinous process of C2 is already larger than those of other cervical vertebrae at birth • In the first decade, anterior wedging of the vertebral bodies is normal (and must not be confused with a compression fracture) • A wide cleft for the supply vessel in dorsal and lumbar vertebral bodies may simulate a longitudinal fracture in lateral view; on axial CT and MR images, the vertebral hilus shows radial vascular clefts • The ossification nuclei of ring epiphyses and uncovertebral joints appear around 9 years of age, with an initial pseudo-fragmented appearance • Primary spondylolysis of C2 is a rare variant, usually associated with other congenital cervical anomalies or pyknodysostosis • Thickening of cervical paravertebral soft tissues is a frequent finding in childhood

develops until 3 years, and fuses with the remainder of the dens between 8 and 12 years of age. The cartilaginous growth plate between the dens and the vertebral body (subdental synchondrosis) ossifies at 4– 6 years. A residual cartilaginous component may also be found as a thin linear lucency on X-ray and more clearly on MRI in about one third of adult patients. The ossification process from C3 to C7 is similar: the ossification nuclei of the posterior hemi-arches, which originate from the base of the transverse process, extend dorsally to form the posterior arch and ventrally to form the peduncles. They also extend caudally towards the posterolateral aspect of the vertebral body, so that the neurocentral synchondrosis is situated on the vertebral body itself, and contributes to the formation of the lateral portions of the vertebral body. At about 5 years of age, antero-superior and anteroinferior indentations of the vertebral body appear as annular recesses for the subsequent development of the ring epiphyses that originate as small bony foci between 6 and 9 years. At 12 years, the ring epiphyses are completely ossified and fuse to the body between 16 and 20 years. The central portion of the epiphyseal

Spinal Trauma

plate may remain cartilaginous and is considered as a component of the disc; both Schmorl nodes and Scheuermann’s disease originate from this portion. Secondary ossification centers appear at the tips of the spinous and transverse processes during early adolescence, and their fusion occurs at the end of vertebral growth. The anterior and posterior longitudinal ligaments provide the main control for a correct motility between the vertebral bodies. At the atlanto-occipital joint, stability is ensured by the ligamentous insertions between the dens and the occipital bone. Due to its mobility, the atlas is loosely connected to both the occipital bone and C2 only by thin occipito-atlantal support membranes. The direct ligamentous insertion that ensures the stability to this joint is the tectorial membrane, a prolongation of the posterior longitudinal ligament. The elasticity of this assembly is more pronounced in children, making the infantile spine an extremely mobile structure. Only after 10 years of age does the situation approach that of adults. The facet surfaces are more horizontal in younger children, and tend to become more vertically oriented as the spine develops, reaching an adult configuration at the end of the first decade. In the lower cervical tract, inclination changes from 55° to 70°, while in the upper cervical tract it varies from 30° to 60°–70°. The intervertebral discs are also different in young children. They are tightly bound to the epiphyseal cartilages, so that traumatic detachments more often occur between the epiphysis and the ossification nucleus, rather than between the disk and the epiphyseal plate [5]. At birth, the discs have a higher water content that persists throughout the whole first decade of life. Furthermore, in neonates the blood supply for the cartilaginous plate is still provided by vessels that perforate the cartilage embedding the ossification nuclei of the vertebral bodies; such vessels undergo progressive obliteration in the first 4 years of life. These vessels may be injured during the traumatic event, with some important implications due to possible ischemia that can cause epiphyseal cartilage growth arrest.

42.3 Biomechanical Features and Injury Mechanisms As was mentioned earlier, the pediatric spine is comprised of several ossification nuclei embedded in the cartilaginous component that determines the peculiar hypermotility of the spine at this age. Therefore,

the kinematics of traumatic vertebral lesions is completely different than in adults, and it is more difficult to classify lesions into stable and unstable for treatment purposes. Lesions affecting the osteocartilaginous structure can be divided into fractures, dislocations, lesions of the ossification nuclei, disc herniations, and epiphyseal detachments. The frequency of unstable trauma is low, a fact that underlines the capability of the developing spine to absorb traumatic energy. Ligamentous instabilities are also very rare in children, while they become relatively more frequent in young adolescents. Therefore, the traumatized child should be evaluated using an accurate diagnostic protocol in order to evaluate both skeletal and myeloradicular damage. Traumatic disc lesions are rare, but are becoming increasingly more common in children above 10 years due to the diffusion of sports activities among adolescents. Such lesions are usually provoked by traumatic impacts and can be complicated by posterior epiphyseal detachments (of the ring epiphysis) or of the epiphyseal plate. To diagnose lesions of the ossification nuclei is not easy because they can be mistaken for lesions of the ligamentous apparatus. These lesions are often associated with epiphyseal detachments in younger children. The detachment of the epiphyseal cartilage from the primary ossification nucleus of the vertebral body is facilitated by the strong adhesion of the epiphyseal plate to the adjacent vertebral discs. Similar interactions occur between the annulus fibrosus and the ring epiphysis, which can be detached from the edge of the vertebral body (especially near the dorsal margin that faces the vertebral canal because of the reduced protective effect of the longitudinal posterior ligament). A correct diagnostic definition with X-rays and MRI is of paramount importance for the prognosis of further spine growth.

42.3.1 Cervical Spine Hypermotility of the developing spine is particularly evident in the cervical segment. The physiological laxity of the ligaments, the insufficient development of paravertebral muscles (especially when compared to the mass of the infant’s head), the reduced angle of the cervical articular facets (with reduced control of flexion and extension movements) and, finally, the incomplete formation of the uncovertebral joints (providing less control of rotation movements) account for the high incidence (70%) of upper cervical traumas in early childhood compared to older ages [6].

1685

1686 P. Tortori-Donati, A. Rossi, M. Calderone, and C. Carollo The fulcrum of maximal flexion/extension is located at C2–C3, where the highest frequency of dislocations and subluxations is found. The latter should be distinguished from the physiological subluxation often seen in flexion radiograms, in which case the vertebrae will appear aligned in hyperextension radiograms. This anatomical condition is found in 40% of children under 4 years at C2–C3 and in 20% of children under 8 years at C4–C5 [6, 7]. During the first decade of life, the fulcrum of flexion/extension gradually moves to the lower vertebrae, reaching C5–C6 (the adult situation) at 8–10 years. Ligamentous laxity also accounts for the physiologically longer distance between the anterior arch of the atlas and the axis in children than in adults (4 mm versus 2 mm). One should keep in mind that, albeit rarely, cervical trauma may produce injury to the large blood vessels of the neck, such as carotid or vertebral artery dissection, thrombosis, and development of posttraumatic aneurysms.

fulcrum of the movement on the posterior one (unstable burst fracture). When the fulcrum of the hyperflexion is on the anterior column or beyond it, the distraction vectors affect the posterior and intermediate columns (seat-belt-type injury), or all the three columns (flexion-distraction injury). Other mechanisms can occur during the traumatic event, such as flexion and rotation or translation (shear injury). While these concepts are well suited for traumas in adults or adolescents, they do not describe well the situation of the pediatric spine. In fact, thanks to the ability of the cartilaginous component to absorb traumatic vectors, unstable vertebral lesions are rare in the pediatric age group.

42.4 Imaging Techniques 42.4.1 X-Rays

42.3.2 Thoracolumbar Spine Even though a large cartilaginous component is present also in the thoracic vertebrae, motility is reduced compared to the cervical segment due to the presence of the ribs. The lumbar segment is also hypermobile, but mostly in flexion/extension. Thoracic kyphosis and lumbar lordosis are determinant for both physiologic and traumatic kinematics at the T12–L1 junction level. Roy-Camille’s theory, expressed in 1983 [8], is still a valid aid to evaluate the stability of these lesions. The theory identifies three longitudinal columns, i.e., (1) posterior column (neural arch, yellow ligaments, interspinous, supraspinous, and zygapophyseal joints); (2) intermediate column (posterior part of the vertebral body, posterior longitudinal ligament, posterior part of the intervertebral disc); and (3) anterior column (anterior longitudinal ligament, anterior part of the vertebral body, anterior part of the intervertebral disc), and postulates that a given vertebral lesion should be considered stable if only one of the columns is affected, and unstable when two or more columns are affected. The various lesion vectors can act variably on the three columns, thereby generating different kinds of injury. Hyperflexion can cause compression of the anterior column and distraction of the posterior one, while the intermediate is the fulcrum of the movement (stable compression fracture). Compression can also affect the anterior and intermediate columns, with the

When possible, the initial evaluation of a child with a traumatic injury to the spine must be performed with plain radiograms in the antero-posterior and lateral projections, integrated, when possible, by dynamic projections on both planes. However, children with moderate to severe cervical spine trauma usually have associated or suspected head trauma and should, therefore, undergo CT scan as the initial imaging method. The lateral scout CT image is sufficient to assess alignment of the cervical vertebral bodies. To visualize the dens, it is preferable to use CT scan with coronal image reconstruction rather than the traditional open-mouth projection due to the incomplete ossification and low compliance. Children with documented neurological damage must be evaluated with CT to visualize bone lesions, and MRI to visualize spinal cord lesions. It is more difficult to set a specific protocol for children with less severe trauma. Lateral projections of the cervical spine have a diagnostic accuracy of 79%–85% [9, 10]; association with antero-posterior projections increases accuracy to about 95%. When there is evidence of a single vertebral lesion, the whole spine should be studied, because in 16% of cases multiple lesions are present.

42.4.2 CT The sensitivity of CT for vertebral fractures is around 93% [5]. There are two main indications for CT, i.e., to

Spinal Trauma

better define bone lesions already found by standard exams (intracranial bone fragments, fractures of articular facets), or to evaluate comprehensively the spine when standard X-rays are not optimal (for difficulties in positioning the patient, bad visualization of C2 and C7, thoracic spine shadowed by scapulae or ribs). Spiral CT acquisition of thin (2–3 mm) axial slices with subsequent sagittal and coronal image reconstruction allows a reliable diagnosis for most vertebral lesions; however, MRI is necessary to evaluate cartilaginous or ligament injuries.

42.5 Spinal Column Trauma Traumatic injury to the spinal column may be due to several mechanisms, including flexion, extension, burst, distraction, and translation, and produce different lesion patterns depending on the involved segment of the spine (Table 42.2). What follows is a brief discussion of the main kinds of vertebral fracture seen in the pediatric age group. Table 42.2. Classification of vertebral fractures and dislocations

42.4.3 MRI To evaluate spinal cord injuries, sagittal fast spinecho T1- and T2-weighted images must be obtained so as to visualize contusion, edema, or ischemia. Axial planes are more useful to evaluate spinal cord compression. In the setting of spinal cord symptomatology and negative radiographic studies, MRI should be performed. Surgically correctable causes of cord compression demonstrated by MRI include disc herniation, epidural hematoma, and retropulsed fracture fragments [11]. Ligamentous lesions are visualized as hyperintense signal in proton density and T2-weighted images, involving the posterior longitudinal ligament, yellow ligaments, articular capsules, and interspinous and supraspinous ligaments. Fat-suppressed, fast spinecho T2-weighted images are also very useful to pick up vertebral body edema. Epidural hematomas can appear iso- or hypointense both in T1- and T2weighted images during the first week after trauma, while it is more common to find hyperintense signal due to methemoglobin in anterior collections due to rupture of the anterior longitudinal ligament. In the subacute phase, the methemoglobin hyperintensity may not be marked, and can be difficult to interpret. In these cases, sequences with fat saturation are useful to subtract the signal of the epidural fat. Moreover, the T2 hypointense hemosiderin ring along the edge of the blood collection may be difficult to distinguish from the low signal of the cortical portion of the vertebral body. In such situations, presence of spinal cord compression from the epidural collection will clear the view. In the chronic phase, MRI can visualize the sequelae of spinal cord lesions, such as atrophy or development of posttraumatic syringomyelia. Children under 10 years with a complete spinal cord lesion develop progressive neurogenic scoliosis in 100% of cases [12, 13].

Cranio-cervical junction Distraction, translation fractures: atlanto-occipital disassociation (airbag injury in infants) or dislocation and/or subluxation Burst (Jefferson) C1 fracture, C2 teardrop fracture Flexion fractures: of the dens, flexion fractures of lateral mass C1 or C2 Extension fractures: C1 posterior or anterior arch, hangman’s fracture, dens fracture, fracture of the body and of the arch of C2 Cervical spine Flexion: compression fracture, unco-vertebral or transverse process detachment, hyperflexion sprain Extension: hyperflexion sprain, spinous fracture, anterior vertebral corner avulsion, spondylytic fracture, pillar fracture Burst: teardrop fracture, classic burst fracture, sagittal body fracture Distraction: hyperflexion sprain Translation: facet subluxation-dislocation Thoracic and lumbar spine Flexion: compression fracture Extension: pedicle or laminar fracture Burst fracture Distraction: seat belt (Chance) fracture Translation: fracture-dislocations

42.5.1 The Cranio-Cervical Junction The cranio-cervical junction is formed by the bony and ligamentous structures that support the head and control its movements. The articulations of the cranio-cervical junction are defined by the middle atlanto-axial joint, which consists of two synovial compartments that surround the dens and allow rotation of C1 and C2 with respect to each other, and the paired lateral atlanto-axial and atlanto-occipital articulations. These joints are bound and supported by several ligaments, including the anterior longitudinal ligament, the anterior atlanto-axial and atlantooccipital ligaments, the cruciform ligaments, the alar ligaments, and the tectorial membrane, which extends

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1688 P. Tortori-Donati, A. Rossi, M. Calderone, and C. Carollo cranially as the cephalic extension of the posterior longitudinal ligament [14]. Normal findings that may mimic fracture at this level include (1) the body of the axis has two ossification nuclei that are usually fused at birth, but that may be still separated until the first or second year of life in some individuals; (2) the ossification nuclei of the dens appear at 1 year, develop until 3 years of age, and are fused with the body of the axis by 8–12 years; (3) the ossification centers of the C2 body and dens are fused between 5 and 7 years; and (4) a residual cartilaginous component between the body and dens may be seen on MRI in up to 30% of adult subjects.

42.5.1.1 Atlanto-Occipital Dislocation

It is a rare event, characterized by rupture of the ligamentous structures and separation of the skull from the spinal axis. It is usually due to hyperflexion or hyperextension of the skull and cranio-cervical distraction with or without associated rotation. High-speed motor vehicle collisions are the most common cause. Airbag deployment during frontal car crashes has also been implicated as a cause of atlanto-occipital dislocation in children traveling in the passenger front seat [15–17]. Children are usually severely polytraumatized with associated head, thoracoabdominal, and extremity trauma. Although the condition is often fatal, survival is possible with aggressive resuscitation and early surgical fixation [18, 19]. There is usually anterior dislocation (65% of cases), but posterior or vertical atlanto-occipital dislocation may sometimes be seen [20]. Accordingly, atlantooccipital dislocation is classified into types I (ante-

a

b

rior displacement of the occiput with respect to the atlas), II (longitudinal distraction), and III (posterior displacement of the occiput with respect to the atlas). There is always disruption of the apical and alar ligaments and of the tectorial membrane [21]. On lateral cervical spine radiograms (Fig. 42.1), there is misalignment and increased distance between the dens tip and the basion (the normal distance in children being 8.3 mm +/- 4.2) [22], and anterior or posterior displacement of the occipital condyles relative to the superior articular facets of the atlas. Prevertebral tissue swelling is usually present [14]. A fracture of the tip of the dens or of the occipital condyle may also be associated. The gap between the occipital condyle and atlas fossae is wider than 5 mm [23]. There is usually severe medullary damage (often complete section), and most survivors have severe neurological damage [19]. There also is association with brain damage due to subarachnoid hemorrhage and disruption of the base of the skull. MRI can show ligament injury and evaluate full versus partial ligamentous disruption, spinal cord, and brainstem damage. All this information is important for early and appropriate surgical management. However, conventional MRI may fail to detect medullary contusion in the acute stage, while the diagnosis becomes clear on follow-up imaging studies [24]. Newborns and young children are particularly susceptible to atlanto-occipital dislocation because of the horizontal orientation of the atlanto-occipital joint and the relatively small occipital condyles. Patients with Down syndrome are especially prone to this type of injury because of the ligamentous laxity associated with such condition. Other predisposing conditions include skeletal dysplasias (especially Morquio syndrome), chronic arthropathies, pharyngeal infections, and hypoplasia of the axis.

Fig. 42.1a,b. Atlanto-occipital dislocation. a Lateral radiogram clearly shows separation of the atlas from the occipital bone. b Sagittal T2-weighted image obtained in a 13-year-old patient. There is increased intensity in the region of the tectorial membrane and alar ligaments. There is separation of the clivus with respect to the dens. Significant injury to the spinal cord can also be seen. (Reproduced with permission from Steinmetz MP, Lechner RM, Anderson JS. Atlanto-occipital dislocation in children: presentation, diagnosis, and management. Neurosurg Focus 14 (2):Clinical Pearl, 2003. Available online at: http://www.aans.org/education/journal/ neurosurgical/feb03/14-2-cp.pdf)

Spinal Trauma

42.5.1.2 Atlas Injuries

tical or oblique fracture of the C2 body, dens, or of a lower cervical body [27].

Atlas fractures are less common than subluxation; the most frequent are the Jefferson’s “burst” fracture, and anterior and posterior arch fractures [2, 20].

Anterior and Posterior Arch Fractures

Jefferson’s Fracture

The Jefferson’s fracture is the result of an axial compression force, such as a fall onto the head vertex; fractures occur in the anterior or posterior arches of the atlas or both, typically in four places. Patients complain with neck pain, cervical muscle spasm, and head tilt [25]. Open mouth radiograms shows bilateral or unilateral displacement of the lateral masses of C1 relative to the odontoid. Total offset greater than 3 mm is suggestive of Jefferson’s fracture, while displacement greater than 6–7 mm is highly suggestive of transverse ligament rupture with atlanto-axial instability. If the transverse ligament is intact the injury is stable. The lateral X-ray film can demonstrate prevertebral tissue swelling, but CT is recommended when Jefferson fracture is suspected (Fig. 42.2). CT can also well differentiate fracture from normal variants of the C1 ossification pattern, as in normal variants the cortical margins are preserved. CT may be useful to distinguish fracture from the so-called pseudospread of the atlas, i.e., lateral offset of one or both C1 lateral masses relative to C2, which may be seen as a normal variant in infancy [26]. In about 40% of cases of atlas fracture there is an associated fracture, usually a ver-

Fig. 42.2. Jefferson’s fracture. Axial CT scan shows C1 fracture involving left anterior arc and right posterior arc. Small fragment is noted posteromedially to the fracture site of anterior arc (arrowhead). (Copyright protected material used with permission of the author and the University of Iowa’s Virtual Hospital, www.vh.org)

Fractures of the posterior arch of the atlas are more common than anterior ones. The lesion mechanism is due to segmental C1–C2 hyperextension, with a lever effect on the primary axis of the dens and body, which are tilted and luxated anteriorly, thereby pushing anteriorly the C1 anterior arch; as such, these fractures are similar to epiphyseal detachments. A possible additional mechanism is related to tangential forces acting during cervical spine hyperextension.

42.5.1.3 Axis Injuries

Axis injury can be classified into fractures of odontoid process, body, and neural arch. Fractures of the Odontoid Process (Anderson’s Fracture)

According to Anderson’s classification [28], there are three different types of odontoid fracture. Type 1 is an avulsion of the dens tip and is associated with atlantooccipital dissociation; it is a rare event in children. Type 2 is a transverse fracture occurring at the base of the dens or above the level of superior facets. Type 3 is a transverse fracture extending below the level of superior facets across the subdental synchondrosis. However, this classification is not fully satisfactory in the pediatric age group. Especially in infants, fractures of the dens are basically represented by epiphyseal detachments occurring at the tip and base of the dens, respectively [29]. As such, type 3 fracture is the most frequent fracture in children under 7 years due to the fact that the subdental synchondrosis fuses at 5–7 years of age. This fracture occurs as a hyperflexion injury with anterior angulation and displacement of the dens and anterior arch of the atlas. Lateral Xray films can show the fracture. Axial CT images can miss undisplaced odontoid fractures but reconstruction imaging shows the fracture very well. MRI is indicated to show associated spinal cord involvement or hematomas (Fig. 42.3). Hangman’s Fracture

The hangman’s fracture is the result of a traumatic hyperextension with bilateral or unilateral fracture of the posterior arch of C2, usually at the level of the pars interarticularis. Anterior displacement of C2

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1690 P. Tortori-Donati, A. Rossi, M. Calderone, and C. Carollo

a

b

on C3 is very often associated. The hangman’s fracture is very rare in children under 3 years, and may belie nonaccidental trauma [30, 31]. The considerable normal variations can complicate the diagnosis. On lateral X-ray films, the posterior cervical line from the anterior cortex of the tip of C1 to the same level of C3 misses the anterior cortex of the spinous tip of C2 by 1.5 mm or more when there is a hangman’s fracture (Fig. 42.4), but always crosses it in the case of pseudoluxation of C2–C3 [32]. If the fracture is bilateral, it is unstable. The hangman’s fracture is well detected on lateral X-ray films. However, MRI can show associated disc contusion or displacement.

Fig. 42.3a,b. Type 3 Anderson’s fracture. a Sagittal T1-weighted image; b sagittal T2weighted image. The fracture line (arrows) runs across the body of C2 with anterior displacement of the subdental synchondrosis and dens, resulting in a stenosis of the spinal canal. There is an epidural hematoma anterior to the cord (arrowheads). Notice marked prevertebral swelling (asterisk)

dens, while there is a tendency to reduction of the sagittal diameter of the spinal canal. Patients basically complain with extremely painful torticollis (“cock-robin” position), and diminished range of motion [34]. On lateral X-ray films, atlanto-axial subluxation is revealed by a distance between the posteroinferior

42.5.1.4 Atlanto-Axial Subluxation

In the pediatric age group, traumatic rupture of the transverse ligament between the dens and anterior arch of the atlas with resultant rotary atlanto-axial subluxation is a rarer event than epiphyseal detachments at the tip and base of the dens, because ligaments are more resistant to traumatic vectors than epiphyseal cartilages. This injury results from falls or motor vehicle accidents that can be minor, sometimes resulting in considerably delayed diagnosis [33]; it is characterized by anterior motion of the atlas with consequent increased distance between the anterior arch and the

Fig. 42.4. Hangman’s fracture. Laterolateral X-ray film shows anterior displacement of C2. As a consequence, the posterior cervical line, drawn to connect the anterior cortices of the tips of C1 and C3, misses the corresponding spot on C2 (double end arrow). The fracture line is not clearly distinguishable in this radiogram

Spinal Trauma

margin of the anterior arch of the atlas and the dens greater than 5 mm (Fig. 42.5). Additional findings on MRI include edema of the anterior soft tissues, revealed as hyperintensity on T2-weighted images.

As is the case with atlanto-occipital dislocations, conditions such as Down syndrome, skeletal dysplasias, pharyngeal infection, and dens hypoplasia are predisposing factors to atlanto-axial subluxation (Fig. 42.6). These patients should be carefully examined for instability with dynamic X-ray films during flexion and extension of the head. Analogous information may be obtained with MRI, which has the additional advantage of revealing associated signs of spinal cord injury and myelomalacia. It is crucial that trained, experienced personnel perform these potentially dangerous maneuvers in order not to inadvertently provoke, or increase the degree of, dislocation and spinal cord injury.

42.5.2 The Mid-Inferior Cervical Spine

Fig. 42.5. Atlanto-axial subluxation. Latero-lateral radiogram shows increased distance between the postero-inferior margin of the anterior arch of the atlas and the dens (double end arrow). Also notice offset of the posterior arch of the atlas as a result of rotary displacement, resulting in separate visualization of the two halves of the arch (black arrows). There is concurrent marked prevertebral swelling, as revealed by the distance between the endotracheal tube (T) and the spine.

The fractures of this portion of the spine are similar to those of adults, and usually affect children older than 7–8 years. Because of the physiological hyperlaxity of ligaments, it is common to find dislocations of the articular facets in the absence of fractures. Both the lesion mechanisms and the traumatic vectors are similar to those typical of adults. The differences in the structure of the pediatric spine do not determine different types of lesions, but rather a different distribution of lesion types. In fact, flexion-compression fractures are the most frequent, while ligamentous instabilities are rare.

b

a

Fig. 42.6a,b. Atlanto-axial subluxation in a patient with Down syndrome. a Sagittal T2-weighted image shows retroflexion of the cervical spine which forms a 90° angle with the basiocciput. There is abundant amorphous tissue ventral to the dens tip (asterisk). Notice spinal canal stenosis with spinal cord hyperintensity, consistent with edema (arrowhead). b Axial CT scam shows increased distance between the anterior arch of C1 and the dens (thick double end arrow) and reduced distance between the dens and the posterior arch of C1 (thin double end arrow)

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1692 P. Tortori-Donati, A. Rossi, M. Calderone, and C. Carollo 42.5.2.1 Compression Fractures

In compression injury, the traumatic vectors do not cause true burst fractures but, rather, depressions of the osteocartilaginous complex of the vertebral body, thereby producing anterior wedging. These lesions may be difficult to identify because of the physiological wedging of the developing vertebral bodies, but they are very important for the repercussions on the future development of the spine because of the damage to the cartilaginous portions, with striking long-term effects. The reduction in height of the anterior portion of the cervical vertebrae should be considered pathological when it exceeds 50%; in fact, one should consider that some degree of anterior shortening might be due to physiological ossification of growth plates. It is also important to evaluate the integrity of the posterior longitudinal ligament, as dislocations and luxations do not occur with an intact ligament. MRI may be helpful to confirm the diagnosis by showing both vertebral body deformation and signal alterations consistent with bone marrow edema (Fig. 42.7).

42.5.2.2 Hyperflexion Fractures

Among hyperflexion fractures, it is noteworthy to mention the “clay shoveler’s fracture,” an oblique

a

b

fracture with avulsion of the spinous process of C6, C7, or T1, resulting from either a sudden load on a flexed spine or secondary to rotational injury. Cervical hyperflexion sprains are the consequence of hyperflexion damage with kyphotic angulation and anterior subluxation secondary to the rupture of the posterior longitudinal ligament. Dislocation of the articular facets may be associated with fractures of the vertebral bodies and spinous processes. It is also possible to observe horizontal fractures of the bodies and of the neural arches; such lesions are best visualized by lateral radiograms in flexion/extension.

42.5.2.3 Teardrop Fractures

Teardrop fractures are due to traumatic vectors that cause flexion and axial compression, producing avulsion of the anteroinferior corner of a cervical vertebral body along with subluxation and dislocation of the interfacetal joints and disruption of the soft tissues. Backward displacement of the inferior-posterior portion of the vertebral body that protrudes into the spinal canal produces damage to the spinal cord. These lesions usually affect C4, C5, and C6, and are associated with kyphosis. The anterior longitudinal ligament is also damaged, and prevertebral edema is usually associated. Sagittal fractures of the body or laminae may also cause also dislocation of the

Fig. 42.7a,b. Compression cervical fractures in a 13-year-old girl who dove into shallow water. a Sagittal T1-weighted and b sagittal T2-weighted images show reduced height and anterior wedging of the C5, C6, and C7 vertebral bodies (arrows) due to collapse of the vertebral endplates. The same vertebral bodies also appear T1 hypointense and T2 hyperintense due to bone marrow edema. The spinal cord is intact. The cervical spine is rigid with loss of the physiologic lordosis

Spinal Trauma

inferior articular facet. Patients may be asymptomatic, experience partial neurological involvement, or present with complete tetraplegia. Usually, flexion teardrop fractures cause anterior cord syndrome, characterized by tetraparesis and loss of pain and tactile sensation, while proprioception and vibratory sensation are spared. On X-rays (Fig. 42.8), the most characteristic feature is posterior displacement of the upper column of the divided cervical spine (78% of cases). Other radiographic findings include backward displacement of the posterior fragment of the involved body, widening of the interlaminar and interspinous spaces, widening of the facet joint with backward displacement of the inferior facet, and kyphotic deformity of the cervical spine at the level of injury [35].

spinal cord injury without radiographic abnormalities (SCIWORA). Orenstein [36] studied nine children with delayed diagnosis of cervical fractures: only one of them had a lesion of the cervico-thoracic junction and, moreover, none of the patients was asymptomatic. Baker et al. [37] reported 72 children with lower cervical trauma, only 18% of whom were without spinal cord symptoms. Oblique projections are the method of choice to obtain a better definition of the lesion because other techniques, such as traction of the arms or the swimmer’s position, may cause further stress to the patient. Moreover, if the anteroposterior projection does not show vertebral misalignment and there are no neurological signs, there is no need of further projections.

42.5.3 The Cervico-Thoracic Junction

42.5.4 The Thoracic Spine

Fractures of the cervico-thoracic junction are extremely uncommon in patients under 10 years of age. However, this region is the most frequent level of

Thoracic spine fractures account for about 30% of all vertebral fractures in children, thereby representing the most common region of fracture in pediatric trauma patients [38]. They are caused by flexo-extension vectors, and are usually associated with intrathoracic or abdominal lesions. Fractures of the transverse processes of T1 and T2, as well as C7, are often associated with lesions of the brachial plexus, whereas seat-belt fractures of the inferior portion of the thoracic spine or the superior portion of the lumbar spine are associated with parenchymal lesions (hepatic, splenic, or mesenteric contusions) in more than 50% of the cases. The most frequent causes of these types of lesions are motorvehicle accidents, but nonaccidental injury is also a possible cause. The most frequent fractures of the thoracic spine are compression fractures of the vertebral bodies, usually due to falls (Fig. 42.9). Standard radiograms in the lateral projection show anterior wedging of the vertebral body. A difference in height greater than 3 mm between the anterior and the posterior portion of the body is significant and should be differentiated from the harmonious wedging of the developing spine. If the difference in height is greater than 25%, there is usually a severe damage of the posterior ligamentous complex with relative instability. In rare instances, anteroposterior views may be necessary for confirmation. Compression fractures usually affect multiple contiguous vertebral bodies and can result in focal kyphosis. Most fractures in children are located between T4 and T12, and may be underestimated by traditional radiograms, while MRI shows them very

Fig. 42.8. Teardrop fracture of C5. Lateral radiogram shows avulsion of the anteroinferior corner of the C5 vertebral body (arrow) along with posterior displacement of C5 relative to C6 (straight lines) and ensuing kyphosis

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1694 P. Tortori-Donati, A. Rossi, M. Calderone, and C. Carollo

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Fig. 42.9a–c. Thoracic compression fractures in a 14-year-old boy who fell from the motorbike. a Lateral radiogram shows the T6 through T9 vertebral bodies are reduced in height and show concave endplates with resultant moderate anterior wedging. b Sagittal T1-weighted and c sagittal T2-weighted image show T1 hypointensity and T2 hyperintensity within the fractured vertebral bodies as a result of bone marrow edema. There is incidental mild hydromyelia. The child complained with pain but was neurologically intact.

well. Findings on MRI include vertebrae of reduced thickness, hypointense in T1- and slightly hyperintense in T2-weighted images; T2 signal abnormalities typically become more conspicuous on fat-suppressed sequences. Nonaccidental vertebral fractures are usually due to compression mechanisms, and are sometimes associated with avulsion of the spinous processes. The healing process depends on the age of the child and on the severity of the lesion. Sometimes a normal body is seen after a compression fracture, while lesions of the epiphyses or of the disc usually impair vertebral growth and may cause focal kyphosis.

42.5.5 The Lumbar Spine Seventeen to 27% of all spinal traumas in children involve the lumbar spine. Fractures of the thoracolumbar junction are associated with spinal cord

lesions in 40% of cases. Because the spinal cord ends at the level of L1, lower fractures may only involve the cauda, with milder neurological symptoms. The relatively higher percentage of lesions at the thoracolumbar junction is due to the high mobility of this segment, to the laxity of support structures, and to the change in the orientation of the articular facets. Multiple compression fractures are often present.

42.5.5.1 Chance Fracture

The use of the seat belt or lap belt in motor vehicles, particularly to restrain young rear seat passengers, remains an issue of some concern, as the occurrence of lumbar spinal flexion-distraction injuries (“Chance fracture”) in lap-belt-restrained children and adolescents during traffic accidents is a well-known phenomenon. Moreover, high velocity pediatric Chance fractures are frequently associated with significant

Spinal Trauma

intra-abdominal trauma [39]. Anterior wedging of the vertebral body results from lesion to the posterior elements and extension of the fracture line horizontally across the body. In Chance fractures, there is a horizontal fracture extending through the spinous process, the pedicles, and the posterior portion of the vertebral body. Smith fractures are similar, but the posterior bony elements are spared while the lesion affects the posterior spinal ligaments. In anteroposterior radiograms, it is possible to observe an apparent “empty vertebral body” because of the distraction and dislocation of the posterior elements that are normally seen through the vertebral body [40]. Lateral projections show the fracture and the associated structural dislocations. CT images are necessary to thoroughly evaluate the lesion; since the fracture courses horizontally, reconstruction images on coronal and sagittal planes are also necessary. MRI depicts the associated spinal cord damage that can be severe when there is associated dislocation of the fractured spine (Fig. 42.10).

a

b

42.5.5.2 Burst Fractures

Axial compression vectors that disrupt the vertebral plate and cause disc herniation into the vertebral body cause burst fractures. Bone fragments, usually from the postero-superior portion of the body, can also penetrate the spinal canal. Burst fractures may be distinguished from simple compression fractures by the disruption of the posterior cortex of the vertebral body and the wider interpeduncular space seen in anteroposterior projections.

42.5.5.3 Fractures of The Neural Arch

Isolated fractures of the neural arch or of the transverse processes are usually due to direct trauma or to lateral hyperflexion or hyperextension. Fractures of the transverse processes of the upper lumbar ver-

c

Fig. 42.10a–c. Lumbar Chance fracture with spinal cord damage in a 7-year-old boy involved in high-speed car accident. a Lateral radiogram shows disruption of the superior L3 endplate with marked dislocation and kyphosis. b Sagittal T1-weighted and c sagittal T2-weighted images obtained 2 days after emergency decompression show extensive spinal cord and caudal nerve root damage

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1696 P. Tortori-Donati, A. Rossi, M. Calderone, and C. Carollo tebrae are associated with renal lesions, while lower fractures can injure the lumbo-sacral plexus. Fractures of lumbar apophyses are usually recognized because of back pain in adolescents, particularly in those that practice gymnastics or sports. The fracture causes the avulsion of the posterior portion of the lumbar apophysis. The disc and the ossification nuclei, and sometimes a metaphyseal fragment, may be dislocated backwards into the vertebral canal and are well recognized by CT. If conservative therapy is instituted, the bone fragment calcifies in this anomalous position causing narrowing of the vertebral canal.

42.6 Child Abuse and Spinal Trauma The spinal lesions associated with child abuse may easily be overlooked and probably represent an underreported phenomenon, although they may significantly contribute to morbidity and mortality [41]. Although, in general, inflicted lesions are similar to those of accidental origin, there are some peculiar features that may suggest child abuse in children with spinal trauma. Spinal fractures or dislocations in the absence of history of trauma should be considered with suspicion [31, 42, 43]. In these cases, vertebral compressions of different severity may be associated with intact vertebral plates and interdiscal spaces. Lesions usually affect the inferior thoracic or superior lumbar segment, but lesions involving multiple sites are also common with subsequent thoraco-lumbar kyphosis. Severe hyperflexion may cause herniation of the vertebral disc into the upper or lower vertebral plate with narrowing of the anterior disc space, contact between the vertebral corners, and sclerosis. Fractures of the spinous processes may be isolated or associated with vertebral body fractures. Cartilaginous or bone protrusions at the site of ligamentous insertions are more frequent in the median or lower thoracic segments, and occasionally in the upper lumbar vertebrae, and may be seen in follow-up studies as abnormal calcifications. Unstable vertebral body injury due to separation of the posterior arch from the vertebral body that is displaced forward is also frequent. Other types of lesions associated with child abuse are the hangman’s fracture of C2 [31], the clay shoveler’s fracture of the inferior cervical portion, spinal subdural hematomas [44], and SCIWORA [45].

42.7 Spinal Cord Lesions The peculiar anatomic situation of the spine accounts for the particular susceptibility of children to spinal cord lesions. The elasticity of the interspinous ligaments, posterior articular capsules, and cartilaginous vertebral endplates accounts for the higher degree of deformability of the pediatric spine when compared to the more rigid adult spine. Moreover, the articular facets are horizontal, causing more motility and less stability. Multiple injuries, chest injuries, reduced Glasgow coma scale (GCS), and concurrent head injury increase the risk of spinal cord injury [46]. In preadolescent children, the vast majority (about 75%) of spinal cord traumas are caused by either a fall or being struck by a vehicle, while an additional 20% are sports related [2].

42.7.1 Clinical Features Spinal cord lesions cause partial or complete loss of motor and/or sensory function. Early symptoms precede by about 4 days the more severe late permanent damage. There is minimal correlation between vertebral and spinal cord lesions. Myelopathy or radiculopathy may be classified as complete, with total loss of motor, sensory, and autonomic function distal to the site of the lesion, or partial, with several clinical syndromes. The latter include: (1) posterior cord syndrome, with preservation of gross sensory function; (2) anterior cord syndrome, with preservation of sensory and proprioceptive function; (3) central cord syndrome, with the upper limbs more severely affected than the lower limbs; (4) Brown-Séquard syndrome, with loss of function homolateral to the lesion and of thermal and pain sensation opposite to the lesion; and (5) radicular syndrome, characterized by pain with or without loss of motor or sensory function. Lesions more often involve the cervical cord, causing tetraparesis or tetraplegia, and less frequently the thoraco-lumbar spine, with resulting paraparesis or irreversible paraplegia. Most spinal cord lesions do not regress; however, about 40% of patients with severe partial lesions experience some degree of sensorimotor functions, while 30% of thoracolumbar lesions have complete function recovery. Frequent sequelae are posttraumatic vertebral instability, progressive deformity, focal kyphosis, and paralytic scoliosis.

Spinal Trauma

The majority of irreversible cord lesions are caused by compression and contusion with edema, hemorrhage, and an ischemic insult. Severe neurological deficit is seen immediately after the trauma, and the clinical picture may worsen in the following days due to a combination of primary traumatic effects and secondary reactive alterations. Traumatic damage may cause vascular tears with petechial hemorrhages and pial rupture with leakage of CSF into the cord, causing axonal injury. Reactive alterations are due to postcapillary vascular stasis with reduced gray matter perfusion. Edema is seen after 4 h and progresses until the end of the second day. Necrosis can be seen as soon as 2 h after trauma and can extend cranially (or caudally) from the original site during the next 4 days. Hemorrhages are followed by intramedullary cavitations and adhesive arachnoiditis.

normal MRI findings, subsequent complete recovery can be anticipated [50]. Possible roles for MRI in children with SCIWORA include ruling out cord/roots compression or ligamentous disruption that might warrant surgical intervention, guiding treatment concerning length of external immobilization, and determining when patients can be allowed to return to full activity [51].

42.7.3 Chronic Cord Lesions Sequelae of cord lesions include myelomalacia, posttraumatic medullary cysts or syringomyelia, arachnoiditis, arachnoid cysts, and neuroarthropathies. Imaging is indicated to distinguish myelomalacia from syringomyelia, and to document radicular or medullar compressions [49].

42.7.2 Spinal Cord Injury Without Radiological Abnormality (SCIWORA) Spinal cord lesions are frequently seen in children without radiological abnormalities. Such lesions are called SCIWORA (spinal cord injury without evidence of vertebral fracture or misalignment on plain radiographs and CT) [47]. SCIWORA is defined as spinal cord injury demonstrated by MRI, when a complete, technically adequate plain radiographic series reveals no injury. SCIWORA is usually due to transitory subluxation without bone fracture, reversible disc prolapse, or spasms/occlusion of the anterior spinal or radiculomedullary arteries. The hypermobility and ligamentous laxity of the pediatric bony cervical and thoracic spine predispose to a SCIWORA-type injury by allowing deformation of the musculoskeletal structures beyond physiologic extremes, with direct cord trauma followed by spontaneous reduction of the bony spine [48]. SCIWORA is seen in 5%–65% of pediatric patients with spinal trauma [49] and is more common in younger children. Neurological symptoms appear within 48 h of the trauma. The mainstay of treatment involves immobilization and stabilization of the affected segment in order to preserve vertebral alignment. On MRI, findings may be variable depending on the severity of spinal cord damage and span the entire spectrum from normal to edema (Fig. 42.11), hemorrhage (Fig. 42.12), or cord transection [50], along with extraneural findings such as disc herniation and ligamentous injury. In symptomatic patients with

42.8 Delivery Trauma Traumatic delivery can be an important cause of spinal cord and nerve root trauma in newborns.

42.8.1 Spinal Cord Injury at Birth Atlanto-occipital and atlanto-axial dislocations associated with spinal cord transection have been reported in autopsy studies, and longitudinal traction during dystocic delivery is the likely cause of the diffuse cord lesion [52]. The superior cervical segment and the cervicothoracic junction are the critical regions during complicated delivery. In such situations, especially when the child is in transverse presentation, the spinal cord is subject to torsion, traction, and flexion because of the movements of the head, neck, and shoulder within the cervical canal in the absence of signs of fracture [53]. Meningeal trauma may be present with an associated epidural hematoma. An alternate mechanism is an exaggerated longitudinal traction of the spinal cord, causing edema, contusion, ischemic or hemorrhagic vascular damage (hematomyelia) (Fig. 42.13) with subsequent necrotic degeneration, or spinal cord transection. Damage to the affected structures may be complete or partial, and the clinical picture may vary from hypotonia to areflexia, respiratory distress, and shock.

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1698 P. Tortori-Donati, A. Rossi, M. Calderone, and C. Carollo

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d

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Fig. 42.11a–d. SCIWORA in a 2-year-old boy involved in a car accident. a Sagittal T1-weighted, b sagittal T2-weighted, and c sagittal FLAIR images show signal abnormality involving the spinal cord from C7 to T2. Focal T1 hyperintensity (arrow, a) suggests petechial hemorrhage. There are no associated vertebral fractures. d Axial gradient-echo T2-weighted image confirms central spinal cord involvement

42.8.2 Brachial Plexus Injury

42.9 Spondylolysis and Spondylolisthesis

Brachial plexus and is caused by tearing and laceration of the nerve roots with leakage of CSF from the subarachnoid space, resulting in avulsion pseudomeningoceles [54] (Fig. 42.14). Fractures of the clavicles can be associated. Very rarely, similar injuries resulting in avulsion pseudomeningoceles can be seen in older patients with accidental trauma (Fig. 42.15).

Spondylolysis represents a particular subset among traumatic spinal lesions. The term spondylolysis refers to a bone defect of the neural arch, usually at level of the pars interarticularis. While such defects are not uncommon in children aged 10–12 years (7%–8% of imaging studies), they are extremely uncommon in newborns. This observation has led to the hypothesis

Spinal Trauma

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Fig. 42.12a–d. SCIWORA in a 2-year-old boy involved in a car accident. a Sagittal T1weighted and b sagittal T2-weighted images show hemorrhagic focus (arrowhead) associated with diffuse T2 cord hyperintensity. c, d Axial gradient-echo T2*-weighted images confirm the presence of acute cord hematoma extending superficially (arrows)

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Fig. 42.13a–d. Hematomyelia in a 7-day newborn born from dystocic delivery. a Sagittal T1-weighted, b sagittal T2-weighted, c coronal T1-weighted, and d axial T1-weighted image show diffuse cord signal alteration with prevailing T1 hyperintensity, consistent with hematomyelia. Notice the spinal column is intact

d

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1700 P. Tortori-Donati, A. Rossi, M. Calderone, and C. Carollo

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Fig. 42.14a,b. Avulsion pseudomeningoceles due to shoulder dystocia. a Conventional anteroposterior myelogram shows large avulsion pseudomeningocele of the left C6 root sleeve. b MR myelography, coronal projection in a 4-month-old child shows avulsion pseudomeningocele of the right C7 root sleeve

[55] that spondylolysis has a traumatic origin, namely a stress fracture. However, dysplastic forms, due to congenital abnormalities of the lumbo-sacral passage such as partial sacralization of L5, also exist. Spondylolysis accounts for the majority of cases of low back pain in children older than 7–8 years, and is commonly seen in individuals who practice sports [56, 57]. Spondylolysis is more often bilateral than unilateral and involves L5 in the vast majority of cases. This condition allows for excessive motility, and therefore potential instability, of the lumbar spine with respect to the sacrum, often leading to spondylolisthesis, i.e., anterior dislocation, of L5 with respect to S1. The diagnosis is already clear on plain X-rays using laterolateral and oblique projections. On CT, a thin, irregular interruption of the neural arch at level of the isthmus is seen (Fig. 42.16). Care must be employed not to mistake a lytic defect with the adjacent normal facet joint. In doubtful cases, sagittal reconstructions will clear the view. On MRI, the defect may not be seen equally well; however, MRI is more useful to evaluate associated features, such as disc pseudobulging (not a true herniation) and foraminal stenosis, which determine the degree of nerve root compression (Fig. 42.16). MRI also shows redundant masses of tissue surrounding the pars defect, with MR characteristics of cartilaginous and fibrous low signal intensity on T1-weighted images and low to interme-

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Fig. 42.15a–d. Avulsion pseudomeningocele due to accidental trauma. a, b Coronal MR myelogram and c axial T2-weighted image in a 12-year-old boy who fell while skiing shows multiple lumbar root avulsion pseudomeningoceles to the left. d Axial CT myelogram in a different patient shows right cervical root avulsion pseudomeningocele causing dural sac compression

Spinal Trauma

diate signal intensity on T2-weighted images, which may impinge on the thecal sac [58]. In chronic lesions, reactive sclerosis (Gill nodules) with hypertrophy and calcification of the lytic margins appear. Unilateral spondylolysis is often associated with sclerosis of the contralateral pedicle, which should not be mistaken for an osteoid osteoma.

One must be aware that, during childhood, the posterior margin of the annulus fibrosus is normally convex (Fig. 42.19). This normal appearance must not be mistaken for disc herniation.

42.10.2 Slipped Vertebral Apophysis Avulsion of the postero-inferior apophysis with dislocation of the bony fragment and disc into the spinal canal is a rare lesion that preferentially involves L4. Symptoms are similar to those of disc herniations [60].

42.10 Other Traumatic Lesions 42.10.1 Disc Herniations Prolapse of the intervertebral disc is rare in children [59], is often associated with sports trauma, and can be associated with a fracture of the posterior portion of the vertebral plate, such as detachment of an epiphyseal fragment. Patients complain with low back pain and muscular spasm, but neurologic deficits are rarer than in adults. The L4–L5 and L5–S1 spaces are involved more commonly. In our experience, pediatric disc herniations have usually been large, and the extruded disc fragment is usually markedly hydrated (Fig. 42.17). A predisposing condition, such as Scheuermann disease, can be present (Fig. 42.18).

42.10.3 Disc Space Calcification Disc space calcification typically involves the cervical spine but may be also found at thoraco-lumbar level or involve multiple disc spaces [61]. The cause of calcification is often uncertain, although trauma and inflammation have been implicated as causal mechanisms. Most patients are boys between 6 and 10 years of age who complain with local pain. Herniation of a calcified disc fragment may be associated and cause neurologic signs [61] (Fig. 42.20).

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Fig. 42.16a–c. Spondylolysis of L5 with spondylolisthesis in a 15-year-old girl. a Axial CT scan shows lytic defect of the pars interarticularis (isthmus) of L5 bilaterally (arrows). b, c Sagittal T1-weighted images show marked anterolisthesis of L5 and confirm isthmic spondylolysis (black arrow, c). Notice pseudobulging of the L5–S1 disc (white arrow, b) and foraminal stenosis (arrowhead, c)

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b Fig. 42.17a,b. Disc herniation in a 9-year-old girl. a Sagittal T2-weighted shows markedly hydrated L5– S1 disc herniation associated with posterior bulging of the L4–5 disc. b Axial T1-weighted image shows compression of the right S1 nerve root (arrow)

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Fig. 42.18a,b. Disc herniations in a patient with Scheuermann disease. a Sagittal T2weighted image at age 6 years shows dehydrated L5–S1 disc with large posterior herniation. Notice that the L4–L5 disc is normal. b Sagittal T2-weighted image at age 11 years shows slight size reduction of the L5–S1 herniation and a new L4–L5 herniation with marked dehydration of the parent disc

Fig. 42.19. Normal appearance of the lumbar discs in an asymptomatic 8-year-old boy. Notice apparent pseudobulging of the posterior annular margin of the lumbar discs (arrowheads). This appearance is normal in the pediatric age group and should not be mistaken for herniation

Spinal Trauma

c

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Fig. 42.20a–e. Calcified intervertebral disc with associated herniation in a 12-yearold boy. a Anteroposterior radiogram shows calcified thoracic disc (arrow). b Sagittal T2-weighted image shows hypointense herniation (arrow). c–e Axial CT scans show calcified central disc portion (arrowhead, c), herniation of calcified disc material (open arrow, d), and downward migration of extruded calcified disc material (arrow, e)

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1704 P. Tortori-Donati, A. Rossi, M. Calderone, and C. Carollo 16. Bailey H, Perez N, Blank-Reid C, Kaplan LJ. Atlanto-occipital dislocation: an unusual lethal airbag injury. J Emerg Med 2000; 18:215-219. 17. Shkrum MJ, McClafferty KJ, Nowak ES, German A. Driver and front seat passenger fatalities associated with air bag deployment. Part 1: A Canadian study. J Forensic Sci 2002; 47:1028-1034. 18. Houle P, McDonnell DE, Vender J. Traumatic atlanto-occipital dislocation in children. Pediatr Neurosurg 2001; 34:193-197. 19. Labbe JL, Leclair O, Duparc B. Traumatic atlanto-occipital dislocation with survival in children. J Pediatr Orthop B 2001; 10:319-327. 20. Sun PP, Poffenbarger GJ, Durham S, Zimmerman RA. Spectrum of occipitoatlantoaxial injury in joung children. J Neurosurg Spine 2000; 93:28-39. 21. Werne S. Studies in spontaneous atlas dislocation. Acta Orthop Scand Suppl 1957; 23:12-83. 22. Bulas DI, Fitz CR, Johnson DL. Traumatic atlanto-occipital dislocation in children. Radiology 1993; 188:155-158. 23. Costello MW. Images in emergency medicine. Traumatic atlanto-occipital dislocation. Ann Emerg Med 2004; 44:277, 285. 24. Bani A, Gilsbach JM. Atlantooccipital distraction: a diagnostic and therapeutic dilemma: report of two cases. Spine 2003; 28:E95-E97. 25. Judd DB, Liem LK, Petermann G. Pediatric atlas fracture: a case of fracture through a synchondrosis and review of the literature. Neurosurgery 2000; 46:991-994. 26. Suss RA, Zimmerman RD, Leeds NE. Pseudospread of the atlas: false sign of Jefferson fracture in young children. AJR Am J Roentgenol 1983; 140:1079-1082. 27. Mazur JM, Loveless EA, Cummings RJ. Combined odontoid and jefferson fracture in a child: a case report. Spine 2002; 27:E197-E199. 28. Anderson LD, D’Alonzo RT. Fractures of the odontoid process of the axis. J Bone Joint Surg Am 1974; 56:1663-1674. 29. Connolly B, Emery D, Armstrong D. The odontoid synchondrotic slip: an injury unique to young children. Pediatr Radiol 1995; 25 (Suppl 1):S129-S133. 30. Kleinman PK, Shelton YA. Hangman’s fracture in an abused infant: imaging features. Pediatr Radiol 1997; 27:776-777. 31. Ranjith RK, Mullett JH, Burke TE. Hangman’s fracture caused by suspected child abuse. A case report. J Pediatr Orthop B 2002; 11:329-332. 32. Swischuk LE. Anterior displacement of C2 in children: physiologic or pathologic. Radiology 1977; 122:759-763. 33. Floman Y, Kaplan L, Elidan J, Umansky F. Transverse ligament rupture and atlanto-axial subluxation in children. J Bone Joint Surg Br 1991; 73:640-643. 34. Muniz AE, Belfer RA. Atlantoaxial rotary subluxation in children. Pediatr Emerg Care 1999; 15:25-29. 35. Kim KS, Chen HH, Russell EJ, Rogers LF. Flexion teardrop fracture of the cervical spine: radiographic characteristics. AJR Am J Roentgenol 1989; 152:319-326. 36. Orenstein JB, Klein BL, Ochsenschlager DW. Delayed diagnosis of pediatric cervical spine injury. Pediatrics 1992; 89:1185-1188. 37. Baker C, Kadish H, Schunk JE. Evaluation of pediatric cervical spine injuries. Am J Emerg Med. 1999; 17:230-234. 38. Reddy SP, Junewick JJ, Backstrom JW. Distribution of spinal fractures in children: does age, mechanism of injury, or gender play a significant role? Pediatr Radiol 2003; 33:776-781. 39. Walsh A, Sheehan E, Walsh MG. Lumbar Chance fracture associated with use of the lap belt restraint in an adolescent. Ir Med J 2003; 96:148-149.

40. Willen J, Lindahl S, Irstam L, Aldman B, Nordwall A. The thoracolumbar crush fracture. An experimental study on instant axial dynamic loading: the resulting fracture type and its stability. Spine 1984; 9:624-631. 41. Ghatan S, Ellenbogen RG. Pediatric spine and spinal cord injury after inflicted trauma. Neurosurg Clin N Am 2002; 13:227-233. 42. Gabos PG, Tuten HR, Leet A, Stanton RP. Fracture-dislocation of the lumbar spine in an abused child. Pediatrics 1998; 101:473-477. 43. Levin TL, Berdon WE, Cassell I, Blitman NM. Thoracolumbar fracture with listhesis--an uncommon manifestation of child abuse. Pediatr Radiol 2003; 33:305-310. 44. Soto-Ares G, Denes M, Noule N, Vinchon M, Pruvo JP, Gosset D. [Subdural hematomas in children: role of cerebral and spinal MRI in the diagnosis of child abuse]. J Radiol 2003; 84:1757-1765. 45. Brown RL, Brunn MA, Garcia VF. Cervical spine injuries in children: a review of 103 patients treated consecutively at a level 1 pediatric trauma center. J Pediatr Surg 2001; 36:11071114. 46. Martin BW, Dykes E, Lecky FE. Patterns and risks in spinal trauma. Arch Dis Child 2004; 89:860-865. 47. Pang D, Wilberger JE. Spinal cord injury without radiographic abnormalities in children. J Neurosurg 1982; 57:114-129. 48. Kriss VM, Kriss TC. SCIWORA (spinal cord injury without radiographic abnormality) in infants and children. Clin Pediatr (Phila) 1996; 35:119-124. 49. Barnes PD. Acquired abnormalities of the spine and spinal neuraxis. In: Wolpert SM, Barnes PD (eds) MRI in Pediatric Neuroimaging. St. Louis: Mosby year Book, 1992. 50. Grabb PA, Pang D. Magnetic resonance imaging in the evaluation of spinal cord injury without radiographic abnormality in children. Neurosurgery 1994; 35:406-414; 51. Davis PC, Reisner A, Hudgins PA, Davis WE, O’Brien MS. Spinal injuries in children: role of MR. AJNR Am J Neuroradiol 1993; 14:607-617. 52. Proctor MR. Spinal cord injury. Crit Care Med 2002; 30 (11 suppl):S489-S99. 53. Menticoglou SM, Perlman M, Manning FA. High cervical spinal cord injury in neonates delivered with forceps: report of 15 cases. Obstet Gynecol 1995; 86:589-594. 54. Piatt JH Jr. Birth injuries of the brachial plexus. Pediatr Clin North Am 2004; 51:421-440. 55. Marchetti PG, Bartolozzi P, Binazzi R, Vaccari V, Girolami M, Impallomeni C, Morici F, Bevoni R. Preoperative reduction of spondylolisthesis. Chir Organi Mov 2002; 87:203-215. 56. Lim MR, Yoon SC, Green DW. Symptomatic spondylolysis: diagnosis and treatment. Curr Opin Pediatr 2004; 16:37-46. 57. Waicus KM, Smith BW. Back injuries in the pediatric athlete. Curr Sports Med Rep 2002; 1:52-58. 58. Major NM, Helms CA, Richardson WJ. MR imaging of fibrocartilaginous masses arising on the margins of spondylolysis defects. AJR Am J Roentgenol 1999; 173:673-676. 59. Martinez-Lage JF, Fernandez Cornejo V, Lopez F, Poza M. Lumbar disc herniation in early childhood: case report and literature review. Childs Nerv Syst 2003; 19:258-260. 60. Callahan DJ, Pack LL, Bream RC, Hensinger RN. Intervertebral disc impingement syndrome in a child. Report of a case and suggested pathology. Spine 1986; 11:402-404. 61. Gerlach R, Zimmermann M, Kellermann S, Lietz R, Raabe A, Seifert V. Intervertebral disc calcification in childhood-a case report and review of the literature. Acta Neurochir (Wien) 2001; 143:89-93.

Spine and Spinal Cord: Arteriovenous Shunts in Children

43 Spine and Spinal Cord: Arteriovenous Shunts in Children Siddhartha Wuppalapati, Georges Rodesch, Hortensia Alvarez, and Pierre Lasjaunias

43.1 Introduction

CONTENTS 43.1

Introduction

43.2

Classification of Spinal AVS 1705

1705

43.2.1 43.2.1.1 43.2.1.2 43.2.1.3 43.2.2 43.2.2.1

Groups by Location 1706 Intradural Arteriovenous Shunts 1706 Extradural Arteriovenous Shunts 1706 Paraspinal Arteriovenous Shunts 1707 Groups by Embryology 1707 Single Shunts Associated with Genetic and Hereditary Disorders 1709 43.2.2.2 Multiple SCAVSs 1709 43.2.2.3 Solitary AVMs or MicroAVFs 1709 43.3

Natural History and Clinical Aspects

43.4

Diagnosis

43.5

Angioarchitecture

43.6

Treatment

43.6.1 43.6.2 43.6.3

Therapeutic Abstention 1712 Embolization 1713 Other Treatments 1713 References

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Spinal arteriovenous shunts (AVS) can be separated according to their location. Several entities can thus be recognized: 쐌 Intradural: spinal cord arteriovenous malformations (SCAVM), perimedullary fistulae, radicular AVMs, and filum terminale AVMs; 쐌 Epidural (including paraspinal): epidural AVMs, paraspinal AVMs (PSAVMs), vertebro-vertebral fistula and maxillary arteriovenous fistulae (AVFs) [11]. These lead to neurological symptoms through various pathophysiological mechanisms, including venous congestion, venous compression, and vascular rupture. Hemorrhagic venous infarcts are not seen in the spinal cord. Intradural AVS are rare, representing only one tenth of central nervous system AVMs in all age groups in the Caucasian population [3]. Very few of these AVS are present in children, although pediatric onset is frequently noted in lesions diagnosed in adulthood. With better imaging technology and higher indices of suspicion, it is now feasible to pick up these lesions early in life. Most are cervical or thoraco-lumbar spinal cord lesions.

43.2 Classification of Spinal AVS Spinal AVS can be classified in two ways, i.e., (1) according to their precise location with respect to the spinal cord, dural, and vertebral elements; and (2) according to potential relationships with genetics, the influence of triggers on the vascular biology, and angiogenesis, in other words as disease entities.

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1706 S. Wuppalapati, G. Rodesch, H. Alvarez, and P. Lasjaunias 43.2.1 Groups by Location 43.2.1.1 Intradural Arteriovenous Shunts

These can affect the cord, the nerve roots, or the filum terminale. According to their location, the radiculomedullary and/or radiculo-pial arteries will feed the spinal cord AVS. They can be found at the surface of the cord or embedded within it, and drain through spinal cord veins. They will be revealed by progressive or acute neurological symptoms. We further separated SCAVMs into two types: (1) nidus type, in which an abnormal network is interposed between arteries and veins; and (2) fistulas, in which a direct communication is seen between an artery and a vein. Although both types of lesions are found in the subpial space, niduses may be partially or totally buried in the spinal cord itself (Fig. 43.1). Conversely, large AVFs always remain superficial to the cord, as in the rest of the central nervous system, being located within the subarachnoid space, either dorsally or ventrally within the ventral sulcus in the subpial space. The venous drainage is likely to be mostly subpial in the former group, and subarachnoid in the latter. In the pediatric age group, SCAVMs form the major part of the AVS. There are two types of the less often seen AVFs: the microAVFs, which have normalsized draining veins, and the macroAVFs, which have enormously dilated draining veins. Greater than 80% of macroAVFs are associated with hereditary hemor-

a

b

c

rhagic telangiectasia (HHT), also called Rendu-OslerWeber disease (Figs. 43.2, 3) (see Chapter 17). Most spinal cord AVS in all age groups are single. However, 28% can be associated with some type of dysplasia, cutaneous vascular malformation, or spinal metameric (i.e., Cobb) syndrome (skin, vertebrae, and cord involvement at the same metameric level). In 9% of cases, HHT and a high-flow fistula were noted, and in 5% a Klippel-Trenaunay syndrome was found. Radicular AVSs are rare. Some angioarchitectural appearances suggest a malformative AV sleeve around one nerve root, but in fact this corresponds to a congested radicular vein accompanying the spinal nerve.

43.2.1.2 Extradural Arteriovenous Shunts

These lesions are located in the epidural space. They are vascularized by dural or epidural branches of segmental arteries, and drain primarily into epidural venous plexuses. Neurological symptoms will occur if the venous drainage is rerouted towards spinal cord veins, thus creating a venous congestive myelopathy.

d

e

Fig. 43.1a–e. SCAVM in a 13-year-old female with left sided radicular pain. a Sagittal T2-weighted MR image shows flow voids of the nidus in the dorsal aspect of cord. b, c Transmedullary supply to dorsally located SCAVM. Presence of a network of draining veins emerging around the lower cervical nerves. d, e Ventral and contralateral dorsal pial arteries contribute to the dorsal SCAVM

Spine and Spinal Cord: Arteriovenous Shunts in Children

a

g

b

c

d

h

e

f

i

j

Fig. 43.2a–j. Hereditary hemorrhagic telangiectasia (HHT). a–g 2-year-old child with a medical history beginning at 1 month of age with sudden paraparesis and hypotonia with rectal prolapse. The child’s mother presented with telangiectasias and epistaxis, as did her father. a, b Sagittal T2-weighted MR images detect lesion at the level of the conus, initially considered as a teratoma. The patient was operated upon posterior laminectomy decompression. Biopsy showed nervous tissue and vascular anomaly. The child recovered totally. c–g Angiography shows macro-fistula suggestive of HHT. h Chest MRA shows a pulmonary arteriovenous fistula. i, j The patient is referred for embolization of the macro-fistula of the spinal cord, that is cured with glue (i). Control at 6 months shows remodeling (j)

43.2.1.3 Paraspinal Arteriovenous Shunts

Paraspinal arteriovenous shunts are usually seen in the pediatric age group. They can drain only into the paraspinal veins, but sometimes may have transdural reflux into the spinal cord veins. They rarely present with neurological deficit. These vascular malformations are similar to the extracranial branchial AVS, as the embryonic center of these malformations is

the notochord. The extracranial branchial and paraspinal AVS are therefore similar in nature, although located in different anatomical compartments.

43.2.2 Groups by Embryology Classification based on embryological timing identifies three groups of entities.

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1708 S. Wuppalapati, G. Rodesch, H. Alvarez, and P. Lasjaunias

a

b

c

d

e

f

Fig. 43.3a–f. One-year-old boy with familial history of HHT first admitted with disturbances of consciousness. a Axial CT scan shows intraventricular hemorrhage. b Right vertebral artery angiogram revealed three AVMs, two in the right cerebellar lobe and one SCAVM at C2 and C3. The main cerebellar arteriovenous shunt, supplied by the right anterior inferior cerebellar artery, showed ectatic venous drainage of the posterior fossa and venous pseudo-aneurysms. Due to the predicted risk of rebleeding related to angioarchitectural features and based on the location of hemorrhage, this lesion was considered to have bled and was embolized partially with bucrylate. At the time of discharge, the baby had clinically recovered. c, d One month later, the child presented with an acute tetraplegia. T1- (c) and T2-weighted (d) MR images reveal hematomyelia at C5 and swelling of the cervical spinal cord. e, f On angiography, the C2-C3 nidus-type AVS was supplied by a ventral transverse pial branch of anterior spinal axis. The angioarchitecture was modified (from the latter angiogram) due to the presence of a medullary venous pseudo-aneurysm. The primary aim in this acute presentation was to obliterate the morphological feature of the lesion responsible of the bleeding. The transverse pial branch of anterior spinal artery was catheterized and embolized with bucrylate. During the same session, the residual part of the main cerebellar AVS was embolized. Embolization and administration of steroids improved paresis within 1 month, with almost normal strength in upper limbs despite persistent sphincter dysfunction and lower limbs paresis. The 8-month follow-up showed minimal clinical changes with slight improvement of the neurological deficits

Spine and Spinal Cord: Arteriovenous Shunts in Children

43.2.2.1 Single Shunts Associated with Genetic and Hereditary Disorders

In this group, the vascular cells are clearly affected by the disease at the germinal stage. The main syndrome in which genetic links can be seen is the hereditary hemorrhagic telangiectasia (HHT). The endothelial cells form abnormal vessels, particularly following injury. It appears that the earliest event in the expression of endoglin dysfunction is a dilatation of the postcapillary venules. The intradural SCAVSs associated with HHT are always single, i.e., macroAVFs [1].

43.2.2.2 Multiple SCAVSs

Entities in this group share potential metameric links. They are not related to a hereditary disorder. The initial process of vessel formation in the embryo, known as vasculogenesis, involves differentiation and sprouting of mesoderm-derived endothelial cells to form the primitive capillary network, which is then extended and remodeled by angiogenesis. These primary capillary vessels become progressively ensheathed by differenti-

a

b

c

ating smooth muscle cells. A somatic mutation developing in the region of the neural crest prior to migration could be expected to produce malformations with a metameric distribution, resulting in metameric AVMs of the spinal cord and the cutaneous involvement of the related dermatome. Multiple shunts with metameric links occur when the myelomere involved with the intradural SCAVS corresponds to that of the involved nerve [2]. So, the Cobb syndrome can be called spinal arteriovenous metameric syndrome (SAMS) (Fig. 43.4). There are 31 myelomeres with each segment having a correspondingly named SAMS, from 1 to 31. Multiple shunts, where the metameric disposition cannot always be clearly demonstrated, can be postulated. In these cases, intradural SCAVSs have been found associated with limb vascular malformations, such as the Klippel-Trenaunay syndrome or Park-Weber syndrome.

43.2.2.3 Solitary AVMs or MicroAVFs

If one considers that a full spectrum is the most complete phenotypic expression of a disease, this group may represent an incomplete spectrum of the abovedescribed situations.

d

Fig. 43.4a–d. SAMS 26. a–c Spinal cord angiography shows the medullary lesion. d Lower limb angiography shows the foot lesion in the corresponding metamere. (Courtesy of R. Piske, Hospital da Beneficencia Portuguesa, Sao Paulo, Brazil)

1709

1710 S. Wuppalapati, G. Rodesch, H. Alvarez, and P. Lasjaunias

43.3 Natural History and Clinical Aspects SCAVMs in the pediatric population represent a therapeutic challenge, as the effects of the disease may produce serious functional disorders and residual handicap. Most of the lesions are SCAVMs (including the AVFs), followed by PSAVMs, which are mostly seen in the pediatric age group. There are no primary dural shunts seen in the pediatric age group [1]. Pediatric AVSs show male predominance. One fourth of the pediatric population is diagnosed with the lesion in the first decade. Most of the remaining cases are symptomatic and are ultimately seen in the second decade. Neonatal presentation is very rare, often with neurological deficit and rarely with cardiac overload due to the shunt. The stenosis of the transdural segment protects the heart from overloading, unless the dural opening is defective and allows high flow. The diagnosis is now made more rapidly, in contrast to older series in the literature, thanks to the advances in diagnostic possibilities for this disease in this particular age group. The time elapsing between the initial symptom and the diagnosis is only a few days or weeks. Some patients have a longer prodrome before their lesion is recognized; the initial symptom rapidly subsides and the possibility of SCAVM is not entertained until a later event occurs. A moderate deficit is noted early, but the child is not brought for consultation and diagnosis until a few years after. Most of the symptoms in the pediatric population have a sudden onset, due to hemorrhage associated with significant low back pain [3-5]. Although thoraco-lumbar lesions present earlier than cervical ones, both locations are equally frequent. Spontaneous total or subtotal recovery occurs in 72% of cases that had bled. Early recurrent hemorrhages occur in 4.5% of cases. The hemorrhage is responsible for the acute neurological central deficit. When large, the hematoma has significant associated motor, sensitive, and sphincter disorders; when small, it causes limited acute motor deficit and minimal sensitive or sphincter deficits. Recovery of the symptoms depends on the intensity of the bleed, leaving the patient with permanent sequelae or minimal complaints at follow-up. The venous drainage of the lesion creates progressive congestion of the venous perimedullary pial network and also compression of the cord from venous ectasia, causing neurological symptoms to develop slowly. This is seen only in one third of patients. The onset of these deficits is either progressive (40%) or

acute (60%). Most of the lesions in our series were present in the thoracolumbar region, and one fifth in the cervical spinal cord. Neurological deficits that arise suddenly are likely due to local hemodynamic disturbances following venous outlet thromboses, rather than to arterial steal. The effects of anticoagulants in these situations, as well as angiographically demonstrated venous occlusions in some rare cases, support this pathophysiological mechanism. Finally, patients with single-hole arteriovenous fistulas (AVF), which should be expected to provoke “steal” manifestations, usually present with hemorrhagic incidents, and not with acute nonhemorrhagic onset. The lesion can be an incidental finding during exploration of a cutaneo-thoracic vascular dysplasia in 6% of neurologically asymptomatic children. MRI may fail to demonstrate any abnormal intraspinal lesion, and a SCAVM will be seen at angiography, a Cobb syndrome eventually being diagnosed.

43.4 Diagnosis SCAVSs are characterized by their draining veins. These are well depicted on MRI, and the vascular origin of the symptoms can therefore be made early. However, it may be difficult, or even impossible, to determine the type or the location of the shunt involved. The MRI appearance of an associated hemorrhage, whatever its type, will be identical to that of any other bleed. In fact, 94% of SCAVMs are seen on MRI (Figs. 43.3, 5). SCAVMs are detected as typical serpiginous signal-voids on T1- and T2-weighted images (Figs. 43.1, 5). In intradural shunts, MRI shows dilated perimedullary or intramedullary vessels, with signal voids on all spin echo-sequences due to flow phenomena, and deformation of the cord if the nidus is intramedullary. While MRI allows one to make the diagnosis of intradural SCAVS by showing the tangle of tortuous congested veins and the suffering of the cord, it often fails to determine the type of shunt, the exact location of small-sized lesions (microfistulas or microniduses), and their association with myelomeric lesions. Large lesions are easy to depict. Macrofistulas are characterized by large venous ectasias, superficial to the cord, surrounded by tortuous vessels, among which it is difficult to distinguish arteries from veins. Associated lesions or evolving complications, such as hematomyelia, edema, thrombosis, or cord atrophy, are well depicted on multiplanar sections. Compared

Spine and Spinal Cord: Arteriovenous Shunts in Children

a

e

b

f

c

g

to routine spin-echo sequences, contrast-enhanced MR angiography (MRA) offers improved characterization of the spinal vasculature and allows visualization of large arteries and veins. In PSAVSs, T1 or T2 serpiginous signal voids or tubular structures, corresponding to large draining veins, are located outside the spinal canal or the spine. The cord may be compressed and deviated by venous channels or ectasias, or congested with high signal intensity on T2-weighted images. The intradural course of the draining veins can be identified. Cord edema, ischemia, or venous congestion of the cord is associated with cord enhancement. The high signal may be reversible after treatment, either by endovascular or surgical methods, due to regression of the cytotoxic edema resulting from the congestive myelopathy and hypoxia. On the contrary, persistence of these abnormalities (i.e., enhancement, high signal

d

h

Fig. 43.5a–h. Three-month-old child presenting with difficulty in moving the distal right upper limb. No abnormal movements were noted. Obstetric brachial plexus paralysis was initially diagnosed. a, b Gd-enhanced sagittal T1-weighted images show a vascular spinal cord lesion with intramedullary edema. The clinical situation is stable. c, d Angiography at 11 months shows a paraspinal lesion draining into the intradural veins and supplied by epidural arteries from both sides. The lesion was embolized. e–g Postembolization vertebral and intercostal angiograms. h Postembolization sagittal T1-weighted image shows near normal signal in the spinal cord

intensity of the cord, secondary atrophy) represents irreversible spinal cord damage. Within this small population of patients, there often are metameric and multiple lesions of the spinal cord. This fact stresses the need to consider all SCAVMs as potential metameric or systemic alterations, since current advances allow a more complete diagnosis with noninvasive techniques. It certainly justifies the use of MRI as a screening modality in situations where peripheral vascular anomalies are found. The bony changes usually include enlargement of the spinal canal at the site of the medullary lesion. Scalloping of the posterior wall and erosion of the bony pedicles alone are no longer clues for diagnosis, although they are often present in SCAVMs with large venous pouches. The diagnosis is confirmed by spinal cord angiography, which remains the gold standard for precise

1711

1712 S. Wuppalapati, G. Rodesch, H. Alvarez, and P. Lasjaunias analysis of the vascular anatomy. The information provided by MRA does not contribute to an accurate analysis of SCAVMs. For diagnostic and pretherapeutic evaluation, we rely on selective angiographic assessment. The procedures are performed under general anesthesia with a 4F or 5F sheath, depending on the child’s weight. Spinal cord arteries in the pediatric population have a more tortuous appearance than in adults. A good-quality normal angiogram in children includes opacification of the venous network and drainage of the spinal cord. Not only is spinal cord angiographic exploration intended to confirm the diagnosis established by the clinical picture and MRI, but also to provide all the necessary pretherapeutic information. Only selective injections can precisely assess the feeding arteries, the draining veins, the angioarchitecture of the lesion, and the vascularization of the surrounding spinal cord.

43.5 Angioarchitecture Eighty-eight per cent of the lesions are of the nidus type, and 12% are fistulas. Family history will suggest possible HHT, particularly if the lesion is an AVF. The diagnosis does not require multifocality or mucocutaneous telangiectasias, which are rare at this age. Arterial stenosis and aneurysms are seldom demonstrated. Spinal cord arterial aneurysms seen in the pediatric age group are usually unruptured, and mostly associated with thoracic SCAVM [1]. The most remarkable architectural features are situated on the venous side of the lesion, pointing to the key role played by the veins in the clinical eloquence of SCAVMs. Venous ectasias and stenoses are frequently seen. These pouches can be very large, giving rise to few symptoms and yet enlarging the spinal canal and eroding the bony pedicles. The pouches and ectasias are associated with the highest flow lesions in young children, often located at the thoraco-lumbar level, and they drain caudally to join the caval system. Pial perimedullary venous reflux and congestion (absence of immediate drainage into a radicular vein and into extradural lakes) are almost constant. Although true isolated AVFs exist as a distinct type of lesion, hidden fistulas can be detected within a nidus during superselective catheterization. False aneurysms (Fig. 43.3) are present when hemorrhagic manifestations have occurred, and they point to the site of the rupture of the SCAVM on the arterial or venous side. They represent the weakest

and most dangerous part of the SCAVM itself [6], and should be disconnected as a matter of priority whenever possible. They often result from an upstream rupture due to thrombosis. In contrast to what is seen in brain AVMs, false spinal cord aneurysms tend to thrombose also on the venous side. Their persistence is an indication to perform at least partially targeted embolization, if better exclusion cannot be offered.

43.6 Treatment Therapeutic management is proposed when analysis of the lesional and regional angioarchitecture is completed in an attempt to understand the past history of the lesion and its clinical expression and to predict (postulate) its natural history. Our therapeutic goal is primarily to completely exclude the AVS in order to protect the child from future rebleeding or deficit. Total exclusion is rarely obtained in SCAVMs, whatever treatment is applied [3, 5]. Our therapeutic objectives depend upon the predictable embolization risks. If they seem too high according to the clinical status of the child, partial occlusion constitutes an acceptable therapeutic choice if embolization is targeted to the weak points of the architecture and performed with a permanent agent. In general, the challenges involved in the management of SCAVMs are different for niduses and fistulas.

43.6.1 Therapeutic Abstention The decision not to treat is taken because of the technical difficulty (predicted or noted) in either reaching a safe position or pulling out from it (when the ideal point for injection of the permanent agent runs over three or four vertebral bodies). Such decisions are not definitive, and can be specific to the moment and the individual. Medical aggressiveness, interpretation of the available data, personal experience, individual beliefs, and anatomic knowledge lead to very different strategies for apparently the same clinical and radiological information. Failure may occur if kinking in the subarachnoid space follows the usual transdural stenosis, which should not be looked upon as a high-flow angiopathic phenomenon.

Spine and Spinal Cord: Arteriovenous Shunts in Children

43.6.2 Embolization In most patients, embolization is chosen as the first treatment modality. Embolization of SCAVMs usually entails distal injection of a permanent embolic agent into the AVM itself, and not a proximal occlusion. In the ruptured SCAVM group, with hematomyelia and deficit, the first therapeutic procedure is performed after clinical recovery and/or resorption of the hematoma (Fig. 43.5), usually 6–8 weeks after the initial accident. The superselective approach to the nidus is accomplished with microcatheters of various types through radiculo-pial (posterior spinal) or radiculo-medullary (anterior spinal) arteries. More than 50% of the nidus is necessarily embolized in one or more sessions. All of our patients improved after embolization, and half of them are neurologically normal. Follow-up of the patients is performed by MRI looking for restoration of the normal signal in the cord. All children have one control angiogram 1 or 2 years following the last endovascular procedure. One partial recanalization was noted in an otherwise clinically stable child embolized with particles in 1982. The other results obtained are stable. No rebleeding was noted, even in partially treated lesions that had previously bled. Although 88% of children have had partial treatment, no patients have worsened after embolization. Of the children whose initial clinical status at the time of the treatment was poor, 45% have totally recovered and are now neurologically normal. The remainder have slight neurological sequelae from their initial accident (hemorrhagic in 80% of cases). Although this disease is rare, particularly in this population, and despite the eloquence of the surrounding tissues, which require a specific anatomic and technical experience, management of pediatric SCAVM does not represent a significantly different challenge from that posed by other AVSs of the central nervous system in the same age group. Embolization is a generic name that encompasses many techniques and approaches. The results depend in each individual case on the possibility of reaching the lesion via the safest route and of delivering the most efficient agent. Longer follow-up is needed to

appreciate more precisely the encouraging course of these embolized SCAVMs. The risk of severe handicap after aggressive treatment should be balanced against the apparently favorable course of a partially embolized SCAVM.

43.6.3 Other Treatments The role of surgery in spinal cord vascular diseases is limited, since endovascular alternatives can lead to significant, safe, and stable results, particularly in children. At present, conventional radiotherapy, gamma knife radiosurgery, or stereotactic surgery are not used in SCAVMs.

Acknowledgements

The authors thank Allan Thomas, MD, for editorial assistance.

References 1.

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5.

6.

Rodesch G, Hurth M, Alvarez H, Tadie M, Lasjaunias P. Classification of spinal cord arteriovenous shunts: proposal for a reappraisal. The Bicêtre experience with 155 consecutive patients treated between 1981 and 1999. Neurosurgery 2002; 51:374–380. Lasjaunias P, Berenstein A, Terbrugge K. Spine and spinal cord arteries and veins. In: Lasjaunias P, Berenstein A, Terbrugge K (eds) Surgical Neuroangiography, vol. 1. Clinical Vascular Anatomy and Variations. New York: Springer, 2001:73–164. Berenstein A, Lasjaunias P. Spinal cord arterio-venous malformations. In: Berenstein A, Lasjaunias P (eds) Surgical Neuroangiography, vol. 5. Endovascular Treatment of Spine and Spinal Cord Lesions. New York: Springer, 1992:24–109. Hurth M, Houdart R, Djindjian R, Rey A, Djindjian M. Arteriovenous malformations of the spinal cord. Clinical, anatomical and therapeutic considerations: a series of 150 cases. Prog Neurol Surg 1978; 9:238–266. Mourier KL, Gobin YP, George B, Lot G, Merland JJ. Intradural perimedullary arteriovenous fistulae: results of surgical and endovascular treatment in a series of 35 cases. Neurosurgery 1993; 32:885–891. Garcia Monaco R, Rodesch G, Alvarez H, Iizuka Y, Hui F, Lasjaunias P. Pseudoaneurysms with ruptured intracranial arteriovenous malformations: diagnosis and early endovascular management. AJNR Am J Neuroradiol 1993; 14:315–321.

1713

Spine and Spinal Cord Sonography

44 Spine and Spinal Cord Sonography Paolo Tomà

44.1 Technique and Normal Anatomy

CONTENTS 44.1

Technique and Normal Anatomy

44.2

Variants 1717

44.3

Congenital Anomalies

44.3.1 44.3.1.1 44.3.1.2 44.3.1.3 44.3.1.4 44.3.1.5 44.3.1.6

Cord Tethering 1719 Tight Filum Terminale 1719 Hydromyelia and Syringomyelia 1721 Dermal Sinuses 1721 Spinal Lipoma 1721 Diastematomyelia 1721 Caudal Agenesis (Caudal Regression Syndrome) 1721

44.4

Acquired Diseases

44.4.1 44.4.2

Birth Trauma 1722 Mass Lesions 1722 References

1722

1715

1718

1722

Spinal sonography provides a detailed panoramic view of the spinal canal and its contents in neonates and young infants [1]. Scanning must be performed with high-resolution/ high-frequency 5–15 MHz linear-array transducers [2, 3]. A high-frequency curved-array transducer may be useful to study the cranio-cervical junction or in older infants when the acoustic window is small [2–4]. In the neonatal period sonographic anatomic detail is excellent, because the incompletely ossified and predominantly cartilaginous spinal arches create an acoustic window that permits transmission of the ultrasound beam [1]. As the baby grows larger and spine ossification advances, sonographic visualization of the spinal canal becomes more limited, less panoramic, and confined to segmental views between ossified posterior spinous elements [2, 3]. Typically, the newborn is examined in the prone position [1, 4]. A small pillow placed under the chest and abdomen creates an adequate flexion of the spine, improving the acoustic window between the spinous processes [3]. The decubitus position may be used [1], always bending the spine. To examine the craniocervical junction and upper cervical spine, the neck must be flexed [2]. Routinely, sagittal and axial scans of the spinal cord are obtained from the cranio-cervical junction to the conus medullaris and cauda equina. When the posterior elements of the vertebrae are partially ossified and thus interfere with ultrasound beam transmission, paramedian scans may allow sufficient examination of the spinal cord; the probe is placed paravertebrally to give a 15° medially inclined section [4]. In older children, although visualization is limited, the tip of the conus medullaris can often be identified [5]. Bony defects (as in malformation or after partial laminectomy) allow the sonographic visualization of spinal structures, irrespective of age [4]. High-resolution sonography displays the details of the spinal canal, subarachnoid space, spinal cord, and some emerging nerve roots in axial and sagittal planes.

1715

1716 P. Tomà Direct scanning at the cranio-cervical junction is easily performed and allows good evaluation of this area in normal infants [6). Good evaluation of cisterna magna, medulla, tonsils, vermis, cervical cord, and central echo complex is possible in most cases [2]. This technique also allows visualization of subarachnoid blood and clots obstructing the outlet of the fourth ventricle. In patients with Chiari II malformation, a downward dislocation of the medulla and cerebellum is evident; the cisterna magna is obliterated and the normal landmarks of the posterior fossa are no longer seen [2, 7–9]. On a sagittal scan (Fig. 44.1), the spinal cord is a hypoechoic tubular structure with an echogenic center, the so-called central echo complex. The central echo complex is produced by the interface between the myelinated ventral white commissure and the central end of the anterior median fissure. Variations in the shape of the central echo complex seem to reflect varying degrees of flaring of the central end of the anterior median fissure [10]. The inconstant residual central canal and islands of residual ependymal cells are clearly not the source of the central echo complex. The gray and white matter that form the mantle of the cord are both hypoechoic and cannot be visualized separately [1]. The signal from the ventral and the dorsal border of the myelon is due to the abruptly changing impedance from solid myelon to liquid cerebrospinal fluid (CSF) in the subarachnoid space [4]. The spinal cord is surrounded by the anechoic CSF of the subarachnoid space. The arachnoid-dura mater complex of the thecal sac corresponds to the echogenic border of the spinal canal dorsal and ventral to the subarachnoid space [2]. The lumbar cord exhibits a typically bulbous enlargement and then tapers caudally to terminate at the conus medullaris. In normal children, conus level is at or cephalad to the upper limit of L3, in 98%–99% of cases at or above L2 vertebral body [11–15]. Longitudinal scans below the level of the conus medullaris show a linear echogenic density representing the filum terminale, that is surrounded by nerve roots (cauda equina). These latter give rise to a collection of less intense, less sharply defined echoes. The normal thickness of the filum terminale ranges between 0.5 mm and 2 mm at the level of L5-S1 [2, 16]. According to DiPietro, several methods for assigning vertebral level with sonography can be used [11], i.e., (1) follow the lowest rib to the spine and call that vertebra T12. Do this on both sides; (2) identify the lumbosacral junction in the longitudinal plane by the change in the angle between the posterior aspect of S1 and L5 [17]; (3) identify the unossified coccyx and follow the five sacral elements cephalad to find L5 [18]; and (4) identify the caudal extent of the thecal sac, often found

a

b

c Fig. 44.1a–c. Normal anatomy of the spinal canal and its contents in a 10-day-old newborn. a Sagittal scan of the thoracic spinal canal shows the spinal cord (open white arrows), central echo complex (arrowheads), arachnoid-dura mater complex (white arrow), and vertebral bodies (small rings). b Sagittal scan of the lumbar spinal canal shows the spinal cord (open white arrows), central echo complex (arrowheads), nerve roots (white arrow), subarachnoid space (asterisk), and vertebral bodies (small rings). c Longitudinal scan below the level of the conus medullaris shows the filum terminale (white arrow), nerve roots, subarachnoid space (asterisk), and vertebral bodies (small rings)

Spine and Spinal Cord Sonography

at S2. As the child might have an abnormal number of ribs or lumbosacral vertebrae, all counting methods should be used [19]. During real-time examination (Fig. 44.2), a slow dorsal-ventral movement of the myelon superimposed on the arterial pulsation can be observed, whereas the fibers of the cauda show a rapid fibrillation [9]. Also cord motion due to patient’s breathing and crying can be evaluated. At the border of the surrounding epidural fat, both posterior spinal arteries and the anterior spinal artery can be identified by their pulsations, whereas the venous plexus cannot be distinguished under normal conditions [9]. An axial scan (Fig. 44.3) of the spinal cord shows the hypoechoic, oval or round spinal cord with the echogenic central echo complex within the anechoic subarachnoid space. The spinal cord originates the

paired dorsal and ventral nerve roots. The spinal cord is fixed by the dentate ligaments, which pass laterally to the spinal cord. The ligaments correspond to transversely positioned echogenic arachnoid duplications, and can be seen in part of the thoracic spinal canal on axial scans [2]. The size of the spinal cord varies, and is broadest in the cervical and lumbar regions. In infants 1– 3 months of age, the sagittal diameters of the cervical, thoracic, and lumbar portions of the cord are 5.3 ± 0.28 mm, 4.4 ± 0.42 mm, and 5.8 ± 0.66 mm, respectively [20].

44.2 Variants

Fig. 44.2. Normal anatomy of the spinal canal and its contents in a 10-day-old newborn. Dorsal-ventral movement of the cauda equina (arrow) evaluated with real-time ultrasound with Mmode scanning

Initially, a slight dilatation of the central canal of the spinal cord can be detected in newborns (Fig. 44.4). This seems to be an incidental finding in healthy newborns, and disappears in most cases during the first weeks of postnatal life. It is considered a transient dilatation of the central canal [2, 21]. The ventriculus terminalis (Fig. 44.5) is a small cavity of the conus medullaris that forms during the embryonic stages of secondary neurulation (canalization) and retrogressive differentiation, and regresses in size during the first weeks after birth. It is a small, ependyma-lined, oval, cystic structure positioned at the transition from the tip of the conus medullaris to the origin of the filum terminale [22]. The dilated ventriculus terminalis appears on images as a small ovoid cavity with regular margins; intralesional fluid resembles CSF. This variant causes no clinical symptoms, and has a longitudinal diameter of 8–10 mm and a transverse diameter of 2–4 mm [2, 23, 24].

a

b Fig. 44.3a, b. Normal anatomy of the spinal canal and its contents in a 10-day-old newborn. a Axial scan of the thoracic spinal canal shows the spinal cord (open white arrows), central echo complex (arrowhead), nerve roots (R), subarachnoid space (asterisk), vertebral arch (a), and vertebral body (b). b Axial scan of the spinal canal at the level of L3 shows nerve roots (R), filum terminale (white arrow), and subarachnoid space (asterisk)

1717

1718 P. Tomà

a

b Fig. 44.4a, b. Transient dilatation of the central canal in a healthy 16-day-old newborn. a Sagittal and b axial scans show dilatation of the central canal of the lumbar spinal cord (open white arrows)

a

b Fig. 44.5a, b. Ventriculus terminalis in a healthy 28-day-old newborn. a Sagittal and b axial scans at the level of the conus tip show a ventriculus terminalis (white arrows)

44.3 Congenital Anomalies Spinal sonography seems to represent a valuable diagnostic tool for congenital anomalies of the lower spine in infants, and is recommended as the primary imaging modality in those patients. According to Rohrschneider et al. [25], sonography would allow exactly the same diagnostic accuracy as magnetic resonance imaging (MRI); however, only in selected cases does ultrasound depict the main abnormality, with MRI imaging revealing additional findings. Whenever sonographic scans are normal, even MRI does not depict any spinal disorder. In all examinations with abnormal MRI findings, sonography enables detection of the abnormality. The most common indication for spinal canal sonography is the presence of cutaneous or subcutaneous anomaly of the lower back or an imperforate

anus requiring a search for occult tethered spinal cord [19, 26, 27]. Ultrasound can be a useful screening tool in newborns with suspected closed spinal dysraphism for two main reasons, namely: first, it occurs in the neonate and young infant in whom incomplete ossification of posterior elements provides an acoustic window, and second, the associated lack of fusion of vertebral arches further improves ultrasound visualization of intraspinal structures [25]. Closed spinal dysraphism may be categorized on a clinical basis, depending on the presence of a subcutaneous mass in the back (see Chap. 39). Closed spinal dysraphisms with a mass are mainly represented by lipomas with dural defects and meningoceles. Closed spinal dysraphisms without a mass may be simple (i.e., tight filum terminale, filar lipoma, intradural lipoma) or complex (i.e., diastematomyelia, caudal regression) [28].

1719

Spine and Spinal Cord Sonography

Simple midline dimples are the most commonly encountered dorsal cutaneous stigmata in neonates and indicate low risk for spinal dysraphism, especially if the bottom of the pit is visible [19]. They usually have a low coccygeal location. Only atypical dimples are associated with high risk for spinal dysraphism, particularly when large (>5 mm), high on the back, or associated with other lesions [29]. Highrisk cutaneous stigmata in neonates include hemangiomas, upraised lesions (i.e., masses, tails, and hairy patches), and multiple cutaneous stigmata [30–32]. Sonography of the neonatal lumbar spine and canal is the initial investigation also in presence of congenital abnormalities, such as the cloacal exstrophy-anorectal malformation spectrum (CEARMS), which are associated to a variable extent with occult tethered spinal cords [33]. Sonographic findings suggestive of closed spinal dysraphism include low position of the conus, nontapered bulbous appearance of the conus, dorsal location of the cord within the bony canal, solid or cystic masses in the distal canal or in soft tissues of the back extending toward the canal, patulous distal thecal sac, and thick filum [16].

a

44.3.1 Cord Tethering The term “tethered cord syndrome” refers to progressive neurologic deterioration, urinary incontinence, spastic gait, or orthopedic deformities due to traction on a low-lying (below L3) conus medullaris [28]. Cord tethering can occur as a complication of myelomeningocele repair or as the presentation of closed spinal dysraphisms, including spinal lipomas, the tight filum terminale, diastematomyelia, and caudal agenesis. The ultrasound appearance of tethering is a lowlying or blunt-ended conus medullaris due to abnormal fixation of the spinal cord. Movement of the spinal cord and cauda equina can be evaluated with realtime ultrasound with M-mode scanning (Fig. 44.2). Abnormal dorsal fixation of the spinal cord adjacent to the arches of the vertebrae is seen with the patient in the prone position. Typically, the tethered cord is positioned eccentrically and demonstrates reduced or absent undulations at or above the site of tethering [2]. According to Zieger et al. [9], sonographic findings in patients with tethered cord syndrome include low position of the conus (Fig. 44.6); atypically shaped, dumpy conus; thickened, echogenic filum; dorsal location of the myelon with enlarged ventral subdural space (Fig. 44.7); absent movement of the caudal myelon; and caudal soft tissue mass (Fig. 44.8).

b Fig. 44.6a, b. Low position of the conus medullaris in a 1-day-old newborn. a Longitudinal view shows the position of the conus medullaris (open black arrow) at the lower limit of L4. b Sagittal T1-weighted MR image confirms the diagnosis

44.3.1.1 Tight Filum Terminale

In tight filum terminale, spinal ultrasound shows an abnormally thickened filum terminale, whose transverse diameter is almost consistently greater than 2 mm. Centrally located small cysts or lipomas may be present, but they are commonly detected only by MRI. The tip of the conus medullaris is located below L2–3, and reduced or absent spinal cord movements are demonstrated [3, 16].

1720 P. Tomà

Fig. 44.7. Tethering of the spinal cord in a 10-day-old newborn with lumbosacral myelomeningocele. Axial scan shows a dorsally displaced lumbar spinal cord (open white arrow) due to tethering

a

b

d

c Fig. 44.8a–d. Caudal agenesis (caudal regression syndrome) type II in a 40-day-old infant. a Sagittal scan of the thoracic spinal canal shows a slight dilatation of the central canal (open white arrows) of the spinal cord (arrowheads). b Longitudinal scan through the distal spine shows a thickened echogenic filum that indicates a lipomatous infiltration (L). The conus (arrowhead) is elongated, tapered, and low-positioned (S1). An abnormality of the spine below S1 is suggested. c Axial view of the lipoma (L). d Anteroposterior radiograph confirms the malformation of the caudal spine

1721

Spine and Spinal Cord Sonography

44.3.1.2 Hydromyelia and Syringomyelia

Spinal dysraphism is often associated with hydromyelia or syringomyelia. In hydromyelia, sonography shows a dilated central canal (Fig. 44.8). In syringomyelia, paracentral cavities connected with a dilated central canal are detected [34]. 44.3.1.3 Dermal Sinuses

Dermal sinuses are focal segmental adhesions between cutaneous ectoderm and neural ectoderm. Ultrasound scan of the lumbar spinal canal may depict an echogenic band from the skin to the spinal cord, well detectable within the anechoic subarachnoid space. If the lumen is wide enough to be visualized, the dermal sinus may appear as a triple tract formed by parallel hyperechoic lines around a central hypoechoic space. Actually, it may be difficult to establish by ultrasonography whether the sinus extends into the spinal canal or to detect possible associated intracanalicular (epi)dermoids [2, 34].

Successful ultrasound, performed in the axial plane, typically shows both hemicords in cross section, lying side by side or ventrodorsal to each other, each with a central canal and ipsilateral nerve roots. When present, associated bone spur and hydromyelia may also be visualized [2, 21, 34, 36]. 44.3.1.6 Caudal Agenesis (Caudal Regression Syndrome)

Caudal agenesis, or caudal regression syndrome, refers to a spectrum of findings comprising absence of the lower portion of the caudal spine (Fig. 44.8). In patients in whom the cord is not tethered (caudal agenesis type I), the distal end of the spinal cord has a characteristic blunted or wedge-shaped appearance.

44.3.1.4 Spinal Lipoma

Spinal lipomas are the most common type of closed spinal dysraphism. Ultrasound shows an echogenic intraspinal mass adjacent to the deformed spinal cord. Lipomas (Fig. 44.9) are homogeneous, well-delineated mass lesions that are slightly more echogenic than epidural fat [7, 34, 35]. Due to its dorsal position, the intradural part of the lipoma causes ventral displacement of the myelon or of the cauda. With a normal conus, a thickened echogenic filum indicates lipomatous infiltration (Fig. 44.8); with absent ascent of the myelon, the tip of the conus lying within the lipoma can no longer be identified [35]. In patients with lipomyelomeningocele, dilated subarachnoid space can be demonstrated.

a

44.3.1.5 Diastematomyelia

The term diastematomyelia identifies a clefting of the spinal cord into two, possibly asymmetrical hemicords. The ultrasound diagnosis of diastematomyelia may be difficult because the associated posterior spina bifida does provide an acoustic window, but the intersegmental laminar fusion and associated scoliosis may obscure the region of greatest interest.

b Fig. 44.9a, b. Lumbosacral lipomyelocele in a 6-week-old infant. a Sagittal scan of the lumbosacral region shows an echogenic lipoma (L). The tip of the lumbar spinal cord (arrowheads) lies within the lipoma. A slight dilatation of the central canal (open white arrows) is evident. b Sagittal scan of the sacral region. The lipoma (L) is contiguous with and more echogenic than the subcutaneous fat

1722 P. Tomà When the cord is tethered (caudal agenesis type II), it is difficult to determine where the conus medullaris ends and the filum terminale begins [3, 21].

References 1.

2.

44.4 Acquired Diseases 44.4.1 Birth Trauma

3.

4.

Birth trauma to the spinal cord is a serious complication of delivery. Sonography is useful in evaluating neonates with severe spinal cord injury. Sagittal scan shows ventral displacement of the dura mater by an epidural fluid collection [37]. Internal cord echogenicity is helpful in demonstrating edema, venous congestion, hematomyelia (hyperechogenicity), and the changes of myelomalacia (hypoechogenicity) [2, 38–40].

44.4.2 Mass Lesions

5.

6.

7.

8.

9.

10.

In mass lesions, spinal ultrasound is useful for disease diagnosis and follow-up, although additional imaging procedures are needed for confirmation of the diagnosis. Spinal neoplasms may be intramedullary or extramedullary, intradural or intraspinalextradural. Intramedullary tumors are astrocytomas and ependymomas. They may be solid or cystic, homogeneous or heterogeneous, and produce either focal or diffuse cord enlargement. Real-time techniques reveal the diminished rhythmical movement of the myelon at the infiltrated segment [9, 35, 41]. In extramedullary intradural tumors, such as schwannomas and neurofibromas, sonography shows the spinal cord displaced and compressed by a solid mass (if an arachnoid cyst is present, the cord is compressed by the cyst). Usually, intradural extramedullary tumors are not distinguishable from intraspinal extradural neoplasms [9, 35]. Actually, intraspinal extradural neoplasms are vertebral tumors or extensions from intrathoracic or intra-abdominal tumors. A typical occurrence in infants is the intraspinal extension of neuroblastoma [21, 42]. Sometimes it is possible to detect both the intraspinal and the extraspinal parts of the mass [3, 9, 44].

11. 12.

13.

14.

15.

16.

17.

18.

19.

20.

Gusnard DA, Naidich TP, Yousefzadeh DK, Haughton VM. Ultrasonic anatomy of the normal neonatal and infant spine: correlation with cryomicrotome sections and CT. Neuroradiology 1986; 28:493–511. Unsinn KM, Geley T, Freund MC, Gassner I. US of the spinal cord in newborns: spectrum of normal findings, variants, congenital anomalies, and acquired diseases. Radiographics 2000; 20:923–938. Coley BD, Siegel MJ. Pediatric sonography. In: Siegel MJ (ed) Spinal Ultrasonography. Philadelphia: Lippincott Williams & Wilkins, 2002: 673–698. Zieger M, Dorr U. Pediatric spinal sonography. Part I: Anatomy and examination technique. Pediatr Radiol 1988; 18:9–13. DiPietro MA. The pediatric spinal canal. In: Rumack CM, Wilson SR, Charboneau JW (eds) Diagnostic Ultrasound. Chicago: Mosby Year Book, 1998: 1589–1615. Cramer BC, Jequier S, O’Gorman AM. Sonography of the neonatal craniocervical junction. AJR Am J Roentgenol 1986; 147:133–139. Miller JH, Reid BS, Kemberling CR. Utilization of ultrasound in the evaluation of spinal dysraphism in children. Radiology 1982; 143:737–740. Jequier S, Cramer B, O’Gorman AM. Ultrasound of the spinal cord in neonates and infants. Ann Radiol (Paris) 1985; 28:225–231. Zieger M, Dorr U, Schulz RD. Pediatric spinal sonography. Part II: Malformations and mass lesions. Pediatr Radiol 1988; 18:105–111. Nelson MD Jr., Sedler JA, Gilles FH. Spinal cord central echo complex: histoanatomic correlation. Radiology 1989; 170:479–481. DiPietro MA. The conus medullaris: normal US findings throughout childhood. Radiology 1993; 188:149–153. Wolf S, Schneble F, Troger J. The conus medullaris: time of ascendance to normal level. Pediatr Radiol 1992; 22:590– 592 Sahin F, Selcuki M, Ecin N, Zenciroglu A, Unlu A, Yilmaz F, Mavis N, Saribas S. Level of conus medullaris in term and preterm neonates. Arch Dis Child Fetal Neonatal Ed 1997; 77:F67–69. Hill CA, Gibson PJ. Ultrasound determination of the normal location of the conus medullaris in neonates. AJNR Am J Neuroradiol 1995; 16:469–472. Wilson DA, Prince JR. MR imaging determination of the location of the normal conus medullaris throughout childhood. AJR Am J Roentgenol 1989; 152:1029–1032. Korsvik HE, Keller MS. Sonography of occult dysraphism in neonates and infants with MR imaging correlation. Radiographics 1992; 12:297-306. Beek FJ, van Leeuwen MS, Bax NM, Dillon EH, Witkamp TD, van Gils AP. A method for sonographic counting of the lower vertebral bodies in newborns and infants. AJNR Am J Neuroradiol 1994; 15:445–449. Beek FJ, Bax KM, Mali WP. Sonography of the coccyx in newborns and infants. J Ultrasound Med 1994; 13:629– 634. DiPietro MA. Cranial and spinal sonography: observations, opinions, practices (OOPS). In: Syllabus of Postgraduate Course of SPR. Philadelphia: The Society for Pediatric Radiology, 2002. Kawahara H, Andou Y, Takashima S, Takeshita K, Maeda K. Normal development of the spinal cord in neonates and

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infants seen on ultrasonography. Neuroradiology 1987; 29:50–52. Toma PL, Rossi UG. Paediatric ultrasound. II. Other applications. Eur Radiol 2001; 11:2369–2398. Sigal R, Denys A, Halimi P, Shapeero L, Doyon D, Boudghene F. Ventriculus terminalis of the conus medullaris: MR imaging in four patients with congenital dilatation. AJNR Am J Neuroradiol 1991; 12:733–737. Kriss VM, Kriss TC, Babcock DS. The ventriculus terminalis of the spinal cord in the neonate: a normal variant on sonography. AJR Am J Roentgenol 1995; 165:1491–1493. Kriss VM, Kriss TC, Coleman RC. Sonographic appearance of the ventriculus terminalis cyst in the neonatal spinal cord. J Ultrasound Med 2000; 19:207–209. Rohrschneider WK, Forsting M, Darge K, Troger J. Diagnostic value of spinal US: comparative study with MR imaging in pediatric patients. Radiology 1996; 200:383-388. Glasier CM, Chadduck WM, Leithiser RE, Jr., Williamson SL, Seibert JJ. Screening spinal ultrasound in newborns with neural tube defects. J Ultrasound Med 1990; 9:339–343. Scheible W, James HE, Leopold GR, Hilton SV. Occult spinal dysraphism in infants: screening with high-resolution realtime ultrasound. Radiology 1983; 146:743–746. Tortori-Donati P, Rossi A, Cama A. Spinal dysraphism: a review of neuroradiological features with embryological correlations and proposal for a new classification. Neuroradiology 2000; 42:471–491. Herman TE, Oser RF, Shackelford GD. Intergluteal dorsal dermal sinuses. The role of neonatal spinal sonography. Clin Pediatr (Phila) 1993; 32:627–628. Kriss VM, Kriss TC, Desai NS, Warf BC. Occult spinal dysraphism in the infant. Clin Pediatr (Phila) 1995; 34:650–654. Albright AL, Gartner JC, Wiener ES. Lumbar cutaneous hemangiomas as indicators of tethered spinal cords. Pediatrics 1989; 83:977–980.

32. Gibson PJ, Britton J, Hall DM, Hill CR. Lumbosacral skin markers and identification of occult spinal dysraphism in neonates. Acta Paediatr 1995; 84:208–209. 33. Beek FJ, Boemers TM, Witkamp TD, van Leeuwen MS, Mali WP, Bax NM. Spine evaluation in children with anorectal malformations. Pediatr Radiol 1995; 25 (Suppl 1):S28–32. 34. Naidich TP, Radkowski MA, Britton J. Real-time sonographic display of caudal spinal anomalies. Neuroradiology 1986; 28:512–527. 35. Raghavendra BN, Epstein FJ. Sonography of the spine and spinal cord. Radiol Clin North Am 1985; 23:91–105. 36. Raghavendra BN, Epstein FJ, Pinto RS, Genieser NB, Horii SC. Sonographic diagnosis of diastematomyelia. J Ultrasound Med 1988; 7:111–113. 37. Leadman M, Seigel S, Hollenberg R, Caco C. Ultrasound diagnosis of neonatal spinal epidural hemorrhage. J Clin Ultrasound 1988; 16:440–442. 38. Babyn PS, Chuang SH, Daneman A, Davidson GS. Sonographic evaluation of spinal cord birth trauma with pathologic correlation. AJR Am J Roentgenol 1988; 151:763–766. 39. Fotter R, Sorantin E, Schneider U, Ranner G, Fast C, Schober P. Ultrasound diagnosis of birth-related spinal cord trauma: neonatal diagnosis and follow-up and correlation with MRI. Pediatr Radiol 1994; 24:241–244. 40. Filippigh P, Clapuyt P, Debauche C, Claus D. Sonographic evaluation of traumatic spinal cord lesions in the newborn infant. Pediatr Radiol 1994; 24:245–247. 41. Braun IF, Raghavendra BN, Kricheff II. Spinal cord imaging using real-time high-resolution ultrasound. Radiology 1983; 147:459–465. 42. Patel RB. Sonographic diagnosis of intraspinal neuroblastoma. J Clin Ultrasound 1985; 13:565–569. 43. Garcia CJ, Keller MS. Intraspinal extension of paraspinal masses in infants: detection by sonography. Pediatr Radiol 1990; 20:437–439.

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Prenatal Ultrasound: Spine and Spinal Cord

45 Prenatal Ultrasound: Spine and Spinal Cord Mario Lituania and Ubaldo Passamonti

45.1 Normal Anatomy of the Spine

CONTENTS 45.1

Normal Anatomy of the Spine

45.2

Spinal Dysraphisms

1725

1725

45.2.1 Prenatal Diagnosis of Spinal Dysraphisms 1727 45.2.2 Associated Anomalies 1730 45.2.3 Accuracy of Ultrasonography in the Diagnosis of Spina Bifida 1731 45.2.4 Prognosis, Counseling, and Management 1733 45.3

Sacrococcygeal Teratoma

45.3.1 Prenatal Ultrasound 45.4

1734

Caudal Agenesis (Caudal Regression Syndrome) 1734

45.4.1 Prenatal Ultrasound 45.5

1734

Sirenomelia 17353 References

1736

1735

Mineralization of the spine begins at about the 6th week of embryonic development. Every vertebra presents three centers of ossification: a single center of ventral ossification for the vertebral body and two dorsal ossification centers located in the lamina-vertebral pedicles junction, from which the lateral masses and posterior arches originate. The ossification of posterior arches would present a progression in cephalic-caudal direction starting from the middle-thoracic region. The ossification of posterior arches of the distal tract of the spine occurs according to a predictable pattern, in the caudal direction, one vertebra every 2–3 weeks, after 16 weeks of gestation. All fetuses show a complete ossification of L5 at the 16th week, S1 at the 19th week, S2 at the 22nd week, S3 at the 24th week, and S5 at the 27th week of gestation. The spine can be studied with a standardized procedure that includes different scanning planes, i.e., midsagittal and parasagittal, coronal and axial planes.

45.2 Spinal Dysraphisms The term spinal dysraphisms includes a wide spectrum of anomalies that can be divided into ventral and dorsal lesions. The former are very rare and are characterized by defect of vertebral bodies and presence of a neurenteric cyst; they are located more frequently at the level of the inferior cervical and superior thoracic vertebrae. Dorsal defects are more frequent, and are divided into two types, i.e., open spinal dysraphisms and closed spinal dysraphisms (see Chap. 39). Closed spinal dysraphisms occur in at least 5% of the population and are most often asymptomatic; they account for about 15% of cases of spinal dysraphisms

1725

1726 M. Lituania and U. Passamonti and include a group of skin-covered entities, without neural tissue exposure. Accompanying associated features may include dermal hyperpigmentation, a patch of hair, a lump, or a dermal sinus. The spectrum of closed spinal dysraphism includes distortion of the spinal cord, intraspinal lipomas, dermoid or epidermoid cysts, fibrolipomas, lipomyelomeningoceles, and diastematomyelia. Open spinal dysraphisms are characterized by a whole-thickness skin defect with dorsal protrusion of the spinal content through the posterior bony defect; the dorsal vertebral arches are absent, with typical enlargement of vertebral pedicles. The neural canal can be exposed or a thin meningeal membrane may cover the defect. The lesion is defined a meningocele (Figs. 45.1, 2) or myelomeningocele on the basis of

a

b

the absence or presence of the neural tissue elements. Meningocele is not associated with Chiari II malformation. In most cases the lesion presents a cystic aspect and is covered by skin, therefore belonging to closed spinal dysraphisms (see Chap. 39). There is a variable appearance of neural tube defects. Myelomeningoceles may appear as a flat, nonprotruding defect associated with skin defect, or may be detected as a mixed-appearing dorsal sac (Fig. 45.3). In virtually all cases of myelomeningocele a Chiari II malformation is found. The Chiari II malformation is characterized by downward displacement of the cerebellar vermis; the fourth ventricle and medulla oblongata are dislocated caudally, leading to frequent obstruction of cerebrospinal fluid (CSF) flow and consequent hydrocephalus.

c

d

Meningocele

Fig. 45.1a–d. Meningocele. a–c Sagittal views of a lumbosacral meningocele at 20 weeks. Meningocele (M) is characterized by protrusion of meninges and cerebrospinal fluid through the spinal defect. B, bladder. d. Pathologic specimen shows skin-covered lumbosacral mass

Prenatal Ultrasound: Spine and Spinal Cord

a

b

c

Fig. 45.2a–c. Meningocele. a, b Coronal view of a lumbosacral meningocele at 20 weeks. Absence of neural elements into the protruding meningeal sac. c Pathologic specimen shows skin-covered lumbosacral mass

Fig. 45.3. Myelomeningocele. Sagittal view of a lumbosacral myelomeningocele at 19 weeks. Cystic appearing dorsal sac (arrows)

45.2.1 Prenatal Diagnosis of Spinal Dysraphisms The prenatal diagnosis is based on visualization of direct and indirect ultrasonographic signs [1–3]. Direct signs involve the vertebral arches, the skin at the level of the defect, and the defect itself; they are

diagnostic (Figs. 45.4–6). Indirect signs are the consequence of the Chiari II malformation and represent high sensitive markers of spina bifida. The direct ultrasonographic signs are (1) enlargement or disappearance of “parallel track image” and reconjunction of the vertebral arches below the defect in coronal views; (2) U- or V-shaped appearance of the vertebrae in axial views; and (3) direct visualization of the myelomeningocele (Fig. 45.7). A myelomeningocele is distinguished from a meningocele because of a more heterogeneous echo structure due to the presence of neural elements in the cystic sac, while meningoceles have a transonic content due to the presence of CSF often covered by skin. The visualization of a cystic lesion depends on its dimension, fetal position, and the amount of amniotic fluid around the fetus. The meningeal sac may not be visualized if located between the fetal body and the uterine wall. In case of rupture of the meningeal sac, the diagnosis is based on the presence of a vertebral and skin defect. The diagnosis of myelomeningocele requires the direct visualization of the lesion, but, perhaps surprisingly, the evidence of cranial findings is more helpful for ultrasonographic screening of neural tube defects in the second trimester of pregnancy (Fig. 45.8). These signs are the consequence of the Chiari II malformation, associated with virtually all cases of myelomeningocele, and include: (1) borderline or mild ventriculomegaly; (2) frontal bone scalloping (“lemon sign”), which may be seen at the level of biparietal scanning

1727

1728 M. Lituania and U. Passamonti

a

a

Fig. 45.4a,b. Different appearances of myelomeningocele. a Sagittal plane shows a nonprotruding defect, characterized by skin and laminar defects (curved arrow). b Axial plane shows a defect of the soft tissue overlying the vertebral lesions, a V-shaped vertebral appearance due to absence of the laminae, and splayed posterior ossifications centers (curved arrows). This section plane shows the neural root elements entering the neural plate located at the bottom of the malformed sac

b

b

c

Fig. 45.5a–c. Myelomeningocele. Coronal plane shows defects of the vertebral arches with widening of the spinal canal and splaying of the lateral processes (a, b). A posterior coronal plane demonstrates the cystic myelomeningocele (curved arrows, c)

plane; and (3) obliteration of the cisterna magna with lack of visualization or hypoplasia of cerebellum and abnormal anterior curvature of the cerebellar hemispheres (“banana sign”). The sensitivity of indirect signs for the identification of spina bifida is more than 99%. Above all, demonstration of a normal cisterna magna in the second trimester excludes the possibility of Chiari II malformation.

False negatives are rarely possible only in some cases of lipomyelomeningoceles, meningoceles, or very low myelomeningoceles, associated with a good prognosis. No false positives for cerebellar signs have been described, while the lemon sign is present in 1% of normal fetuses, as well as in other pathologies. The finding of ventriculomegaly should raise the suspicion of spina bifida; ventriculomegaly of vary-

Prenatal Ultrasound: Spine and Spinal Cord

a

b

c

Fig. 45.6a–c. Large myelomeningocele. Sagittal (a), axial (b), and coronal (c) planes show a cystic lumbar myelomeningocele (arrows)

a

b

a

b

Fig. 45.7a,b. Myelomeningocele. Transvaginal sonograms at 15 weeks. a Parasagittal scan shows posterior arch defect at lumbosacral level (arrow). b Coronal scan demonstrates the small cystic myelomeningocele (arrows)

c

Fig. 45.8a–c. Cranial indirect signs associated with myelomeningocele in the second trimester. a Axial scan of the fetal head shows ventriculomegaly borderline or mild ventriculomegaly with choroid plexus dangling (open arrows). b Axial sonogram of the cranium demonstrates a “lemon-shaped” frontal calvarium (arrows). c Transcerebellar scan shows obliteration of the cisterna magna and compression of the cerebellar hemispheres, resulting in the so-called banana sign (arrows)

1729

1730 M. Lituania and U. Passamonti ing degree is present in 90% of cases of spina bifida at term of pregnancy, and in 70% of fetuses in the second trimester. In most cases, the size of the cerebral ventricles is only slightly increased. Other less frequent indirect signs can be found at the level of the spine, such as angular kyphosis caudally to the lesion (Fig. 45.9) and scoliosis or an abnormal vertebral bending (Fig. 45.10). Ultrasonography can also evaluate the level and the extension of the defect with a high degree of accuracy; even though axial views permit a detailed evaluation of the anatomy of a single vertebra, coronal and sagittal views are more useful for this purpose. While ultrasonographic visualization of normal movements of the legs and of normal micturition does not mean a good prognosis, demonstration of in utero spinal paralysis portends a very severe prognosis. Rare varieties of closed spinal dysraphisms that can be diagnosed with ultrasonography are represented by lipomyelocele and diastematomyelia. The prenatal diagnosis of lipomyelocele is based on the ultrasonographic evidence of an echogenic mass posterior to the lumbosacral spine [4]. The mass involves the lumbosacral spine and is covered by

a

skin. Detection of an anechoic cystic structure within the echogenic mass is an expression of an associated meningocele (lipomyelomeningocele). Diastematomyelia is characterized by a segmental separation of the spinal cord in two hemicords [5] (Fig. 45.11). Some cases without either spina bifida or vertebral anomalies are extremely difficult to identify even by skilled sonologists.

45.2.2 Associated Anomalies The most frequent anomalies associated with spinal dysraphisms are the Chiari II malformation (Fig. 45.12) (always present in patients with myelomeningocele and associated with ventriculomegaly of variable degree), holoprosencephaly, agenesis of the corpus callosum, Dandy-Walker malformation, hydrosyringomyelia (associated with spina bifida in 29%–77% of cases) [6], hemivertebra (Fig. 45.13), chromosomal anomalies (found in 4%–28% of fetuses with spina bifida) (Fig. 45.14), and clubfoot (Fig. 45.15).

b Fig. 45.9a,b. Severe kyphosis with associated thoracolumbar spina bifida. Sagittal scans show severe anterior angulation of the spine (thick arrow) located caudally to the spina bifida. The skin and vertebral defects are outlined by thin arrows

Prenatal Ultrasound: Spine and Spinal Cord

a

d

c

b

e

Fig. 45.10a–e. Segmentation anomalies of the vertebrae and ribs associated with thoracolumbar spina bifida. a, b Coronal planes show multiple vertebral anomalies, severe kyphoscoliosis, and a wide neural tube defect (arrows). c Pathologic correlation confirms a large open defect and severe multiple anomalies. d, e Roentgenograms confirms severe kyphoscoliosis and a marked disorganization of the rib cage, so-called monstrance-like

45.2.3 Accuracy of Ultrasonography in the Diagnosis of Spina Bifida

Fig. 45.11. Diastematomyelia associated with multiple segmental vertebral anomalies. Longitudinal scan shows a deranged spinal canal (thin arrows) and widening of the spine with division of the spinal canal (large arrows) by a central bony spur

The diagnostic accuracy depends on different factors: experience of the sonologist, quality of ultrasound equipment, and type of lesion. Different studies show detection rates for the diagnosis of spina bifida of 80%–85% [7], but with large differences between centers, ranging from 33% to 100%. It is not clear from these studies whether the presence of cranial signs of spina bifida were systematically researched. It is commonly believed that the accuracy of ultrasonography, in second and third level centers, is close to 100%, with the possible exception of minor closed spinal dysraphisms carrying a favorable prognosis.

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1732 M. Lituania and U. Passamonti

b a

c

a

b

Fig. 45.12a–d. Complex multiple anomalies: microcephaly, ventriculomegaly, cranial meningocele, and Chiari II malformation in a fetus with spina bifida. a Sagittal scan of the fetal head shows microcephaly, ventriculomegaly, absent parietal cranial vault (white arrows), and meningocele. b Coronal scan of the fetal head shows a meningocele covered by meninges and skin; the superior edges of the calvaria are indicated (black arrows). c Axial scan at the level of the cerebellum demonstrates the banana sign (calipers) and lemon sign (arrows), indirect signs of spina bifida. d Pathologic photograph shows microcephaly, cranial meningocele, microphthalmia, hypotelorism, and cebocephaly

d

c

d

Fig. 45.13a–d. Hemivertebra and spina bifida. a, b Coronal scan of the fetal spine demonstrates a hemivertebra (curved arrow) associated with lumbosacral spina bifida. c Axial scan shows spina bifida with U-shaped vertebra (arrows). d Coronal scan shows large lumbosacral defect (curved arrows)

Prenatal Ultrasound: Spine and Spinal Cord

b

a

Fig. 45.14a,b. Spina bifida and triploidy. a Transvaginal sonogram at 14 weeks demonstrates lumbosacral myelomeningocele (arrow) and early asymmetric intrauterine growth retardation. b Fetal karyotype shows triploidy with double Robertsonian translocation between chromosomes 13 and 14: 67, XXX, der (13;14), der (13;14)

a

b

c

d

Fig. 45.15a–d. Myelomeningocele and clubfoot. a Sagittal scan of the lower limbs show clubfoot (arrow). Sagittal (b), axial (c), and coronal (d) scans of the spine show a cystic lumbosacral myelomeningocele (arrows)

45.2.4 Prognosis, Counseling, and Management The prognosis depends on the type of lesion, location and extension of the defect, presence of ventriculomegaly or of other cranial and extracranial

associated anomalies, presence of associated chromosomal anomalies, and ultrasonographic signs of spinal paralysis. The prognosis is largely dependent on the location of spina bifida; a low (i.e., sacral) lesion is associated with absent mortality, and normal IQ and ambulation in 83% of cases; a high (i.e., tho-

1733

1734 M. Lituania and U. Passamonti raco-lumbar) lesion is associated with 35% mortality, low IQ, and significant lower limb dysfunction. The prognosis of lipomyelo(meningo)cele is excellent, although meticulous surgery is needed to separate the lipoma from the nerve rootlets. Fetal karyotyping is warranted for counseling and prognosis; the evidence of chromosomal abnormality modifies the recurrence risk in next pregnancies. In continuing pregnancies, delivery can occur at term, with the only exception of a rapid development of severe ventriculomegaly. In this case, intrauterine ventricle-amniotic shunt does not modify the outcome and is not recommended. At present, conclusive clinical information based on randomized trials about the risks and benefits of the different types of delivery is unavailable; it seems reasonable to recommend that all fetuses with spina bifida should be electively delivered by cesarean section, to minimize the risk of rupture or of contamination of the myelomeningocele sac. A retrospective large case-control study demonstrated a significant reduction of the risk of paralysis when the delivery was accomplished with caesarean section before the beginning of labor [8]. The role of intrauterine surgery for the closure of myelomeningocele is being debated; experimental evidence exists that in utero closure of spina bifida reduces the risk of handicap, due to the amniotic fluid toxicity. Reduction of the severity of the Chiari II malformation with diminished degree of hindbrain herniation has been reported after intrauterine myelomeningocele repair [9]. For most authors, however, this form of treatment is still considered experimental and restricted to only a few centers.

45.3 Sacrococcygeal Teratoma Sacrococcygeal teratoma is a tumor derived from embryonic totipotent cells, localized at the apex of coccyx, and originating from a regression defect of the Hensen’s node at the end of the embryonic period. The prevalence is 1:40,000 births, with a 1:4 male to female ratio. Malignant degeneration is more frequent in males. Most of these forms are sporadic, in which case the recurrence risk is not greater than in the general population; sometimes, they can be associated with anorectal atresia and caudal agenesis (Currarino triad), with an autosomal dominant transmission. Sacrococcygeal teratomas are categorized in 4 types: (1) prevalent external, with minimal presacral component; (2) prevalent external, with a significant

intrapelvic component; (3) prevalent internal, with abdominal extension; and (4) entirely internal. Types I and II account for 80% of cases. In 85% of cases, the tumor has a solid or mixed structure, whereas it is cystic in the remaining 15%. Histologically, sacrococcygeal teratomas are categorized into mature, immature, and malignant forms; the latter are less frequent (7%–13% of cases in different series).

45.3.1 Prenatal Ultrasound Prenatal ultrasonography can show the mass and its relation to pelvic and abdominal structures, while MRI can be useful for demonstrating the size and extent of sacrococcygeal teratoma, particularly the intrapelvic extension (Fig. 45.16) [10]. The ultrasonographic features are different according to the tissue composition of the mass. The density of the solid portion is often not homogeneous due to the presence of different tissue components and possible calcified areas. The cystic zones appear as anechoic areas delimited by irregular walls made of nervous, respiratory, gastrointestinal, or epithelial tissue. Polyhydramnios and hydrops may develop in 70% and 18% of cases, respectively, as a consequence of a high output cardiac failure due to hypervascularization or anemia following intratumoral hemorrhage. Other anomalies involving the CNS, skeletal system, and kidneys are present in 18% of affected newborns. In continuing pregnancies elective cesarean section is indicated to avoid dystocia or traumatic hemorrhage in the mass. The prognosis is related to the presence of hydrops, histological type, size, and extension of the lesion. The prognosis is generally favorable in less extensive teratomas that develop externally and have a cystic and avascular structure.

45.4 Caudal Agenesis (Caudal Regression Syndrome) Caudal agenesis, or caudal regression syndrome, is due to an axial posterior defect of the mesodermic caudal blastema, which occurs in the second–third week of embryonic development due to defective gastrulation (see Chap. 39). The syndrome is heterogeneous, varying from less severe forms, such as partial

Prenatal Ultrasound: Spine and Spinal Cord

a

b

c

Fig. 45.16a–c. Sacrococcygeal teratoma. a, b Sonograms show a large mixed teratoma with cystic and solid elements (arrows) arising from the sacrococcygeal area. c Postnatal MRI confirms prenatal diagnosis

agenesis of the sacrum, to its most severe expression, represented by a complete agenesis of the sacrum and inferior portion of vertebral column. The prevalence at birth is 1:100,000; association with maternal diabetes is found in 16% of cases.

The prognosis depends on the severity of sacral agenesis and associated anomalies.

45.5 Sirenomelia 45.4.1 Prenatal Ultrasound The sonographic appearance may vary from abnormalities of the sacrum to complete absence of the sacrum and lower lumbar spine. Agenesis of the thoracic spine, flexion deformities of the limbs, and club feet can coexist. Polyhydramnios is common. Associated anomalies are represented by renal agenesis, renal dysplasia, duodenal atresia, and tracheo-esophageal atresia.

a

b

Sirenomelia is characterized by fusion of lower extremities (Fig. 45.17), frequently associated with bilateral renal agenesis, sacral agenesis, anorectal atresia, and absence of the bladder. Congenital heart defects, skeletal deformities (Fig. 45.18), abdominal wall defects, and pulmonary hypoplasia following severe oligohydramnios are frequently associated [11]. Sirenomelia is a lethal condition that can be detectable in the second trimester of pregnancy, allowing for termination of pregnancy [12].

Fig. 45.17a,b. Sirenomelia. a Ultrasound. The main feature is the complete fusion of the lower extremities. Notice the fused feet (arrows). b Corresponding pathologic photograph shows similar findings

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1736 M. Lituania and U. Passamonti

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b

Fig. 45.18a,b. Sirenomelia. a Fetal sonogram shows lumbosacral vertebral anomalies associated with pelvic defects (arrows). b Roentgenogram. Note fusion of lower limbs, vertebral and pelvic anomalies

References 1.

2.

3.

4. 5.

6.

7.

Benacerraf BR, Stryker J, and Frigoletto FD Jr. Abnormal US appearance of the cerebellum (banana sign): indirect sign of spina bifida. Radiology 1989; 171:151-153. Campbell J, Gilbert WM, Nicolaides KH, Campbell S. Ultrasound screening for spina bifida: cranial and cerebellar signs in a high-risk population. Obstet Gynecol 1987; 70:247-250. Nicolaides KH, Campbell S, Gabbe SG, Guidetti R. Ultrasound screening for spina bifida: cranial and cerebellar signs. Lancet 1986; 2(8498):72-74. Seeds JW, Powers SK. Early prenatal diagnosis of familial lipomyelomeningocele. Obstet Gynecol 1988; 72:469-471. Sepulveda W, Kyle PM, Hassan J, Weiner E. Prenatal diagnosis of diastematomyelia: case reports and review of the literature. Prenat Diagn 1997; 17:161-165. Toma P, Dell’Acqua A, Cordone M, Passamonti U, Lituania M. Prenatal diagnosis of hydrosyringomyelia by high-resolution ultrasonography. J Clin Ultrasound 1991; 19:51-54. Sebire NJ, Noble PL, Thorpe-Beeston JG, Snijders RJ, Nicolaides KH. Presence of the ‚lemon‘ sign in fetuses with spina

bifida at the 10-14-week scan. Ultrasound Obstet Gynecol 1997; 10:403-405. 8. Luthy DA, Wardinsky T, Shurtleff DB, Hollenbach KA, Hickok DE, Nyberg DA, Benedetti TJ. Cesarean section before the onset of labor and subsequent motor function in infants with meningomyelocele diagnosed antenatally. N Engl J Med 1991; 324:662-666. 9. Tulipan N, Hernanz-Schulman M, Bruner JP. Reduced hindbrain herniation after intrauterine myelomeningocele repair: A report of four cases. Pediatr Neurosurg 1998; 29:274-278. 10. Avni FE, Guibaud L, Robert Y, Segers V, Ziereisen F, Delaet MH, Metens T. MR imaging of fetal sacrococcygeal teratoma: diagnosis and assessment. AJR Am J Roentgenol 2002; 178:179-183. 11. Sirtori M, Ghidini A, Romero R, Hobbins JC. Prenatal diagnosis of sirenomelia. J Ultrasound Med 1989; 8:83-88. 12. Valenzano M, Paoletti R, Rossi A, Farinini D, Garlaschi G, Fulcheri E. Sirenomelia. Pathological features, antenatal ultrasonographic clues, and a review of current embryogenic theories. Hum Reprod Update 1999; 5:82-86.

Subject Index

Subject Index

A Abnormally elongated spinal cord 1581 Acrania-exencephaly 1508 Acute cerebellitis 517 – different infectious etiologies 519 Acute demyelinating polyradiculoneuritis 1665 Acute disseminated encephalomyelitis (ADEM) 750, 1655 – acute hemorrhagic encephalomyelitis (AHEM) 757 – acute necrotic encephalomyelitis (ANEM) 757 – acute necrotizing encephalopathy 757 – acute relapsing disseminated encephalomyelitis (ARDEM) 755 – advanced MRI techniques 757 – biphasic demyelinating encephalomyelitis (BDEM) 755 – differential diagnosis 759 Acute hemorrhagic encephalomyelitis (AHEM) 757 Acute necrotic encephalomyelitis (ANEM) 757 Acute necrotizing encephalopathy 757 Acute relapsing disseminated encephalomyelitis (ARDEM) 755 Acute transverse myelopathy 1654 ADCA see autosomal dominant cerebellar ataxia ADEM see acute disseminated encephalomyelitis Adrenoleukodystrophy 676 – neonatal 674, – pseudoneonatal 676 – X-linked 676 Adrenomyeloneuropathy 680 Agnathia-otocephaly complex 1524 Agyria-pachygyria see lissencephaly AHEM see acute hemorrhagic encephalomyelitis (AHEM) Aicardi syndrome 57 Aicardi-Goutières syndrome 690 – differential diagnosis 692 β-ketothiolase deficiency 606 Alexander disease 688 Alexander syndrome 1367 Alpers disease 726 Ammon’s horn sclerosis see mesial temporal sclerosis Amniotic band syndrome 86 Anderson’s fracture 1689 ANEM see acute necrotic encephalomyelitis (ANEM) Anemia 1278 Anencephaly see also acrania-exencephaly 1508 Aneurysmal bone cyst 1632 Aneurysm 277 Angiopathy 297 – hemorrhagic 297 – proliferative 297 Anophthalmos 1321 – clinical conditions associated 1321, 1322, 1325 Anterior membranous area (AMA) 139 Antiphospholipid antibodies 268 AOA see ataxia with oculomotor apraxia

β-oxidation defect 650 Apert syndrome 1305 Apparent diffusion coefficient 1076 Aqueductal stenosis 965 – aqueductal web 966 – atresia 963 – forking 963 – prenatal 1163 – prenatal US 1163 – secondary obstruction 967 Arachnoid cyst 152, 975, 1131 – intracystic hemorrhage 978 – intrasellar arachnoid diverticulum 979 – locations 978 – of the posterior fossa 152 – – prenatal US 1196 – of the spine 1626 – and US 1119 – – prenatal US 1119, 1199 Arachnoiditis 1670 Archicerebellum 139 ARDEM see acute relapsing disseminated encephalomyelitis (ARDEM) Arima syndrome 156 Arnold-Chiari malformation see Chiari II malformation Arteriovenous malformations 287, 1129 – angioarchitecture 292 – CAVF 296 – CAVM 296 – cerebral arteriovenous malformations (CAVMs) 287 – classification 290 – cortical arteriovenous fistula (CAVF) 291 – dural lesions 297 – location 295 – multiplicity 295 – pineal lesions 296 – prenatal US 1202 – size 294 – timing of genesis 292 – treatment 310 Arteriovenous shunt 1461 – US 1463 Aspergillus 527 Astrocytoma 339 – anaplastic 359 – cyst 344 – diffuse 358 – fibrillary 1612 – holocord 1612 – pilocytic 339, 363, 1612 – pineal region 404 – solid portion 344 – spinal cord 1611 – subependymal giant cell 366, 795

1737

1738 Subject Index Astroblastoma 371 Astrocytoma 1612 Astrocytoma, chiasmatic-hypothalamic see Chiasmatichypothalamic astrocytoma Ataxia, inherited 733 Ataxia telangiectasia (AT) 819 – differential diagnosis 821 Ataxia with oculomotor apraxia (AOA) 737 Ataxia with vitamin E deficiency (AVED) 738 Atlanto-axial subluxation 1690 Atlanto-occipital dislocation 1688 ATRT see atypical teratoid rhabdoid tumor Atypical teratoid rhabdoid tumor (ATRT) 354 – of the spine 1624 – supratentorial 380 Aural atresia 1363 Autosomal dominant cerebellar ataxia (ADCA) 733 – classification 734 Autosomal recessive ataxia 736 AVED see ataxia with vitamin E deficiency Avulsion pseudomeningoceles see brachial plexus injury B Balò’s concentric sclerosis 749 Banana sign 1728 Basal cell nevus syndrome (BCNS) 842 Basilar invagination 1276 Bathrocephaly 1297 Batten-Spielmayer-Vogt disease 725 – Finnish variant 726 – Kufs-Parry disease 726 – Lake-Cavenagh disease 726 Battered child see child abuse BCNS see basal cell nevus syndrome BDEM see biphasic demyelinating encephalomyelitis (BDEM) Bean syndrome see blue rubber bleb nevus syndrome Benign enlargement of the subarachnoid spaces in infants 972 – and US 1131 Benign intracranial hypertension see pseudotumor cerebri Bezold abscess 1376 Bickerstaff encephalitis 522 Bilateral parieto-occipital calcifications with epilepsy and celiac disease 809 Bing-Siebenmann syndrome 1367 Biotinidase deficiency 605 Biotin-responsive encephalopathy 698 Biphasic demyelinating encephalomyelitis (BDEM) 755 Birth trauma 893 Blake’s pouch 139 – persistent 147 Bloch-Sulzberger syndrome see incontinentia pigmenti Blue rubber bleb nevus syndrome (BRBNS) 823 Bone marrow transplantation 461 – graft-versus-host-disease (GVHD) 462 Bonnet-Dechaume-Blanc syndrome (see also Wyburn-Mason syndrome) 295 Brachial plexus injury 1698 – avulsion pseudomeningoceles 1698 Brachycephaly 1301 Brain abscess 498 – abscess 499 – cerebritis 499 – complications 501 – differential diagnosis 502

– diffusion-weighted images 502 – early capsule 498, 499 – early cerebritis 498 – late capsule 498, 499 – late cerebritis 498 – MR spectroscopy 502 – US 1150 Brain death 496 – criteria for establishment of brain death 496 – US 1148, 1150 Brain swelling 917 – in blunt trauma 918 – in child abuse 941 – in electric trauma 919 Brain tumors 329 – advanced neuroimaging 332 – cellularity 330 – classification 334 – clinical findings 329 – contrast enhancement 330 – conventional neuroimaging 330 – epidemiology 329 – in the first year of life 330 – nuclear-to-cytoplasmic ratio 330 – US 1148, 1150 Brainstem encephalitis 522 – Bickerstaff encephalitis 522 Brainstem glioma 346 – classification 349 – exophytic growth 347 – medullary 350 – midbrain 352 – pontine 350 Brainstem hypoplasia/dysplasia 170 – in horizontal gaze palsy with scoliosis 171 – hypertrophy of the corticospinal tracts 172 – isolated 170 – segmental brainstem agenesis 171 Branchial arches 1419 – cellulitis 1453 – congenital abnormalities 1422 – derivatives of 1421 – parapharyngeal abscess 1452 Branchial cleft anomalies 1423 – cyst, - US 1485 – first 1423 – second 1423 – third and fourth 1425 BRBNS see blue rubber bleb nevus syndrome Burkitt lymphoma 1447 Burst fracture 1695

C Calcifying epithelioma see pilomatrixoma Callosal agenesis see commissural agenesis CAMS see cerebrofacial arteriovenous metameric syndrome CAMS see craniofacial arteriovenous metameric syndrome Canavan disease 682 Candida albicans 526 Capillary hemangioma 425, 1471 – cervico-facial 1471 – intracranial 425 – of the neck 1436

Subject Index – of the orbit 1346 – and PHACES syndrome 824 – prenatal US 1517, 1527, 1528 – subglottic 425 – US 1462 Capillary telangiectasias see telangiectasias Caput succedaneum 894 Carbohydrate-deficient glycoprotein (CDG) 164 Carbonic anhydrase II deficiency 695 Carcinoma 1448 – squamous cell 1448 – thyroid 1449 Cardiac rhabdomyoma 786 Carnitine cycle defect 650 Carpenter syndrome 1311 Cat’s eye reflex see retinoblastoma Caudal agenesis 1596 – prenatal US 1734 – type I 1597 – type II 1600 – US 1721 Caudal cell mass 1557 Caudal neuropore 1554 Caudal regression syndrome see caudal agenesis Cavernous hemangiomas 320, 1022 – aggressive 1628 – association with capillary telangiectasias 323 – association with developmental venous anomalies (DVAs) 322 – clinical features 320 – and epilepsy 1020 – extradural locations 323 – – spinal 1643 – of the orbit 1347 – of spinal cord 1619 – vertebral 1628 Cavitations 223 congenital periventricular white matter 223 Cavum septi pellucidi 987, 1121 – dilatation 987 – progressive expansion 991 – and US 1119 Cavum veli interpositi 991 – cystic dilatation 991 Cavum vergae see cavum septi pellucidi CDG (carbohydrate-deficient glycoprotein, congenital disorder of glycosylation) 143, 164 Cellular metabolism 1053 – astroglia 1051 – neuroaxonal unit 1053 – oligodendroglia 1055 Central echo complex 1716 Central giant cell (reparative) granuloma 1398 – fibrous dysplasia 1399 Cephaloceles 72, 1124 – bregmatic cephaloceles 77 – classification and neuroradiological features 75 – clinical features 74 – embryology 74 – interfrontal cephaloceles 77 – internal cephaloceles 82 – lateral cephaloceles 77 – nasoethmoidal cephaloceles 79 – nasofrontal or glabellar cephaloceles 78 – nasoorbital cephaloceles 79

– naso-pharyngeal cephaloceles 82 – occipital cephaloceles 75 – prenatal US 1510 – sagittal (interparietal) cephaloceles 77 – sphenoidal cephaloceles 80 – spheno-maxillary cephaloceles 82 – spheno-orbital cephaloceles 82 – syndromes associated with cephaloceles 82 Cephalohematoma 894 Cerebellar agenesis 162 Cerebellar atrophy 730 Cerebellar cortical dysplasia 167 Cerebral edema see brain swelling Cerebral gigantism see Sotos syndrome Cerebral herniation 920 Cerebritis see brain abscess Cerebrofacial arteriovenous metameric syndrome (CAMS) 295 Cerebrofacial venous metameric syndrome (CVMS) 295 Cerebrotendinous xanthomatosis (van Bogaert-Scherer-Epstein disease) 698 Cervical aortic arch 1486 Cervical thymus 1487 Chamberlain’s line 1276 Chance fracture 1694 Charcot-Marie-Tooth syndrome 1665 CHARGE 89, 863 Chédiak-Higashi disease 669 Chemotherapy 459 – cytarabine neurotoxicity 461 – L-asparaginase neurotoxicity 460 – methotrexate neurotoxicity 460 – steroids 461 Cherubism 1400 Chiari I malformation 172 – bulbar variant 176 – clinical findings 175 – imaging findings 175 – myelencephalic variant 176 – pathogenesis 173 Chiari II malformation 178, 1124 – accessory lobe 183 – callosal dysgenesis 183 – cerebellar peg 181 – cervico-medullary kink 181 – clinical features 178 – hydrocephalus 183 – imaging findings 179 – minimal features 183 – pathogenesis 178 – prenatal US 1727 – spinal cord 183 – stenogyria 182 – tectal beak 182 – towering cerebellum 182 Chiari III malformation 184 – associated features 185 Chiari IV malformation 186 Chiasmatic-hypothalamic astrocytoma 876 – biological behaviour and neuropathology 877 – diencephalic syndrome 876 – epidemiology and clinical picture 876 – imaging studies 877 – pilomyxoid 877

1739

1740 Subject Index Chickenpox 516 – acute cerebellitis 517 – basal ganglia infarcts 516 – vasculitis 516 Child abuse 929 – contusions 941 – differential diagnosis 945 – diffuse axonal injury 941 – edema 943 – hematomas 940 – imaging protocol 931 – imaging strategies 936 – long-term intracranial changes and clinical outcome 944 – medico-legal aspects 946 – retinal hemorrhages 935 – spinal lesions 1696 Childhood ataxia with central hypomyelination (CACH) see vanishing white matter disease Chloromas 440 Choanal atresia see nasopharyngeal agenesis Choanal obstruction 1409 Cholesteatoma 1371 – acquired 1376 – congenital 1371 Chondrosarcoma 1285, 1640 Chordoma 421, 1280 – of the spine 1635 Choriocarcinoma 397 Choroid plexus 406 – diffuse villous hyperplasia 961 Choroid plexus carcinoma 407 Choroid plexus papilloma 406 Citrullinemia 609 Clay shoveler’s fracture 1692 Cleidocranial dysplasia 1276 Clinocephaly 1297 Cloquet, chanel of 1320 COACH syndrome 156 Coagulopathy 279 Coats’ disease 1333 – differential diagnosis 1335 – – with retinoblastoma 1336 – stages characterizing 1333 Cobblestone complex 121 – isolated 123 Coccidioidomycosis 527 Cochlea, agenesis 1373 Cochlear aplasia and hypoplasia 1367 Cochlear implantation 1372 Cockayne disease 692 Coffin-Siris syndrome 863 Cohen syndrome 167 Colloid cyst 981 – paraphysis cerebri 981 – of the sellar region 982 Colobomas 1325 – clinical conditions associated 1321, 1322, 1325 – morning glory syndrome 1326 – tilted disc syndrome 1326 Commissural agenesis 41, 1126 – classical complete 50 – classical partial posterior 53 – hypoplasia, complete or partial, isolated or associated with agenesis 63 – with interhemispheric lipomas 59

– with interhemispheric meningeal cystic dysplasia 55 – isolated agenesis of the anterior commissure 59 – isolated agenesis of the corpus callosum 62 – – prenatal US 1182 – isolated agenesis of the hippocampal commissure 59 – lobar holoprosencephaly 65 – with meningeal dysplasia 54 – of a single commissure 59 Commissure 42 – anterior 42 – commissuration 49 – corpus callosum 44 – development 47 – hippocampal 45 – limbic structures 46 – normal radiological anatomy 42 – septum pellucidum 45 Common cavity deformity 1368 Compression fracture 1692 Concha bullosa 1392 Congenital cystic eye 1327 Congenital disorder of glycosylation (CDG) 143 Congenital retinal telangiectasia see Coats’ disease Congenital X-linked hydrocephalus 966 – nonsyndromic forms 967 – syndromic forms 967 Contusion 911 – in child abuse 939 – hemorrhagic 909 – in the newborn 895 – simple 912 Conus apex level, normal 1558 Corpus callosum 44, 1126 Cortical organization 103 Cowden-Lhermitte-Duclos (COLD) syndrome see LhermitteDuclos disease Craniocervical juncture 1276 Craniofacial arteriovenous metameric syndrome (CAMS) 309 Craniofacial vascular malformation 1459 – arteriolar-capillary malformations 1465 – arteriovenous malformations 1481 – arteriovenous shunts 1461 – capillary-venous malformations 1466 – embryogenesis 1460 – lymphangiomas 1468 – port-wine stains 1466 – veno-lymphatic malformations 1469 – venous malformations 1459 Craniopharyngioma 878 – adamantinous 881 – biological behaviour and neuropathology 880 – epidemiology and clinical picture 878 – imaging studies 881 – rule of the 90s 881 – squamous-papillary 881 Craniosynostosis 1289 – classification – – primary forms 1292 – – secondary forms 1292 – 3D spiral CT 1295 – epidemiology 1290 – isolated (idiopathic) 1292 – pathogenesis 1290 – prenatal US 1506 – radiological evaluation 1292

Subject Index – syndromic 1292, 1303 Cranium bifidum occultum 1406 Creatine deficiency 697 Criswick-Schepens syndrome see familial exudative vitreoretinopathy Croup (laryngotracheitis) 1455 Crouzon syndrome 1304 Cryptococcus 525 Cryptophthalmos 85 CSF pathways 952 – physiology 952 CSF shunt malfunction 968 – infections 970 – nonsyndromic forms, prenatal US 964 – syndromic forms, prenatal US 1160, 1163 Currarino triad 1596 CVMS see cerebrofacial venous metameric syndrome Cyclosporine (CsA) neurotoxicity 462 Cystic hygroma see lymphangioma Cystic lingual masses 1527 Cysticercosis 527 – cerebrovascular complications 531 – colloidal vesicular stage 529 – encephalitic form 529 – granular nodular stage 529 – intraventricular cysts 529 – nodular calcified stage 529 – racemose cysts 530 – of the spinal cord 1663 – subarachnoid (leptomeningeal) 530 – vesicular stage 528 Cytomegalovirus 471 – anomalies of cortical development 472 – cystic formations 474 – differential diagnosis 476 – – with Aicardi-Goutières syndrome 477 – hippocampal dysplasia 474 – intracranial calcifications 474 – of the spinal cord 1663 – timing of infection during gestation 472 – white-matter involvement 473

D Dandy-Walker malformation 142, 1129 – associated conditions 142 – clinical findings 143 – imaging findings 143 – pathogenesis 142 – prenatal US 1193 – torcular-lambdoid inversion 143 Dandy-Walker variant 146 – prenatal US 1194 DAVSs see dural arteriovenous shunts Déjerine-Sottas disease 1670 Dentatorubral-pallidoluysian atrophy (DRPLA) 735 Dermal sinus 1582 – US 1721 Dermoid cyst 418 – from inclusion 1553 – of the neck 1428 – – US 1485 – of the orbit 1349 – of the spine 1625

Desmoplastic infantile ganglioglioma 390 Developmental venous anomalies 325, 1026 – in blue rubber bleb nevus syndrome 326 – as complication after brain irradiation 456 – and epilepsy 1024 Devic’s disease (neuromyelitis optica, see also optic neuromyelitis) 747, 1659 Diabetes insipidus 867 – absence of the pituitary bright 868 – causes 868 – hereditary 867 – idiopathic 867 – rare conditions 869 Diastematomyelia 1587 – US 1721 DIDMOAD see Wolfram’s syndrome 867 Diencephalic syndrome 876 Diffuse axonal injury 913 – in child abuse 939 Diffusion anisotropy see apparent diffusion coefficient Diffusion tensor imaging 1078 Digastric line 1276 Dilated perivascular (Virchow-Robin) spaces 987 – with neuroepithelial cysts 987 Diplomyelia see diastematomyelia Disc herniation 1701 – calcification 1701 Discitis 1673 – bacterial 1674 – epidural abscess 1675 – tuberculous 1674 DNT see dysembryoplastic neuroepithelial tumor Doppler imaging 1123 – pitfalls 1124 Dorsal enteric fistula 1587 DRPLA see dentatorubral-pallidoluysian atrophy DSM see dural sinus malformation Dual pathology 1019 Dural arteriovenous shunts (DAVSs) 297 Dural sinus malformation (DSM) 300 DWI, clinical applications 1080 Dyke-Davidoff-Mason syndrome 802 Dysembryoplastic neuroepithelial tumor (DNT) 388 – complex form 388, 390 – simple form 388 Dysontogenetic masses 418, 1282 – dermoid 1282 – epidermoid 1282 Dysplasia of the semicircular canals 1368 Dyssegmental dwarfism 85

E Ears, US 1524 Echinococcosis 531 – echinococcus granulosus 531 – echinococcus multilocularis (alveolaris) 532 Edema 567 – cytotoxic 567 – interstitial 568 – myelin 568 – vasogenic 568 Electron transfer defect 650 Embryonal carcinoma 397

1741

1742 Subject Index Empty sella 859 – primary 859 – secondary 59 Empyemas 503 – epidural 503 – subdural 503 Encephalotrigeminal angiomatosis (see also Sturge-Weber syndrome) 800 Endodermal sinus tumor 397 Endolymphatic sac tumor 1388 Energy metabolism 1056 Eosinophilic granuloma (see also histiocytosis) 1282 Ependymoblastoma 379 Ependymoma 344 – anaplastic 346 – of the fourth ventricle 344 – myxopapillary 1621 – plastic development 345 – of the spinal cord 1616 – subependymoma 345 – supratentorial 370 Epidermal nevus syndrome organoid nevus syndrome Epidermoid cyst 418 – of the neck 1486 – of the orbit 1349 – of the spine 1626 Epiglottitis 1454 Epignathus 1526 Epilepsy 995 – H-MRS 1061 – international classification of epileptic seizures 996 – international classification of epilepsies and epileptic syndromes 997 – and MR spectroscopy 1059 – postoperative MRI changes 1035 – surgical treatment 1035 – temporal lobe 1014 Epstein-Barr virus (EBV) infection 518 Epulis 1526 Erythrophagocytic lymphohistiocytosis – brain involvement 449 – familial 449 – leukoencephalopathy 449 Esophageal atresia 1434 Ethylmalonic aciduria 591 Exophytic growth 347 Extra-axial locations of typically intra-axial tumor 427 Extramedullary erythropoiesis 1647 Extraosseous sarcoma 164 Eye 1317 – causes of calcifications 1333 – congenital cystic 1327 F Face 1402 – development 1402 Facial cleft 1403 – bilateral complete 1405 – classifications 1403 – complete cleft lip and palate 1405 – and holoprosencephaly 1407 – medial upper lip 1408 – midline syndromes 1406 – oblique 1408

– simple 1404 – transverse 1407 Familial exudative vitreoretinopathy 1340 FCMD (Fukuyama congenital muscular dystrophy) 123 Fetal MRI 1219 – normal CNS development 1219 – physiological fetal hydrocephalus 1236 Fetal warfarin syndrome 86 Fetus in fetu 1206 Fiber tracking 1080 Fibrolipoma of the filum terminal 1580 Fibromatosis 1443 – aggressive 1443 – colli 1443 – of the spine 1627 – US 1488 Fibromuscular dysplasia 270 Fibrous dysplasia 1279 – of the maxilla 1399 – in temporal bone 1380 Focal cortical dysplasia 108, 136, 1004 Focal transmantle dysplasia (Taylor’s focal cortical dysplasia) 108 – differential diagnosis 110 – imaging findings 109 – pathology 109 Foramen of Magendie 139 Foramina of Luschka 139 Friedreich’s ataxia 736 Fronto-nasal dysplasia 83, 1404 Fructose metabolism abnormality 628 Fucosidosis 666 Fukuyama congenital muscular dystrophy (FCMD) 123 Functional MRI 1104 Fungal infections 525

G Galactosemia 628 Gangliocytoma 382 Ganglioglioma 383 – of the spinal cord 1615 Gascoyne’s syndrome see blue rubber bleb nevus syndrome Gastrulation 1534 – embryology 1552 Gaucher disease 665 Gelastic seizure 886 Genoa syndrome 88 Germ cell tumor 394 – of the spine 1630 Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) 217 – complications 219 – neuroimaging 221 – pathogenesis 217 – prognosis 222 – timing 219 Germinoma 395 – suprasellar 884 Glioblastoma multiforme 362 – of the pineal gland 404 Glio-ependymal cyst see neuroepithelial cyst Gliomatosis cerebri 374 Globoid cell leukodystrophy see Krabbe disease

Subject Index Glomus tympanicum tumor 1387 Glutaric aciduria type 1 596 GM gangliosidoses 662 GMH-IVH see germinal matrix hemorrhage-intraventricular hemorrhage Goldenhar syndrome 86 Gorlin-Goltz syndrome see basal cell nevus syndrome Gradenigo’s syndrome 1375 Graft-versus-host-disease (GVHD) 462 – parenchymal hemorrhage 465 – vasculitis 464 Granular layer aplasia 168 Granulocytic sarcoma see chloromas 440 Grave’s ophthalmopathy 1353 Growing fracture 902 Guillain-Barré syndrome see acute demyelinating polyradiculoneuritis GVHD see graft-versus-host-disease

H Hajdu-Cheney syndrome 1276 Haller cells 1392 Hallervorden-Spatz syndrome 727 – eye-of-the-tiger 728 Hamartoma of the tuber cinereum (hypothalamic hamartoma) 886 – gelastic seizure 886 Hand-Schüller-Christian disease (see also histiocytosis) 1282 Hangman’s fracture 1689 HARP syndrome 728 Hemangioblastoma 355 – in von Hippel-Lindau disease 809 – of the spine 1618 Hemangioma see capillary hemangioma Hemangiopericytoma 414 Hematomas 903 – cerebral 913 – in child abuse 938 – epidural 903 – intraventricular 911 – subdural 907 Hemiconvulsion-hemiplegia-epilepsy syndrome 1033 Hemimegalencephaly 112, 1004 – associated conditions 115 – imaging findings 112 – pathology 112, 1128 – prenatal US 1190 Hemimyelo(meningo)cele 1566 Hemolymphoproliferative disease (HLDs) 437 – CNS manifestations 437 – hematological and cerebrovascular complications 450 – intracranial infection 452 – radiotherapy 454 – treatment-related complications 437, 453 Hemorrhage 219, 257 – cerebellar 223 – – prenatal US 1169, 1171 – choroid plexus 222 – etiology 263 – germinal matrix 217 – imaging 257 – incidence 262 – nontraumatic intracerebral 277

– parenchymal 219 Hereditary hemorrhagic telangiectasia (HHT) see RenduOsler-Weber syndrome Hereditary motor and sensory neuropathies 1665 Herniation see cerebral herniation Herpes simplex – hydranencephaly 482 – meningoencephalitis 482 – multicystic encephalomalacia 482 – neonatal 482 Herpes simplex virus (HSV) encephalitis in children 513 – differential diagnosis 515 Herpes zoster – myelitis 1662 Herpes zoster oticus see Ramsay Hunt syndrome Herpesvirus-6 infection 515 Heterotopia 126, 1006, 1129 – subependymal 126 – pathology 126 – subcortical 126 – transmantle 130 HHT (hereditary hemorrhagic telangiectasia) see Rendu-OslerWeber syndrome HI (hypomelanosis of Ito) 115 HIE see hypoxic-ischemic encephalopathy Hippocampal sclerosis see mesial temporal sclerosis Histiocytosis 445, 1282 – cerebellar involvement 447 – eosinophilic granuloma 448 – of the hypothalamic-pituitary axis 873 – Langerhans cell (LCH) 445 – malignant 445 – meningeal involvement 447 – non-Langerhans cell 445 – pituitary stalk infiltration 446 – in sinonasal diseases 1398 – skull involvement 445 – spinal involvement 447, 1628, 1635 – of the temporal bone 1386 – vertebra plana 447 HIV infection (see also human immunodeficiency virus) – acquired 515 – of the spinal cord 1663 HLDs see hemolymphoproliferative disease H-MRS in pediatric pathology 1058 Hodgkin’s disease 1446 Holocarboxylase synthetase deficiency 604 Holoprosencephaly 86, 1124 – alobar holoprosencephaly 89 – associated conditions 88 – clinical features 88 – embryogenesis and pathogenetic theories 87 – lobar holoprosenencephaly 91 – middle interhemispheric holoprosenencephaly 92 – semilobar holoprosenencephaly 91 Homocystinuria 268 HTWS (Klippel-Trenaunay-Weber syndrome) 115 Human immunodeficiency virus (HIV) – cerebral atrophy 483 – congenital 483 – meningoencephalitis 483 – mineralizing microangiopathy 484 – progressive multifocal leukoencephalopathy (PML), advanced MR imaging 485 – spinal cord demyelination 484

1743

1744 Subject Index Hunter disease 652 Huntington’s disease 729 Hurler disease 652 Hurler’s syndrome 1277 Hurler-Scheie disease 652 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A lyase deficiency 595 D-2-hydroxyglutaric aciduria 601 L-2-hydroxyglutaric aciduria 599 Hydranencephaly 1166 Hydranencephaly-hydrocephaly 1167 Hydrocephalus 925, 951, 1132 – classical bulk flow model 954 – classification 954 – – new 956 – – traditional 955 – clinical findings 955 – communicating 961 – complications 968 – congenital X-linked 966 – differential diagnosis 967 – distortion of brain related 960 – external 972 – in head trauma 923 – imaging studies 958 – in metabolic disorders 962 – mono- or biventricular 965 – morphological finding 960 – multilocular 967 – neuropathology 956 – new hemodynamic model 954 – noncommunicating (obstructive) 964 – normal pressure 964 – pathogenesis 954 – prenatal US 949, 1158 – primary pathophysiologic mechanisms 957 – pseudo-Chiari appearances 959 – secondary empty sella 959 – secondary pathophysiologic mechanisms 958 – secondary to CSF overproduction 961 – and spinal tumors 963 – tetraventricular 967 – treatment 968 – triventricular 965 – and US 1130 – and venous hypertension 961 – ventricular measurements 959 – in Walker-Warburg syndrome 962 Hydrolethalus syndrome 1165 Hydromyelia 1603 – US 1721 – presyrinx state 1605 Hyperhomocystinemias 621 – homocystinuria 623 – 5,10-MTHFR deficiency 623 Hyperpipecolic academia 675 Hypertelorism 1517 Hypertension 279 Hypomelanosis of Ito (HI) 115, 829 Hypophisitis see lymphocytic hypophysitis Hypopituitarism (pituitary dwarfism) 865 – idiopathic 865 – secondary 865 – genetically determined GHD 866 Hypotelorism 1517

Hypothalamic hamartoma see hamartoma of the tuber cinereum Hypoxia 275 Hypoxic-ischemic encephalopathy (HIE) 235 – advanced MRI features 248 – conventional MRI features 240 – multicystic encephalomalacia 245 – neuropathology 235 – neuroradiology 237 – parasagittal cerebral injury 237 – pathogenesis 235 – selective neuronal necrosis 236 – ulegyria 246 I Idiopathic facial vascular (venous) dilatations 1471 INAD see infantile neuroaxonal dystrophy Incontinentia pigmenti (IP) 831 Indusium griseum 48 Infantile neuroaxonal dystrophy (INAD) 730 – differential diagnosis 732 Infantile onset spinocerebellar ataxia (IOSCA) 737 Infarction 219, 257 – cardiac causes 267 – chemotherapeutic agents 269 – coagulopathies 268 – etiology 263 – genetic causes 275 – hemorrhagic 279 – imaging 257 – incidence 262 – neurofibromatosis type I (NF1) 269 – of preterm 230 – primary and secondary vascular wall disease 269 – venous 219 Infection, CNS 470 – terminology 470 Influenza virus infection 517 Iniencephaly 1514 Internal jugular phlebectasia 1482 Intracranial hypotension syndrome 974 – meningeal enhancement 974 – pseudo-Chiari I 974 IOSCA see infantile onset spinocerebellar ataxia IP see incontinentia pigmenti Ischemic infarction 254 – in the newborn 254 Isolated or trapped fourth ventricle 970 Isovaleric acidemia 603 J Jadassohn’s nevus phakomatosis see organoid nevus syndrome Jefferson’s fracture 1689 Joubert syndrome see molar tooth malformation Juvenile ankylosing spondylitis 1672 Juvenile nasopharyngeal angiofibroma 1397 Juvenile rheumatoid arthritis 1671

Subject Index K Kallmann syndrome 97, 863 – imaging findings 99 – pathogenesis 99 Kasabach-Merritt syndrome 1437, 1472 Kearns-Sayre disease 641 Ketone synthesis defect 652 Kinky/steedy hair disease see Menkes disease Klippel-Feil syndrome 85, 1276 Klippel-Trenaunay-Weber syndrome (KTWS) 115, 801 Knobloch syndrome 85 Krabbe disease 658 Kufs-Parry disease 726

L Labyrinthitis 1377 Lake-Cavenagh disease 726 Langerhans cell histiocytosis see histiocytosis Large vestibular aqueduct syndrome 1370 Laryngeal 1433 – cysts 1430 – – US 1486 – webs 1433 Laryngeal malacia 1431 Laryngotacheitis see Croup Laryngotracheal trauma 1455 Laryngotracheoesophageal cleft 1434 Leber hereditary optic neuropathy (LHON) 648, 1345 Leber’s military aneurysm see Coats’ disease Leigh disease 639 Lemon sign 1727 Leptocephaly 1297 Letterer-Siwe disease (see also histiocytosis) 1282 Leukemia 437 – calvarial changes 1278 – chloromas 440 – cranial nerve involvement 440 – meningeal disease 438 – of the spine 1640 Leukocoria 1327 – differential diagnosis 1328 Leukodystrophy with brainstem and spinal cord involvement and high lactate 688 Leukodystrophy with chronic CSF lymphocytosis and calcifications of the basal ganglia see Aicardi-Goutières syndrome Leukoencephalopathy associated with polyol metabolism abnormality 697 Lhermitte-Duclos disease (LDD) 846 LHON see Leber hereditary optic neuropathy Limited dorsal myeloschisis 1577 Lip and palate cleft, prenatal US 1520 Lipoblastoma see lipoblasomatosis Lipoblastomatosis 1443 – US 1483 Lipoma 421, 1431 – with dural defects 1568 – of the filum 1580 – intradural and intramedullary 1577 – of the neck 1430 – US 1483 Lipomyelocele 1568

Lipomyelomeningocele 1568 Liponeurocytoma 387 Lissencephaly 116, 1008, 1127 – with cerebellar hypoplasia (LCH) 120, 163 – Dobyns grade 1 117 – Dobyns grades 2–4 117 – Dobyns grades 5–6 118 – genotype-phenotype correlations 116 – isolated 116 – Miller-Dieker syndrome (MDS) 116 – pathology 117 – prenatal US 1189 – X-linked with abnormal genitalia 118 Longitudinal bundle of Probst 52 Louis Bar syndrome see ataxia telangiectasia Lyme disease (neuroborreliosis) 510 – cranial neuropathy 511 – differential diagnosis 511 – primary leptomeningeal enhancement 511 – white-matter involvement 511 Lymphangioma 1427, 1468 – of the orbit 1347 – prenatal US 1528 – US 1479 Lymphatic malformation see lymphagioma Lymphocytic hypophysitis 887 – adenohypophysitis 888 – granulomatous 888 – infundibuloneurohypophysitis 888 Lymphoma 443 – Burkitt lymphoma 443, 1447 – cerebral 443 – head and neck 444, 1446 – Hodgkin’s disease 1446 – Non-Hodgkin lymphoma 1447 – sinonasal 1401 – spinal 445, 1640 M Macrocephaly, prenatal US 1506 Macrocerebellum 169 Macroglossia 1523 Magnetoencephalographic system (MEG) 1003 Mandibulofacial dysostosis see Treacher-Collins syndrome 1277 Maple syrup urine disease 610 Maroteaux-Lamy disease 652 MAS see McCune-Albright syndrome Mastoiditis 1374, coalescent 1374 – Bezold abscess 1375 McCune-Albright syndrome (MAS) 839 McGregor’s line 1276 MDS (Miller-Dieker syndrome) 1116 Measles 515 MEB (muscle-eye-brain disease) 123 Meckel-Gruber syndrome 85 Medulloblastoma 333 – atypical form 337 – classical 333 – desmoplastic 333 – extraaxial 335 – large cell/anaplastic 335 – typical form 335 – with extensive nodularity (MBEN) 335

1745

1746 Subject Index Medulloepithelioma 379 Medullomyoblastoma 335 MEG see magnetoencephalographic system Mega cisterna magna 150 – prenatal US 1196 Megalencephalic leukoencephalopathy with subcortical cysts (van der Knaap disease) 684 MELAS see mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes Melting-brain syndrome 307 Membrane constituents 1055 – myelin 1056 Meningeal sarcoma 416 Meningioangiomatosis 391 Meningioma 411, 1280 – in NF2 782 – of the optic nerve 1343 – of the spine 1623 Meningitis 486 – acute bacterial meningitis in children 487 – arachnoiditis 488, 490 – arteritis 490 – background 486 – bacterial agents 487 – causes of recurrent bacterial meningitis 486 – cerebral edema 488, 494 – choroid plexitis 488, 489 – complications 494 – etiology by age 487 – hydrocephalus 494 – late-stage destructive lesions 496 – neonatal bacterial leptomeningitis 486 – recurrent bacterial meningitides 487 – subdural effusions 489, 494 – US 1147 – vasculitis 488, 490 – venous thrombosis 493 – ventriculitis 488, 489 Meningocele 1573 – anterior 1573 – cranial 72 – intrasacral 1573 – manqué 1594 – posterior 1573 Meninx primitiva 55 Menkes disease 630 MERFF see myoclonus epilepsy and ragged-red fibers Mesial temporal sclerosis 1014 – dual pathology 1019 Mesoderm induction 1535 Metabolic disorder 544 – age of onset 576 – classification 544 – dysmyelination 551 – general considerations 544 – gray matter structures 558 – head circumference 580 – leukodystrophies 549 – molecular genetic aspects 581 – non-specific MRI patterns 565 – pandystrophies 550 – pathognomonic MRI patterns 564 – pattern recognition 556 – poliodystrophies 550 – principles of imaging 552

– selective vulnerability 550 – spinal cord involvement 559 – suggestive MRI patterns 564 – systemic manifestations 576 – white matter structures 557 Metabolites in the brain 570 – abnormal 571 – normal 570 – quantitative abnormalities 572 Metachromatic leukodystrophy 654 Metastases 427 – cystic dissemination 1621 – neoplastic leptomeningitis 1621 – nodular 1621 – sedimentation 1621 – spinal 1620 – vertebral 1641 3-methylcrotonyl-coenzyme A carboxylase deficiency 606 3-methylglutaconic aciduria 592 Methylmalonic acidemia 589 Michel anomaly 1367 Michel dysplasia see cochlea, agenesis Microcephaly 103 – prenatal US 1503 Microdysgenesis 136 Microglossia 1523 Micrognathia 1524 Microlissencephaly 105 Microphthalmos 1322 – with cyst 1324 – differential diagnosis 1325 – nanophthalmos 1324 Megalencephaly 106 – with megalic corpus callosum 107 – polymicrogyria-hydrocephalus syndrome 107 Migraine headaches 275 Miller-Dieker syndrome (MDS) 116 Miller-Fisher syndrome 1666 Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) 644 Mitochondrial respiratory chain defects 163 Mixed germ cell tumor 402 Mixed gliomas 369 Moebius syndrome 170 Molar tooth malformation (Joubert syndrome) 156 – background 156 – clinical picture 157 – imaging findings 157 – pathology 156 – prenatal US 1197 Molecular diffusion 1074 Mondini malformation 1368 Morning glory syndrome 1326 Morquio disease 652, 1277 Moyamoya syndrome 270 Mucolipidoses 667 Mucopolysaccharidose 652 Multicystic encephalomalacia 245 – prenatal US 1166 Multicystic encephalomalacia and asphyxia 226 Multiple carboxylase deficiency 603 Multiple sclerosis 742 – advanced MRI techniques 746 – black holes 746 – bull’s eye 744

Subject Index – conventional MRI techniques 744 – Dawson’s fingers 744 – epidemiology and clinical features 742 – imaging studies 744 – lumpy bumpy 744 – MRI criteria 744 – ovoid sign 744 Multiple sulfatase deficiency 657 Multisite closure theory 1554 Muscle-eye-brain disease (MEB) 123 Mycoplasma pneumoniae infection 519 Myelination 21 – myelin structure 21 – progression 23 Myelinoclastic diffuse sclerosis see Schilder’s disease Myelitis see acute transverse myelopathy Myelocele 1565 Myelocystocele 1574 – and Chiari II 1577 – limited dorsal myeloschisis 1577 – manqué 1577 – nonterminal 1576 – syringocele 1574 – terminal 1574 Myelomeningocele 1562 – and Chiari II 1567 – dermoids 1565 – dietary supplementation with folic acid 1562 – hydrocephalus 1565 – post-surgical retethering 1565 – prenatal US 1727 Myeloschisis see myelocele 1565 Myoclonus epilepsy and ragged-red fibers (MERRF) 647 Myofibromatosis of the skull 1281

N Nasal glioma 79 Nasolacrimal duct cyst 1410 Nasopharyngeal agenesis 1411 NCM see neurocutaneous melanosis Neck 1419 – embryology 1419 – lymphadenitis, US 1487 – neurogenic tumors 1445 Nelson syndrome (NS) 841 Neocerebellar aplasia and hypoplasia 161 Neocerebellum 139 Nesidioblastosis 696 Neural crest 1543 Neural induction 1533 Neurenteric cyst 984, 1587 Neuroblastoma 1644 – of the neck 1445 Neuroborreliosis see Lyme disease Neurocutaneous melanosis (NCM) 835 Neurocytoma 385 – central 385 – cerebral 386 Neuroepithelial cyst 983 – of the choroid plexus 983 – prenatal US 1201 Neurofibromas 772 – cutaneous and plexiform 772

– malignant 774 – of the neck 1444 – neurofibrosarcomas 774 – orbital 775 – spinal 777, 1623 Neurofibromatosis type 1 (NF1) 764 – arachnoidal gliomatosis 767 – brain gliomas 769 – buphthalmos 774 – clinical findings 764 – diagnostic criteria 764 – differential diagnosis with isolated OPGs 769 – disorder associated 780 – dural ectasia 774, 775 – dysplasia of the greater sphenoidal 774 – global cognitive deficit 767 – kyphoscoliosis 775 – lateral meningoceles 775 – macrocephaly 764 – NBOs 765 – neurofibromas 772 – optic pathway glioma 767 – posterior scalloping of the vertebral bodies 776 – spontaneous regression of OPGs 769 – thickening of the cropus callosum 764 – UBOs see NBOs – vascular abnormalities 780 Neurofibromatosis type 2 (NF2) 780 – diagnostic criteria 780 – – in childhood 785 – ependymomas 344, 784 – Gardner type 780 – meningiomas 411, 781 – schwannomas 416, 781 – spinal manifestations 782 – Wishart type 780 Neuromyelitis optica see Devic’s disease Neuronal and mixed neuronal-glial tumor 382 Neuronal ceroid lipofuscinosis 723 – Batten-Spielmayer-Vogt disease 725 – classification 724 Neuronal migration 102 Neuronal-gial proliferation and apoptosis 100 Neurosecretory region 856 Nevoid basal cell carcinoma syndrome see basal cell nevus syndrome Nevus of Ota (NO) 837 NF see neurofibromatosis Niemann-Pick disease 663 NO see nevus of Ota Nocardia 527 Non-Hodgkin lymphoma 1447 Nonketotic hyperglycinemia 625 Non-Taylor’s focal cortical dysplasia 136 – architectural 136 – clinical findings 136 – cytoarchitectural 136, 137 Nose 1408 – agenesis 1412 – anomalies 1409 – development 1408 NS see Nelson syndrome

1747

1748 Subject Index O Oculodermal melanocytosis (see also nevus of Ota) 837 OEIS syndrome 1596 Oligodendroglioma 367 – oligodendrogliomatosis 367 – of the spinal cord 1613 Ollier disease see chondrosarcoma ONS (see also organoid nevus syndrome) 115 Optic nerve 1343 – causes 1343 – enlargement 1343 – glioma, isolated 1343 – injury 1356 – meningioma 1343 – neuritis 1344 – tram-track sign 1344 Optic neuromyelitis 747 Optic pathway glioma 767, 1343 – NF1-associated 877 Orbit 1317, 1351 – blunt trama 1355 – cellulitis 1352 – choroidal hemangioma 1341 – embryology 1317 – fractures 1354 – hemolymphoproliferative disease 1351 – infection and inflammation 1351 – intraocular injury 1356 – penetrating injuries 1355 – pseudotumor 1352 Organoid nevus syndrome (ONS) 115, 844 Ossicular dysplasias 1365 Osteoblastoma 1630 Osteochondroma 1631 Osteogenesis imperfecta 1276, 1381 Osteogenic sarcoma 1281 Osteoid osteoma 16292 Osteomyelitis see discitis Osteopetrosis 1276, 1382 Osteosarcoma 1638 Otitic hydrocephalus 1374 Otitis media see mastoiditis Oxycephaly 1301

P Paleocerebellum 139 Pallister-Hall syndrome 863 Pantothenate kinase-associated neurodegeneration (PKAN) see Hallervorden-Spatz syndrome Papillomatosis 440 – recurrent respiratory 1440 Paranasal sinus 1391 – development 1391 Parapharyngeal abscess 1453 – US 1487 Parasagittal cerebral injury 237 – US 1144 Parasagittal cerebral injury 246 Parasitic infections 527 Parathyroids, US 1497 Parinaud syndrome 394 Pars intermedia, cysts 858

Pelizaeus-Merzbacher disease 693 Perfusion weighted imaging 1098 Perilymph fistulas 1383 Perinatal trauma see birth trauma Periventricular leukomalacia (PVL) 210 – neuroimaging 211 – pathogenesis 210 – prognosis 217 – US 1140 Persistent hyperinsulinemic hypoglycemia (nesidioblastosis) 696 Persistent hyperplastic primary vitreous (PHPV) 1335 – clinical conditions associated 1336 – bilateral 1338 Pfeiffer syndrome 1311 PHACE syndrome 826, 1473 Phenylketonuria 615 – classical 619 – malignant 619 3-phosphoglycerate dehydrogenase deficiency 627 PHPV see persistent hyperplastic primary vitreous Pilomatrixoma (calcifying epithelioma) 1489 Pineal cyst 404 Pinealomas 394 Pineoblastoma 402 Pineocytoma 402 Ping-pong fracture 898 Piriform aperture stenosis 1411 Pituitary adenomas 872 – hemorrhagic 873 – macroadenomas 873 – microadenomas 873 Pituitary dwarfism see hypopituitarism Pituitary gland 855 – adenomas 872 – anatomy 855 – aplasia 863 – apoplexy 872 – colloid cysts 981 – duplication 864 – dystopia 865 – ectopic posterior lobe 865 – embryology 857 – hyperplasia 870, 875 – hypoplasia 863 – Langerhans cell histiocytosis 875 – neurosecretory regions 856 – normal evolution and MRI appearance 858 – pituitary stalk interruption syndrome 865 – at puberty 858 – Rathke’s pouch 857 Pituitary stalk interruption syndrome 865 Placode 1560, 1563 Placode-lipoma interface 1562 Plagiocephaly 1299 – anterior 1299 – posterior 1299 Platybasia 1276 PML see progressive multifocal leukoencephalopathy PNET see primitive neuroectodermal tumor Poliomyelitis 1662 Polymicrogyria 130, 1011 – bilateral 131 – bilateral frontal 133 – bilateral parasagittal parieto-occipital 131

Subject Index – bilateral posterior parietal 133 – clinical findings 131 – diffuse 133 – pathology 130 – unilateral 131 Polyposis 1394 – nasal 1394 – sinonasal 1395 Pontocerebellar hypoplasia 163 – neuroradiology 165 – prenatal US 1198 – type 1 of Barth 164 – type 2 of Barth 164 Posterior membranous area (PMA) 139 Posterior reversible encephalopathy syndrome (PRES) 462 – CsA neurotoxicity 462 – cytokine storm 462 Pott’s puffy tumor 1391 Precocious puberty 868 – causes 869 Prenatal US: spine and spinal cord 1725 – accuracy in the diagnosis of spina bifida 1731 – normal anatomy 1725 PRES see posterior reversible encephalopathy syndrome Preterm infants 199 – normal appearances of the developing brain 199, 201 – pathology 210 – at term 208 Primary lactic acidosis 609 Primary neurulation 1537, 1553 Primitive neuroectodermal tumor (PNET) 376 – of the spine 1624 Primitive streak 1534 Progressive multifocal leukoencephalopathy (PML) 485 Proliferative vasculopathy 1167 Propionic acidemia 586 Protein C and S deficiency 268 Proteus syndrome (PS) 115 Pseudo-Meckel syndrome 85 Pseudotumor cerebri 972 Purtscher retinopathy 1341 PVL see periventricular leukomalacia Pyroglutamic aciduria (5-Oxoprolinuria) 602 Pyruvate carboxylase deficiency 636 Pyruvate dehydrogenase complex deficiency 636

R Radiation vasculopathy 270 Radiotherapy 454 – and cavernomatous malformations 456 – focal radiation necrosis 454 – mineralizing microangiopathy 456 – neuroendocrine pathology 457 – neuropsychological delay 458 – radiation leukoencephalopathy 454 – second neoplasms 459 Ramsay Hunt syndrome 1378 Rasmussen’s encephalitis 522, 1019 – clinical findings 521 – epilepsia partialis continua 521 Rathke’s cleft cysts 871

– differential diagnosis 872 Refsum disease 1670 – infantile form 675 Renal angiomyolipomas 786 Rendu-Osler-Weber syndrome (ROW) 296, 822 Retinoblastoma 403, 1329 – Abramson staging system 1331 – diffuse infiltrating 1329 – gadolinium enhancement within the implant 1333 – ocular implants 1333 – and prenatal US 1206 – trilateral 403, 1329 Retinopathy of prematurity (ROP) 1338 – stages 1340 Retrogressive differentiation 1557 Reversal sign 919 Reye syndrome 524 – different etiologies 525 Rhabdomyosarcoma 1448 – of the orbit 1350 – of the skull vault 1281 – of the temporal bone 1385 Rhizomelic chondrodysplasia punctata 676 Rhombencephaloschisis 156 Rhombencephalosynapsis 158 Ritscher-Schinzel cranio-cerebello-cardiac syndrome 143 Roberts syndrome 86 ROP see retinopathy of prematurity Rostral neuropore 1554 ROW see Rendu-Osler-Weber syndrome Rubella 480 – meningoencephalitis 481 – vasculopathy 481

S Saethre-Chotzen syndrome 1309 Salivary gland neoplasms, US 1492 Salla disease 668 Sandhoff disease 663 Sanfilippo disease 652 Sarcoidosis 532 – cranial nerve involvement 534 – granulomatous leptomeningitis 533 – hypothalamus and pituitary stalk involvement 534 – pachymeningitis 533 – parenchymal sarcoid granulomas 534 – periventricular white matter lesions 534 – serum angiotensin converting enzyme (SACE) 533 SBH (subcortical band heterotopia) 117 Scalp cleft 1408 Scaphocephaly 1297 Scheie disease 652 Scheuermann disease 1701 Schiebe syndrome 1367 Schilder’s disease 746 – Poser’s criteria for the diagnosis 746 Schimmelpenning-Feuerstein-Mims syndrome see organoid nevus syndrome Schizencephaly 134, 1006, 1128 – closed lips 135 – open lips 134 – prenatal US 1190

1749

1750 Subject Index Schwannomas 416 – isolated 416 – of the neck 1446 – in NF2 780 – of the spine 1621, 1642 SCIWORA see spinal cord injury without radiological abnormality Secondary neurulation 1539, 1556 Segmental spinal dysgenesis 1601 Segmentation 998 Selective neuronal necrosis 236, 241 – US 1144 Senior-Löken syndrome 156 Sensorineural hearing loss 1366 Septo-commissural dysplasia 64 Septo-optic dysplasia 95 – clinical findings 96 – isolated 96 – pathogenesis 3, 95 – plus 96 – prenatal US 1188 – septo-commissural dysplasia 64 Septum pellucidum 45 – fetal and neonatal 45 – midline cyst 46 Shaken-baby see child abuse Shaking-impact syndrome see child abuse Shearing injury see diffuse axonal injury SHH (Sonic Hedgehog, see holoprosencephaly) 8 Sialadenitis 1490 – bacterial 1490 – chronic 1490 – intraparotid 1492 – viral 1490 Sickle cell disease 263, 1278, 1353 SIDS (sudden infant death syndrome) 276 Sinus pericranii 326, 1131, 1469 – US 1131 Sinusitis 1390 – acute 1390 – chronic 1392 – with cystic fibrosis 1396 – fungal 1393 – intracranial complications 1391 – mucus retention cysts 1396 – orbital complications 1391 Sirenomelia see caudal agenesis Sjögren’s syndrome 1492 Sjögren-Larsson syndrome 700 Skull 1255, 1271 – chondrosarcoma 1285 – chordoma 1280 – disorders 1276 – dysontogenitic masses – – dermoid 1282 – – epidermoid 1282 – embryogenesis 1271 – hemangiomas 1280 – histiocytosis 1282 – meningioma 1280 – metastasis 1286 – normal calcifications 1273 – normal development 1271 – normal suture closure 1273 – osteogenic sarcoma 1281

– pathological intracranial calcifications 1271 – prenatal US 1503 Slipped vertebral apophysis 1701 Slit ventricle syndrome 970 Smith-Lemli-Opitz syndrome 88 – facial malformations, prenatal US 1180 – prenatal US 1176 Solomon’s syndrome see organoid nevus syndrome Sonic hedgehog (SHH, see also holoprosencephaly) 8, 1542 Sonography, brain 1115 – cavum septi pellucidi and cavum vergae 1121 – normal anatomy 1115 – normal variants and pitfalls 1120 – peritrigonal echogenic Blush 1122 Sotos syndrome (cerebral gigantism) 107 Spina bifida 1559 – aperta 1559 – cystica 1559 – occulta 1559 – posterior 1577 Spinal arteriovenous shunt 1705 – angioarchitecture 1712 – classification 1705 – embolization 1713 – extradural 1706 – intradural 1706 – paraspinal 1707 – therapeutic abstention 1712 – treatment 1712 Spinal cord 1533 – embryology 1533 Spinal cord abscess 1660 Spinal cord injury at birth 1697 – US 1722 Spinal cord injury without radiological abnormality (Sciwora) 1697 Spinal dysraphism 1558 – classification 1561 – closed 1568 – cutaneous birthmarks 1562 – open 1562 – placode-lipoma interface 1562 – prenatal US 1725 Spine 1683 – cranio-cervical junction 1687 – developmental anatomy 1684 Spine and spinal cord – central echo complex 1716 – congenital anomalies 1718 – normal anatomy 1715 – sonography 1715 Spinocerebellar ataxia see autosomal dominant cerebellar ataxia Split cord malformation 1588 Spondylodiscitis see discitis Spondylolisthesis see spondylolysis Spondylolysis 1698 Staphyloma 1327 Status epilepticus 1032 – brain MRI abnormalities 1032 Stenogyria 182 Sturge-Weber syndrome 800, 1030 – calcifications 806 – choroid plexus enlargement 803 – cortical atrophy 806

Subject Index – differential diagnosis 807 – – with bilateral parieto-occipital calcifications with epilepsy and celiac disease 810 – Dyke-Davidoff-Mason syndrome 802 – enlarged, enhancing deep intraparenchymal veins 807 – and epilepsy 1028 – facial angioma 802 – Klippel-Trenaunay-Weber syndrome 801 – leptomeningeal angiomatosis 801, 803 – ocular abnormalities 807 – subtypes 801 Subacute necrotizing encephalomyopathy see Leigh disease Subacute sclerosing panencephalitis 519 Subcortical band heterotopia (SBH) 117 Subgaleal hemorrhage 894 Subglottic stenosis 1433 Sublobar dysplasia 138 Sudden infant death syndrome see SIDS Surface rendering 998 Sylvian aqueduct syndrome 394 Syntelencephaly 92 – pathogenesis and relationship with HPE 93 – prenatal US 1179 Syphilis, congenital 485 Syringomyelia see hydromyelia

T Taylor’s focal cortical dysplasia see focal transmantle dysplasia Tay-Sachs disease 663 Teardrop fracture 1692 Tectocerebellar dysraphia 160 Telangiectasias 319 – craniofacial 1467 – imaging finding 319 Temporal bone 1361 – congenital abnormalities 1363 – embryology 1361 – exostoses 1361 – fractures 1384 – hemolymphoproliferative diseases 1387 – inflammatory disorders 1374 – malformations of the inner ear 1366 – mesenchymoma 1385 – metastases 1387 – plexiform neurofibroma 1385 – sarcomas 1385 – tumors 1385 Teratoma 397 – malignant (immature) 399 – of the neck 1436 – – US 1488 – of the orbit 1350 – and prenatal US 1204, 1517, 1528, 1734 – sacrococcygeal, of the spine 1637 Terminal ventricle, persistent 1583 Tethered cord syndrome 1560, US 1719 Thalassemia major 1278 Thymic cyst 1486 Thyroglossal duct cyst 1427 – US 1484 Thyroid – congenital diseases 1493 – Graves’ disease 1494

– Hashimoto’s disease 1494 – infection 1496 – multinodular goiter 1494 – neoplasms 1496 – US 1493 Thyromegaly 1528 Tight filum terminale 1581 – US 1719 Tilted disc syndrome 1326 TORCH infection 470, US 1147 Touraine syndrome see neurocutaneous melanosis Toxin-induced neurological disease 505 Toxocaral disease 532 Toxocaral endophthalmitis 1339 Toxoplasmosis – calcifications 478 – congenital 478 – cortical dysplasia 480 – hydranencephaly 480 – hydrocephalus 478 – meningoencephalitis 478 – microcephaly 478 – microphthalmos 478 – multicystic encephalomalacia 480 – porencephaly 478 – timing of intrauterine infection 480 Tracheal stenosis, congenital 1435 Tracheoesophageal fistula (see also esophageal atresia) 1434 Tracheomalacia 1433 Trapped fourth ventricle see isolated or trapped fourth ventricle Treacher-Collins syndrome 1277 Trichopoliodystrophy see Menkes disease Trigonocephaly 1301 – anterior 1301 – posterior 1303 Tuberculosis 505 – granulomatous tuberculous meningitis 508 – meningitis 506 – pachymeningitis 508 – tuberculomas 508 – tuberculous abscess 509 Tuberous sclerosis 785 – cardiac rhabdomyoma 786 – cerebellar tubers 792 – cortical tubers 787 – diagnostic criteria 786 – differential diagnosis 800 – and focal cortical dysplasia (FCD) 800 – forma frusta of TSC 787, 800 – gyral core 790 – hypomelanotic patches 786 – relationships with other phakomatoses 786 – renal angiomyolipomas 786 – subependymal giant cell astrocytoma 366, 796 – subependymal nodules 793 Tuberous sclerosis (Continued) – sulcal island 790 – vascular abnormalities 799 – white-matter abnormalitites 795 Two-site closure theory 1555

1751

1752 Subject Index U Ulegyria 246 Urea cycle defect 609

V VACTERL syndrome 1596 van Bogaert-Scherer-Epstein disease see cerebrotendinous xanthomatosis van der Knaap disease see megalencephalic leukoencephalopathy with subcortical cysts Vanishing white matter disease 686 Varicella, congenital 486 Vascular 271 – hypoplasia 271 – trauma 273 Vasculitis 263 – infectious 263 – other 266 – Takayasu’s arteritis 266 Vein of Galen aneurysmal malformation (VGAM) 302, 1131 – choroidal type 304 – mural type 304 Venous angiomas see developmental venous anomalies Venous malformation 1439, 1468 – US 1481 Venous thrombosis 280 – in preterm 226 Ventricular system and subarachnoid spaces 951 – embryology 951 Ventriculomegalies – diagnosis 1172 – fetal MRI 1238 – isolated mild 1172 – outcome 1175 – prenatal US 1172 – unilateral 1173 – ventriculomegaly 1238 Vertebra plana 447

Vestibulocochlear nerve, abnormality 1370 VGAM see vein of Galen aneurysmal malformation Viral infections 512 – background 512 Virchow-Robin spaces see dilated perivascular spaces Vocal cord paralysis 1432 Vogt syndrome 1309 Von Hippel-Lindau syndrome 810 – CNS manifestations 810 – hemangioblastomas 810 – ocular manifestations 812 – papillary cystadenomas of the endolymphatic sac 813, 1361 Von Voss-Cherstvoy syndrome 84

W Waardenburg syndrome (WS) 832, 1311 Wada test 1000 Walker-Warburg syndrome (WWS) 121 Whiplash shaken-baby syndrome see child abuse White cerebellum sign 919 Wilson disease 630 Wolfram’s syndrome 867 WS see Waardenburg syndrome WWS (Walker-Warburg syndrome) 121 Wyburn-Mason syndrome 295, 807, 821 X Xanthoastrocytoma, pleomorphic 363 Y Yolk sac tumor see endodermal sinus tumor Z Zellweger syndrome 138, 672